bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalizability of A Neural Network Model for Circadian Phase Prediction in Real-World Conditions
Authors: Stone Julia E. , Phillips Andrew J. K. , Ftouni Suzanne , Magee Michelle , Howard Mark , Lockley Steven W. , Sletten Tracey L. , Anderson Clare , Rajaratnam Shantha M. W. , Postnova Svetlana
Published: July 2019

A neural network model was previously developed to predict melatonin rhythms accurately from blue light and skin temperature recordings in individuals on a fixed sleep schedule. This study aimed to test the generalizability of the model to other sleep schedules, including rotating shift work. Ambulatory wrist blue light irradiance and skin temperature data were collected in 16 healthy individuals on fixed and habitual sleep schedules, and 28 rotating shift workers. Artificial neural network models were trained to predict the circadian rhythm of (i) salivary melatonin on a fixed sleep schedule; (ii) urinary aMT6s on both fixed and habitual sleep schedules, including shift workers on a diurnal schedule; and (iii) urinary aMT6s in rotating shift workers on a night shift schedule. To determine predicted circadian phase, center of gravity of the fitted bimodal skewed baseline cosine curve was used for melatonin, and acrophase of the cosine curve for aMT6s. On a fixed sleep schedule, the model predicted melatonin phase to within ± 1 hour in 67% and ± 1.5 hours in 100% of participants, with mean absolute error of 41 ± 32 minutes. On diurnal schedules, including shift workers, the model predicted aMT6s acrophase to within ± 1 hour in 66% and ± 2 hours in 87% of participants, with mean absolute error of 63 ± 67 minutes. On night shift schedules, the model predicted aMT6s acrophase to within ± 1 hour in 42% and ± 2 hours in 53% of participants, with mean absolute error of 143 ± 155 minutes. Prediction accuracy was similar when using either 1 (wrist) or 11 skin temperature sensor inputs. These findings demonstrate that the model can predict circadian timing to within ± 2 hours for the vast majority of individuals on diurnal schedules, using blue light and a single temperature sensor. However, this approach did not generalize to night shift conditions.
Simulation of action potential propagation based on the ghost structure method
Authors: Wang Yongheng , Cai Li , Luo Xiaoyu , Ying Wenjun , Gao Hao
Published: July 2019

In this paper, a ghost structure (GS) method is proposed to simulate the monodomain model in irregular computational domains using finite difference without regenerating body-fitted grids. In order to verify the validity of the GS method, it is first used to solve the Fitzhugh-Nagumo monodomain model in rectangular and circular regions at different states (the stationary and moving states). Then, the GS method is used to simulate the propagation of the action potential (AP) in transverse and longitudinal sections of a healthy human heart, and with left bundle branch block (LBBB). Finally, we analyze the AP and calcium concentration under healthy and LBBB conditions. Our numerical results show that the GS method can accurately simulate AP propagation with different computational domains either stationary or moving, and we also find that LBBB will cause the left ventricle to contract later than the right ventricle, which in turn affects synchronized contraction of the two ventricles.
Temporin L and aurein 2.5 have identical conformations but subtly distinct membrane and antibacterial activities
Authors: Manzo Giorgia , Ferguson Philip M. , Hind Charlotte K. , Clifford Melanie , Gustilo V. Benjamin , Ali Hind , Bansal Sukhvinder S. , Bui Tam T. , Drake Alex F. , Atkinson R. Andrew , Sutton J. Mark , Lorenz Christian D. , Phoenix David A. , Mason A. James
Published: July 2019

Frogs such as Rana temporaria and Litoria aurea secrete numerous closely related antimicrobial peptides (AMPs) as an effective chemical dermal defence. Damage or penetration of the bacterial plasma membrane is considered essential for AMP activity and such properties are commonly ascribed to their ability to form secondary amphipathic, α-helix conformations in membrane mimicking milieu. Nevertheless, despite the high similarity in physical properties and preference for adopting such conformations, the spectrum of activity and potency of AMPs often varies considerably. Hence distinguishing apparently similar AMPs according to their behaviour in, and effects on, model membranes will inform understanding of primary-sequence-specific antimicrobial mechanisms. Here we use a combination of molecular dynamics simulations, circular dichroism and patch-clamp to investigate the basis for differing anti-bacterial activities in representative AMPs from each species; temporin L and aurein 2.5. Despite adopting near identical, α-helix conformations in the steady-state in a variety of membrane models, these two AMPs can be distinguished both in vitro and in silico based on their dynamic interactions with model membranes, notably their differing conformational flexibility at the N-terminus, ability to form higher order aggregates and the characteristics of induced ion conductance. Taken together, these differences provide an explanation of the greater potency and broader antibacterial spectrum of activity of temporin L over aurein 2.5. Consequently, while the secondary amphipathic, α-helix conformation is a key determinant of the ability of a cationic AMP to penetrate and disrupt the bacterial plasma membrane, the exact mechanism, potency and spectrum of activity is determined by precise structural and dynamic contributions from specific residues in each AMP sequence.
Electron collimator in Weyl semimetals with periodic magnetic barriers
Authors: Hu Xunwu , Cheng Fang
Published: July 2019

We investigate theoretically the effect of periodic magnetic barriers on the transport for a Weyl semimetal. We find that there are momentum and spin filtering tunneling behaviors, which is controlled by the numbers of the magnetic barriers. For the tunneling through periodic square-shaped magnetic barriers, the transmission is angular φ asymmetry, and the asymmetrical transmission probability becomes more pronounced with increasing the superlattice number n. However, the transmission is symmetric with respect to angle γ, and the window of the transmission become more and more narrower with increasing the number of barriers, i.e., the collimator behavior. This feature comes from the electron Fabry-Pérot modes among the barriers. We find that the constructive interference of the backscattering amplitudes suppress transmissions, and consequently form the minigaps of the transmission. The transmission can be switched on/off by tuning the incident energies and angles, the heights and numbers of the magnetic barriers, and result in the interesting collimator behavior.
A revised acceleration rate from the altimetry-derived global mean sea level record
Authors: Kleinherenbrink Marcel , Riva Riccardo , Scharroo Remko
Published: July 2019

Satellite radar altimetry has been providing estimates of global mean sea level (GMSL) since 1992. The early TOPEX record originates from two identical instruments, which requires the estimation of an intermission bias and careful handling of the problematic first part of the record. Calibration of TOPEX is crucial to obtain a continuous and consistent record, which is needed to quantify any recent acceleration. We propose a novel approach to calibrate TOPEX altimeter data using sea surface height differences at crossovers of TOPEX and ERS. Tide gauges are only used to determine a drift in one of the two datasets. We provide a new and more accurate estimate of the intra-mission bias, which leads to a much reduced GMSL acceleration over the whole record. Hence, the conundrum of an uncertain GMSL acceleration from altimetry is still unsolved, in spite of recent opposite claims, and in contrast to the expected effect of ocean warming and continental freshwater fluxes.
Evaluating the Utility of EPIK in a Finger Tapping fMRI Experiment using BOLD Detection and Effective Connectivity
Authors: Yun Seong Dae , Weidner Ralph , Weiss Peter H. , Shah N. Jon
Published: July 2019

EPI with Keyhole (EPIK) is a hybrid imaging technique that overcomes many of the performance disadvantages associated with EPI. Previously, EPIK was shown to provide a higher temporal resolution and fewer image distortions than EPI whilst maintaining comparable performance for the detection of BOLD-based signals. This work carefully examines the putative enhanced sensitivity of EPIK in a typical fMRI setting by using a robust fMRI paradigm – visually guided finger tapping – to demonstrate the advantages of EPIK for fMRI at 3 T. The data acquired were directly compared to the community standard fMRI protocol using single-shot EPI to ascertain a clear comparison. Each sequence was optimised to offer its highest possible spatial resolution for a given set of imaging conditions, i.e., EPIK and EPI achieved an in-planar resolution of 2.08 × 2.08 mm2 with 32 slices and 3.13 × 3.13 mm2 with 36 slices, respectively. EPIK demonstrated a number of clear improvements, such as superior spatial resolution with favourable robustness against susceptibility artefacts. Both imaging sequences revealed robust activation within primary motor, premotor and visual regions, although significantly higher BOLD amplitudes were detected using EPIK within the primary and supplementary motor areas. Dynamic causal modelling, in combination with Bayesian model selection, identified identical winning models for EPIK and EPI data. Coupling parameters reflecting task-related modulations and the connectivity of fixed connections were comparably robust for both sequences. However, fixed connections from the left motor cortex to the right visual cortex were estimated as being significantly more robust for EPIK data.
Transient Receptor Potential vanilloid 4 ion channel in C-fibres is involved in mechanonociception of the normal and inflamed joint
Authors: Richter Frank , Segond von Banchet Gisela , Schaible Hans-Georg
Published: July 2019

The Transient Receptor Potential vanilloid 4 ion channel (TRPV4) is an important sensor for osmotic and mechanical stimuli in the musculoskeletal system, and it is also involved in processes of nociception. In this study we investigated the putative role of TRPV4 ion channels in joint pain. In anesthetized rats we recorded from mechanosensitive nociceptive A∂- and C-fibres supplying the medial aspect of the knee joint. The intraarticular injection of the TRPV4 antagonist RN-1734 into the knee joint reduced the responses of C-fibres of the normal joint to noxious mechanical stimulation and the responses of the sensitized C-fibres of the acutely inflamed joint to innocuous and noxious mechanical stimulation. The responses of nociceptive A∂-fibres were not significantly altered by RN-1734. The intraarticular application of the TRPV4 agonists 4αPDD, GSK 1016790 A, and RN-1747 did not consistently alter the responses of A∂- and C-fibres to mechanical stimulation of the joint nor did they induce ongoing activity. We conclude that TRPV4 ion channels are involved in the responses of C-fibres to noxious mechanical stimulation of the normal joint, and in the enhanced sensitivity of C-fibres to mechanical stimulation of the joint during inflammation of the joint.
Methane formation in tropical reservoirs predicted from sediment age and nitrogen
Authors: Isidorova Anastasija , Grasset Charlotte , Mendonça Raquel , Sobek Sebastian
Published: July 2019

Freshwater reservoirs, in particular tropical ones, are an important source of methane (CH4) to the atmosphere, but current estimates are uncertain. The CH4 emitted from reservoirs is microbially produced in their sediments, but at present, the rate of CH4 formation in reservoir sediments cannot be predicted from sediment characteristics, limiting our understanding of reservoir CH4 emission. Here we show through a long-term incubation experiment that the CH4 formation rate in sediments of widely different tropical reservoirs can be predicted from sediment age and total nitrogen concentration. CH4 formation occurs predominantly in sediment layers younger than 6–12 years and beyond these layers sediment organic carbon may be considered effectively buried. Hence mitigating reservoir CH4 emission via improving nutrient management and thus reducing organic matter supply to sediments is within reach. Our model of sediment CH4 formation represents a first step towards constraining reservoir CH4 emission from sediment characteristics.
Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer
Authors: Honkanen Tiia J. , Tikkanen Antti , Karihtala Peeter , Mäkinen Markus , Väyrynen Juha P. , Koivunen Jussi P.
Published: July 2019

Disease outcomes of HER2+ breast cancers have dramatically improved after targeted therapies, such as trastuzumab became available. The main mechanism of action of trastuzumab depends on immunoactivation, while immunosuppressive tumour phenotype has been linked to adverse outcomes. Current study included metastatic HER2+ breast cancer patients treated with trastuzumab (n = 40). Immunohistochemistry was conducted to detect nitric oxide synthase 2 (iNOS) expressing M1 polarized and CD163+ M2 polarized macrophages, FoxP3+ regulatory T-cells (Tregs), CD47 and indoleamine 2,3-dioxygenase 1 (IDO1). High number of iNOS+ M1-like macrophages, both in the center of the tumour (CT) and invasive margin (IM), was significantly associated with improved survival (p = 0.009) while high expression of IDO1 or CD47 in the malignant cells was associated with worsened prognosis (p = 0.018, p = 0.046). High number of CD163+ M2-like macrophages in the CT, but not in the IM, and high number of FoxP3+ Tregs in both locations showed non-significant tendencies towards poor prognosis. Moreover, high number of iNOS+ M1-like macrophages combined with high number of CD8+ T-cells in the CT was significantly associated with improved survival (p = 0.0003), and this combined marker predicted patient’s ability to remain progression-free without trastuzumab after responding to the therapy (p = 0.003). Current study highlights the role of M1 polarized macrophages alone and in combination with CD8+ cells in HER2+ breast cancer.
Development of wirelessly-powered, extracranial brain activator (ECBA) in a large animal model for the future non-invasive human neuromodulation
Authors: Lee Hyungwoo , Lee Jin San , Chung Yeongu , Chung Woo Ram , Kim Sang Joon , Kang Joon Seong , Park Sung Min , Kang Wonok , Seo Dae Won , Na Duk L. , Shon Young-Min
Published: July 2019

As transcranial electrical stimulation (tES) is an emerging and promising technique for neuromodulation, we developed a novel device; wirelessly-powered, extracranial brain activator (ECBA), which is mounted subcutaneously, and its neuromodulation effect was investigated. The oscillatory changes in electrocorticography (EcoG) were analyzed from two types of stimulation. Two weeks prior to the recording experiment, we underwent surgery for implantation of subdural strips and ECBA module over centroparietal regions of anesthetized beagles. Low-frequency stimulation (LFS) and subsequent high-frequency stimulation (HFS) protocols (600 pulses respectively) were applied. Then, the power changes before and after each stimulation in five different bands were compared. A significantly larger voltage difference with subcutaneous than transcutaneous stimulation measured at EcoG channels indicated a substantial current attenuation between the skin and skull. Compared with the baseline, all subjects showed consistently decreased delta power and increased gamma power after HFS. LFS also induced a similar, but opposite, pattern of power change in four beagles. The results from this study indicate that LFS and HFS with our novel ECBA can consistently and effectively modulate neural activity of the cortex, inducing neural inhibition and facilitation functions, respectively. Future studies are necessary to further ensuring a consistent efficacy and long-term safety.
New insights into the role of plasmids from probiotic Lactobacillus pentosus MP-10 in Aloreña table olive brine fermentation
Authors: Abriouel Hikmate , Pérez Montoro Beatriz , de la Fuente Ordoñez Juan José , Lavilla Lerma Leyre , Knapp Charles W. , Benomar Nabil
Published: July 2019

In silico analysis of Lactobacillus pentosus MP-10 plasmids (pLPE-1 to pLPE-5) suggests that plasmid-borne genes mediate the persistence of lactobacilli during olive fermentation and enhance their probiotic properties and their competitiveness in several ecological niches. The role of plasmids in the probiotic activities of L. pentosus MP-10 was investigated by plasmid-curing process which showed that plasmids contribute in increased metal tolerance and the biosequestration of several metals such as iron, aluminium, cobalt, copper, zinc, cadmium and mercury. Statistically significant differences in mucin adhesion were detected between the uncured and the cured L. pentosus MP-10, which possibly relied on a serine-rich adhesin (sraP) gene detected on the pLPE-2 plasmid. However, plasmid curing did not affect their tolerance to gastro-intestinal conditions, neither their growth ability under pre-determined conditions, nor auto-aggregation and pathogen co-aggregation were changed among the cured and uncured L. pentosus MP-10. These findings suggest that L. pentosus MP-10 plasmids play an important role in gastro-intestinal protection due to their attachment to mucin and, thus, preventing several diseases. Furthermore, L. pentosus MP-10 could be used as a bioquencher of metals in the gut, reducing the amount of these potentially toxic elements in humans and animals, food matrices, and environmental bioremediation.
Early detection of unilateral ureteral obstruction by desorption electrospray ionization mass spectrometry
Authors: Banerjee Shibdas , Wong Anny Chuu-Yun , Yan Xin , Wu Bo , Zhao Hongjuan , Tibshirani Robert J. , Zare Richard N. , Brooks James D.
Published: July 2019

Desorption electrospray ionization mass spectrometry (DESI-MS) is an emerging analytical tool for rapid in situ assessment of metabolomic profiles on tissue sections without tissue pretreatment or labeling. We applied DESI-MS to identify candidate metabolic biomarkers associated with kidney injury at the early stage. DESI-MS was performed on sections of kidneys from 80 mice over a time course following unilateral ureteral obstruction (UUO) and compared to sham controls. A predictive model of renal damage was constructed using the LASSO (least absolute shrinkage and selection operator) method. Levels of lipid and small metabolites were significantly altered and glycerophospholipids comprised a significant fraction of altered species. These changes correlate with altered expression of lipid metabolic genes, with most genes showing decreased expression. However, rapid upregulation of PG(22:6/22:6) level appeared to be a hitherto unknown feature of the metabolic shift observed in UUO. Using LASSO and SAM (significance analysis of microarrays), we identified a set of well-measured metabolites that accurately predicted UUO-induced renal damage that was detectable by 12 h after UUO, prior to apparent histological changes. Thus, DESI-MS could serve as a useful adjunct to histology in identifying renal damage and demonstrates early and broad changes in membrane associated lipids.
Multi-view Co-training for microRNA Prediction
Authors: Sheikh Hassani Mohsen , Green James R.
Published: July 2019

MicroRNA (miRNA) are short, non-coding RNAs involved in cell regulation at post-transcriptional and translational levels. Numerous computational predictors of miRNA been developed that generally classify miRNA based on either sequence- or expression-based features. While these methods are highly effective, they require large labelled training data sets, which are often not available for many species. Simultaneously, emerging high-throughput wet-lab experimental procedures are producing large unlabelled data sets of genomic sequence and RNA expression profiles. Existing methods use supervised machine learning and are therefore unable to leverage these unlabelled data. In this paper, we design and develop a multi-view co-training approach for the classification of miRNA to maximize the utility of unlabelled training data by taking advantage of multiple views of the problem. Starting with only 10 labelled training data, co-training is shown to significantly (p < 0.01) increase classification accuracy of both sequence- and expression-based classifiers, without requiring any new labelled training data. After 11 iterations of co-training, the expression-based view of miRNA classification experiences an average increase in AUPRC of 15.81% over six species, compared to 11.90% for self-training and 4.84% for passive learning. Similar results are observed for sequence-based classifiers with increases of 46.47%, 39.53% and 29.43%, for co-training, self-training, and passive learning, respectively. The final co-trained sequence and expression-based classifiers are integrated into a final confidence-based classifier which shows improved performance compared to both the expression (1.5%, p = 0.021) and sequence (3.7%, p = 0.006) views. This study represents the first application of multi-view co-training to miRNA prediction and shows great promise, particularly for understudied species with few available training data.
Controlled generation of array beams of higher order orbital angular momentum and study of their frequency-doubling characteristics
Authors: Harshith B. S. , Samanta G. K.
Published: July 2019

We report on a simple and compact experimental scheme to generate high-power, ultrafast, higher-order vortex-array beams. Simply by using a dielectric microlens-array (MLA) and a plano-convex lens, we have generated array-beams carrying the spatial property of the input beam. Considering the MLA as a 2D sinusoidal phase-grating, we have numerically calculated the intensity pattern of the array-beams in close agreement with the experimental results. Using vortex beams of order as high as l = 6, we have generated vortex array-beam with individual vortices of orders up to l = 6. We have also theoretically derived the parameters controlling the intensity pattern, size, and the array-pitch and verified experimentally. The single-pass frequency-doubling of vortex-array at 1064 nm in a 1.2 mm long BiBO crystal produced green vortex-array of order, lsh = 12, twice the order of pump beam. Using lenses of different focal lengths, we have observed the vortex-arrays of all orders to follow a focusing dependent conversion similar to the Gaussian beam. The maximum power of the green vortex-array is measured to be 138 mW at a single-pass efficiency as high as ~3.65%. This generic experimental scheme can be used to generate the array beams of desired spatial intensity profile across a wide wavelength range by simply changing the spatial profile of the input beam.
Rational drug-design approach supported with thermodynamic studies — a peptide leader for the efficient bi-substrate inhibitor of protein kinase CK2
Authors: Winiewska-Szajewska Maria , Płonka Dawid , Zhukov Igor , Poznański Jarosław
Published: July 2019

Numerous inhibitors of protein kinases act on the basis of competition, targeting the ATP binding site. In this work, we present a procedure of rational design of a bi-substrate inhibitor, complemented with biophysical assays. The inhibitors of this type are commonly engineered by combining ligands carrying an ATP-like part with a peptide or peptide-mimicking fragment that determines specificity. Approach presented in this paper led to generation of a specific system for independent screening for efficient ligands and peptides, by means of thermodynamic measurements, that assessed the ability of the identified ligand and peptide to combine into a bi-substrate inhibitor. The catalytic subunit of human protein kinase CK2 was used as the model target. Peptide sequence was optimized using peptide libraries [KGDE]-[DE]-[ST]-[DE]3–4-NH2, originated from the consensus CK2 sequence. We identified KESEEE-NH2 peptide as the most promising one, whose binding affinity is substantially higher than that of the reference RRRDDDSDDD peptide. We assessed its potency to form an efficient bi-substrate inhibitor using tetrabromobenzotriazole (TBBt) as the model ATP-competitive inhibitor. The formation of ternary complex was monitored using Differential Scanning Fluorimetry (DSF), Microscale Thermophoresis (MST) and Isothermal Titration Calorimetry (ITC).
The Role of Visual Experience in Auditory Space Perception around the Legs
Authors: Aggius-Vella Elena , Campus Claudio , Kolarik Andrew Joseph , Gori Monica
Published: July 2019

It is widely accepted that vision plays a key role in the development of spatial skills of the other senses. Recent works have shown that blindness is often associated with auditory spatial deficits. The majority of previous studies have focused on understanding the representation of the upper frontal body space where vision and actions have a central role in mapping the space, however less research has investigated the back space and the space around the legs. Here we investigate space perception around the legs and the role of previous visual experience, by studying sighted and blind participants in an audio localization task (front-back discrimination). Participants judged if a sound was delivered in their frontal or back space. The results showed that blindfolded sighted participants were more accurate than blind participants in the frontal space. However, both groups were similarly accurate when auditory information was delivered in the back space. Blind individuals performed the task with similar accuracy for sounds delivered in the frontal and back space, while sighted people performed better in the frontal space. These results suggest that visual experience influences auditory spatial representations around the legs. Moreover, these results suggest that hearing and vision play different roles in different spaces.
Comparative genomics suggests loss of keratin K24 in three evolutionary lineages of mammals
Authors: Ehrlich Florian , Laggner Maria , Langbein Lutz , Burger Pamela , Pollreisz Andreas , Tschachler Erwin , Eckhart Leopold
Published: July 2019

Keratins are the main cytoskeletal proteins of epithelial cells and changes in the expression of keratins have contributed to the evolutionary adaptation of epithelia to different environments. Keratin K24 was proposed to be a differentiation marker of epidermal keratinocytes but the significance of K24 expression in the epidermis versus other tissues has remained elusive. Here, we show by RT-PCR, western blot, and immunofluorescence analyses that K24 is highly expressed in the epithelium of the cornea whereas its expression levels are significantly lower in other stratified epithelia including in the epidermis. To investigate the evolutionary history of K24, we screened the genome sequences of vertebrates for orthologs of the human KRT24 gene. The results of this comparative genomics study suggested that KRT24 originated in a common ancestor of amniotes and that it was lost independently in three clades of mammals, i.e. camels, cetaceans, and a subclade of pinnipeds comprising eared seals and the walrus. Together, the results of this study identify K24 as component of the cytoskeleton in the human corneal epithelium and reveal previously unknown differences of keratin gene content among mammalian species.
Serum PlGF and EGF are independent prognostic markers in non-metastatic colorectal cancer
Authors: Schölch Sebastian , Bogner Andreas , Bork Ulrich , Rahbari Mohammad , Győrffy Balázs , Schneider Martin , Reissfelder Christoph , Weitz Jürgen , Rahbari Nuh N.
Published: July 2019

The aim of this study was to determine the prognostic value of circulating angiogenic cytokines in non-metastatic colorectal cancer (CRC) patients. Preoperative serum samples of a training (TC) (n = 219) and a validation cohort (VC) (n = 168) were analyzed via ELISA to determine PlGF, EGF, VEGF, Ang1, PDGF-A, PDGF-B, IL-8 and bFGF levels. In addition, survival was correlated with PlGF and EGF expression measured by microarray and RNAseq in two publicly available, independent cohorts (n = 550 and n = 463, respectively). Prognostic values for overall (OS) and disease-free survival (DFS) were determined using uni- and multivariate Cox proportional hazard analyses. Elevated PlGF is predictive for impaired OS (TC: HR 1.056; p = 0.046; VC: HR 1.093; p = 0.001) and DFS (TC: HR 1.052; p = 0.029; VC: HR 1.091; p = 0.009). Conversely, elevated EGF is associated with favorable DFS (TC: HR 0.998; p = 0.045; VC: HR 0.998; p = 0.018) but not OS (TC: p = 0.201; VC: p = 0.453). None of the other angiogenic cytokines correlated with prognosis. The prognostic value of PlGF (OS + DFS) and EGF (DFS) was confirmed in both independent retrospective cohorts. Serum PlGF and EGF may serve as prognostic markers in non-metastatic CRC.
Thermal damage in three-dimensional vivo bio-tissues induced by moving heat sources in laser therapy
Authors: Ma Jingxuan , Yang Xianfeng , Sun Yuxin , Yang Jialing
Published: July 2019

The thermal damage of a three-dimensional bio-tissue model irradiated by a movable laser beam was studied in this work. By employing the DPL biological heat conduction model and Henriques’ thermal damage assessment model, the distribution of burn damage of vivo human tissue during laser therapy was analytically obtained. The influences of laser moving velocity, laser spot size, phase lags of heat flux and temperature gradient were discussed. It was found that the laser moving speed and the laser spot size greatly influence the thermal damage degree by affecting the energy concentration degree. The increases of the laser moving speed and laser spot size can enlarge the irradiated region and reduce the burn degree. A greater phase lag of temperature gradient led to lower accumulation of thermal energy and lower burn degree. However, the increment of heat flux phase lag leads to the thermal energy accumulation and more serious burn degree in the irradiated region.
Hybrid nanocomposite as a chest wall graft with improved integration by adipose-derived stem cells
Authors: Buschmann Johanna , Yamada Yoshito , Schulz-Schönhagen Konstantin , Hess Samuel C. , Stark Wendelin J. , Opelz Christine , Bürgisser Gabriella Meier , Weder Walter , Jungraithmayr Wolfgang
Published: July 2019

Surgery of the chest wall is potentially required to cover large defects after  removal of malignant tumours. Usually, inert and non-degradable Gore-Tex serves to replace the missing tissue. However, novel biodegradable materials combined with stem cells are available that stimulate the healing. Based on poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/aCaP) and pure PLGA, a dual layer biodegradable hybrid nanocomposite was generated. Mouse adipose-derived stem cells were cultered on electrospun disks (ASCs of C57BL/6), and biomechanical tests were performed. The cell-seeded scaffolds were engrafted in C57BL/LY5.1 mice to serve as a chest wall substitute. Cell invasion into the bi-layered material, extent of CD45+ cells, inflammatory response, neo-vascularization and ECM composition were determined at 1 and 2 months post-surgery, respectively. The bi-layered hybrid nanocomposite was stable after a 2-week in vitro culture, in contrast to PLGA/aCaP without a PLGA layer. There was a complete biointegration and good vascularization in vivo. The presence of ASCs attracted more CD45+ cells (hematopoietic origin) compared to cell-free scaffolds. Inflammatory reaction was similar for both groups (±ASCs) at 8 weeks. A bi-layered hybrid nanocomposite fabricated of electrospun PLGA/aCaP and a reinforcing layer of pristine PLGA is an ideal scaffold for chest wall reconstruction. It is stable and allows a proper host tissue integration. If ASCs are seeded, they attract more CD45+ cells, supporting the regeneration process.
Comparative study on the catalytic activity of Fe-doped ZrO2 nanoparticles without significant toxicity through chemical treatment under various pH conditions
Authors: Song Hye-in , Hong Jung A. , Lee Hangil , Lim Kwang-il
Published: July 2019

Despite advances in the construction of catalysts based on metal oxide nanoparticles (MO NPs) for various industrial, biomedical, and daily-life applications, the biosafety concerns about these NPs still remain. Recently, the need to analyze and improve the safety of MO NPs along with attempts to enhance their catalytic performance has been strongly perceived. Here, we prepared multiple variants of Fe-doped zirconium oxide (Fe@ZrO2) NPs under different pH conditions; then, we assessed their toxicity and finally screened the variant that exhibited the best catalytic performance. To assess the NP toxicity, the prepared NPs were introduced into three types of human cells originally obtained from different body parts likely to be most affected by NPs (skin, lung, and kidney). Experimental results from conventional cellular toxicity assays including recently available live-cell imaging indicated that none of the variants exerted severe negative effects on the viability of the human cells and most NPs were intracellular localized outside of nucleus, by which severe genotoxicity is unexpected. In contrast, Fe@ZrO2 NPs synthesized under a basic condition (pH = 13.0), exhibited the highest catalytic activities for three different reactions; each was biochemical (L-cysteine oxidation) or photochemical one (4-chlorophenol degradation and OH radical formation with benzoic acid). This study demonstrates that catalytic Fe@ZrO2 NPs with enhanced activities and modest or insignificant toxicity can be effectively developed and further suggests a potential for the use of these particles in conventional chemical reactions as well as in recently emerging biomedical and daily-life nanotechnology applications.
Adiponectin levels among individuals with varied employment status in Japan: a cross-sectional analysis of the J-SHINE study
Authors: Amano Hoichi , Shirakawa Yoshimi , Hashimoto Hideki
Published: July 2019

The purpose of this study was to examine the association between employment status and adiponectin levels. This cross-sectional study was a part of the Japanese Stratification, Health, Income, and Neighborhood study, a population-based survey in metropolitan Japan. The analysis included data from 848 individuals. A one-way analysis of variance was used to assess differences in log-transformed adiponectin levels among individuals according to their employment status. Multiple linear regression analysis was used to assess these differences after adjusting for other cardiovascular disease risk factors. The main outcome was log-transformed adiponectin. Of the participants, 6.2% of the men and 15.1% of the women were precarious workers. Mean adiponectin values differed significantly by employment status in men, but not in women. In men, multiple regression analysis showed that precarious workers had significantly lower adiponectin levels than permanent workers (β = −0.16, P = 0.02). However, in women, adiponectin levels were significantly lower only in precarious workers with low household incomes (β = −0.35, P = 0.02). Male precarious workers and their female counterparts with low annual household incomes had significantly lower levels of adiponectin. These results might help us to understand mechanisms underlying the relationship between employment status and cardiovascular disease.
CETP, LIPC, and SCARB1 variants in individuals with extremely high high-density lipoprotein-cholesterol levels
Authors: Lee Chan Joo , Park Mun Su , Kim Miso , Ann Soo-jin , Lee Jaeho , Park Sungha , Kang Seok-Min , Jang Yangsoo , Lee Ji Hyun , Lee Sang-Hak
Published: July 2019

The concentration of high-density lipoprotein-cholesterol (HDL-C) in humans is partially determined by genetic factors; however, the role of these factors is incompletely understood. The aim of this study was to examine the prevalence and characteristics of CETP, LIPC, and SCARB1 variants in Korean individuals with extremely high HDL-C levels. We also analysed associations between these variants and cholesterol efflux capacity (CEC), reactive oxygen species (ROS) generation, and vascular cell adhesion molecule-1 (VCAM-1) expression. Of 13,545 participants in the cardiovascular genome cohort, 42 subjects with HDL-C levels >100 mg/dL were analysed. The three target genes were sequenced by targeted next-generation sequencing, the functional effects of detected variants were predicted, and CEC was assessed using a radioisotope and apolipoprotein B-depleted sera. We observed two rare variants of CETP in 13 individuals (rare variant c.A1196G [p.D399G] of CETP was discovered in 12 subjects) and one rare variant of SCARB1 in one individual. Furthermore, all subjects had at least one of four common variants (one CETP and three LIPC variants). Two additional novel CETP variants of unknown frequency were found in two subjects. However, the identified variants did not show significant associations with CEC, ROS generation, or VCAM-1 expression. Our study provides additional insights into the role of genetics in individuals with extremely high HDL-C.
Tinospora cordifolia protects against inflammation associated anemia by modulating inflammatory cytokines and hepcidin expression in male Wistar rats
Authors: Ghatpande Niraj S. , Misar Ashwini V. , Waghole Ravindra J. , Jadhav Sachin H. , Kulkarni Prasad P.
Published: July 2019

Systemic iron homeostasis dysregulation is primarily associated with inflammation- associated anemia (AI) due to hepcidin up-regulation. Tinospora cordifolia (TC) has shown remarkable anti-inflammatory properties and has been found useful in the treatment of inflammatory disorders. However, the effects and mechanisms of TC on AI have not been studied yet. We conducted in vivo and in vitro studies to evaluate the effect of TC on AI. HPLC studies were also carried out to find out active constituents in TC extract. Model system exhibiting AI was developed by repeated injections of HKBA in Wistar rats. TC treated groups showed significantly higher levels of Hb and RBC count compared to the inflammatory control group. TC treatment showed reduction in the expression of the HAMP (hepcidin) gene in the rat liver. TC extract also inhibited gene expression of inflammatory cytokines (TNF-α, IL-1β) and decreased NO production in RAW 264.7 cells. The HPLC analysis revealed the presence of tinosporaside, which could have synergistically contributed to the above findings. Overall results indicate that TC therapy was able to maintain circulating iron through reduction of inflammatory cytokines and expression of hepcidin in rats.
Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action
Authors: Lasič Eva , Lisjak Marjeta , Horvat Anemari , Božić Mićo , Šakanović Aleksandra , Anderluh Gregor , Verkhratsky Alexei , Vardjan Nina , Jorgačevski Jernej , Stenovec Matjaž , Zorec Robert
Published: July 2019

Ketamine is an antidepressant with rapid therapeutic onset and long-lasting effect, although the underlying mechanism(s) remain unknown. Using FRET-based nanosensors we found that ketamine increases [cAMP]i in astrocytes. Membrane capacitance recordings, however, reveal fundamentally distinct mechanisms of effects of ketamine and [cAMP]i on vesicular secretion: a rise in [cAMP]i facilitated, whereas ketamine inhibited exocytosis. By directly monitoring cholesterol-rich membrane domains with a fluorescently tagged cholesterol-specific membrane binding domain (D4) of toxin perfringolysin O, we demonstrated that ketamine induced cholesterol redistribution in the plasmalemma in astrocytes, but neither in fibroblasts nor in PC 12 cells. This novel mechanism posits that ketamine affects density and distribution of cholesterol in the astrocytic plasmalemma, consequently modulating a host of processes that may contribute to ketamine’s rapid antidepressant action.
Deletion of NFKB1 enhances canonical NF-κB signaling and increases macrophage and myofibroblast content during tendon healing
Authors: Best Katherine T. , Lee Fredella K. , Knapp Emma , Awad Hani A. , Loiselle Alayna E.
Published: July 2019

Flexor tendon injuries heal with excessive scar tissue that limits range of motion and increases incidence of re-rupture. The molecular mechanisms that govern tendon healing are not well defined. Both the canonical nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways have been implicated in tendon healing. The gene NFKB1 (proteins p105/p50) is involved in both NF-κB and MAPK signaling cascades. In the present study, we tested the hypothesis that global NFKB1 deletion would increase activation of both NF-κB and MAPK through loss of signaling repressors, resulting in increased matrix deposition and altered biomechanical properties. As hypothesized, NFKB1 deletion increased activation of both NF-κB and MAPK signaling. While gliding function was not affected, NFKB1 deletion resulted in tendons that were significantly stiffer and trending towards increased strength by four weeks post-repair. NFKB1 deletion resulted in increased collagen deposition, increase macrophage recruitment, and increased presence of myofibroblasts. Furthermore, NFKB1 deletion increased expression of matrix-related genes (Col1a1, Col3a1), macrophage-associated genes (Adgre1, Ccl2), myofibroblast markers (Acta2), and general inflammation (Tnf). Taken together, these data suggest that increased activation of NF-κB and MAPK via NFKB1 deletion enhance macrophage and myofibroblast content at the repair, driving increased collagen deposition and biomechanical properties.
Particle coating alters mucociliary transit in excised rat trachea: A synchrotron X-ray imaging study
Authors: Gardner Mark , McCarron Alexandra , Morgan Kaye , Parsons David , Donnelley Martin
Published: July 2019

We have previously developed non-invasive in vivo mucociliary transport (MCT) monitoring methods using synchrotron phase contrast X-ray imaging (PCXI) to evaluate potential therapies for cystic fibrosis (CF). However, previous in vivo measurements of MCT velocity using this method were lower than those from alternate methods. We hypothesise this was due to the surface chemistry of the uncoated particles. We investigated the effect of particle surface coating on MCT marker performance by measuring the velocity of uncoated, positively-charged (aminated; NH2), and negatively-charged (carboxylated; COOH) particles. The effect of aerosolised hypertonic saline (HS) was also investigated, as previous in vivo measurements showed HS significantly increased MCT rate. PCXI experiments were performed using an ex vivo rat tracheal imaging setup. Prior to aerosol delivery there was little movement of the uncoated particles, whilst the NH2 and COOH particles moved with MCT rates similar to those previously reported. After application of HS the uncoated and COOH particle velocity increased and NH2 decreased. This experiment validated the use of COOH particles as MCT marker particles over the uncoated and NH2 coated particles. Our results suggest that future experiments measuring MCT using synchrotron PCXI should use COOH coated marker particles for more accurate MCT quantification.
Comprehensive feature selection for classifying the treatment outcome of high-intensity ultrasound therapy in uterine fibroids
Authors: Suomi Visa , Komar Gaber , Sainio Teija , Joronen Kirsi , Perheentupa Antti , Blanco Sequeiros Roberto
Published: July 2019

The study aim was to utilise multiple feature selection methods in order to select the most important parameters from clinical patient data for high-intensity focused ultrasound (HIFU) treatment outcome classification in uterine fibroids. The study was retrospective using patient data from 66 HIFU treatments with 89 uterine fibroids. A total of 39 features were extracted from the patient data and 14 different filter-based feature selection methods were used to select the most informative features. The selected features were then used in a support vector classification (SVC) model to evaluate the performance of these parameters in predicting HIFU therapy outcome. The therapy outcome was defined as non-perfused volume (NPV) ratio in three classes: <30%, 30–80% or >80%. The ten most highly ranked features in order were: fibroid diameter, subcutaneous fat thickness, fibroid volume, fibroid distance, Funaki type I, fundus location, gravidity, Funaki type III, submucosal fibroid type and urinary symptoms. The maximum F1-micro classification score was 0.63 using the top ten features from Mutual Information Maximisation (MIM) and Joint Mutual Information (JMI) feature selection methods. Classification performance of HIFU therapy outcome prediction in uterine fibroids is highly dependent on the chosen feature set which should be determined prior using different classifiers.
Exosites in Hypervariable Loops of ADAMTS Spacer Domains control Substrate Recognition and Proteolysis
Authors: Santamaria Salvatore , Yamamoto Kazuhiro , Teraz-Orosz Adrienn , Koch Christopher , Apte Suneel S. , de Groot Rens , Lane David A. , Ahnström Josefin
Published: July 2019

ADAMTS (A Disintegrin-like and Metalloproteinase domain with Thrombospondin type 1 Motif)-1, -4 and -5 share the abilities to cleave large aggregating proteoglycans including versican and aggrecan. These activities are highly relevant to cardiovascular disease and osteoarthritis and during development. Here, using purified recombinant ADAMTS-1, -4 and -5, we quantify, compare, and define the molecular basis of their versicanase activity. A novel sandwich-ELISA detecting the major versican cleavage fragment was used to determine, for the first time, kinetic constants for versican proteolysis. ADAMTS-5 (kcat/Km 35 × 105 M−1 s−1) is a more potent (~18-fold) versicanase than ADAMTS-4 (kcat/Km 1.86 × 105 M−1 sec−1), whereas ADAMTS-1 versicanase activity is comparatively low. Deletion of the spacer domain reduced versicanase activity of ADAMTS-5 19-fold and that of ADAMTS-4 167-fold. Co-deletion of the ADAMTS-5 cysteine-rich domain further reduced versicanase activity to a total 153-fold reduction. Substitution of two hypervariable loops in the spacer domain of ADAMTS-5 (residues 739–744 and 837–844) and ADAMTS-4 (residues 717–724 and 788–795) with those of ADAMTS-13, which does not cleave proteoglycans, caused spacer-dependent reductions in versicanase activities. Our results demonstrate that these loops contain exosites critical for interaction with and processing of versican. The hypervariable loops of ADAMTS-5 are shown to be important also for its aggrecanase activity. Together with previous work on ADAMTS-13 our results suggest that the spacer domain hypervariable loops may exercise significant control of ADAMTS proteolytic activity as a general principle. Identification of specific exosites also provides targets for selective inhibitors.