General Properties Research Articles

An augmented transformer model trained on protein family specific variant data leads to improved prediction of variants of uncertain significance.

Variants of uncertain significance (VUS) represent variants that lack sufficient evidence to be confidently associated with a disease, thus posing a challenge in the interpretation of genetic testing results. Here we report an improved method for predicting the VUS of Arylsulfatase A (ARSA) gene as part of the Critical Assessment of Genome Interpretation challenge (CAGI6). Our method uses a transfer learning approach that leverages a pre-trained protein language model to predict the impact of mutations on the activity of the ARSA enzyme, whose deficiency is known to cause a rare genetic disorder, metachromatic leukodystrophy. Our innovative framework combines zero-shot log odds scores and embeddings from the ESM, an evolutionary scale model as features for training a supervised model on gene variants functionally related to the ARSA gene. The zero-shot log odds score feature captures the generic properties of the proteins learned due to its pre-training on millions of sequences in the UniProt data, while the ESM embeddings for the proteins in the ARSA family capture features specific to the family. We also tested our approach on another enzyme, N-acetyl-glucosaminidase (NAGLU), that belongs to the same superfamily as ARSA. Our results demonstrate that the performance of our family models (augmented ESM models) is either comparable or better than the ESM models. The ARSA model compares favorably with the majority of state-of-the-art predictors on area under precision and recall curve (AUPRC) performance metric. However, the NAGLU model outperforms all pathogenicity predictors evaluated in this study on AUPRC metric. The improved AUPRC has relevance in a diagnostic setting where variant prioritization generally entails identifying a small number of pathogenic variants from a larger number of benign variants. Our results also indicate that genes that have sparse or no experimental variant impact data, the family variant data can serve as a proxy training data for making accurate predictions. Attention analysis of active sites and binding sites in ARSA and NAGLU proteins shed light on probable mechanisms of pathogenicity for positions that are highly attended.

Structural and Dynamical Response of Lipid Bilayers to Solvation of an Amphiphilic Anesthetic.

The structural response of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC)/water bilayers to addition and subsequent solvation of a small amphiphilic molecule - an anesthetic benzyl alcohol - was studied by means of solid-state NMR (2H NMR, 31P NMR) spectroscopy and low-angle X-ray diffraction. The sites of binding of this solute molecule within the bilayer were determined - the solute was shown to partition between several sites in the bilayer and the equilibrium was shown to be dynamic and dependent on the level of hydration and temperature. At the same time, it was shown that solubilization of benzyl alcohol reached a solubility limit and was terminated when the ordering profile of DMPC hydrocarbon chains adopted finite limiting values throughout the whole chain. Such findings were made probably for the first time for any lipid bilayer system and possibly have more general implications for dissolution of other small-molecule amphiphilic solutes in lipid bilayer systems other than DMPC. The limit to the hydrocarbon chain profile is probably a more general property and corresponds to the balance of intrabilayer and interbilayer forces established in combination with the elastic properties of the bilayer system that still consists of one single phase just before the solute forms an excess phase. It is not necessary to quantify the contribution of each individual intrabilayer and interbilayer force acting within such a bilayer system. A model of the dependence of surface density of lipid chains on the chain segment order parameter was also developed - an empirical mathematical model based on experimental data was derived and it was proposed to represent a relationship between intrinsic bilayer forces and bilayer deformation characteristics and might be proven to be of more general significance in the future.

Structural basis for metal ion transport by the human SLC11 proteins DMT1 and NRAMP1

Iron and manganese are essential nutrients whose transport across membranes is catalyzed by members of the SLC11 family. In humans, this protein family contains two paralogs, the ubiquitously expressed DMT1, which is involved in the uptake and distribution of Fe2+ and Mn2+, and NRAMP1, which participates in the resistance against infections and nutrient recycling. Despite previous studies contributing to our mechanistic understanding of the family, the structures of human SLC11 proteins and their relationship to functional properties have remained elusive. Here we describe the cryo-electron microscopy structures of DMT1 and NRAMP1 and relate them to their functional properties. We show that both proteins catalyze selective metal ion transport coupled to the symport of H+, but additionally also mediate uncoupled H+ flux. Their structures, while sharing general properties with known prokaryotic homologs, display distinct features that lead to stronger transition metal ion selectivity.

Carbon nanotube/bentonite @ polyvinylidene fluoride tri-flouro ethylene nanocomposite matrix for surpior elimination of carcinogenic dye from wastewater

Abstract This study examines the sorption behavior of Congo Red (CR) dye from water-based solutions using a synergistic nanocomposite made of Bentonite (BT), multi-walled carbon nanotubes (MWCNTs), and a Poly (vinylidene fluoride tri-flouroethylene) (P(VDF-TRFE)) polymer matrix with exceptional adsorption capacity for the selective removal of Congo red dye from aqueous solutions. This is done in order to address the urgent concerns surrounding the health and environmental implications of CR dye. Utilizing modern analytical technique such as FTIR, XRD, SEM, TEM, and TGA, the adsorption physicochemical interaction and nanocomposite manufacturing were carefully investigated, offering thorough insights into the composite's general properties. Nanocomposite structures of between 31 and 37 nm in diameter were discovered by TEM examination. The adsorption process was pH dependent, reaching a peak removal effectiveness of 94.5% at pH 3.0. The correlation coefficients obtained from kinetic modeling using pseudo-first-order and pseudo-second-order equations were 0.97389 and 0.96802, respectively, suggesting that the adsorption mechanism adhered to first-order rate kinetics. Thermodynamic investigation revealed an exothermic and spontaneous reaction, with a negative ΔG value between − 7.45 and − 7.95 J/mol. The nanocomposite outperformed the capacities reported for individual components in earlier investigations, with an impressive monolayer sorption capacity (qmax) of 143.88 mg/g. As a result, there is great potential for this innovative nanocomposite to be a very successful adsorbent for treating industrial wastewater. Graphical Abstract

Loss-resilient, x ray interaction-free measurements

Interaction-free measurement (IFM) is a promising technique for low-dose detection and imaging, offering the unique advantage of probing an object with an overall reduced absorption of the interrogating photons. We propose an experiment to demonstrate IFM in the single x ray photon regime. The proposed scheme relies on the triple-Laue (LLL) symmetric x ray interferometer, where each Laue diffraction acts as a lossy beam splitter. In contrast to many quantum effects which are highly vulnerable to loss, we show that an experimental demonstration of this effect in the x ray regime is feasible and can achieve detection with reduced dose and high IFM efficiency even in the presence of substantial loss in the system. The latter aspect is claimed to be a general property of IFM based on our theoretical analysis. We scrutinize two suitable detection schemes that offer a dose reduction of up to half compared with direct detection. The successful demonstration of IFM with x rays promises intriguing possibilities for measurements with reduced dose, mainly advantageous for biological samples, where radiation damage is a significant limitation.

Infectious Laryngotracheitis Virus and Avian Metapneumovirus: A Comprehensive Review.

Respiratory avian viral diseases significantly impact the world poultry sector, leading to notable economic losses. The highly contagious DNA virus, infectious laryngotracheitis virus, and the RNA virus, avian metapneumovirus, are well known for their prevalent effects on avian respiratory systems. The infectious laryngotracheitis virus (ILTV), stemming from the Herpesviridae family, manifests as an upper respiratory disease within birds. Characterized by acute respiratory signs, it sporadically emerges worldwide, presenting a persistent threat to poultry health. Avian metapneumovirus (aMPV), belonging to the Pneumoviridae family is identified as the cause behind severe rhinotracheitis in turkeys and swollen head syndrome in chickens. This disease can lead to heightened mortality rates, especially when coupled with secondary bacterial infections. This review offers a comprehensive analysis and understanding of the general properties of these specific avian respiratory viruses, control measures, and their global status.

The Protective Effect of Docosahexaenoic Acid on Mitochondria in SH-SY5Y Model of Rotenone-Induced Toxicity.

Background: Polyunsaturated fatty acids in particular omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients and components of the plasma membrane. They are involved in various processes, including synaptic development, functionality, integrity, and plasticity, and are therefore thought to have general neuroprotective properties. Considerable research evidence further supports the beneficial effects of omega-3 fatty acids, specifically on mitochondria, through their antioxidant and anti-apoptotic properties, making them an attractive addition in treatment options for neurodegenerative disorders in which mitochondrial alterations are commonly observed. However, precise information on the underlying protective mechanisms is still lacking. Methods: We utilized the most common neuronal cell line (SH-SY5Y) and induced mitochondrial oxidative stress through the addition of rotenone. To study the potential protective effect of DHA, the cells were additionally pre-treated with DHA prior to rotenone administration. By combining SILAC labeling, mitochondria enrichment, and subsequent proteomic analyses, we aimed to determine the capacity of DHA to alleviate mitochondrial oxidative stress in vitro and further shed light on the molecular mechanisms contributing to the proposed neuroprotective effect. Results: We confirmed a reduced cell viability and an increased abundance of reactive oxygen species upon rotenone treatment, DHA pre-treatment was shown to decrease said species. Additionally proteomic analysis revealed an increased expression of mitochondrial proteins in DHA pre-treated cells. Conclusions: With our study, we were able to define a potential compensatory mechanism by which the inhibition of complex I is overcome by an increased activity of the fatty acid beta oxidation in response to DHA.

Flo: A Semantic Foundation for Progressive Stream Processing

Streaming systems are present throughout modern applications, processing continuous data in real-time. Existing streaming languages have a variety of semantic models and guarantees that are often incompatible. Yet all these languages are considered "streaming"---what do they have in common? In this paper, we identify two general yet precise semantic properties: streaming progress and eager execution. Together, they ensure that streaming outputs are deterministic and kept fresh with respect to streaming inputs. We formally define these properties in the context of Flo, a parameterized streaming language that abstracts over dataflow operators and the underlying structure of streams. It leverages a lightweight type system to distinguish bounded streams, which allow operators to block on termination, from unbounded ones. Furthermore, Flo provides constructs for dataflow composition and nested graphs with cycles. To demonstrate the generality of our properties, we show how key ideas from representative streaming and incremental computation systems---Flink, LVars, and DBSP---have semantics that can be modeled in Flo and guarantees that map to our properties.

Sex hormones and allergies: exploring the gender differences in immune responses.

Allergies are closely associated with sex-related hormonal variations that influence immune function, leading to distinct symptom profiles. Similar sex-based differences are observed in other immune disorders, such as autoimmune diseases. In allergies, women exhibit a higher prevalence of atopic conditions, such as allergic asthma and eczema, in comparison to men. However, age-related changes play a significant role because men have a higher incidence of allergies until puberty, and then comes a switch ratio of prevalence and severity in women. Investigations into the mechanisms of how the hormones influence the development of these diseases are crucial to understanding the molecular, cellular, and pathological aspects. Sex hormones control the reproductive system and have several immuno-modulatory effects affecting immune cells, including T and B cell development, antibody production, lymphoid organ size, and lymphocyte death. Moreover, studies have suggested that female sex hormones amplify memory immune responses, which may lead to an excessive immune response impacting the pathogenesis, airway hyperresponsiveness, inflammation of airways, and mucus production of allergic diseases. The evidence suggests that estrogens enhance immune humoral responses, autoimmunity, mast cell reactivity, and delayed IV allergic reactions, while androgens, progesterone, and glucocorticoids suppress them. This review explores the relationship between sex hormones and allergies, including epidemiological data, experimental findings, and insights from animal models. We discuss the general properties of these hormones, their effects on allergic processes, and clinical observations and therapeutic results. Finally, we describe hypersensitivity reactions to these hormones.

Fire performance of wood–steel hybrid elements: finite element analysis and experimental validation

Wood-steel hybrid (WSH) elements are gaining popularity in the construction industry due to their reduced environmental impact and high load capacity. However, fire resistance remains a crucial challenge for advancing wood as a construction material. The proposed WSH slab consists of a trapezoidal steel profile sandwiched between two laminated veneer lumber (LVL) beech panels. This research aims to numerically predict the fire performance of the proposed WSH slab element by generating heat transfer models that consider convection, radiation, and conduction. The objectives are to predict the temperature profile of the system's components, assess the charring rate of the LVL panels, and validate the results with experimental fire tests. Computed Tomography (CT) scanning was additionally used to detect the material density variation in the remaining LVL layers after fire tests. Simulations reveal that the size and shape of the internal cavity significantly influence heat flow within the system. Analysis of different thicknesses and heights of the steel sheet shows a substantial impact on the charring initiation time of the upper LVL layer. Temperature profiles of the components from numerical analysis exhibit similar behavior to that observed in the experiments. The experimental charring rate averages between 0.88—1.00 mm/min, while the numerical rate averages between 0.95—1.06 mm/min, with a 5–8% average deviation attributed to conduction interaction between LVL and the steel sheet. This variation may also be caused by the definition of generic thermal properties of wood according to EN1995-1-2, which may not accurately represent the behavior of the LVL element under fire.

Organoid Ethical Typology: varieties of three-dimensional stem cell constructs and the many issues they raise in bioethics.

The advancement of and prospects for stem cell research raise a number of specific ethical issues. While navigating the ethical landscape of stem cell research is often challenging for biology researchers and biotechnology innovators, it is also difficult for the public and other persons of concern (from ethicists to policy-makers) to grasp the technicalities of a burgeoning field that develops in many directions. Organoids are one of these new biotechnological constructs that are currently eliciting a rich debate in bioethics. In this guide, we argue that different types of organoids have different emerging properties with different ethical implications. Going from general properties to particular ones, we propose a typology of organoid technology and other associated biotechnology from a philosophical and ethical perspective. We point to relevant ethical issues and try to convey the sense of uncertainty peculiar to ongoing research and emerging technological objects.

Interplay between conformational dynamics and substrate binding regulates enzymatic activity: a single-molecule FRET study.

Proteins often harness extensive motions of domains and subunits to promote their function. Deciphering how these movements impact activity is key for understanding life's molecular machinery. The enzyme adenylate kinase is an intriguing example for this relationship; it ensures efficient catalysis by large-scale domain motions that lead to the enclosure of the bound substrates ATP and AMP. Surprisingly, the enzyme is activated by urea, a compound commonly acting as a denaturant. We utilize this phenomenon to decipher the involvement of conformational dynamics in the mechanism of action of the enzyme. Combining single-molecule FRET spectroscopy and enzymatic activity studies, we find that urea promotes the open conformation of the enzyme, aiding the proper positioning of the substrates. Further, urea decreases AMP affinity, paradoxically facilitating a more efficient progression towards the catalytically active complex. These results allow us to define a complete kinetic scheme that includes the open/close transitions of the enzyme and to unravel the important interplay between conformational dynamics and chemical steps, a general property of enzymes. State-of-the-art tools, such as single-molecule fluorescence spectroscopy, offer new insights into how enzymes balance different conformations to regulate activity.

Force free magnetic flux rope with a high current density on the axis

A new model of a force-free magnetic flux rope with a high concentration of electric current on the axis is presented. The general property of axisymmetric force-free magnetic ropes is that with the exit of the top of the magnetic loop-rope into the corona, the external pressure that keeps it from lateral expansion steadily decreases, and with some critical decrease in this pressure, the longitudinal magnetic field of the rope becomes zero on the surface where the electric current changes its sign (it is current inversion surface — CIS). In this case, the force-free parameter α(r) and the azimuthal electric current experience a second-order discontinuity on this surface, so that in the vicinity of CIS their values begin to increase without limit. The current (drift) speed of electrons here will inevitably exceed the speed of ion sound. This serves as a trigger for the heating of non-isothermal plasma (so it turns out Te Ti) and the excitation of plasma ion-acoustic instability of the plasma not only near the CIS, but also in the central region of the rope, on its axis, where the current density is especially high. The appearance of anomalous resistance leads to rapid dissipation of the magnetic field and the generation of a super-Dreicer electric field. The Parker effect, associated with the equalization (with some delay) of the torque along the axis of the rope due to the transfer of the azimuthal field to the region of energy release, leads to quasiperiodic pulsations of hard flare radiation and, ultimately, ensures the flare release of the most part of free magnetic energy accumulated in the rope.

Robinsonade of fictional objects and the poverty of arbitrary objects

The paper is devoted to the consideration of the conception of fictional objects as objects with the finite set of special (non-generic) properties. The paper provides a formulation of this concept, and compares fictional objects with arbitrary objects and real objects in the context of their possessing of generic and non-generic properties, as well as in the context of the existence of these objects in the actual world and in possible worlds. The paper ends with a discussion of several comments related to the mentioned conception of fictional objects, which were proposed after a talk on this topic at the 7th Lem’s Readings conference.

A theoretical study of the bond-dissociation enthalpies (BDH), N–R bond lengths and proton affinities of N-substituted pyrroles, imidazoles and pyrazoles with R substituents along the periodic table

The properties (geometry, bond-dissociation enthalpies and proton affinities) of three azoles, pyrrole, imidazole and pyrazole, with twenty-two N-substituents R covering a significant part of the periodic table [1 (lithium group, alkaline), 2 (beryllium group, alkaline earth), 13 (boron group, triel), 14 (carbon group, tetrel), 15 (nitrogen group, pnictogen), 16 (oxygen group, chalcogen) and 17 (fluorine group, halogen) of the periods 2, 3 and 4 plus the hydrogen] have been calculated with the G4 composite ab initio method. These three properties were discussed with regard to the azole and to the group R using as model compound the amines H2N–R. The large set of compounds and their consistency allowed finding many equations that related different calculated properties. General properties such as bond-dissociation enthalpies, BDH, N–R bond lengths and proton affinities were tested in search of simple equations that explain the calculated properties.Graphical abstract

General properties, biosynthesis, pharmacological properties, biological activities and daily uses of luteolin

Phenolic molecules are secondary metabolites that facilitate several biological processes. Secondary metabolites are non-nutritive substances that hold significant medicinal value. Our study combined the biological activities, general features, daily usage conditions, and biosynthesis of luteolin as reported in the literature. The literature review revealed that luteolin exhibits biological activities including antioxidant, antibacterial, anticancer, and anti-inflammatory properties. It was observed that it exerts effects on illnesses including cardioprotection, cholesterol regulation, neuroprotection, autistic spectrum disorders, gastrointestinal issues, obesity, insulin sensitivity, anxiety/depression, and arthritis. In this regard, luteolin was identified as a significant molecule for pharmacological applications.

RESEARCH ON THE ELECTROMAGNETIC COMPATIBILITY OF MATERIALS FOR ORTHOPEDIC PROSTHETICS

Introduction. Acrylic plastics are widely used in orthopedic dentistry and orthodontics. They are the main material for the manufacture of various types of dental prostheses. To create an orthopedic product, a mixture of powder (polymer) and liquid (monomer) is obtained, from which a product of the required shape and size is formed and solidified. The resulting designs must meet the requirements for compatibility with living tissues, including the little-studied compatibility of the electromagnetic component. Main part. Dielectric materials when heated form their own electromagnetic radiation in the millimeter range, which is a general property of heated dielectrics. By this, electromagnetic flows (EMF) of different directions arise. These flows can have a positive or negative direction and in a certain way affect the adjacent biotissues and the human body as a whole. Therefore, the authors conducted studies of electromagnetic radiation (EMR) of 6 types of acrylic plastics, determined their levels and compared them with the level of EMR of biotissues of the human body. Based on the obtained results, conclusions were drawn regarding their electromagnetic compatibility (EMC). “Colorless basic plastic” and “Vertex Implacryl” have the highest level of EMC (up to 58%), “Ftorax” and “Sinma-M” plastics have a slightly lower level (48-53%) and the lowest EMC (35-36%) is recorded in “Vertex Basio” and “Ethakryl – 02”. Conclusions. Compared to the level of human electromagnetic radiation, acrylic plastics and, accordingly, dental prostheses from them form negative currents in relation to adjacent biotissues. The conducted studies allow to recommend the choice of more acceptable materials for the manufacture of dental permanent and removable prostheses, as well as to determine the correlation between the emission of electromagnetic characteristics and the appearance of complications in patients during the operation of these structures.

On a Holm-related MTP for rejecting at least k hypotheses: general validity, optimality property, confidence regions, and applications

ABSTRACT This article concerns p-value-based multiple testing procedures (MTPs) that can be used in a confirmatory clinical study under minimal assumptions in case the requirement for study-success is that at least k out of m primary/important hypotheses become rejected. Recently, a simple, generally valid Holm-type MTP was discussed that can be used for such a requirement for any k from one to m. It can only reject at least k (or zero) hypotheses, but this increases the power to reject k or more hypotheses compared to Holm’s step-down MTP. The present article provides a simple formulation and proof of strong family-wise error rate (FWER) control for a stepwise MTP that is sharper in that for any k strictly between one and m it: (a) always rejects at least as much, and (b) can potentially reject fewer than k hypotheses. This sharper MTP too is generally valid, without any assumption about logical or stochastic relationships. It has a gatekeeping step, followed by m steps where ordered primary p-values are compared to critical constants and rejections are made in a step-down manner. These constants have the optimality property that under a natural monotonicity restriction, they cannot be increased without losing the general strong FWER control. Confidence regions like those for Holm’s MTP are provided. Applications are discussed in connection with three interesting approaches proposed earlier for confirmatory studies: (a) the Superiority-Noninferiority approach; (b) Fallback tests for co-primary endpoints; and (c) Multistage gatekeeping MTPs that utilize so-called k-truncated Holm MTPs in some stages.

Convex modeling and control of multi-fuel compression ignition engines

Multi-fuel engines are complex machines that operate in varied ambient and operating conditions. For reliable operation of multi-fuel engines in varying operating conditions, proper modeling, and efficient control design for their combustion phasing are required. One of the practically implementable ways this is achieved in practice is by, Gaussian process regression (GPR) models and then designing a feedforward control through look-up tables (LUTs). The main approach of designing LUTs is based on the inversion of GPR models that can be formulated as an optimization problem. Although GPR models have good generalization properties and ensure accuracy with a limited number of data, their usage in optimization problems leads to non-convex costs which are computationally burdensome to solve. To address this problem, this work proposes alternative modeling approaches for multi-fuel engines based on non-parametric convex regression and convex neural networks. First, the experimental data collected from the 4-cylinder diesel engine is exploited to obtain convex models and then, the resulting convex models are used in the LUT design process. To demonstrate the success of the method, we compare the convex models and the GPR model in terms of accuracy, computational time in control design, and control performance, as well as present a comparison in terms of model complexity between the investigated model structures.

Testing colour–magnitude pattern as a method in the search for changing-look AGNs

ABSTRACT We develop a simple method to search for changing-look (CL) active galactic nucleus (AGN) candidates, and conduct a test run. In this method, optical variations of AGNs are monitored and CL-AGNs may appear to have a pattern of being bluer when in brightening flare-like events. Applying this method, previously classified type 2 AGNs that show the bluer-when-brighter (BWB) pattern are selected. Among more than ten thousands type 2 AGNs classified in the Sloan Digital Sky Survey (SDSS), we find 73 candidates with possibly the strongest BWB pattern. We note that 13 of them have previously been reported as CL-AGNs. We have observed nine candidates, and found that five among them showed the CL transition from type 2 to type 1. In addition, we also test extending the selection to previously classified type 1 AGNs in the SDSS by finding sources with a possible redder-when-brighter pattern, but none of the three sources observed by us is found to show the transition from type 1 to type 2. We discuss the variation properties in both the success and failure cases, and plan to observe more candidates selected with the method. From the observational results, a detailed comparison between the CL-AGNs and none CL-AGNs will help quantitatively refine the selection criteria and in turn allow us to configure the general properties of CLAGNs.