bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective analysis of ocular neuropathies in diabetic dogs following cataract surgery
Authors: Foote Braidee C. , Michau Tammy M. , Welihozkiy Anja , Stine Jessica M.
Published: August 2018

Objectives

To describe and compare the cumulative incidence and clinical progression of ocular neuropathies in diabetic dogs vs nondiabetic dogs following cataract surgery.

Methods

Medical records of 196 diabetic and 442 nondiabetic dogs who underwent cataract surgery between 2004 and 2015 were reviewed. The percentage of patients affected by neuropathy and potential risk factors were compared between groups.

Results

Patients with diabetes mellitus (DM) were 20.4 times more likely to develop an ocular neuropathy than patients withoutDM(12.24% vs 0.68%). Twenty‐four diabetic patients were affected by mononeuropathies or polyneuropathies including Horner's syndrome (n = 20), facial neuropathy (n = 5), and neurogenic keratoconjunctivitis sicca (NKCS) (n = 5). The odds of a diabetic patient developing Horner's syndrome andNKCSwere 86.3 and 20.7 times higher than a nondiabetic patient, respectively. The average duration ofDMprior to diagnosis of neuropathy was 659 days (range 110‐2390 days; median 559 days). Complete resolution was achieved in 10 of 22 neuropathies (45%) within an average of 248 days (range 21‐638 days; median 187 days) after diagnosis.

Conclusions

The odds of developing an ocular neuropathy, specifically Horner's syndrome andNKCS, are statistically higher in diabetic patients compared to nondiabetic patients. Neuropathies were observed as a long‐term complication in this group of diabetic patients, and complete resolution of the neuropathy was observed in less than half of the affected population.
Microbiota of the conjunctival sac of 120 healthy cats
Authors: Büttner Jessica Nina , Schneider Marianne , Csokai Jaqueline , Müller Elisabeth , Eule Johanna Corinna
Published: August 2018

Objectives

To describe the bacterial and fungal microbiota of the conjunctiva and factors influencing these microbiota of healthy cats. To evaluate the antimicrobial resistance profile and discuss the use of appropriate antimicrobial drugs.

Animals studied

One hundred and twenty healthy cats

Procedures

Conjunctival samples with dry or premoistened swabs were obtained from both eyes and cultured for aerobic and anaerobic bacteria and fungi. In vitro bacterial, susceptibility testing was performed. The effects of age, sex, breed, season, living environment, and sample collection technique on the frequency and composition of microbial isolation were evaluated.

Results

In 49 of 120 cats (40.8%) and 73 of 240 swabs (30.4%), microorganisms were isolated. Of the isolates, 71% (61/86) were Gram‐positive bacteria, 26% (22/86) were Gram‐negative bacteria, and 3% (3/86) were fungi.Staphylococcus felis(17/86; 19.8%) was the most commonly isolated species.Moraxella osloensis(5/86; 5.8%) was the most frequent Gram‐negative species. The season had a statistically significant influence (P = 0.04) on the frequency of isolation. The use of premoistened swabs increased the rate of Gram‐positive bacterial detection significantly (P = 0.03). The in vitro susceptibility testing showed high efficacy of chloramphenicol, gentamicin, pradofloxacin, and enrofloxacin.

Conclusions

The isolated microbiota aligns with previous studies performed in other countries, although the microbiota of cats in the present study showed wider bacterial diversity, and more Gram‐negative species were isolated. Swab sampling should be performed with premoistened swabs. The topical antimicrobials gentamicin and chloramphenicol are suitable therapeutics for first‐line treatment.
Ventral stabilization of thoracic kyphosis through bilateral intercostal thoracotomies using SOP (String of Pearls) plates contoured after a 3‐dimensional print of the spine
Authors: Mathiesen Christina B. , de la Puerta Benito , Groth Anna M. , Rutherford Scott , Cappello Rodolfo
Published: August 2018

Objective

To describe a novel vertebral body stabilization and report its outcome in dogs with thoracic kyphosis and secondary myelopathy.

Study design

Case series.

Animals

Six pugs with thoracic kyphosis and secondary myelopathy.

Methods

Medical records (2012‐2017) of dogs with chronic progressive pelvic limb ataxia and ambulatory proprioceptive paraparesis due to thoracic kyphosis were reviewed. Dogs were evaluated via MRI and computed tomography. A 3‐dimensional print of the kyphotic vertebral segment was used to precontour the SOP (String of Pearls) plates. Bilateral double, dorsal intercostal thoracotomies were performed to place precontoured SOP on the vertebral bodies. Long‐term (6‐16 months) clinical outcome was determined on the basis of neurological scoring (NS) and owner questionnaire.

Results

The only intraoperative complication consisted of a lung laceration due to preexisting adhesions. Postoperative complications included seroma formation (n = 2) and incidental radiographic evidence of screw breakage (n = 2). NS at presentation ranged between 2 and 4 and improved to 1 at long‐term follow‐up in all dogs but 1 (NS = 2). All owners felt that their dog had excellent quality of life at follow‐up.

Conclusion

In spite of the challenging local anatomy, all dogs undergoing vertebral stabilization with SOP placement experienced a good clinical outcome.

Clinical significance

Stabilization of vertebral bodies with precontoured SOP placed through bilateral thoracotomies may be considered as a treatment option for dogs with thoracic kyphosis and secondary myelopathy.
Fatigue‐related group III/IV muscle afferent feedback facilitates intracortical inhibition during locomotor exercise
Authors: Sidhu Simranjit K. , Weavil Joshua C. , Thurston Taylor S. , Rosenberger Dorothea , Jessop Jacob E. , Wang Eivind , Richardson Russell S. , McNeil Chris J. , Amann Markus
Published: August 2018

Key Points

This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron‐mediated inhibition as a potential underlying mechanism.

The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise.

Firing of these interneurons probably contributes to the development of central fatigue during physical activity.

We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABAB neuron‐mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n = 11) cycled at a comparable vastus‐lateralis EMG signal (∼0.26 mV) before (PRE; 100 W) and immediately after (POST; 90 ± 2 W) fatiguing constant‐load cycling exercise (80% Wpeak; 221 ± 10 W; ∼8 min). During, PRE and POST cycling, single and paired‐pulse (100 ms interstimulus interval) transcranial magnetic stimulations (TMS) were applied to elicit unconditioned and conditioned motor‐evoked potentials (MEPs), respectively. To distinguish between cortical and spinal contributions to the MEPs, cervicomedullary stimulations (CMS) were used to elicit unconditioned (CMS only) and conditioned (TMS+CMS, 100 ms interval) cervicomedullary motor‐evoked potentials (CMEPs). While unconditioned MEPs were unchanged from PRE to POST in CTRL, unconditioned CMEPs increased significantly, resulting in a decrease in unconditioned MEP/CMEP (P < 0.05). This paralleled a reduction in conditioned MEP (P < 0.05) and no change in conditioned CMEP. During FENT, unconditioned and conditioned MEPs and CMEPs were similar and comparable during PRE and POST (P > 0.2). These findings reveal that feedback from group III/IV muscle afferents innervating locomotor muscle decreases the excitability of the motor cortex during fatiguing cycling exercise. This impairment is, at least in part, determined by the facilitating effect of these sensory neurons on inhibitory GABAB intracortical interneurons.
Experimental and Computational Investigation of Flow Instabilities in Turbine Rim Seals
Authors: Horwood Joshua T. M. , Hualca Fabian P. , Scobie James A. , Wilson Michael , Sangan Carl M. , Lock Gary D.
Published: August 2018

In high-pressure turbines, cool air is purged through rim seals at the periphery of wheel-spaces between the stator and rotor disks. The purge suppresses the ingress of hot gas from the annulus but superfluous use is inefficient. In this paper, the interaction between the ingress, purge, and mainstream flow is studied through comparisons of newly acquired experimental results alongside unsteady numerical simulations based on the DLR TRACE solver. New experimental measurements were taken from a one-and-a-half stage axial-turbine rig operating with engine-representative blade and vane geometries, and overlapping rim seals. Radial traverses using a miniature CO2 concentration probe quantified the penetration of ingress into the rim seal and the outer portion of the wheel-space. Unsteady pressure measurements from circumferentially positioned transducers on the stator disk identified distinct frequencies in the wheel-space, and the computations reveal these are associated with large-scale flow structures near the outer periphery rotating at just less than the disk speed. It is hypothesized that the physical origin of such phenomenon is driven by Kelvin–Helmholtz instabilities caused by the tangential shear between the annulus and egress flows, as also postulated by previous authors. The presence and intensity of these rotating structures are strongly dependent on the purge flow rate. While there is general qualitative agreement between experiment and computation, it is speculated that the underprediction by the computations of the measured levels of ingress is caused by deficiencies in the turbulence modeling.
Thermoacoustic Modes of Quasi-One-Dimensional Combustors in the Region of Marginal Stability
Authors: Silva Camilo F. , Yong Kah Joon , Magri Luca
Published: August 2018

It may be generally believed that the thermoacoustic eigenfrequencies of a combustor with fully acoustically reflecting boundary conditions depend on both flame dynamics and geometry of the system. In this work, we show that there are situations where this understanding does not strictly apply. The purpose of this study is twofold. In the first part, we show that the resonance frequencies of two premixed combustors with fully acoustically reflecting boundary conditions in the region of marginal stability depend only on the parameters of the flame dynamics but do not depend on the combustor's geometry. This is shown by means of a parametric study, where the time delay and the interaction index of the flame response are varied and the resulting complex eigenfrequency locus is shown. Assuming longitudinal acoustics and a low Mach number, a quasi-1D Helmholtz solver is utilized. The time delay and interaction index of the flame response are parametrically varied to calculate the complex eigenfrequency locus. It is found that all the eigenfrequency trajectories cross the real axis at a resonance frequency that depends only on the time delay. Such marginally stable frequencies are independent of the resonant cavity modes of the two combustors, i.e., the passive thermoacoustic modes. In the second part, we exploit the aforementioned observation to evaluate the critical flame gain required for the systems to become unstable at four eigenfrequencies located in the marginally stable region. A computationally efficient method is proposed. The key ingredient is to consider both direct and adjoint eigenvectors associated with the four eigenfrequencies. Hence, the sensitivity of the eigenfrequencies to changes in the gain at the region of marginal stability is evaluated with cheap and accurate calculations. This work contributes to the understanding of thermoacoustic stability of combustors. In the same manner, the understanding of the nature of distinct resonance frequencies in unstable combustors may be enhanced by employing the analysis of the eigenfrequency locus here reported.
Experimental Investigation on the Motion of Particle Cloud in Viscous Fluids
Authors: Azimi Amir H.
Published: August 2018

Laboratory experiments were conducted to study the dynamics of particle clouds in viscous fluids. Different shapes of frontal head and trailing stems were observed, and particle clouds were classified using data mining methodology. The stability of the frontal head of particle clouds was found to be correlated with the nozzle diameter and mass of sand particles in the form of an initial aspect ratio. The formation of particle clusters into a torus and the split of the frontal head into two or three clusters were investigated in detail. The cluster of particles flow through viscous fluid experienced partial separation due to the release of air bubbles from the rear of frontal head. It was observed that the time and location of major particle separation increase linearly with the aspect ratio. The oscillatory motion of the frontal head, caused by an uneven release of air bubbles from the rear of the frontal head, was found to be correlated with the initial aspect ratio. Both amplitude and wavelength exhibited a linear relationship with nondimensional time. The average drag coefficient of particle clouds Cd in viscous fluids was calculated for different aspect ratios, and the results were compared with the drag coefficient of individual particles. It was found that the averaged drag coefficients of particle clouds were smaller than the drag coefficient of individual particles, and Cd slightly increases with the increasing initial aspect ratio.
Fuel Variation Effects in Propagation and Stabilization of Turbulent Counter-Flow Premixed Flames
Authors: Abbasi-Atibeh Ehsan , Jella Sandeep , Bergthorson Jeffrey M.
Published: August 2018

Sensitivity to stretch and differential diffusion of chemical species are known to influence premixed flame propagation, even in the turbulent environment where mass diffusion can be greatly enhanced. In this context, it is convenient to characterize flames by their Lewis number (Le), a ratio of thermal-to-mass diffusion. The work reported in this paper describes a study of flame stabilization characteristics when Le is varied. The test data are comprised of Le≪1 (hydrogen), Le≈1 (methane), and Le>1 (propane) flames stabilized at various turbulence levels. The experiments were carried out in a hot exhaust opposed-flow turbulent flame rig (HOTFR), which consists of two axially opposed, symmetric jets. The stagnation plane between the two jets allows the aerodynamic stabilization of a flame and clearly identifies fuel influences on turbulent flames. Furthermore, high-speed particle image velocimetry (PIV), using oil droplet seeding, allowed simultaneous recordings of velocity (mean and rms) and flame surface position. These experiments, along with data processing tools developed through this study, illustrated that in the mixtures with Le≪1, turbulent flame speed increases considerably compared to the laminar flame speed due to differential diffusion effects, where higher burning rates compensate for the steepening average velocity gradient and keeps these flames almost stationary as bulk flow velocity increases. These experiments are suitable for validating the ability of turbulent combustion models to predict lifted, aerodynamically stabilized flames. In the final part of this paper, we model the three fuels at two turbulence intensities using the flamelet generated manifolds (FGM) model in a Reynolds-averaged Navier–Stokes (RANS) context. Computations reveal that the qualitative flame stabilization trends reproduce the effects of turbulence intensity; however, more accurate predictions are required to capture the influences of fuel variations and differential diffusion.
Thermal Boundary Layer Response to Periodic Fluctuations for Turbulent Flow
Authors: Saavedra J. , Paniagua G. , Chazot O.
Published: August 2018

The detailed characterization of the thermal boundary layer under periodic fluctuations is vital to improve the performance of cooled turbine airfoils, as well as to assess noise thermal and structural fatigue. In the present contribution, we performed detailed unsteady Reynolds-averaged Navier–Stokes (URANS) simulations to investigate wall heat flux response to periodic flow velocity fluctuations over a flat plate. We also investigated the boundary layer response to sudden flow acceleration including periodic flow perturbations, caused by inlet total pressure variations. During a flow acceleration phase, the boundary layer is first stretched, resulting in an increase of the wall shear stress. Later on, due to the viscous diffusion, the low momentum flow adjusts to the new free stream conditions. The behavior of the boundary layer at low frequency is similar to the response to an individual deceleration followed by one acceleration. However, at higher frequencies, the mean flow topology is completely altered. One would expect that higher acceleration rates would cause a further stretching of the boundary layer that should cause even greater wall shear stresses and heat fluxes. However, we observed the opposite; the amplitude of the skin friction coefficient is abated, while the peak level is a full order of magnitude smaller than at low frequency.
Reactivity of heterogeneous surfaces: Modeling precursor–surface interaction using absorbing Markov chains
Authors: Yanguas-Gil Angel
Published: August 2018

Heterogeneous reactive surfaces involving a spatial distribution of reactive sites are ubiquitous in thin film growth, from defect nucleation to step flow growth. In this work, the interaction of gas phase species with heterogeneous reactive surfaces was explored using a model combining absorbing Markov chains and local balance equations. Through this model, single particle statistics can be extracted of the adsorption–diffusion–desorption/reaction process even beyond the transport-limited regime, where the surface coverage of adsorbates, and hence adsorbate–adsorbate interaction, is not negligible, and local rates can be connected with macroscopic quantities, such as the sticking probability and desorption rates. In the transport-limited regime, a similarity law was identified for the sticking probability for both step flow growth and nucleation on randomly distributed reactive sites in which the sticking probability is a function of the product of the local diffusion and reaction probabilities. Finally, the model can be applied to extract local reactivity maps providing the probability that a particle adsorbing on a given site reacts with the surface. This allows one to explore the development of capture zones and the impact of site-blocking and desorption on the local sticking probabilities.
VEGF–neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP β2-chimaerin
Authors: Elaimy Ameer L. , Guru Santosh , Chang Cheng , Ou Jianhong , Amante John J. , Zhu Lihua Julie , Goel Hira Lal , Mercurio Arthur M.
Published: August 2018

The growth factor VEGF induces a Rac1-TAZ–mediated positive feedback loop that sustains the proliferation of stem-like cells in breast cancer.
Efficacy and Safety of Low-Dose Liposomal Amphotericin B in Adult Patients Undergoing Unrelated Cord Blood Transplantation
Authors: Yasu Takeo , Konuma Takaaki , Oiwa-Monna Maki , Kato Seiko , Tanoue Susumu , Isobe Masamichi , Mizusawa Mai , Kuroda Seiichiro , Takahashi Satoshi , Tojo Arinobu
Published: August 2018

Liposomal amphotericin B (L-AMB) is widely used for empirical or preemptive therapy and treatment of invasive fungal infections after cord blood transplantation (CBT). We retrospectively examined the efficacy and safety of low-dose L-AMB in 48 adult patients who underwent CBT between 2006 and 2017 in our institute.
Multi-omic Analyses of Extensively Decayed Pinus contorta Reveal Expression of a Diverse Array of Lignocellulose-Degrading Enzymes
Authors: Hori Chiaki , Gaskell Jill , Cullen Dan , Sabat Grzegorz , Stewart Philip E. , Lail Kathleen , Peng Yi , Barry Kerrie , Grigoriev Igor V. , Kohler Annegret , Fauchery Laure , Martin Francis , Zeiner Carolyn A. , Bhatnagar Jennifer M.
Published: August 2018

The deconstruction of recalcitrant woody substrates is a central component of carbon cycling and forest health. Laboratory investigations have contributed substantially toward understanding the mechanisms employed by model wood decay fungi, but few studies have examined the physiological processes in natural environments. Herein, we identify the functional genes present in field samples of extensively decayed lodgepole pine (
Pinus contorta
), a major species distributed throughout the North American Rocky Mountains. The classified transcripts and proteins revealed a diverse array of oxidative and hydrolytic enzymes involved in the degradation of lignocellulose. The evidence also strongly supports simultaneous attack by fungal species employing different enzymatic strategies.
Formate and Hydrogen as Electron Shuttles in Terminal Fermentations in an Oligotrophic Freshwater Lake Sediment
Authors: Montag Dominik , Schink Bernhard
Published: August 2018

In the terminal steps of methane formation in freshwater lake sediments, fermenting bacteria cooperate syntrophically with methanogens and homoacetogens at minimum energy increments via interspecies electron transfer. The energy yields of the partner organisms in these cooperations have so far been calculated based mainly on
in situ
hydrogen partial pressures. In the present study, we also analyzed pools of formate as an alternative electron carrier in sediment cores of an oligotrophic lake. The formate and hydrogen pools appeared to be energetically nearly equivalent and are likely to be used simultaneously for interspecies electron transfer. Calculations of reaction energies of the partners involved suggest that propionate degradation may also proceed through the
Smithella
pathway, which converts propionate via butyrate and acetate to three acetate residues, thus circumventing one energetically difficult fatty acid oxidation step.
OpuF, a New Bacillus Compatible Solute ABC Transporter with a Substrate-Binding Protein Fused to the Transmembrane Domain
Authors: Teichmann Laura , Kümmel Henriette , Warmbold Bianca , Bremer Erhard
Published: August 2018

The high-affinity import of compatible solutes from environmental sources is an important aspect of the cellular defense of many bacteria and archaea against the harmful effects of high external osmolarity. The accumulation of these osmostress protectants counteracts high-osmolarity-instigated water efflux, a drop in turgor to nonphysiological values, and an undue increase in molecular crowding of the cytoplasm; they thereby foster microbial growth under osmotically unfavorable conditions. Importers for compatible solutes allow the energy-preserving scavenging of osmoprotective and physiologically compliant organic solutes from environmental sources. We report here the discovery, exemplary physiological characterization, and phylogenomics of a new compatible solute importer, OpuF, widely found in members of the
Bacillus
genus. The OpuF system is a representative of a growing subgroup of ABC transporters in which the substrate-scavenging function of the substrate-binding protein (SBP) and the membrane-embedded substrate translocating subunit (TMD) are fused into a single polypeptide chain.
Host- and Helminth-Derived Endocannabinoids That Have Effects on Host Immunity Are Generated during Infection
Authors: Batugedara Hashini M. , Argueta Donovan , Jang Jessica C. , Lu Dihong , Macchietto Marissa , Kaur Jaspreet , Ge Shaokui , Dillman Adler R. , DiPatrizio Nicholas V. , Nair Meera G.
Published: August 2018

Helminths have coevolved with their hosts, resulting in the development of specialized host immune mechanisms and parasite-specific regulatory products. Identification of new pathways that regulate helminth infection could provide a better understanding of host-helminth interaction and may identify new therapeutic targets for helminth infection.
Drooling Reduction Intervention randomised trial (DRI): comparing the efficacy and acceptability of hyoscine patches and glycopyrronium liquid on drooling in children with neurodisability
Authors: Parr Jeremy R , Todhunter Emma , Pennington Lindsay , Stocken Deborah , Cadwgan Jill , O’Hare Anne E , Tuffrey Catherine , Williams Jane , Cole Mike , Colver Allan F
Published: August 2018

Objective

Investigate whether hyoscine patch or glycopyrronium liquid is more effective and acceptable to treat drooling in children with neurodisability.

Design

Multicentre, single-blind, randomised controlled trial.

Setting

Recruitment through neurodisability teams; treatment by parents.

Participants

Ninety children with neurodisability who had never received medication for drooling (55 boys, 35 girls; median age 4 years). Exclusion criteria: medication contraindicated; in a trial that could affect drooling or management.

Intervention

Children were randomised to receive a hyoscine skin patch or glycopyrronium liquid. Dose was increased over 4 weeks to achieve optimum symptom control with minimal side-effects; steady dose then continued to 12 weeks.

Primary and secondary outcomes

Primary outcome: Drooling Impact Scale (DIS) score at week-4. Secondary outcomes: change in DIS scores over 12 weeks, Drooling Severity and Frequency Scale and Treatment Satisfaction Questionnaire for Medication; adverse events; children’s perception about treatment.

Results

Both medications yielded clinically and statistically significant reductions in mean DIS at week-4 (25.0 (SD 22.2) for hyoscine and 26.6 (SD 16) for glycopyrronium). There was no significant difference in change in DIS scores between treatment groups. By week-12, 26/47 (55%) children starting treatment were receiving hyoscine compared with 31/38 (82%) on glycopyrronium. There was a 42% increased chance of being on treatment at week-12 for children randomised to glycopyrronium relative to hyoscine (1.42, 95% CI 1.04 to 1.95).

Conclusions

Hyoscine and glycopyrronium are clinically effective in treating drooling in children with neurodisability. Hyoscine produced more problematic side effects leading to a greater chance of treatment cessation.

Trial registration numbers

ISRCTN75287237; EUDRACT: 2013-000863-94; Medicines and Healthcare Products Regulatory Agency: 17136/0264/001-0003
How to write an Interpretation
Authors: Waterfield Thomas , Behjati Sam
Published: August 2018

Every day we interpret examination findings and clinical tests with the aim of coming to a diagnosis. But how well do we interpret these tests? Whether it is a traditional examination technique used by doctors for centuries or a new cutting edge biomarker, the diagnostic landscape shifts over time. The aim of interpretations is to produce a library of evidence-based resources directing the use of clinical tests including examination techniques. In this article we discuss how best to tackle writing an interpretation. Interpretations are succinct evidence-based summaries that draw together research findings to provide practical answers for clinicians.
Long noncoding RNA NEAT1 promotes the growth of cervical cancer cells via sponging miR-9-5p
Authors: Xie Qiuxian , Lin Shanna , Zheng Manjia , Cai Qiutao , Tu Ya
Published: August 2018

Evidence has accumulated demonstrating that long noncoding RNAs (lncRNAs) participate in the initiation and progression of cancers. In this study, we found that the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) is significantly increased in both cervical cancer tissues and cell lines. Overexpression of NEAT1 promoted the proliferation and migration of cervical cancer cells. Molecular studies uncovered that NEAT1 functions as competitive endogenous RNA (ceRNA), binding the micro-RNA miR-9-5p and suppressing its expression. However, we consistently found that when NEAT1 was highly expressed, it attenuated the inhibitory effect of miR-9-5p on the expression of PTEN and POU2F1, which are the targets of miR-9-5p. Consistent with the negative regulation of NEAT1 on miR-9-5p, restoration of miR-9-5p inhibited the growth-promoting effects of NEAT1 on cervical cancer cells. Taken together, these results indicated that NEAT1 plays an important role in the regulation cervical cancer cell growth by targeting miR-9-5p. Our findings characterized the possible mechanism of NEAT1 in cervical cancer.
Long noncoding RNA H19, and not microRNA miR-326, is over-expressed and predicts survival in glioblastoma
Authors: Fawzy Manal S. , Ellawindy Alia , Hussein Mohammad H. , Khashana Moataz S. , Darwish Marwa K. , Abdel-Daim Mohamed M. , Toraih Eman A.
Published: August 2018

Glioblastoma (GB) represents the most common malignant brain tumor, which, despite extensive research, remains of poor prognosis. The focus of recent studies of GB pathogenesis has shifted to the study of the role of noncoding RNAs (ncRNAs). In this study, we examined the expression levels of the microRNA miR-326 and the long ncRNA H19 (on which a miR-326 putative binding site was found by in-silico analysis) in brain tumor tissue from GB patients as compared to cancer-free brain tissue. Relative expression levels of miR-326 were not found to be significantly altered in GB patients. By comparison, H19 was consistently over-expressed in all GB patients (p < 0.001), and correlated with poorer overall survival (OS) and progression-free survival (PFS) (p = 0.026 and p = 0.045, respectively). At a cutoff value of 5.27, H19 up-regulation could predict OS in GB patients, with a 71.4% sensitivity and 59.6% specificity (p = 0.026). The current GB patients were clustered by the multivariate analysis into 4 groups based on miR-326 and H19 expression profiles, age at diagnosis, and PFS. Our data suggest a role for H19 in the pathogenesis of GB and could be a potential prognostic biomarker for GB.
Sand and silty-sand soil stabilization using bacterial enzyme–induced calcite precipitation (BEICP)
Authors: Hoang Tung , Alleman James , Cetin Bora , Ikuma Kaoru , Choi Sun-Gyu
Published: August 2018

This paper examines the bio-derived stabilization of sand-only or sand-plus-silt soils using an extracted bacterial enzyme application to achieve induced calcite precipitation (ICP). As compared to conventional microbial induced calcite precipitation (MICP) methods, which use intact bacterial cells, this strategy that uses free urease catalysts to secure bacterial enzyme–induced calcite precipitation (BEICP) appears to offer an improved means of bio-stabilizing silty-sand soils as compared to that of MICP processing. Several benefits may possibly be achieved with this BEICP approach, including bio-safety, environmental, and geotechnical improvements. Notably, the BEICP bio-stabilization results presented in this paper demonstrate (i) higher rates of catalytic urease activity, (ii) a wider range of application with sand-plus-silt soil applications bearing low-plasticity properties, and (iii) the ability to retain higher levels of soil permeability after BEICP processing. Comparative BEICP versus MICP results for sand-only systems are presented, along with BEICP-based results for stabilized soil mixtures at 90:10 and 80:20 percentile sand:silt ratios. This BEICP method’s ability to obtain unconfined compressive strength results in excess of 1000 kPa with sand-plus-silt soil mixtures is particularly noteworthy.
Phenotypic investigation of fine milk components in bovine milk and their prediction using mid-infrared spectroscopy
Authors: Fleming A. , Schenkel F.S. , Ali R.A. , Corredig M. , Carta S. , Gregu C.M. , Malchiodi F. , Macciotta N.P.P. , Miglior F.
Published: August 2018

This study aimed to examine the phenotypic variation observed in fine milk components, the use of mid-infrared (MIR) spectroscopy to predict these components, and the correlations with other milk production traits. A total of 4116 milk samples were collected from 414 dairy cows from 44 Canadian herds. Overall 3117 samples were analyzed for casein micelle size, 986 and 937 for total and soluble calcium, respectively, and 2054 for lactoferrin. Individual milk MIR spectra were obtained. Linear mixed models with repeated records were used to test the effects of herd nested within breed, breed, days in milk class, parity, and season on milk components. Lactoferrin content in milk increased with stage of lactation and parity number. Prediction equations were developed by partial least squares regression to predict each milk component using MIR spectroscopy, with the greatest coefficient of determination achieved for lactoferrin (0.55). Pearson correlation coefficients for lactoferrin with somatic cell score and protein percentage were 0.49% and 0.40%, respectively. The estimated correlation increased to 0.53% for predicted lactoferrin and protein percentage. The examined fine milk components exhibited variation, but low accuracies for their MIR prediction may limit the utility of this technology for their phenotyping.
The Mazon Creek Lagerstätte: a diverse late Paleozoic ecosystem entombed within siderite concretions
Authors: Clements Thomas , Purnell Mark , Gabbott Sarah
Published: August 2018

One of the best records of late Paleozoic ecosystems, the Mazon Creek Lagerstätte is world famous for its striking flora and fauna preserved within siderite concretions. Distinct from other late Carboniferous concretionary Lagerstätten because of the remarkable fidelity of soft tissues and pigments that are frequently preserved, the Mazon Creek has seen a revival in investigations during the last 10 years using modern palaeontological techniques. However, many of these modern investigations build upon a literature that incorrectly interprets the palaeoenvironment of the Mazon Creek and the separate biotas: there is a lack of evidence to support a distinct freshwater fauna. Here, we present a detailed overview of the Mazon Creek Lagerstätte, including the palaeoenvironmental conditions, organisms present and the complex taphonomic processes involved in fossil formation. Investigation into the formation of siderite concretions and the complex taphonomic processes controlling soft-bodied preservation are still continuing but are reviewed in detail.
Frontiers in Metapopulation Biology: The Legacy of Ilkka Hanski
Authors: Ovaskainen Otso , Saastamoinen Marjo
Published: August 2018

This review of metapopulation biology has a special focus on Professor Ilkka Hanski's (1953–2016) research. Hanski made seminal contributions to both empirical and theoretical metapopulation biology throughout his scientific career. Hanski's early research focused on ecological aspects of metapopulation biology, in particular how the spatial structure of a landscape influences extinction thresholds and how habitat loss and fragmentation can result in extinction debt. Hanski then used the Glanville fritillary system as a natural laboratory within which he studied genetic and evolutionary processes, such as the influence of inbreeding on extinction risk and variation in selection for dispersal traits generated by landscape variation. During the last years of his career, Hanski's work was in the forefront of the rapidly developing field of eco-evolutionary dynamics. Hanski was a pioneer in showing how molecular-level underpinnings of trait variation can explain why evolutionary change can occur rapidly in natural populations and how these changes can subsequently influence ecological dynamics.
Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: implications for pharmacological cardioprotection
Authors: Paradies Giuseppe , Paradies Valeria , Ruggiero Francesca Maria , Petrosillo Giuseppe
Published: August 2018

Mitochondrial dysfunction plays a central role in myocardial ischemia-reperfusion (I/R) injury. Increased reactive oxygen species production, impaired electron transport chain activity, aberrant mitochondrial dynamics, Ca2+overload, and opening of the mitochondrial permeability transition pore have been proposed as major contributory factors to mitochondrial dysfunction during myocardial I/R injury. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a pivotal role in multiple mitochondrial bioenergetic processes, including respiration and energy conversion, in mitochondrial morphology and dynamics as well as in several steps of the apoptotic process. Changes in CL levels, species composition, and degree of oxidation may have deleterious consequences for mitochondrial function with important implications in a variety of pathophysiological conditions, including myocardial I/R injury. In this review, we focus on the role played by CL alterations in mitochondrial dysfunction in myocardial I/R injury. Pharmacological strategies to prevent myocardial injury during I/R targeting mitochondrial CL are also examined.
A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan
Authors: Lee Valerie , Wang Judy , Zahurak Marianna , Gootjes Elske , Verheul Henk M. , Parkinson Rose , Kerner Zachary , Sharma Anup , Rosner Gary , De Jesus-Acosta Ana , Laheru Daniel , Le Dung T. , Oganesian Aram , Lilly Ellen , Brown Thomas , Jones Peter , Baylin Stephen , Ahuja Nita , Azad Nilofer
Published: August 2018

Purpose:

Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan.

Patients and Methods:

In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL −1: guadecitabine 30 mg/m2; DL −1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m2 with GFS].

Results:

Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and −1G), biliary drain infection (DL −1), colonic obstruction (DL −1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment.

Conclusions:

We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.
iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
Authors: Lo Justin H. , Hao Liangliang , Muzumdar Mandar D. , Raghavan Srivatsan , Kwon Ester J. , Pulver Emilia M. , Hsu Felicia , Aguirre Andrew J. , Wolpin Brian M. , Fuchs Charles S. , Hahn William C. , Jacks Tyler , Bhatia Sangeeta N.
Published: August 2018

Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with αvβ3/5 integrins and neuropilin-1, we hypothesized that “tandem” peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPN) capable of delivering siRNA to PDAC. The use of directly conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)-peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold-standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer. Mol Cancer Ther; 17(11); 2377–88. ©2018 AACR.
Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity
Authors: Ishihara Jun , Ishihara Ako , Potin Lambert , Hosseinchi Peyman , Fukunaga Kazuto , Damo Martina , Gajewski Thomas F. , Swartz Melody A. , Hubbell Jeffrey A.
Published: August 2018

CD40 is an immune costimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable antitumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144) to enhance anti-CD40′s effects when administered locally. Peritumoral injection of PlGF-2123-144-anti-CD40 antibody showed prolonged tissue retention at the injection site and substantially decreased systemic exposure, resulting in decreased liver toxicity. In four mouse tumor models, PlGF-2123-144-anti-CD40 antibody demonstrated enhanced antitumor efficacy compared with its unmodified form and correlated with activated dendritic cells, B cells, and T cells in the tumor and in the tumor-draining lymph node. Moreover, in a genetically engineered BrafV600E βCatSTA melanoma model that does not respond to checkpoint inhibitors, PlGF-2123-144-anti-CD40 antibody treatment enhanced T-cell infiltration into the tumors and slowed tumor growth. Together, these results demonstrate the marked therapeutic advantages of engineering matrix-binding domains onto agonistic anti-CD40 antibody as a therapeutic given by tumori-regional injection for cancer immunotherapy.

Implications: Extracellular matrix-binding peptide conjugation to agonistic anti-CD40 antibody enhances antitumor efficacy and reduces treatment-related adverse events. Mol Cancer Ther; 17(11); 2399–411. ©2018 AACR.
The Endocranial Cavity of Oviraptorosaur Dinosaurs and the Increasingly Complex, Deep History of the Avian Brain
Authors: Balanoff Amy M. , Norell Mark A. , Hogan Aneila V.C. , Bever Gabriel S.
Published: August 2018

Unraveling the origins of the character complexes diagnosing major crown clades is one of the greatest challenges in evolutionary biology. These origination events tend to optimize along extraordinarily long stem lineages where the comparative biology of extant lineages is relatively weak in its heuristic power. Here we add to a growing paleontological literature on the evolutionary origins of the modern avi an brain by describing the endocranial casts of two oviraptorosaur dinosaurs, Citipati osmolskae and Khaan mckennai. These fossil data confirm the antiquity of several avian features, including the expanded cerebrum. They also extend our appreciation of both the inherent variability in the brain-skull relationship along the avian stem and the dynamic nature of these crown characters in the earliest history of their expression.
Mir-758-5p Suppresses Glioblastoma Proliferation, Migration and Invasion by Targeting ZBTB20
Authors: Liu Ji , Jiang Jian , Hui Xiaobo , Wang Weijie , Fang Dazhao , Ding Lianshu
Published: August 2018

Background/Aims: To determine the cellular functions and clinical significance of micro-758-5p (miR-758-5p) in glioblastoma (GBM) by targeting zinc finger and BTB domain-containing protein 20 (ZBTB20). Methods: Fifty-five paired GBM tissues and adjacent normal tissues, GBM cell lines (U118, LN-299, H4, A172, U87-MG, and U251), and normal human astrocyte cell line (HEB) were used. miR-758-5p mimics, ZBTB20 siRNA, and pcDNA3.1-ZBTB20 were transiently transduced into cancer cells independently or together. qRT-PCR was conducted to analyze the expression of miR-758-5p and ZBTB20. Luciferase reporter assays were performed to determine the effect of miR-758-5p on ZBTB20. Western blot was applied to measure the expression of ZBTB20, PCNA, and cleaved caspase3. Cell Counting Kit-8 (CCK8), colony formation, FACS, and Transwell assays were carried out to detect cellular proliferation, apoptosis, migration, and invasion. Xenograft experiments were implemented to evaluate tumor growth and metastasis in vivo. Results: miR-758-5p was significantly downregulated in GBM tissues and cell lines compared with that in adjacent normal tissues and HEB cells. miR-758-5p overexpression inhibited the proliferation, migration, and invasion of GBM cells and induced apoptosis by regulating the ZBTB20 expression. Pearson correlation analysis also confirmed that miR-758-5p was inversely correlated with ZBTB20 in GBM tissues. miR-758-5p suppressed tumor growth and metastasis in vivo. The restored ZBTB20 expression partially rescued the miR-758-5p-induced inhibition of GBM cell proliferation, migration, and invasion. Kaplan–Meier curve analysis revealed that a high miR-758-5p expression indicated an enhanced prognosis of patients with GBM. Conclusion: miR-758-5p suppressed GBM progression by targeting ZBTB20. The miR-758-5p/ZBTB20 axis might be a promising therapeutic target for GBM treatment.