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We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer-small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF-TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein-protein interactions.

The retinoschisin protein is encoded on the short arm of the X-chromosome by RS1, is expressed abundantly in photoreceptor inner segments and in bipolar cells, and is secreted as an octamer that maintains the structural integrity of the retina. Mutations in RS1 lead to X-linked retinoschisis (XLRS), a disease characterized by the formation of cystic spaces between boys' retinal layers that frequently present in ophthalmoscopy as a "spoke-wheel" pattern on their maculae and by progressively worsening visual acuity (VA). There is no proven therapy for XLRS, but there is mixed evidence that carbonic anhydrase inhibitors (CAIs) produce multiple beneficial effects, including improved VA and decreased volume of cystic spaces. Consequently, linear mixed-effects (LME) models were used to evaluate the effects of CAI therapy on VA and central retinal thickness (CRT, a proxy for cystic cavity volume) in a review of 19 patients' records. The mechanism of action of action of CAIs is unclear but, given that misplaced retinoschisin might accumulate in the photoreceptors, it is possible-perhaps even likely-that CAIs act to benefit the function of photoreceptors and the neighboring retinal pigment epithelium by acidification of the extracellular milieu; patients on CAIs have among the most robust photoreceptor responses. Therefore, a small subset of five subjects were recruited for imaging on a custom multimodal adaptive optics retinal imager for inspection of their parafoveal cone photoreceptors. Those cones that were visible, which numbered far fewer than in controls, were enlarged, consistent with the retinoschisin accumulation hypothesis. Results of the LME modeling found that there is an initial benefit to both VA and CRT in CAI therapy, but these wane, in both cases, after roughly two years. That said, even a short beneficial effect of CAIs on the volume of the cystic spaces may give CAI therapy an important role as pretreatment before (or immediately following) administration of gene therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Because preterm birth and retinopathy of prematurity (ROP) are associated with poor visual acuity (VA) and altered foveal development, we evaluated relationships among the central retinal photoreceptors, postreceptor retinal neurons, overlying fovea, and VA in ROP., Methods: We obtained optical coherence tomograms (OCTs) in preterm born subjects with no history of ROP (none; n = 61), ROP that resolved spontaneously without treatment (mild; n = 51), and ROP that required treatment by laser ablation of the avascular peripheral retina (severe; n = 22), as well as in term born control subjects (term; n = 111). We obtained foveal shape descriptors, measured central retinal layer thicknesses, and demarcated the anatomic parafovea using automated routines. In subsets of these subjects, we obtained OCTs eccentrically through the pupil (n = 46) to reveal the fiber layer of Henle (FLH) and obtained adaptive optics scanning light ophthalmograms (AO-SLOs) of the parafoveal cones (n = 34) and measured their spacing and distribution., Results: Both VA and foveal depth decreased with increasing ROP severity (term, none, mild, severe). In severe subjects, foveae were broader than normal and the parafovea was significantly enlarged compared to every other group. The FLH was thinner than normal in mild (but not severe) subjects. VA was associated with foveal depth more than group. Density of parafoveal cones did not differ significantly among groups., Conclusions: Foveal structure is associated with loss of VA in ROP. The preserved FLH in severe (relative to mild) eyes suggests treatment may help cone axon development. The significantly larger parafovea and increased outer nuclear layer (ONL) thickness in ROP hint that some developmental process affecting the photoreceptors is not arrested in ROP but rather is supranormal.

Purpose: We generated a model of eye growth and tested it against an eye known to develop abnormally, one with a history of retinopathy of prematurity (ROP)., Methods: We reviewed extant magnetic resonance images (MRIs) from term and preterm-born patients for suitable images (n = 129). We binned subjects for analysis based upon postmenstrual age at birth (in weeks) and ROP history ("Term" ≥ 37, "Premature" ≤ 32 with no ROP, "ROP" ≤ 32 with ROP). We measured the axial positions and curvatures of the cornea, anterior and posterior lens, and inner retinal surface. We fit anterior chamber depth (ACD), posterior segment depth (PSD), axial length (AL), and corneal and lenticular curvatures with logistic growth curves that we then evaluated for significant differences. We also measured the length of rays from the centroid to the surface of the eye at 5° intervals, and described the length versus age relationship of each ray, L(ray)(x), using the same logistic growth curve. We determined the rate of ray elongation, E(ray)(x), from L(ray)dy/dx. Then, we estimated the scleral growth that accounted for E(ray)(x), G(x), at every age and position., Results: Relative to Term, development of ACD, PSD, AL, and corneal and lenticular curvatures was delayed in ROP eyes, but not Premature eyes. In Term infants, G(x) was fast and predominantly equatorial; in age-matched ROP eyes, maximal G(x) was offset by approximately 90°., Conclusions: We produced a model of normal eye growth in term-born subjects. Relative to normal, the ROP eye is characterized by delayed, abnormal growth.

Purpose: To study the relationship between retinal and tunica vasculosa lentis (TVL) disease in retinopathy of prematurity (ROP). Although the clinical hallmark of ROP is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered., Methods: ROP was induced in Long-Evans pigmented and Sprague Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope near the height of retinal vascular disease, ~20 days of age, and again at 30 and 64 days of age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (Gelman et al. in Invest Ophthalmol Vis Sci 46:4734-4738, 2005)., Results: In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, the TVL in RAR rats had almost fully regressed, while in ROP rats, it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave, and oscillatory potentials were attenuated in ROP rats., Conclusions: These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye.

Single-component molecular tagging velocimetry (1c-MTV) experiments are conducted in an oscillating grid turbulence facility to systematically clarify the trade-offs between maximizing measurement dynamic range and minimizing measurement uncertainty. The primary aim is to obtain reliable turbulence data with the maximum possible vector resolution ( Δ x 1 ). Four optical magnifications ( M 0 =0.11, 0.22, 0.45, 1.11) with four interframe time delay ( Δ t ) values, for each optical magnification case, ranging from 3 to 10 ms, are investigated. The grid oscillates with a frequency (f) of 3.2 and 4.1 Hz, and a single fixed stroke length (S) of 55 mm. The measurement quality is quantified using three important turbulence descriptors — the second-order transverse velocity correlation function (⟨ g (r) ⟩) , the second-order transverse velocity structure function ([ Δ g u ] 2) , and the turbulence energy dissipation rate ( ⟨ ϵ ⟩ ). Other descriptors such as the longitudinal integral length scale (l) and the longitudinal Taylor microscale (λ ) are also used to compare with reference values reported in literature. The degree of agreement with the reference values from literature, and insensitivity of the descriptor estimates to different MTV design parameters are used to determine the most robust means of obtaining high-resolution turbulence data from 1c-MTV. The experimental design parameters are contextualized using the Kolmogorov length (η ), time ( τ η ), and velocity ( u η ) scales that are based on the most reliable ⟨ ϵ ⟩ estimates from the current experiments. The pixel-displacement corresponding to u η (Δ x 2 η) describes the interdependencies between M 0 and Δ t . The data set with M 0 = 0.45 ( η = 18 Δ x 1 for f=3.2 Hz, and η = 13 Δ x 1 for f=4.1 Hz) represents the most reliable and the highest resolution case. This conclusion was deduced by taking the performance of all the turbulence descriptors into account. As far as the interframe time delay is concerned, Δ t ≥ 4 ms ( Δ x 2 η ≥ 0.5 pixels ) works well for all M 0 . To the authors' knowledge, the present study documents the first instance of a series of 1c-MTV experiments conducted for a systematic clarification of the nature of balancing the available dynamic range and the measurement uncertainty. Additionally, since the study involves turbulent flow with negligible mean-flow, it serves as an adequate representation of 1c-MTV performance in a three-dimensional flow. [ABSTRACT FROM AUTHOR]

Motivation Transcriptomic long-read (LR) sequencing is an increasingly cost-effective technology for probing various RNA features. Numerous tools have been developed to tackle various transcriptomic sequencing tasks (e.g. isoform and gene fusion detection). However, the lack of abundant gold-standard datasets hinders the benchmarking of such tools. Therefore, the simulation of LR sequencing is an important and practical alternative. While the existing LR simulators aim to imitate the sequencing machine noise and to target specific library protocols, they lack some important library preparation steps (e.g. PCR) and are difficult to modify to new and changing library preparation techniques (e.g. single-cell LRs). Results We present TKSM, a modular and scalable LR simulator, designed so that each RNA modification step is targeted explicitly by a specific module. This allows the user to assemble a simulation pipeline as a combination of TKSM modules to emulate a specific sequencing design. Additionally, the input/output of all the core modules of TKSM follows the same simple format (Molecule Description Format) allowing the user to easily extend TKSM with new modules targeting new library preparation steps. Availability and implementation TKSM is available as an open source software at https://github.com/vpc-ccg/tksm. [ABSTRACT FROM AUTHOR]

Motivation The Oxford Nanopore Technologies (ONT) ReadUntil API enables selective sequencing, which aims to selectively favor interesting over uninteresting reads, e.g. to deplete or enrich certain genomic regions. The performance gain depends on the selective sequencing decision-making algorithm (SSDA) which decides whether to reject a read, stop receiving a read, or wait for more data. Since real runs are time-consuming and costly, simulating the ONT sequencer with support for the ReadUntil API is highly beneficial for comparing and optimizing new SSDAs. Existing software like MinKNOW and UNCALLED only return raw signal data, are memory-intensive, require huge and often unavailable multi-fast5 files (≥100GB) and are not clearly documented. Results We present the ONT device simulator SimReadUntil that takes a set of full reads as input, distributes them to channels and plays them back in real time including mux scans, channel gaps and blockages, and allows to reject reads as well as stop receiving data from them. Our modified ReadUntil API provides the basecalled reads rather than the raw signal, reducing computational load and focusing on the SSDA rather than on basecalling. Tuning the parameters of tools like ReadFish and ReadBouncer becomes easier because a GPU for basecalling is no longer required. We offer various methods to extract simulation parameters from a sequencing summary file and adapt ReadFish to replicate one of their enrichment experiments. SimReadUntil's gRPC interface allows standardized interaction with a wide range of programming languages. Availability and implementation Code and fully worked examples are available on GitHub (https://github.com/ratschlab/sim_read_until). [ABSTRACT FROM AUTHOR]

The flow velocity plays an important role in the growth and characteristics of biofilm in the bioreactor as well as its treatment efficiency, which has been a hot research topic. In a sewage treatment bioreactor, the type of flow is usually turbulence. According to the methods of Reynolds decomposition, the flow velocity of turbulence consists of the time-mean velocity and fluctuation velocity, which usually exist simultaneously in real flow. However, the current research on the influence of turbulence flow velocity mainly focuses on the time-mean velocity, while the fluctuation velocity has not been reported because of very difficult to control. To this end, in this paper, a laboratory oscillating-grid turbulence (OGT) bioreactor with zero time-mean velocity and only fluctuation velocity was designed. In this bioreactor, the fluctuation velocity could be easily manipulated by varying the operational parameters of the grid. Based on the numerical simulation of Gas-liquid two-phase flow, the distributions of fluctuation velocity and corresponding turbulence fluctuation intensity, gas holdup, and Reynolds stress were obtained. After that, the effects of the turbulent fluctuation intensity on the biofilm thickness, density, and composition of extracellular polymeric substances (EPS) were studied experimentally. The results showed that turbulent fluctuation had a significant effect on the physical and chemical properties of biofilms, and the fluctuation velocity promoted the increase in the biofilm density and the content of protein and carbohydrates in EPS. This study was intended to provide theoretical support for the design and operation optimization of bioreactors., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To create a simplified model of the eye by which we can specify a key optical characteristic of the crystalline lens, namely its power. Methods: Cycloplegic refraction and axial length were obtained in 60 eyes of 30 healthy subjects at eccentricities spanning 40° nasal to 40° temporal and were fitted with a three‐dimensional parabolic model. Keratometric values and geometric distances to the cornea, lens and retina from 45 eyes supplied a numerical ray tracing model. Posterior lens curvature (PLC) was found by optimising the refractive data using a fixed lens equivalent refractive index (neq). Then, neq was found using a fixed PLC. Results: Eccentric refractive errors were relatively hyperopic in eyes with central refractions ≤−1.44 D but relatively myopic in emmetropes and hyperopes. Posterior lens power, which cannot be measured directly, was derived from the optimised model lens. There was a weak, negative association between derived PLC and central spherical equivalent refraction. Regardless of refractive error, the posterior retinal curvature remained fixed. Conclusions: By combining both on‐ and off‐axis refractions and eye length measurements, this simplified model enabled the specification of posterior lens power and captured off‐axis lenticular characteristics. The broad distribution in off‐axis lens power represents a notable contrast to the relative stability of retinal curvature. [ABSTRACT FROM AUTHOR]

The die-casting process creates the opportunity to design and manufacture complex parts in different industrial fields. However, the presence of micro-porosity and cracks can significantly impact the functionality and lifetime of the components. The impregnation technique improves the defect and upgrades the alloy's usability. Hence, identifying the impregnation technique's usefulness in sealing porosity is vital for enhancing the quality of the die casting products. It is hard to detect low atomic number impregnation resin located in the casting defects due to low X-ray attenuation. In this study, microfocus X-ray computed tomography (XCT) with advanced direct conversion detectors could effectively be employed to visualize casting defects in 3D. Also, to recognize the impregnated resin in Al-alloy both qualitatively and quantitatively. Dual-energy XCT recognized the resin material as P601 super sealant quantitatively. Casting defects could be identified in 2D CT images, and it is not easy to detect the impregnated resin with simple intensity-based image processing algorithms. Hence, an approach to improve resin detection through machine learning was studied. With a random forest classifier, trainable weka segmentation was used with three pre-defined classes. It precisely segmented the casting pore, Al-alloy, and resin material after well-trained the known data set. [ABSTRACT FROM AUTHOR]

Introduction: The authors present the prevalence of refractive errors in premature infants, demonstrating the relationship between refractive development and selected demographic characteristics and the forms of treatment used: diode laser, anti-vascular endothelial growth factor (anti-VEGF) and combination therapy. Material and methods: The study included 56 healthy children without retinopathy of prematurity (ROP) and 63 children with ROP. Ophthalmologic evaluation and diagnosis were performed according to the International Classification of Retinopathy of Prematurity assessed in Ret-Cam 3. Treatment of ROP was carried out according to the guidelines of the Polish Ophthalmological Society using a diode laser (IRIDEX IQ 810) and an anti-VEGF intravitreal preparation (ranibizumab, Lucentis) at a reduced dose of 0.18 mg. Refractive measurements were taken at 7 months of age using a handheld computerized autorefractometer (Retinomax) after 1% tropicamide cycloplegia. Results: A statistically significantly higher prevalence of high myopia (p = 0.019) and low astigmatism (p < 0.001) was observed in the eyes of premature infants with ROP and moderate hyperopia in the group without ROP (p = 0.031) regardless of the treatment used [mean +1.33 spherical diopters (Dsfr.); SD ±3.09 for eyes with ROP vs. mean +2.42 Dsfr.; SD ±2.11 for eyes without ROP]. Birth weight (p = 0.01) and gestational age (p = 0.048) correlated with changes in spherical refraction in children with ROP. There were statistically significant differences in high myopia (p = 0.041), low myopia (p = 0.010) and low hyperopia (p = 0.014) in the group of premature infants treated for ROP depending on the form of therapy. Conclusions: There were statistically significant differences in high myopia (p = 0.041), low myopia (p = 0.010) and low hyperopia (p = 0.014) in the groups of premature infants with ROP and high myopia (p = 0.019) and low astigmatism (p < 0.001) in the groups treated with monotherapy or combined therapy. Birth weight (p = 0.01) and gestational age (p = 0.048) had a significant effect on refractive development in eyes with ROP. [ABSTRACT FROM AUTHOR]

Previously, we have reported theory and experiments on the spin-up of a linearly stratified fluid contained in a sealed square cylinder with a bottom sloped at angle α (Munro & Foster, Phys. Fluids, 26, 026603, 2014). The motion is characterized by the small Rossby number, ϵ , the fractional change in the rotation rate, the Ekman number, E, and the Burger number, S, the square of the ratio of the buoyancy frequency (or Brunt-Väisälä frequency) to the base rotation rate. This paper, supplementing what has gone before, is focused on the horizontal and vertical structure of the propagating vorticity waves (Rossby waves), with alternating anti-cyclonic and cyclonic cells, which move across the tank from east to west, thereby accomplishing at least the early stages of the spin-up. We find strong dependence of the modal structure of these Rossby waves, and their speed, on the Burger number. However, what is particularly noteworthy is the observed strong north-south asymmetry of the wave field. We find that the asymmetry is not consistent with typical Rossby-wave theories (Pedlosky and Greenspan, J. Fluid Mech., 27, p. 291, 1967), but is attributable to second-order effects in the asymptotic expansion of the streamfuntion in powers of α . [ABSTRACT FROM AUTHOR]

Characterizing the effect of age and sex on macular retinal layer thicknesses and foveal pit morphology is crucial to differentiating between natural and disease-related changes. We applied advanced image analysis techniques to optical coherence tomography (OCT) to: 1) enhance the spatial description of age and sex effects, and 2) create a detailed open database of normative retinal layer thickness maps and foveal pit shapes. The maculae of 444 healthy subjects (age range 21–88) were imaged with OCT. Using computational spatial data analysis, thickness maps were obtained for retinal layers and averaged into 400 (20 x 20) sectors. Additionally, the geometry of the foveal pit was radially analyzed by computing the central foveal thickness, rim height, rim radius, and mean slope. The effect of age and sex on these parameters was analyzed with multiple regression mixed-effects models. We observed that the overall age-related decrease of the total retinal thickness (TRT) (-1.1% per 10 years) was mainly driven by the ganglion cell-inner plexiform layer (GCIPL) (-2.4% per 10 years). Both TRT and GCIPL thinning patterns were homogeneous across the macula when using percentual measurements. Although the male retina was 4.1 μm thicker on average, the greatest differences were mainly present for the inner retinal layers in the inner macular ring (up to 4% higher TRT than in the central macula). There was an age-related decrease in the rim height (1.0% per 10 years) and males had a higher rim height, shorter rim radius, and steeper mean slope. Importantly, the radial analysis revealed that these changes are present and relatively uniform across angular directions. These findings demonstrate the capacity of advanced analysis of OCT images to enhance the description of the macula. This, together with the created dataset, could aid the development of more accurate diagnosis models for macular pathologies. [ABSTRACT FROM AUTHOR]

This study experimentally investigates the vortex structure induced by sphere-wall collision and a falling sphere in a viscous liquid. The velocity fields of sphere-induced vortices were measured with refractive-index-matched materials and particle tracking velocimetry. The Reynolds number, based on the sphere diameter and the falling velocity, was in the range of 350–3200. The results revealed that the sphere-induced vortex ring was axisymmetric when the Reynolds number Re is ≤ 800. For the case of Re = 2000, the vortex structure developed into a non-symmetric flow after the sphere collided on the wall. Nonetheless, the influence of the Reynolds number on the vortex trajectory is insignificant. The moving speed of the primary vortex increases as the Reynolds number increases. In addition, the trajectories of free-falling spheres at a high Reynolds number of Re = 3200 deviate from a vertical straight line, owing to the non-axisymmetric flow field around the sphere. The experimental results presented in this work can be used to validate numerical schemes for solid/vortex interaction problems. [ABSTRACT FROM AUTHOR]

Genetic disorders that present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis, an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuroglial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study confers a role to RS1 beyond its function as an adhesion molecule, identifies an early onset for dysfunction in the course of disease, establishing a potential window for disease diagnosis and therapeutic intervention. [ABSTRACT FROM AUTHOR]

Scotland once had the largest herring fishery globally, generating local income, identity, and societal change. Following historic stock collapse, in spring 2018/2019 large herring shoals were observed on the west coast for the first time in decades, at a formerly important spawning ground. This highlights the urgency of maintaining historic (and contemporary) benthic spawning habitat, which these fish rely upon, in good condition. However, information on exact location, characteristics, and status of historic and contemporary spawning grounds, if existing, is not easily accessible. We searched over 1190 literature sources, dating back to 1884, using scientific databases and web-based searches, and ran a query for automated search of comprehensive historic reports. We present current knowledge on Scottish herring spawning grounds, retrieved through these searches and fisher interviews, maps showing historic and contemporary spawning grounds, and discuss challenges arising from the methods used to recognize these grounds. Knowledge gaps regarding location and environmental status of past and current spawning grounds, particularly relevant for Scotland's west coast, are identified. Based on the importance of specific environmental and physical variables for herring reproductive success, we advocate the inclusion of essential spawning grounds into herring management plans. This will require additional data on spawning grounds, including historic local ecological knowledge rarely considered. An inclusive ecosystem-based approach to herring management would allow more targeted actions to conserve (and potentially restore) essential spawning habitat. More effective management strategies will also call for reversing the (global) issue of the disconnect between different stakeholder groups. [ABSTRACT FROM AUTHOR]

Purpose: To analyze ocular biometric changes following unilateral cataract surgery in children. Methods: A total of 57 children aged under 13 years who underwent unilateral cataract surgery were analyzed. Groups were classified according to their age at surgery: group I (age <3), II (3≤ age <6), III (6≤ age <9), and IV (age ≥9). The myopic shift, axial growth, and corneal curvature changes were compared between the pseudophakic eyes and the fellow phakic eyes. Results: During 7.81 ± 4.39 years, the overall myopic shift (D) and the rate of myopic shift (D/year) were significantly higher at -3.25 ± 3.21 D and -0.45 ± 0.44 D/year in the pseudophakic eyes than -1.78 ± 2.10 D and -0.22 ± 0.29 D/year in the fellow phakic eyes (P = 0.01, 0.004). Group I (-1.14 ± 0.66 vs -0.02 ± 0.45 D/year) and group II (-0.63 ± 0.37 vs -0.31 ± 0.29 D/year) showed significantly higher rate of myopic shift in the pseudophakic eyes than in the phakic eyes. The rate of myopic shift in the pseudophakic eyes decreased in the older age groups (P = 0.001). There was no significant between-eye difference in the changes in axial length and keratometric values postoperatively. Conclusion: Following unilateral cataract surgery, a significant postoperative myopic shift was noticed in the pseudophakic eyes compared to the fellow phakic eyes in groups under 6 years old. Postoperative myopic shift and the resultant anisometropia should be considered when selecting the optimal power of IOL in young children requiring unilateral cataract surgery. [ABSTRACT FROM AUTHOR]

To investigate the mechanism of the Aucklandiae Radix–Amomi Fructus (AR–AF) herb pair in treating gastric cancer (GC) by using network pharmacology and experimental verification. Using the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP), the major active components and their corresponding targets were estimated and screened out. Using Cytoscape 3.7.2 software, a visual network was established using the active components of AR–AF and the targets of GC. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways of the target enrichment were performed. AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The mRNA and protein expression levels of the hub targets were analyzed by the Oncomine, GEPIA, HPA databases and TIMER online tool, and the predicted targets were verified by qRT–PCR in vitro. Eremanthin, cynaropicrin, and aceteugenol were identified as vital active compounds, and AKT1, MAPK3, IL6, MAPK1, as well as EGFR were considered as the major targets. These targets exerted therapeutic effects on GC by regulating the cAMP signaling pathway, and PI3K-Akt signaling pathway. Molecular docking revealed that these active compounds and targets showed good binding interactions. The validation in different databases showed that most of the results were consistent with this paper. The experimental results confirmed that eremanthin could inhibit the proliferation of AGS by reducing the mRNA expression of hub targets. As predicted by network pharmacology and validated by the experimental results, AR–AF exerts antitumor effects through multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of GC. [ABSTRACT FROM AUTHOR]

After revelations of participation by psychiatrists and psychologists in interrogation of prisoners at Guantánamo Bay and Central Intelligence Agency secret detention centers, the American Psychiatric Association and the American Psychological Association adopted Position Statements absolutely prohibiting their members from participating in torture under any and all circumstances, and, to a limited degree, forbidding involvement in interrogations. Some interrogations utilize very aggressive techniques determined to be torture by many nations and organizations throughout the world. This paper explains why psychiatrists and psychologists involved in coercive interrogations violate the Geneva Conventions and the laws of the United States. Whether done with ignorance of professional ethical obligations or not, these psychiatrists and psychologists have crossed an ethical barrier that may best be averted from re-occurring by teaching medical students and residents in all medical specialties about the ethics principles stemming from the 1946-1947 Nuremberg trials and the Geneva Conventions, together with the Ethics Codes of the World Medical Association and the American Medical Association; and, with regard to psychiatric residents and psychological trainees, by the teaching about The Principles of Medical Ethics With Annotations Especially Applicable to Psychiatry and the Ethical Principles of Psychologists and Code of Conduct, respectively. In this way, all physicians and psychologists will clearly understand that they have an absolute moral obligation to "First, do no harm" to the human beings they professionally encounter. [ABSTRACT FROM AUTHOR]

Purpose: To report the corneal tomographic characteristics of eyes that had surgery for controlled primary congenital glaucoma (PCG) and to compare it with an age-matched group of normal children. Methods: The study was conducted on 44 (24 right) eyes of 27 children (18 boys) who had surgery for PCG and 60 (31 right) eyes of 32 age-matched control children (9 boys). Children with PCG had a thorough ophthalmic examination and the demographic and medical and surgical history was retrieved from the patients' clinical chart records. After clinical examination, the study participants underwent Scheimpflug imaging using the Pentacam (Oculus Optikgeräte GmbH). Results: Both study and control children were approximately 9 years of age at the time of the study (P =.39). The eyes with PCG had a spherical equivalent mean ± standard deviation of −4.70 ± 3.50 diopters (D). Eyes with PCG demonstrated a cylinder of −2.80 ± 2.10 D, flatter corneas than control eyes (P =.0002 and.0012 for flat and steep keratometry, respectively), and statistically significantly higher astigmatism (P =.011) and thinner corneas, both at pupil center (P <.001) and thinnest location (P <.001). There was a statistically significant negative correlation between the postoperative axial length (at the time of the scan) and each of the Scheimpflug parameters flat keratometry (P =.002), steep keratometry (P =.003), pachymetry at pupil center (P =.01), and pachymetry at thinnest location (P =.009). Conclusions: The eyes of patients with PCG have thinner, flatter, and more astigmatic corneas than the eyes of age-matched control children. [J Pediatr Ophthalmol Strabismus. 2021;58(4):218–223.] [ABSTRACT FROM AUTHOR]

To increase the size of the flowers for easy plucking, flower yield, pyrethrins content (%), and elite mutant selection in pyrethrum. To increase pyrethrum production and acclimatize in north Indian plain condition, a genetic improvement program was undertaken to widen the range of variations for size and yield of flowers and pyrethrins content (%) in pyrethrum crop. Pyrethrum seeds of the variety Avadh were irradiated with gamma rays at 20 to 300 Gy doses in Gamma chamber 5000 (cobalt-60 research irradiator). Observations gathered visually in M1 based on vigor, synchronization of flowering, and flower's size. Out of 90 M2 families, 20 mutants were raised in M3 along with the check-in preliminary evaluation trial. The four promising mutants, 1 (20 Gy-3), 7 (40 Gy-5), 10 (40 Gy-8), 14 (60 Gy19-10) was grown for four years in a bench-scale trial (randomized block design, replicated thrice) to test the yield performance and selection of high yielding elite mutant (s). It has been found that pyrethrum is sensitive to gamma rays irradiation and produced a high range of qualitative and quantitative variations. After massive screening over four years, two promising mutants for high dry flower yield and pyrethrins content, namely 7 (40 Gy-5), and 10 (40GY-8) were isolated. The mutagenesis changed traits mean in positive or negative directions. Pyrethrum plant is highly sensitive to gamma irradiation and produced a high range of variability in the qualitative and quantitative traits. The mutagenesis changed the mean of traits in both positive and negative directions. Due to mutagenic efficacy, two mutants 7 (40 Gy-5), and 10 (40GY-8) were expressed high performance for pyrethrin percent i.e., 87.23 and 59.78% improvement over the check variety 'Avadh', with synchronous flowering. These two mutants are in the pipeline for release as a variety for cultivation in the North Indian plains. [ABSTRACT FROM AUTHOR]

Oscillating grids are frequently used with water and Newtonian fluids to generate controlled turbulence and mixing. Yet, their use with shear thinning fluids still requires experimental characterization. Proper orthogonal decomposition (POD) is applied to PIV measurements of the flow generated by an oscillating grid in water and a shear thinning dilute polymer solution (DPS) of xanthan gum. The aims are to investigate the ability of POD to isolate periodic flow structures, and to use it to describe the effects of the shear thinning property. A dominance of the low order POD modes is evidenced in DPS. The methods applied in blade stirred tanks to identify oscillatory motion fail here. However, a strong mode coupling in the grid swept region is observed, determined by the working fluid and by an underlying chaotic nature of the flow. Possibilities of reconstructing turbulence properties using high order modes are discussed. [ABSTRACT FROM AUTHOR]

The Age of Reason is first and foremost an age of public reasoning. Equipped with a fresh and indeed unprecedented consciousness of feasibility and responsibility, educated citizens start to participate actively – and in many cases by taking personal risks – in discourses on political, religious and philosophical issues. In this article, I will highlight two core issues of the late eighteenth century – the dispute about the legitimacy of the French Revolution as well as its underlying philosophical conceptions and the rising human rights idea – and thereby revisit the interventions of three women who, though rediscovered in various fields of research, still have to gain their due recognition as pre-eminent political philosophers of their time. [ABSTRACT FROM AUTHOR]

Particle Tracking Velocimetry (PTV) is applied to measure the flow in an oscillating grid stirred tank filled with either water or shear thinning dilute polymer solutions (DPS) of Xanthan Gum (XG). There are many interests of studying turbulence in such complex non-Newtonian fluids (e.g. in the pharmaceutical, cosmetic, or food industry), and grid stirred tanks are commonly used for fundamental studies of turbulence in Newtonian fluids. Yet the case of oscillating grid flows in shear thinning solutions has been addressed recently by Lacassagne et al. (Exp Fluids 61(1):15, Phys Fluids 31(8):083102, 2019a, b), with only a single two dimensional (2D) Particle Image Velocimetry (PIV) characterization of mean flow and turbulence properties in the central vertical plane of the tank. Here, PTV data processed by the Shake The Box algorithm allows for the time resolved, three dimensional (3D) 3 components (3C) measurement of Lagrangian velocities for a large number of tracked particles in a central volume of interest of the tank. The possibility of projecting this Lagrangian information on an Eulerian grid is explored, and projected Eulerian results are compared with 2D PIV data from the previous work. Even if the mean flow is difficult to reproduce at the lowest polymer concentrations, a good agreement is found between measured turbulent decay laws, thus endorsing the use of this 3D-PTV metrology for the study of oscillating grid turbulence in DPS. The many possibilities of further analysis offered by the 3D3C nature of the data, either in the original Lagrangian form or in the projected Eulerian one, are finally discussed. [ABSTRACT FROM AUTHOR]

The presented study investigates the evolution of artificial gravel placements for Atlantic salmon and sea trout in Aurlandselva in Western Norway. Various monitoring methods have been applied including (i) quantifying the spatial extent and dynamics of spawning sites over the monitoring period, (ii) grain size distributions as well as (iii) applying numerical hydraulic and sediment transport modelling with the aim to test the predictability of such numerical tools. The spawning sites were not clogged by fine sediments, but were reshaped due to scouring and sediment transport. The scouring resulted in a volume loss of the gravel banks between 32 and 95% in the monitoring period of 5 years. The application of hydrodynamic-numerical modelling, however, showed that the modelling methods were not sufficient to predict erosion of the gravel or the site. The study showed that the areas are sensitive especially to local scale micro-topographical roughness elements. The complex three-dimensional hydraulic processes and the coarse substrate in the non-fluvial river environment makes it impracticable for multi-dimensional modelling to predict dynamics of gravel. A novel sediment criterion was introduced to estimate the near-bottom turbulence by relating the dm of introduced gravel compared to the d90 of the bed surface substrate composition. [ABSTRACT FROM AUTHOR]

The study of turbulence in complex fluids is of great interest in many environmental and industrial applications, in which the interactions between liquid phase rheology, turbulence, and other phenomena such as mixing or heat and mass transfer have to be understood. Oscillating grid stirred tanks have been used for many purposes in research involving turbulence. However, the mechanisms of turbulence production by the oscillating grid itself have never been studied, and oscillating grid turbulence (OGT) remained undescribed in non-Newtonian, shear-thinning, dilute polymer solutions until recently (Lacassagne et al., in Phys Fluids 31(8):083,102, 2019). The aim of this paper is to study the influence of the shear-thinning property of dilute polymer solutions (DPS), such as xanthan gum (XG), on mean flow, oscillatory flows, and turbulence around an oscillating grid. Liquid phase velocity is measured by particle image velocimetry (PIV) in a vertical plane above the central grid bar. Mean, oscillatory and turbulent components of the velocity fields are deduced by triple Hussain–Reynolds decomposition based on grid phase-resolved measurements. Outside of the grid swept region, the amplitude of oscillatory fluctuations quickly become negligible compared to that of turbulent fluctuations, and the triple and classical Reynolds decomposition become equivalent. Oscillatory jets and wakes behind the grid and their interactions are visualized. Turbulent (Reynolds) and oscillatory stresses are used to evidence a modification of oscillatory flow and turbulence intensity repartition in and around the grid swept region. Energy transfer terms between mean, oscillatory and turbulent flows are estimated and used to describe turbulence production in the grid swept region. Energy is injected by the grid into the oscillatory component. In water, it is transferred to turbulence mostly inside the grid swept region. In DPS, oscillatory flow persists outside of the grid swept zone. Energy is transferred not only to turbulence , in the grid swept region, and far from the tank's walls, but also to the mean flow, leading to an enhancement of the latter. Mean flow production and enhancement mechanisms are explainable by oscillatory jet variable symmetry and intensity, and by time- and space-variable viscosity. Backward transfer from turbulence to oscillatory flow is also evidenced in DPS. Finally, using phased root mean square (rms) values of turbulent velocity fluctuations, it is shown that in water, the decay of turbulence intensity behind an oscillating grid can be related to the decay of fixed grid turbulence for specific grid positions, a result no longer valid in DPS. [ABSTRACT FROM AUTHOR]

Photogrammetry uses images of a three-dimensional structure to derive information about its shape and position. In this work, a photogrammetric technique is implemented with a single camera and a digital projector to measure changes in an underwater sediment bed. This implementation incorporates refraction at an interface allowing for measurements through a deformed or changing water surface. The digital projector provides flexibility in choosing projected patterns and has a high frame rate, which allows to easily increase the spatial and temporal resolution of the measurements. The technique requires first for both the camera and the projector to be calibrated using triangulation. With the calibration, we construct lines in three-dimensional space that originate from the projector and the camera, and intersect on the surface to be measured. To correctly incorporate refraction due to a change of medium, each line in space is recalculated from its intersection with the interface using Snell's law. This has the benefit that only one calibration for measurements is needed if the location and shape of the interface are known. The technique is validated by measuring a submerged undulated surface, plastic objects and a sediment bed. In particular, the undulated plate is reconstructed under a flat and a parabolic water surface. Finally, the technique is used in combination with particle image velocimetry to dynamically measure a changing sediment bed under an oscillating flow and the flow velocity at the free surface. [ABSTRACT FROM AUTHOR]

The estimation of short-term-averaged maximum concentration is of foremost importance, for instance, for the impact assessment of odorant sources, flammable gases and the accidental or intentional release of toxic gases. As dispersion models only give 1-h averaged concentration values, a simple formulation (the power-law function) has been widely used in practical applications to overcome this limitation. The present study investigates the potential of large-eddy simulation (LES) to assess the influence of turbulent eddies on averaged concentration over short time intervals and, thus, on dispersion within a building array, with LES results compared with wind-tunnel data. The results indicate that the LES approach underpredicts the concentration fluctuation intensities governed by the smaller eddy motions and we conclude, not surprisingly, that the particular choice of subgrid-scale model and grid size is important in describing the smallest wavelength concentration motions. However, even though the LES results are not able to predict peak-to-mean values for very short averaging times, the fit of the power-law function can be extrapolated to produce a valid relation for shorter averaging times, implying the LES technique can be used to assess the p value (the exponent) in the commonly-used power-law function. This is found to be smaller (by about one half) for sensors in the central position within the array than for those located in short streets or at intersections, and it also decreases more slowly with distance from the source. No substantial difference is found between sensors located at the canopy height H and at half the canopy height, i.e. within the canopy. In contrast, there is a significant difference for sensors located above the building height at 1.5H. [ABSTRACT FROM AUTHOR]

When considering the possible hazard or nuisance associated with a release of toxic or malodorous gas into the atmosphere, large concentrations are especially important, but relatively little work has been done on measuring or modelling the probability distribution of large concentrations of a contaminant dispersing in a turbulent flow. We have previously applied statistical extreme-value theory to field experiment measurements, analyzing large concentrations at a handful of positions. We have also been involved in using a related moment-based method to give more comprehensive spatial coverage for a steady line source in a wind tunnel. In the latter case, however, we used a method which would be expected to have shortcomings, and we did not calculate confidence intervals for the estimates. In the present paper we use an improved method, with confidence intervals derived from bootstrapping. Again we analyze the measurements from steady line-source wind-tunnel experiments, with particular emphasis on the spatial variation of the estimated maximum possible concentration. We show that the moment-based method agrees well with maximum-likelihood fitting to exceedances of a high threshold. We find that the centreline maximum concentration, normalized by the centreline mean concentration, increases downwind from a value just greater than 1 near the source, to a peak value of 5–6, before decreasing with distance from the source. Across the plume the maximum concentration only varies slowly for the downwind distances in these experiments. These observations are explained in terms of the physical processes of turbulent advection and molecular diffusion. [ABSTRACT FROM AUTHOR]

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In this review paper, literature data on pre- and postnatal eye development are compared between humans and nonclinical species that are commonly used for human safety assessment, namely, mouse, rat, rabbit, dog, minipig, and nonhuman primates. Some new data on rat and minipig ocular development are also included. This compiled information can be helpful for species selection in juvenile toxicity studies or assist in the interpretation of (non)clinical data during pediatric drug development. Despite some differences in developmental windows and anatomical peculiarities, such as the lack of a fovea centralis in nonprimate species or the presence of a nictitating membrane in some nonclinical species, the functioning and development of the eye is strikingly similar between humans and other mammals. As such, all commonly used nonclinical species appear to be relatively good models for human eye development, although some practical constraints such as size may be a limiting factor. Birth Defects Research 109:1540-1567, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: We used a Laser speckle flowgraphy (LSFG)-micro system to examine the relationship between ocular blood flow and retinal vascular endothelial growth factor (VEGF) at retinopathy onset in oxygen-induced ischemic retinopathy (OIR) model rats. Methods: Sixteen 50/10 OIR rats were compared with 17 control rats reared in room air. In postnatal day 14 (P14) and P18 rats, we measured and analyzed the left eye's mean blur rate (MBR) by setting a rubber band on the optic nerve head center, using the LSFG-Micro. At P18, the rats were sacrificed and their left-eye retinas were fixed, flat-mounted and stained with adenosine diphosphatase (ADPase). The right-eye retinas were homogenized; the lysate was centrifuged for an enzyme-linked immunosorbent assay (ELISA). The avascular area was measured as the percentage (%AVA) of the total retinal area. Retinal VEGF was measured by an ELISA. Results: The examination's reproducibility was good. Our multivariate linear mixed model analysis revealed significantly high MBRs in the OIR rats ( p = 0.0017). In the P18 OIR rats, significant correlations were seen between the MBR and %AVA ( r = 0.80, p = 0.0002) and between the MBR and VEGF ( r = 0.76, p = 0.0006). Conclusions: The LSFG-Micro provided reproducible blood flow measurements in neonatal rats. Because of the vitreous blood vessels, measurement of only the retinal vessels was not possible. However, the MBR was higher in the OIR rats than in the control rats, and the MBR and %AVA were correlated, as were the MBR and retinal VEGF. The MBR may thus serve as an indicator of OIR severity. [ABSTRACT FROM AUTHOR]

Having a good estimation of geothermal gradient and the reservoir temperature has a great impact on the methodological reservoir management in the entire reservoir life, from natural depletion phase up to draining the last portion of hydrocarbon by applying an appropriate EOR method. This issue could become crucial in a gas condensate reservoir management as the reservoir temperature has great influence on the time and amount of precipitated condensate in the reservoir and on the surface. It is usual to consider a constant reservoir temperature throughout the field. Also, encountering a constant geothermal gradient, with a similar fluid in a reservoir, is expected. During drilling campaign of two appraisal wells (one in the crest and other in the flank) of one of Middle East gas reservoir, it is aproximately found one geothermal gas gradient in both well; however, with some displacement in the wells. To find out a scientific justification for this phenomenon, a study was set out and results were presented in this paper. By using the analytical solution to unsteady-state conduction heat transfer for a cylinder with a radius of r and infinite length and the available temperature data from FBDSTs, the exact reservoir temperature at different depths is calculated. It is also shown that by using the analytical solution 'affected thermal well bore radius' can be estimated. The affected thermal well bore radius is defined as the radius that beyond it, formation rock is not affected by any down-hole temperature variation. Based on the elaborated work, in addition to confirmation of having one geothermal gradient in the reservoir, it is found out that the 'affected thermal well bore radius' in wells is about 20-60 cm. Also by using the basic steady-state conduction heat transfer equation and assuming that the amount of transferred heat via layers of earth is constant, it is qualitatively shown that having different reservoir temperatures at constant depth throughout a giant deep-reservoir is normal and it should be accounted for the reservoir simulation. [ABSTRACT FROM AUTHOR]

One of the key issues of recent research on the dispersion inside complex urban environments is the ability to predict individual exposure (maximum dosages) of an airborne material which is released continuously from a point source. The present work addresses the question whether the computational fluid dynamics (CFD)–Reynolds-averaged Navier–Stokes (RANS) methodology can be used to predict individual exposure for various exposure times. This is feasible by providing the two RANS concentration moments (mean and variance) and a turbulent time scale to a deterministic model. The whole effort is focused on the prediction of individual exposure inside a complex real urban area. The capabilities of the proposed methodology are validated against wind-tunnel data (CUTE experiment). The present simulations were performed ‘blindly’, i.e. the modeller had limited information for the inlet boundary conditions and the results were kept unknown until the end of the COST Action ES1006. Thus, a high uncertainty of the results was expected. The general performance of the methodology due to this ‘blind’ strategy is good. The validation metrics fulfil the acceptance criteria. The effect of the grid and the turbulence model on the model performance is examined. [ABSTRACT FROM PUBLISHER]

Objective: Examining the Retinal Renin Angiotensin System (RRAS) in the ROP neonates and analyzing the possibility of modulating the RRAS to prevent the progression in Oxygen Induced Retinopathy (OIR) model. Method: Vitreous of ROP patients (n = 44, median age 5.5 months) was quantified for RRAS components, VEGF, HIF-1α and compared with age matched control. The involvement of RRAS in ROP was tested in the rat model of OIR and compared with normoxia. Expressions of RAS components, VEGF and HIF-1α in retina were analyzed using qPCR and retinal structure and function was also analyzed. Effect of Angiotensin Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) was evaluated and compared with Bevacizumab which served as a positive control. Drug penetration into retina was confirmed by liquid chromatography coupled ESI-tandem mass spectroscopy (LC-MS/MS). Results: Multifold increase in the expression of RAS components in human vitreous and rat retina showed their involvement in ROP. ERG & fundus studies in OIR revealed the altered function of retina and were successfully prevented by ARB (telmisartan), ACEI (lisinopril) and bevacizumab. Retinal analysis revealed the presence of ACEI and ARB in their therapeutic levels. Conclusion: This study for the first time demonstrates the upregulated level of RAS components in human ROP vitreous and further that the pharmacological intervention in RRAS can functionally and structurally preserve retina against the progression of ROP in the OIR model. [ABSTRACT FROM AUTHOR]

The peak values observed in a measured concentration time series of a dispersing gaseous pollutant released continuously from a point source in urban environments, and the hazard level associated with them, demonstrate the necessity of predicting the upper tail of concentration distributions. For the prediction of concentration distributions statistical models are preferably employed which provide information about the probability of occurrence. In this paper a concentration database pertaining to a field experiment is used for the selection of the statistical distribution. The inverses of the gamma cumulative distribution function (cdf) for 75th-99th percentiles of concentration are found to be more consistent with the experimental data than those of the log-normal distribution. The experimental values have been derived from measured high frequency time series by sorting first the concentrations and then finding the concentration which corresponds to each probability. Then the concentration mean and variance that are predicted with Computational Fluid Dynamics-Reynolds Averaged Navier-Stokes (RANS) methodology are used to construct the gamma distribution. The proposed model ('RANS-gamma') is included in the framework of a computational code (ADREA-HF) suitable for simulating the dispersion of airborne pollutants over complex geometries. The methodology is validated by comparing the inverses of the model cdfs with the observed ones from two wind tunnel experiments. The evaluation is performed in the form of validation metrics such as the fractional bias, the normalized mean square error and the factor-of-two percentage. From the above comparisons it is concluded that the overall model performance for the present cases is satisfactory. [ABSTRACT FROM AUTHOR]

This study aims to couple a deterministic atmospheric dispersion solver based on Gaussian model with a nonintrusive stochastic model to quantify the propagation of multiple uncertainties. The nonintrusive model is based on probabilistic collocation framework. The advantage of nonintrusive nature is to retain the existing deterministic plume dispersion model without missing the accuracy in extracting the statistics of stochastic solution. The developed model is applied to analyze the SO emission released from coal firing unit in the second stage of the National Thermal Power Corporation (NTPC) in Dadri, India using 'urban' conditions. The entire application is split into two cases, depending on the source of uncertainty. In case 1, the uncertainties in stack gas exit conditions are used to construct the stochastic space while in case 2, meteorological conditions are considered as the sources of uncertainty. Both cases develop 2D uncertain random space in which the uncertainty propagation is quantified in terms of plume rise and pollutant concentration distribution under slightly unstable atmospheric stability conditions. Starting with deterministic Gaussian plume model demonstration and its application, development of stochastic collocation model, convergence study, error analysis, and uncertainty quantification are presented in this paper. [ABSTRACT FROM AUTHOR]