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The omnipresence and diversity of allosteric regulation in proteins and protein associations complemented by the potential for the design of allosterically acting biologics and drugs call for the development of a new generation of computational models for the analysis of allostery and rational engineering/design of desired signaling and effector molecules determining it. One of the most important challenges is the consideration of the role of amino acid sequence in forming the protein's allosteric communication, including the mode and strength of the allosteric signal that is communicated to the regulated functional site. Here, we present the network-based model with a sequence dependence added in consideration of allosteric communication by combining the structure-based statistical mechanical model of allostery with the Miyazawa-Jernigan residue–residue potential. Applying the model in the analysis of five classical allosteric proteins, we found that it is necessary to consider the following two major determinants: (i) the free energy exerted by the allosteric site on the regulated one and (ii) the background (average) change in dynamics of the overall structure. We show that working together these two components determine the allosteric modulation, calling one to study their dependence on structures, oligomerization states, and sequence divergence in different proteins. [ABSTRACT FROM AUTHOR]

WAAM technology (Wire + Arc Additive Manufacture) is a new method of additive manufacturing using wire as a construction material. The high productivity of the process, the ability to construct large-sized products without the need to use a controlled atmosphere chamber, and the low cost of equipment and construction materials allow using the WAAM technology to built products of simple and medium complexity with the highest economic efficiency. However, WAAM technologies in MIG-Pulse/CMT surfacing processes have a number of disadvantages, such as significant size of the heat-affected zone (HAZ) and large sizes of the build-up layer, which leads to undesirable temperature gradients and the accumulation of residual stresses. A further way to improve WAAM technology is to use metal-cored wires. For the research, metal-cored wire Cr20Mn5Ni4Mo2.5Cu3N0.3 Ø 1.6 mm was developed. It has been established that the use of metal-cored wire allows producing a defect-free surfaced metal with an austenite-ferritic structure (δF ≈ 1–3%), which has high strength and plastic characteristics (σB = 810 MPa, σ0,2 = 500 MPa, δ = 40%). The yield strength of the developed composition is more than 2 times higher than that of the widespread austenitic steel of the Kh18N10T type (σ0,2 = 206 MPa). Further research will be aimed at improving the impact strength of the surfaced cast metal by optimizing the composition of the metal-cored wire. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of Boston Type I Keratoprosthesis (BI-Kpro) implantation on retinal and visual pathway function, respectively, assessed by full-field electroretinography (ERG) and visually evoked potentials (VEPs). Methods : This is a prospective interventional longitudinal study, and patients with BI-Kpro implantation were assessed preoperatively and at 3 and 12 months after surgery. ERG, flash, and pattern-reversal VEPs (15' and 60' checks) along with visual acuity (VA) were performed. Results: A total of 13 patients (24 to 88 years of age) were included. Mean baseline VA (logMAR) improved from 2.30 to 1.04 at 3 months and to 1.00 at 12 months. Flash VEPs were normal in 6 (46%) patients and in 10 (77%) patients at the 12-month follow-up. PVEP was non-detectable in all patients preoperatively for both check sizes. For 15' check size, 6 (46%) patients showed responses after 3 and 12 months except for 1 patient with normal responses at 12 months with the remaining non-detectable. For 60' checks, 11 (85%) patients had responses 3 months after surgery with only 9 (70%) showing responses at 12 months. Abnormal full-field ERGs were found in all patients preoperatively. Amplitude improvement was found in 10 (77%) patients from baseline to 3 months and in 8 (62%) patients from the 3- to the 12-month follow-up. Conclusions: In this small cohort of patients with BI-Kpro implantation, a remarkable improvement on visual function quantitatively assessed by electrophysiological testing was found in the majority of cases. Visual electrophysiological testing can contribute to objectively assess functional outcomes in this population. [ABSTRACT FROM AUTHOR]

We investigate the critical phenomena emerging from a statistical mechanics model of musical harmony on a three-dimensional (3D) lattice, and the resulting structure of the ordered phase. In this model, each lattice site represents a tone, with nearest neighbors interacting via the perception of dissonance between them. With dissonance assumed to be an octave-wise periodic function of pitch difference, this model is a 3D XY system with the same symmetry and dimensionality as superfluid helium and models of the cosmological axion field. We use numerical simulation to observe a phase transition from disordered sound to ordered arrangements of musical pitches as a parameter analogous to the temperature is quenched towards zero. We observe the divergence of correlation length and relaxation time at the phase boundary, consistent with the critical exponents in similar systems. Furthermore, the quenched low-temperature phase of these systems displays topological defects in the form of vortex strings that thread throughout the system volume. We observe the formation of these vortex strings in accordance with the Kibble-Zurek mechanism, and discuss the structure of these vortex strings in the context of the theory of musical harmony, finding both similarities to established music theory, and uncovering new avenues to explore. [ABSTRACT FROM AUTHOR]

Manipulation of vortex states in magnetic media provides new routes towards information storage and processing technology. The typical slow relaxation times (~100 ns) of magnetic vortex dynamics may present an obstacle to the realization of these applications. Here, we investigate how a vortex state in a ferromagnetic microdisk can be manipulated in a way that translates the vortex core while enhancing energy dissipation to rapidly damp the vortex dynamics. We use timeresolved differential magneto-optical Kerr effect microscopy to measure the motion of the vortex core in response to applied magnetic fields. We first map out how the vortex core becomes sequentially trapped by pinning sites as it translates across the disk. After applying a fast magnetic field step to translate the vortex from one pinning site to another, we observe long-lived dynamics of the vortex as it settles to the new equilibrium. We then demonstrate how the addition of a short (<10 ns) magnetic field pulse can induce additional energy dissipation, strongly damping the longlived dynamics. A model of the vortex dynamics using the Thiele equation of motion explains the mechanism behind this effect. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate associations between prenatal and childhood exposure to phthalates and prenatal exposure to polychlorinated biphenyls (PCBs) and the development of 4-year-old children. Urinary metabolites of five phthalates were measured in women upon delivery, as well as serum concentrations of four PCB congeners. Postnatal phthalate metabolites were measured from children's urine obtained at the time of developmental assessment. The primary outcome was cognitive function as evaluated by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) administered at 4 years. Secondary outcomes were motor function and response to sensory stimuli as evaluated by the Developmental Coordination Disorder Questionnaire (DCDQ) and Short Sensory Profile (SSP) that the mothers filled out, respectively. The study included 57 mother-child pairs. Higher maternal phthalate metabolite concentrations were inversely associated with WPPSI-III scores among boys and not among girls. After using linear regression models and controlling for confounding variables, we found that higher levels of monobenzyl phthalate (MBzP) were the ones associated with lower WPPSI-III scores (p=0.004, 95 %CI [-14.18; −3.16]), lower DCDQ scores (p=0.007, 95 %CI [-6.08; −1.17] and lower SSP scores (p=0.004, 95 %CI [-7.47; −1.79]). No association was found between child urinary phthalate metabolite concentrations or maternal PCB blood concentrations and developmental function. These findings indicate that higher prenatal phthalate metabolite levels may be associated with deficits in neurologic development of young boys. • Higher prenatal phthalate exposure was associated with lower developmental scores. • Male sex was more susceptible to negative effects of prenatal phthalate exposure. • Higher prenatal exposure to polychlorinated biphenyls did not affect development. • Higher childhood exposure to phthalates did not affect development. [ABSTRACT FROM AUTHOR]

The purpose of the study was to investigate the expression of ferroportin protein following treatments that affect systemic hepcidin. Administration of erythropoietin to C57BL/6J mice decreased systemic hepcidin expression; it also increased heart ferroportin protein content, determined by immunoblot in the membrane fraction, to approximately 200% of control values. This increase in heart ferroportin protein is very probably caused by a decrease in systemic hepcidin expression, in accordance with the classical regulation of ferroportin by hepcidin. However, the control of heart ferroportin protein by systemic hepcidin could apparently be overridden by changes in heart non-heme iron content since injection of ferric carboxymaltose to mice at 300 mg Fe/kg resulted in an increase in liver hepcidin expression, heart non-heme iron content, and also a threefold increase in heart ferroportin protein content. In a separate experiment, feeding an iron-deficient diet to young Wistar rats dramatically decreased liver hepcidin expression, while heart non-heme iron content and heart ferroportin protein content decreased to 50% of controls. It is, therefore, suggested that heart ferroportin protein is regulated primarily by the iron regulatory protein/iron-responsive element system and that the regulation of heart ferroportin by the hepcidin-ferroportin axis plays a secondary role. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the diagnostic contribution of grating visual acuity (GVA) measured by sweep pattern-reversal visually evoked potentials (SPRVEP) in unexplained visual loss (UVL). Methods: This case-control study included adult patients under suspicion of UVL referred to SPRVEP and transient pattern-reversal visually evoked potentials (TPRVEP) testing. Optotype visual acuity (OVA) was measured by ETDRS 4-meter chart and GVA by SPRVEP. UVL patients were assigned into three distinctive categories, according to the presence of ocular disease, motivation, and electrophysiological evaluation, as follows: exaggerators, malingerers, and psychogenic. Healthy controls and patients with organic visual loss were also tested. Receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic performance of GVA and TPRVEP parameters. Results: A total of 76 patients with UVL were analyzed: 60 (79.0%) exaggerators, 11 (14.4%) malingerers, and 5 (6.6%) psychogenic. Controls were 49 subjects evaluated for TPRVEP and 28 subjects for SPRVEP. There were 13 patients with organic visual loss enrolled. Mean difference between OVA and GVA was 1.19±0.67 (median=0.84; 95% CI: 1.04 to 1.34) in UVL and 0.14 ±0.09 (median= 0.14; 95% CI: 0.08 to 0.20) in organic visual loss. The area under the ROC curve (AUC) of GVA to distinguish UVL from healthy controls was 0.998 with a cutoff of 0.09 logMAR showing specificity of 100% and sensitivity of 96.0%. Conclusions: GVA measured by SPRVEP had good diagnostic validity to discriminate patients with unexplained visual loss from healthy controls and patients with organic visual loss, demonstrating its contribution to the diagnosis of this condition. [ABSTRACT FROM AUTHOR]

Recently, it has been recommended that population-based studies report not only frequencies of vision impairment and blindness but also any ocular abnormalities that might lead an individual to seek for eyecare services. The current study aimed to determine prevalence of ocular findings regardless of visual acuity (VA) status in older adults from the Brazilian Amazon Region. Disturbances were grouped into: Eyelids; Anterior Segment; Posterior Segment; Increased intraocular pressure; and Overall Globe. The presence of an ocular finding was considered positive when any abnormality was noted, regardless of VA. Refractive errors were not considered. A total 2384 eligible persons were enumerated and 2041 (85.6%) examined. The prevalence of ocular disturbances in either eye was 87.0% and was associated with male gender, older age, lower education, and rural residence. Overall, main findings were pterygium, cataract, and pinguecula, occurring in 58.8%, 45.4% and 17.4%, respectively. Among individuals with 20/20 VA in both eyes, the most frequent findings were pterygium, pinguecula, and glaucoma cupping, occurring in 47.4%, 31.2% and 6.5%, respectively. The high prevalence of ocular findings observed in this population reinforces that different conditions might not immediately decrease VA but can indicate risk and/or discomfort symptoms and should be considered when planning public health ophthalmic services. [ABSTRACT FROM AUTHOR]

This publication analyses current literary knowledge on selected topics in the fields of oral health and pathology, with a particular emphasis on the potential roles of the oral microbiome and preventative approaches to oral afflictions. An important association with floral dysbiosis has been documented in important oral conditions, sometimes as a predisposing factor and at other times as a result thereof. However, much remains to be elucidated regarding the specific mechanisms at play, as well as their meaning in clinical practice. Continued research into the pathophysiology of certain oral diseases is of particular importance considering how widespread they are. A specific emphasis should be placed on understanding the exact mechanisms through which the microbiota facilitates health, and when disturbed, sickness. And perhaps of most importance is the implementation of knowledge already acquired on disease prevention if the burden of oral diseases worldwide is to decline in the future. [ABSTRACT FROM AUTHOR]

• Allosteric drugs have become an indispensable tool in precision medicine. • Major targets for allosteric drugs: diversity structures and functions. • Allosteric effects of mutations: nsSNPs and latent drivers. • State-of-the-art computational model for the comprehensive allosteric control of protein activity. • Towards design of allosteric drugs and therapeutic use of muations. Allosteric drugs have become an indispensable toolbox of rapidly developing precision medicine, having already established reputation of advantages over traditional medicines. Allosteric mechanisms are also widely involved in the action of SNPs and latent cancer drivers, and can be used in fine and specific tuning of biologics, providing a great potential in diagnostics and therapy. We discuss here major targets for prospected allosteric medicines, currently available allosteric compounds, and drug-candidates at different stages of research and (pre)clinical trials. We describe our computational model of the comprehensive allosteric control of protein activity, outlining the ways of implementing it in pharmacological applications. Finally, we formulate outstanding questions and discuss feasible directions in the work on allosteric drugs and mutations. [ABSTRACT FROM AUTHOR]

An understanding of the dynamics of magnetic textures as they interact with defects in the host material is critical for proposed applications that depend on controlled translation of these magnetic textures. We report on the experimental observation of magnetic vortex core (VC) trajectories as they are affected by a potential energy landscape arising from defects in thin, permalloy disks. We first map the VC pinning landscape using equilibrium Kerr microscopy, and then use multiplexed time-resolved Kerr microscopy to track in-plane dynamics of a magnetic VC in response to a magnetic field pulse with ns time resolution, and several-nm spatial resolution. The initial position of the VC is set by applying a static magnetic field to shift the dynamics relative to the pinning landscape. We observe the expected spiral trajectory as the VC relaxes to equilibrium over several tens of nanoseconds. However, in the presence of strong pinning, we also observe pinning evasion as the VC trajectory is deflected due to the pinning potential, and enhanced damping as the vortex becomes pinned. We compare to a simple model based on the Thiele equation of motion to understand these results. • The motion of magnetic vortices and skyrmions is predicted to depend on disorder. • We use magneto-optical microscopy to map both disorder and vortex trajectories. • Spiraling vortex trajectories are distorted by strong pinning sites. [ABSTRACT FROM AUTHOR]

We report experimental results of magnetic insulation of a space-charge dominated electron flow in a low energy vacuum diode with ferroelectric cathode. Although in the absence of the magnetic field the high current densities are measured well above the estimated space-charge limiting current, the diode is shown to be insulated by a relatively low magnetic field controlled primarily by the anode voltage. A model which accounts for the two-dimensional nature of the electrons flow in the diode has been developed and it reveals the microscopic picture of the flow. From the space-charge dominated vicinity of the cathode, electrons leave the small emitting area towards the large radius anode ring, along a trajectory that is parallel to the applied magnetic field. Only in the close vicinity of the anode plane, their trajectory bends towards the ring. Good agreement between the experimental data and theory was found. © 2003 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Demonstrates that the electrostatic coupling between the ferroelectric capacitor and the anode-cathode gap controls the emission process in ferroelectric cathode. Quantities demonstrated to be directly correlated to the energy stored in the ferroelectric; Impact of the polarity of the triggering voltage on the performance of the diode.

Purpose: To determine the prevalence and causes of visual impairment and blindness in adults aged 45 years and older from Parintins, Brazilian Amazon Region. Methods: A random cluster sampling method was used to identify subjects 45 years of age and older from urban and rural census sectors of Parintins city, Amazonas State, from March 2014 to May 2015. Participants underwent a detailed ocular examination, including presenting (PVA) and best corrected visual acuity (BCVA). The main cause of PVA<20/32 per eye was determined. Results: A total of 2384 subjects were enumerated and 2041 (85.6%) examined. The prevalence of presenting mild visual impairment – MiVI (<20/32 – ≥20/63) in the better-seeing eye was 17.0% [95% CI: 15.3–18.7%], and 8.5% [95% CI: 7.3–9.7%] with best correction. The prevalence of presenting moderate visual impairment – MVI (<20/63 – ≥20/200) was 18.4% [95% CI: 16.2–20.6%], and 6.9% [95% CI: 5.8–8.0%] with best correction. The prevalence of presenting bilateral VA <20/200 was 4.3% [95% CI: 3.6–5.0%], and 3.3% [95% CI: 2.5–4.0%] with best correction and increased with older age. Cataract (47.8%) and glaucoma (7.5%) were its main causes. In less severely affected eyes, uncorrected refractive errors (MVI: 42.6%; MiVI: 79.0%), cataract (MVI: 40.6%; MiVI: 13.7%) and pterygium (MVI: 7.6%; MiVI: 2.7%) were the main causes. Conclusions: Most cases of visual impairment in Parintins are either preventable or treatable, and public health initiatives should target cataract surgical services and refraction with spectacle provision. [ABSTRACT FROM AUTHOR]

• Natural proteins are built from fragments – descendant of primordial peptides. • Modular structure of proteins is beneficial for protein design. • Closed loops are determined by the polymer nature of proteins. • Elementary functional loops are basic units of protein function. • Descriptors of elementary functions should be used in protein design. We review studies of the protein evolution that help to formulate rules for protein design. Acknowledging the fundamental importance of Dayhoff's provision on the emergence of functional proteins from short peptides, we discuss multiple evidences of the omnipresent partitioning of protein globules into structural/functional units, using which greatly facilitates the engineering and design efforts. Closed loops and elementary functional loops, which are descendants of ancient ring-like peptides that formed fist protein domains in agreement with Dayhoff's hypothesis, can be considered as basic units of protein structure and function. We argue that future developments in protein design approaches should consider descriptors of the elementary functions, which will help to complement designed scaffolds with functional signatures and flexibility necessary for their functions. [ABSTRACT FROM AUTHOR]

Highlights • Perturbation nature of signaling is a fundamental feature of allosteric regulation. • Experimental and theoretical studies of allostery using perturbation approach. • Structure-based statistical mechanical model of allostery. • Inducing and fine-tuning targeted allosteric response. • From current understanding of allosteric control to future tasks in its design. Regardless of the diversity of systems, allosteic signalling is found to be always caused by perturbations. This recurring trait of allostery serves as a foundation for developing different experimental efforts and theoretical models for the studies of allosteric mechanisms. Among computational approaches considered here particular emphasis is given to the structure-based statistical mechanical model of allostery (SBSMMA), which allows one to study the causality and energetics of allosteric communication. We argue that the reverse allosteric signaling on the basis of SBSMMA can be used for predicting latent allosteric sites and inducing a tunable allosteric response. Per-residue allosteric effects of mutations can also be explored and 'latent drivers' expanding the cancer mutational landscape can be predicted using SBSMMA. Most recent and important implementations of computational models in web-resources along with a brief outlook on future research directions are also discussed. [ABSTRACT FROM AUTHOR]

The effect of methionine on bone remodeling parameters of young and adult male rats Vistar was studied. The introduction of excess methionine (250 mg / kg for 21 days) in the diet raises the physiological regeneration of bone tissue in young rats. Increasing their alkaline phosphanase activity in bone tissue testifies to the domination of the osteosynthetic phase of osteogenesis relative to osteolytic. Such a reaction is typical for increasing the number of active osteoblasts or increasing the sensitivity of their receptors. Unlike young animals, in adult male rats, age-related bone tissue changes are manifested in the domination of the osteolytic phase. The obtained results testify to the disease-dependent differences in the effect of the same factor dose on the processes of physiological regeneration and the organic matrix of bone tissue rats in males, which should be taken into account when using medicinal preparations. [ABSTRACT FROM AUTHOR]

Focusing on an important biomedical implication of allostery – design of allosteric drugs, we describe characteristics of allosteric sites, effectors, and their modes of actions distinguishing them from the orthosteric counterparts and calling for new principles and protocols in the quests for allosteric drugs. We show the importance of considering both binding affinity and allosteric signaling in establishing the structure–activity relationships (SARs) toward design of allosteric effectors, arguing that pairs of allosteric sites and their effector ligands – the site-effector pairs – should be generated and adjusted simultaneously in the framework of what we call directed design protocol. Key ideas and approaches for designing allosteric effectors including reverse perturbation, targeted and agnostic analysis are also discussed here. Several promising computational approaches are highlighted, along with the need for and potential advantages of utilizing generative models to facilitate discovery/design of new allosteric drugs. • Allosteric drugs: deviation from the "rule of five" and changes in the drug design paradigm. • Key distinctions of allosteric and orthosteric ligands, sites, and modes of action. • Necessary simultaneous design/tuning of allosteric sites and effectors: the site-ligand pairs. • Optimizing both signaling and binding affinity in designing allosteric drugs. • The potential of generative models in obtaining and evolving allosteric site-effector pairs. [Display omitted] [ABSTRACT FROM AUTHOR]

The nose is an important landmark of the face and its shape and beauty is of significant concern. The columella is the subunit between the two nostrils that provides support and projection to the nasal tip and has functional role in nostrils, as well as aesthetic. Ethiology for columellar absence or deficiency is diverse, and it is one of the most complex nasal subunits to reconstruct because of its narrow horizontal dimension, its tenuous vascularity and limited availability of adjacent tissue. We present a patient with columellar, membranous septum and upper lip defect, due to oncological resection. The lip reconstruction was designed using advancement of two upper lip edges with the technique of webster perialar/nasocheek advancement. However, the perialar/nasocheek tissue which is usually discarded was used as inferiorly based skin flaps to reconstruct the membranous septum, columellar skin and nasal vestibule lining. Rib cage cartilage graft was used as columellar strut for support. At 1-year followup, the patient has good nasal contour and projection. Scaring of the columella is very subtle. This is a versatile way for successful reconstruction of a columella and large central facial defect in one-stage operation. It is a method which provides very satisfactory aesthetic result with minimum patient morbidity and discomfort. [ABSTRACT FROM AUTHOR]

Molecular simulations have been employed to explore at the microscopic scale the adsorption of CO in zeolites (MFI, CHA and DDR). On the basis of classical force fields, grand canonical Monte Carlo simulations are performed to predict the adsorption properties (isotherms) of these types of zeolites up to high pressure. Subsequent careful analysis yields details the microscopic mechanism in play, along the whole adsorption process, together with a considering of the arrangements of CO in MFI at high pressure. This work also summarizes an approach which uses single component diffusion data in prediction of multicomponent diffusion. [ABSTRACT FROM AUTHOR]

Time-resolved ferromagnetic resonance is used to study magnetic relaxation in epitaxial Fe[sub 1-χ]Co[sub χ] films grown on vicinal GaAs(100) surfaces. The magnetic free energy of these films is determined by a combination of a four-fold volume anisotropy and a two-fold anisotropy due to surface bonding and morphology. The response following a high bandwidth (∼10 GHz) magnetic field pulse is measured using the polar Kerr effect. Samples with transverse dimensions much larger than the spatial extent of the field pulse show simple free induction decays. The measured precession frequencies are in good agreement with a coherent rotation model in the case of films grown on (100) surfaces with little or no (<2°) miscut. The magnetic response of 20 µm diameter disks is more complicated, particularly for static fields along the hard direction. Long-lived features appear in the response, and single precession frequencies are no longer observed. Micromagnetic simulations indicate the critical role played by the combination of the anisotropy and demagnetizing fields in the patterned structures. [ABSTRACT FROM AUTHOR]

We demonstrate that two distinct surface contributions to the magnetocrystalline anisotropy can be used to control the magnetic properties of thin films of bcc Fe[sub 1-x]Co[sub x] grown on GaAs (100) and Sc[sub 1-y]Er[sub y]As (100). The bare GaAs (100) surface has twofold symmetry, and Fe[sub 1-x]Co[sub x] films grown directly on it show a strong uniaxial magnetic anisotropy. Fourfold symmetry is restored in films grown on interlayers of Sc[sub 1-y]Er[sub y]As, in which the rock-salt structure provides a fourfold symmetric surface. A uniaxial magnetic anisotropy can be induced in this case by miscutting the substrate towards a {111} plane, so that vicinal steps run along a <011> direction. A simple Néel pair-bonding model describes the evolution of the anisotropy with the degree of miscut. For miscut GaAs (100) surfaces without interlayers, both the intrinsic anisotropy originating from the surface bonding and a step-induced term contribute to the total magneti! c anisotropy. Depending on the orientation of the miscut, the step contribution can either enhance or partially suppress the intrinsic uniaxial anisotropy. © 2001 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Objective To evaluate the relationship between CSF total protein concentration (CSF protein) and CSF opening pressure in idiopathic intracranial hypertension (IIH), and to explore the association of age, gender, race, BMI, and Humphrey visual field mean deviation (HVF MD) with CSF total protein. Methods The medical records of all IIH patients seen between 1989 and 2016 at one institution were systematically reviewed for demographics, CSF opening pressure, CSF contents, and HVF MD (at initial evaluation and most recent follow-up). Linear regression of CSF protein on CSF opening pressure was performed also considering BMI, age, gender, race, HVF MD, and year of lumbar puncture. Results We included 266 IIH patients (13 pre-pubertal children, 35 post-pubertal children, 218 adults). There was a negative linear association between CSF opening pressure and CSF protein: CSF protein decreased by 0.18 mg/dL for each 1 cm H 2 O increase in CSF opening pressure ( p < 0.001). After controlling for CSF opening pressure, mean CSF protein was 4.1 mg/dL higher in white patients than in black patients ( p < 0.001). Multivariable analysis found that CSF opening pressure ( p = 0.007), white race ( p < 0.001), and HVF MD (most recent follow-up, worst eye, p = 0.05) remained independently associated with CSF protein controlling for year of lumbar puncture and age. Conclusions There was a negative association between CSF protein and CSF opening pressure. After controlling for CSF opening pressure, CSF protein was higher in white patients and unaffected by age, gender, or BMI. Our findings help clarify inconsistent results of prior studies, but do not really help clarify IIH pathophysiology. [ABSTRACT FROM AUTHOR]

Study of the hierarchy of domain structure with alternative sets of domains and analysis of discontinuous domains, consisting of remote segments of the polypeptide chain, raised a question about the minimal structural unit of the protein domain. The hypothesis on the decisive role of the polypeptide backbone in determining the elementary units of globular proteins have led to the discovery of closed loops. It is reviewed here how closed loops form the loop-n-lock structure of proteins, providing the foundation for stability and designability of protein folds/domain and underlying their co-translational folding. Simplified protein sequences are considered here with the aim to explore the basic principles that presumably dominated the folding and stability of proteins in the early stages of structural evolution. Elementary functional loops (EFLs), closed loops with one or few catalytic residues, are, in turn, units of the protein function. They are apparent descendants of the prebiotic ring-like peptides, which gave rise to the first functional folds/domains being fused in the beginning of the evolution of protein structure. It is also shown how evolutionary relations between protein functional superfamilies and folds delineated with the help of EFLs can contribute to establishing the rules for design of desired enzymatic functions. Generalized descriptors of the elementary functions are proposed to be used as basic units in the future computational design. [ABSTRACT FROM AUTHOR]

Contemporary protein structure is a result of the trade off between the laws of physics and the evolutionary selection. The polymer nature of proteins played a decisive role in establishing the basic structural and functional units of soluble proteins. We discuss how these elementary building blocks work in the hierarchy of protein domain structure, co-translational folding, as well as in enzymatic activity and molecular interactions. Next, we consider modulators of the protein function, such as intermolecular interactions, disorder-to-order transitions, and allosteric signaling, acting via interference with the protein's structural dynamics. We also discuss the post-translational modifications, which is a complementary intricate mechanism evolved for regulation of protein functions and interactions. In conclusion, we assess an anticipated contribution of discussed topics to the future advancements in the field. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate possible functional and structural ocular changes caused by chronic sildenafil therapy to treat pulmonary arterial hypertension (PAH). Methods: Case-control study included patients with pulmonary arterial hypertension: chronically using sildenafil and without sildenafil treatment. A comprehensive ophthalmologic exam including ectoscopy, extrinsic ocular motility, logMAR visual acuity measurement, contrast sensitivity test, color test, anterior segment biomicroscopy, Schirmer test 1, intraocular pressure, fundus exam under pupil dilation, fundus pictures, time domain and spectral domain optical coherence tomography, ocular Doppler ultrasound were performed. Full-field electroretinography (ERG) was tested for each eye in a subgroup of sildenafil-treated patients. Results: Twenty patients from each group were tested. Bilateral severe keratitis was found in seven (35 %) patients under sildenafil therapy. Lacrimal film break-up time (BUT) was significantly reduced ( p = 0.006 respectively) and Doppler ultrasound showed a reduced resistance index of the central retinal artery in the group of sildenafil users ( p = 0.019). No diffuse retinal functional abnormalities were found in ERG in treated patients. Visual acuity, contrast sensitivity and color discrimination were normal in both groups. No abnormalities were found in both time-domain and spectral-domain OCT for retinal parameters. Conclusions: One-third of the treated PAH group showed severe bilateral keratitis. This finding could be related to connective tissue abnormalities usually present in patients with this condition that might be exacerbated with the sildenafil usage. The resistance index of the central retinal artery was diminished in the chronic users group and it could be associated to the vasodilation caused by the medication in the choroidal vessels. An ophthalmic assessment for these patients is recommended to diagnose and treat possible ocular surface and choroidal blood flow abnormalities caused by sildenafil. [ABSTRACT FROM AUTHOR]

The presence of multiple allosteric sites in proteins motivates development of allosteric drugs — modulators of protein activity with potentially higher specificity and less toxicity than traditional orthosteric compounds. A quest for allosteric control of any protein starts from the identification and characterization of allosteric sites. Protein dynamics is the basis for allosteric communication. Binding of effector molecules to allosteric sites modulates structural dynamics, thus affecting activity of remote functional sites. We review here theoretical concepts and experimental approaches for exploring allosteric sites, their role in allosteric regulation, and ways to assess their druggability. Key steps of the design procedure aimed at obtaining allosteric drugs with required agonistic/antagonistic effect are proposed, and their computational and experimental elements are discussed. [ABSTRACT FROM AUTHOR]

Allostery is one of the pervasive mechanisms through which proteins in living systems carry out enzymatic activity, cell signaling, and metabolism control. Effective modeling of the protein function regulation requires a synthesis of the thermodynamic and structural views of allostery. We present here a structure-based statistical mechanical model of allostery, allowing one to observe causality of communication between regulatory and functional sites, and to estimate per residue free energy changes. Based on the consideration of ligand free and ligand bound systems in the context of a harmonic model, corresponding sets of characteristic normal modes are obtained and used as inputs for an allosteric potential. This potential quantifies the mean work exerted on a residue due to the local motion of its neighbors. Subsequently, in a statistical mechanical framework the entropic contribution to allosteric free energy of a residue is directly calculated from the comparison of conformational ensembles in the ligand free and ligand bound systems. As a result, this method provides a systematic approach for analyzing the energetics of allosteric communication based on a single structure. The feasibility of the approach was tested on a variety of allosteric proteins, heterogeneous in terms of size, topology and degree of oligomerization. The allosteric free energy calculations show the diversity of ways and complexity of scenarios existing in the phenomenology of allosteric causality and communication. The presented model is a step forward in developing the computational techniques aimed at detecting allosteric sites and obtaining the discriminative power between agonistic and antagonistic effectors, which are among the major goals in allosteric drug design. [ABSTRACT FROM AUTHOR]

An austenitic metal-cored wire (diameter – 1.6 mm) with additional nitrogen alloying (0.25–0.40 wt.%) was developed for this study. Mechanical tests and metallographic studies of the deposited metal and welded joints made with austenitic metal-cored wire (composition – Cr20Mn5Ni4Mo2.5Cu3N0.3) were conducted. It was found that the values of σu and σ0.2 of the deposited metal obtained by using the developed wire were 20 to 30% higher compared to the utilized electrode materials, while the ductility characteristics were preserved (δ = 43%). It was shown that the use of metal-cored wire (Cr20Mn5Ni4Mo2.5Cu3N0.3) for welding of high-strength steel 20HGSNM (EN 1.6523) makes it possible to obtain defect-free welded joints with austenitic-ferritic structure, which have 20% higher strength characteristics compared to the analogues. [ABSTRACT FROM AUTHOR]

Context: When diabetes is not well-controlled, it can lead to numerous negative sequelae. At present, interventions used to prevent these negative sequelae are tracked, measured, and reported, both in our EHR and nationally, but the outcomes of these interventions are not. Objective: To determine the outcomes of care for our patients with diabetes. Study Design and Analysis: Cross-sectional study calculating incidence and prevalence of diabetes and its associated comorbidities. Setting or Dataset: All JPS patients from January 1, 2010, through February 4, 2022. Population Studied: All JPS patients with a diagnosis of "Diabetes". Intervention/Instrument: SlicerDicer, a software tool accessible in Epic, was used to find all unique medical record numbers (MRNs) associated with a diagnosis of "Diabetes" from January 1, 2010, through February 24 (first batch of data), 2021, and then again from January 1, 2010 through February 4, 2022 (second batch of data). Outcome Measures: Prevalence and incidence of the various negative sequelae of diabetes in comparison to published averages. Results: From the first batch of data, 93,496 unique MRNs had the diagnosis of "Diabetes". The prevalence of each comorbidity was as follows: peripheral neuropathy of 33.93%, chronic kidney disease of 20.09%, retinopathy due to diabetes of 10.32%, myocardial infarction of 10.21%, hypoglycemia of 8.07%, stroke of 6.64%, ketoacidosis of 3.28%, amputations of 2.17%, and hyperosmotic hyperketotic syndrome of 0.40%. From the second batch of data, 100,266 unique MRNs had the diagnosis of "Diabetes", accounting for 6,770 new cases of diabetes to JPS. The incidence and prevalence, respectively, of each comorbidity for that subset of patients was as follows: peripheral neuropathy of 5.11% and 35.13%, chronic kidney disease of 2.24% and 20.55%, retinopathy due to diabetes of 1.04% and 10.56%, myocardial infarction of 0.91% and 10.35%, hypoglycemia of 0.94% and 8.40%, stroke of 0.85% and 7.00%, ketoacidosis of 0.30% and 3.36%, amputations of 0.15% and 2.17%, and hyperosmotic hyperketotic syndrome of 0.03% and 0.41%. Conclusions: At JPS, until present, the incidence and prevalence of the negative sequelae of our patients with diabetes was unknown; therefore, the outcomes of care for our patients with diabetes was unknown. When compared to available information published by the CDC, JPS demonstrates better outcomes for its patients with diabetes compared to the national average. [ABSTRACT FROM AUTHOR]

Purpose: To determine uptake, barriers and outcomes in the follow-up of patients referred for free-of-charge, expedited cataract surgery in the Sao Paulo Eye Study (SPES). Methods: SPES was a population-based study of urban, low-middle income residents aged ≥50 years. Presenting visual acuity (PVA), best-corrected visual acuity, refraction, and slit-lamp examination were performed in 3677 participants. For subjects with cataract as a principal cause of best-corrected visual acuity ≤20/40, surgery was offered free of charge. Two years after the baseline study, surgery uptake, barriers to surgery, and visual outcomes were analyzed. Results: Among 210 (5.71%) participants who had a cataract surgery indication at baseline, 164 (78.1%) were successfully contacted and 55 (33.5%) reported being operated on for cataract, with 51 agreeing to be re-examined. In a multiple logistic regression model, age, sex, schooling, previous cataract surgery, and PVA at baseline were not significantly associated with surgery uptake. Co-existing health conditions (20.4%), fear of surgery (12.2%) and fear of losing eyesight (11.6%) were the most frequent barriers to cataract surgery adherence. Among the 69 eyes operated on in the interval between baseline and follow-up, PVA ≥20/63 was observed in 50 (72.6%, 95% confidence interval, CI, 62.2-82.3%), PVA <20/63-20/200 in 11 (15.8%, 95% CI 8.9-22.9%) and PVA <20/200 in 8 (11.6%, 95% CI 5.3-17.9%). Conclusions: Quality of surgery is an increasing determinant of uptake rates. Although free-of-charge and expedited cataract surgery was offered, surgical outcomes might have influenced the low uptake. Aside from cataract surgery campaigns, improvement of surgeon skills, accurate biometry, treatment of ocular comorbidities, postoperative follow-up and eye-care education are needed. [ABSTRACT FROM AUTHOR]

Background Mutations in nucleotide sequences provide a foundation for genetic variability, and selection is the driving force of the evolution and molecular adaptation. Despite considerable progress in the understanding of selective forces and their compositional determinants, the very nature of underlying mutational biases remains unclear. Results We explore here a fundamental tradeoff, which analytically describes mutual adjustment of the nucleotide and amino acid compositions and its possible effect on the mutational biases. The tradeoff is determined by the interplay between the genetic code, optimization of the codon entropy, and demands on the structure and stability of nucleic acids and proteins. Conclusion The tradeoff is the unifying property of all prokaryotes regardless of the differences in their phylogenies, life styles, and extreme environments. It underlies mutational biases characteristic for genomes with different nucleotide and amino acid compositions, providing foundation for evolution and adaptation. Reviewers This article was reviewed by Eugene Koonin, Michael Gromiha, and Alexander Schleiffer. [ABSTRACT FROM AUTHOR]

We perform photoluminescence excitation measurements on individual CdSe/ZnS nanocrystal quantum dots (NCQDs) at room temperature to study optical transition energies and broadening. The observed features in the spectra are identified and compared to calculated transition energies using an effective mass model. The observed broadening is attributed to phonon broadening, spectral diffusion, and size and shape inhomogeneity. The former two contribute to the broadening transitions in individual QDs, while the latter contributes to the QD-to-QD variation. We find that phonon broadening is often not the dominant contribution to transition line widths, even at room temperature, and that broadening does not necessarily increase with transition energy. This may be explained by differing magnitude of spectral diffusion for different quantum-confined states. [ABSTRACT FROM AUTHOR]

The high-mobility group-box transcription factor sex-determining region Y-box 2 (Sox2) is essential for the maintenance of stem cells from early development to adult tissues. Sox2 can reprogram differentiated cells into pluripotent cells in concert with other factors and is overexpressed in various cancers. In glioblastoma (GBM), Sox2 is a marker of cancer stemlike cells (CSCs) in neurosphere cultures and is associated with the proneural molecular subtype. Here, we report that Sox2 expression pattern in GBM tumors and patient-derived mouse xenografts is not restricted to a small percentage of cells and is coexpressed with various lineage markers, suggesting that its expression extends beyond CSCs to encompass more differentiated neoplastic cells across molecular subtypes. Employing a CSC derived from a patient with GBM and isogenic differentiated cell model, we show that Sox2 knockdown in the differentiated state abolished dedifferentiation and acquisition of CSC phenotype. Furthermore, Sox2 deficiency specifically impaired the astrocytic component of a biphasic gliosarcoma xenograft model while allowing the formation of tumors with sarcomatous phenotype. The expression of genes associated with stem cells and malignancy were commonly downregulated in both CSCs and serum-differentiated cells on Sox2 knockdown. Genes previously shown to be associated with pluripontency and CSCs were only affected in the CSC state, whereas embryonic stem cell self-renewal genes and cytokine signaling were downregulated, and the Wnt pathway activated in differentiated Sox2-deficient cells. Our results indicate that Sox2 regulates the expression of key genes and pathways involved in GBM malignancy, in both cancer stemlike and differentiated cells, and maintains plasticity for bidirectional conversion between the two states, with significant clinical implications. [ABSTRACT FROM AUTHOR]

Background. Being predictive of the entire nodal bed, sentinel lymph node biopsy (SLNB) is invaluable in the surgical management of melanoma. Although the concept is simple, sentinel lymph node (SLN) identification and removal can be technically challenging. Methods. A total of 102 consecutive patients have undergone SLNB in the Division of Plastic and Reconstructive Surgery of Soroka University Medical Center from 2009 to 2012. Patients have undergone SLNB using a radioactive tracer and blue stain in order to identify the SLN. Although SLNB usually precedes the wide excision of melanoma, primary lesions in close proximity (<10 cm) to the lymph basin require wide excision before beginning the SLN quest. Results. All pathology reports confirmed the excision of lymph nodes. Conclusions. When treating MM in close proximity to the lymph basin, changing the sequence of the SLNB procedure seems to increase the efficacy of the method. [ABSTRACT FROM AUTHOR]

Background. Being predictive of the entire nodal bed, sentinel lymph node biopsy (SLNB) is invaluable in the surgical management of melanoma. Although the concept is simple, sentinel lymph node (SLN) identification and removal can be technically challenging. Methods. A total of 102 consecutive patients have undergone SLNB in the Division of Plastic and Reconstructive Surgery of Soroka University Medical Center from 2009 to 2012. Patients have undergone SLNB using a radioactive tracer and blue stain in order to identify the SLN. Although SLNB usually precedes the wide excision of melanoma, primary lesions in close proximity (<10 cm) to the lymph basin require wide excision before beginning the SLN quest. Results. All pathology reports confirmed the excision of lymph nodes. Conclusions. When treating MM in close proximity to the lymph basin, changing the sequence of the SLNB procedure seems to increase the efficacy of the method. [ABSTRACT FROM AUTHOR]

Background. Being predictive of the entire nodal bed, sentinel lymph node biopsy (SLNB) is invaluable in the surgical management of melanoma. Although the concept is simple, sentinel lymph node (SLN) identification and removal can be technically challenging. Methods. A total of 102 consecutive patients have undergone SLNB in the Division of Plastic and Reconstructive Surgery of Soroka University Medical Center from 2009 to 2012. Patients have undergone SLNB using a radioactive tracer and blue stain in order to identify the SLN. Although SLNB usually precedes the wide excision of melanoma, primary lesions in close proximity (<10 cm) to the lymph basin require wide excision before beginning the SLN quest. Results. All pathology reports confirmed the excision of lymph nodes. Conclusions. When treating MM in close proximity to the lymph basin, changing the sequence of the SLNB procedure seems to increase the efficacy of the method. [ABSTRACT FROM AUTHOR]

We perform and analyze a series of time-resolved Faraday rotation measurements of coherent spin dynamics in a room-temperature ensemble of CdSe nanocrystal quantum dots (NCQDs) to study the decoherence and dephasing mechanisms that limit the transverse spin lifetime. Coherent spin lifetimes on the order of nanoseconds have been previously observed in CdSe NCQDs, but the presence of multiple components with distinct dynamics and strong inhomogeneous dephasing have made it difficult to study the relevant spin decay mechanisms quantitatively. Here, we obtain reliable fitting results by ensuring that cross-correlations between model parameters are minimized for the parameters of interest. Furthermore, we characterize the morphological inhomogeneity of the NCQD ensemble using transmission electron microscopy to constrain the model parameters that specify inhomogeneous dephasing. We find that g-factor inhomogeneity-induced dephasing (gID) is not sufficient to explain the magnetic- field-dependent decay of the spin signal. We propose an additional decoherence mechanism arising from rapid transitions between the fine structure states of the exciton referred to as fine-structure decoherence (FSD). By including both gID and FSD in the model, excellent fits are obtained to the data, including a prominent short-time-scale feature, which has typically been excluded from the fits in previous work. [ABSTRACT FROM AUTHOR]

Abstract: We overview here our recent work on the thermodynamic view of allosteric regulation and communication. Starting from the geometry-based prediction of regulatory binding sites in a static structure, we move on to exploring a connection between ligand binding and the intrinsic dynamics of the protein molecule. We describe here two recently introduced measures, binding leverage and leverage coupling, which allow one to analyze the molecular basis of allosteric regulation. We discuss the advantages of these measures and show that they work universally in proteins of different sizes, oligomeric states, and functions. We also point the problems that have to be solved before completing an atomic level description of allostery, and briefly discuss ideas for computational design of allosteric drugs. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly. [Copyright &y& Elsevier]

The multimedia information technology to implement tools of mathematical modeling in anomalous diffusion processes are considered. The basic information tasks are studied and the basic requirements for information technology, focused on solving the problems of mathematical modeling are analyzed. [ABSTRACT FROM AUTHOR]

We present the evolutionary algorithm that evolves the population of numerical solutions of the variational problem. The evolved solutions are model-independent, smooth, can have a predefined shape (if needed), and satisfy boundary or any other additional conditions (if imposed). To exemplify the performance of the proposed algorithm, we show how to solve the variational problem of searching for the spatially modulated distribution of the field of order parameter that gives a minimum to the Landau-type thermodynamic potential in the theory of ferroelectrics with incommensurate phases. [ABSTRACT FROM AUTHOR]

Abstract: We develop a generalized phenomenological theory of the paraelectric – incommensurate – commensurate phase transitions in type II ferroelectrics. The linear temperature dependence of the sixth-power term coefficient in the thermodynamic potential expansion is proposed. Contrary to the pre-existing theoretical approaches, the developed model eliminates a number of long-standing problems in the theory of type II ferroelectrics and can provide a correct description of the experimental data on the temperature dependence of the properties of type II ferroelectrics in the incommensurate phase. [Copyright &y& Elsevier]

Background: The burned hand is a common and difficult to care-for entity in the field of burns. Due to the anatomy of the hand (important and delicate structures crowded in a small limited space without sub-dermal soft tissue), surgical debridement of the burned tissue is technically difficult and may cause considerable complications and, therefore, should be performed judiciously. Selective enzymatic debridement of the burn wound can preserve the spontaneous epithelialisation potential and reduce the added injury to the traumatised tissue added by a surgical debridement. Objective: The aim of the study was to assess the implication of a selective enzymatic compound (Debrase® – Ds) in the special field of deep hand burns, by comparing the actual burn area that required surgical coverage after enzymatic debridement to the burn area clinically judged to require skin grafting prior to debridement. Materials and methods: This was a retrospective data collection and analysis from 154 complete files of prospective, open-label study in 275 hospitalised, Ds-treated burn patients. Results: A total of 69 hand burns diagnosed as ‘deep’ was analysed; 36% of the wounds required surgical intervention after enzymatic debridement; 28.6% of the total burned area estimated initially as deep was covered by skin graft (statistically significant p <0.001). Conclusion: Debridement of deep-hand burns with a selective enzymatic agent decreased the perceived full-thickness wound area and skin-graft use. [Copyright &y& Elsevier]

Background: Despite recent progress in studies of the evolution of protein function, the questions what were the first functional protein domains and what were their basic building blocks remain unresolved. Previously, we introduced the concept of elementary functional loops (EFLs), which are the functional units of enzymes that provide elementary reactions in biochemical transformations. They are presumably descendants of primordial catalytic peptides. Results: We analyzed distant evolutionary connections between protein functions in Archaea based on the EFLs comprising them. We show examples of the involvement of EFLs in new functional domains, as well as reutilization of EFLs and functional domains in building multidomain structures and protein complexes. Conclusions: Our analysis of the archaeal superkingdom yields the dominating mechanisms in different periods of protein evolution, which resulted in several levels of the organization of biochemical function. First, functional domains emerged as combinations of prebiotic peptides with the very basic functions, such as nucleotide/phosphate and metal cofactor binding. Second, domain recombination brought to the evolutionary scene the multidomain proteins and complexes. Later, reutilization and de novo design of functional domains and elementary functional loops complemented evolution of protein function. [ABSTRACT FROM AUTHOR]

Conformational changes in allosteric regulation can to a large extent be described as motion along one or a few coherent degrees of freedom. The states involved are inherent to the protein, in the sense that they are visited by the protein also in the absence of effectors ligands. Previously, we developed the measure binding leverage to find sites where ligand binding can shift the conformational equilibrium of a protein. Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom. In this paper, to analyze allosteric communication between binding sites, we introduce the concept of leverage coupling, based on the assumption that only pairs of sites that couple to the same conformational degrees of freedom can be allosterically connected. We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones. Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites. [ABSTRACT FROM AUTHOR]