Accurate structure prediction of biomolecular interactions with AlphaFold 3.

The introduction of AlphaFold 21 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design2-6. Here we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture that is capable of predicting the joint structure of complexes including proteins, nucleic acids, small molecules, ions and modified residues. The new AlphaFold model demonstrates substantially improved accuracy over many previous specialized tools: far greater accuracy for protein-ligand interactions compared with state-of-the-art docking tools, much higher accuracy for protein-nucleic acid interactions compared with nucleic-acid-specific predictors and substantially higher antibody-antigen prediction accuracy compared with AlphaFold-Multimer v.2.37,8. Together, these results show that high-accuracy modelling across biomolecular space is possible within a single unified deep-learning framework.

Supported Ionic Liquid-Phase Materials (SILP) as a Multifunctional Group of Highly Stable Modifiers and Hardeners for Carbon and Flax Epoxy Composites.

This paper introduces a novel approach to enhance epoxy resin formulations by using SILP materials as multifunctional hardeners and fillers in composite structures reinforced with carbon and flax fibers. This study explores the integration of ionic liquids (ILs) onto a silica support structure, presenting various permutations involving silica selection, ionic liquid choice, and concentration. The focus of this study was to elucidate the influence of SILP on resin curing ability and the mechanical properties of the resulting composites. Detailed research was conducted, including Brunauer-Emmett-Teller analysis (BET) for SILP materials and curing characterization for epoxy resin formulations with different SILP materials. Furthermore, the mechanical properties of the obtained composites were determined by Scanning Electron Microscopy analysis (SEM) (the force at break, the maximum elongation at break, tensile strength, and modulus of elasticity). Through SILP incorporation, the mechanical properties of composites, including the modulus of elasticity and tensile strength, are substantially improved, a phenomenon akin to traditional filler effects. The findings highlight SILP materials as prospective candidates for concurrent hardening and filling roles within composites (through a single-step procedure, with prolonged storage stability and controlled processing conditions), particularly pertinent as the composite industry veers toward epoxy bioresins necessitating liquefaction via temperature application.

In situ growth of N-doped carbon nanotubes from the products of graphitic carbon nitride etching by nickel nanoparticles.

The in situ growth of N-doped multi-walled carbon nanotubes (N-MWCNTs) from the products of graphitic carbon nitride (g-C3N4) etching by Ni nanoparticles in a hydrogen atmosphere has been confirmed for the first time. During the etching process of g-C3N4, the building blocks, notably methane, ammonia, and hydrogen cyanide, are formed. The formation of N-MWCNTs was confirmed by Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and scanning (SEM) and transmission electron microscopy (TEM). A sponge-like carbonaceous structure was obtained with a specific surface area of 384 m2 g-1 from initial g-C3N4 (32 m2 g-1).

Supported Gold Catalysts for Base-Free Furfural Oxidation: The State of the Art and Machine-Learning-Enabled Optimization.

Supported gold nanoparticles have proven to be highly effective catalysts for the base-free oxidation of furfural, a compound derived from biomass. Their small size enables a high surface-area-to-volume ratio, providing abundant active sites for the reaction to take place. These gold nanoparticles serve as catalysts by providing surfaces for furfural molecules to adsorb onto and facilitating electron transfer between the substrate and the oxidizing agent. The role of the support in this reaction has been widely studied, and gold-support interactions have been found to be beneficial. However, the exact mechanism of furfural oxidation under base-free conditions remains an active area of research and is not yet fully understood. In this review, we delve into the essential factors that influence the selectivity of furfural oxidation. We present an optimization process that highlights the significant role of machine learning in identifying the best catalyst for this reaction. The principal objective of this study is to provide a comprehensive review of research conducted over the past five years concerning the catalytic oxidation of furfural under base-free conditions. By conducting tree decision making on experimental data from recent articles, a total of 93 gold-based catalysts are compared. The relative variable importance chart analysis reveals that the support preparation method and the pH of the solution are the most crucial factors determining the yield of furoic acid in this oxidation process.

Accurate proteome-wide missense variant effect prediction with AlphaMissense.

The vast majority of missense variants observed in the human genome are of unknown clinical significance. We present AlphaMissense, an adaptation of AlphaFold fine-tuned on human and primate variant population frequency databases to predict missense variant pathogenicity. By combining structural context and evolutionary conservation, our model achieves state-of-the-art results across a wide range of genetic and experimental benchmarks, all without explicitly training on such data. The average pathogenicity score of genes is also predictive for their cell essentiality, capable of identifying short essential genes that existing statistical approaches are underpowered to detect. As a resource to the community, we provide a database of predictions for all possible human single amino acid substitutions and classify 89% of missense variants as either likely benign or likely pathogenic.

Methanation of CO2 over Ruthenium Supported on Alkali-Modified Silicalite-1 Catalysts.

This study focuses on the catalytic properties of ruthenium catalysts supported on modified silicalite-1 (with an MFI structure). By post-synthesis modification of silicalite-1 with solutions of alkali metal compound, a novel and cost-effective method was discovered to create basic centers on the surface of silicalite-1 supports. The modification not only affected the basicity of the supports but also their porosity. The influence of the type of alkali solution (KOH or NaOH) and its concentration (0.1 M or 1.0 M) on both the basicity and porosity was investigated. The modified silicalite-1 materials were employed as supports for ruthenium catalysts (1 wt.% Ru) and evaluated for their CO2 methanation activity. The results were compared with the hydrogenation performance of ruthenium catalysts supported on unmodified silicalite-1. Characterization of the supports and catalysts was conducted using techniques such as BET, XRD, FT-IR, ICP-OES, TPR-H2, H2 chemisorption, TPD-CO2, SEM, and TEM. Remarkably, the catalytic activity of ruthenium supported on silicalite-1 treated with 1.0 M NaOH (exhibiting selectivity toward methane above 90% in a reaction temperature range of 250-450 °C) outperformed both unmodified and KOH-modified silicalite-1 supported Ru catalysts.

Small bowel segment with Meckel's diverticulum volvulus related to short mesodiverticular band: a case report.

BACKGROUND: Meckel's diverticulum is a remnant of the omphalomesenteric duct and occurs in only about 2% of people. Mesodiverticular band is the congenital remnant of the vitelline artery and is an even less often occurring phenomenon. PRESENTED CASE: We present the case of a 56-year-old Caucasian male who was admitted to the emergency department with a very intense, sudden abdominal pain, without past abdominal surgery history. Contrast enhanced computed tomography showed a possibly ischemic closed loop of the small intestine. Urgent laparotomy was performed, during which bloody content in the peritoneal cavity and torsed loop of the small intestine with Meckel's diverticulum were found. The bowel loop and Meckel's diverticulum were ischemic. At the tip of Meckel's diverticulum there was a broken fibrous band extending to mesentery with pulsating artery. We did segmental resection of small intestine including Meckel's diverticulum and primary end-to-end anastomosis. The patient had an unremarkable postoperative hospital stay and was discharged home after 5 days. CONCLUSION: In our case, we describe a patient with the volvulus of a segment of small bowel and Meckel's diverticulum, which eventually led to small bowel obstruction and ischemia. It was a very rare case that required urgent surgical treatment.

Chronic treatment with escitalopram and venlafaxine affects the neuropeptide S pathway differently in adult Wistar rats exposed to maternal separation.

Neuropeptide S (NPS), which is a peptide that is involved in the regulation of the stress response, seems to be relevant to the mechanism of action of antidepressants that have anxiolytic properties. However, to date, there have been no reports regarding the effect of long-term treatment with escitalopram or venlafaxine on the NPS system under stress conditions. This study aimed to investigate the effects of the above-mentioned antidepressants on the NPS system in adult male Wistar rats that were exposed to neonatal maternal separation (MS). Animals were exposed to MS for 360 min. on postnatal days (PNDs) 2-15. MS causes long-lasting behavioral, endocrine and neurochemical consequences that mimic anxiety- and depression-related features. MS and non-stressed rats were given escitalopram or venlafaxine (10mg/kg) IP from PND 69 to 89. The NPS system was analyzed in the brainstem, hypothalamus, amygdala and anterior olfactory nucleus using quantitative RT-PCR and immunohistochemical methods. The NPS system was vulnerable to MS in the brainstem and amygdala. In the brainstem, escitalopram down-regulated NPS and NPS mRNA in the MS rats and induced a tendency to reduce the number of NPS-positive cells in the peri-locus coeruleus. In the MS rats, venlafaxine insignificantly decreased the NPSR mRNA levels in the amygdala and a number of NPSR cells in the basolateral amygdala, and increased the NPS mRNA levels in the hypothalamus. Our data show that the studied antidepressants affect the NPS system differently and preliminarily suggest that the NPS system might partially mediate the pharmacological effects that are induced by these drugs.

Crystal field splitting and spontaneous polarization in InP crystal phase quantum dots.

Crystal phase quantum dots are formed by vertically stacking zinc-blende and wurtzite phases during nanowire growth. In this work, we show, using an atomistic many-body approach, that crystal field splitting in the wurtzite phase, as well as spontaneous polarization originating from the phase interfaces, will strongly affect the properties of lowest hole states in InP crystal phase quantum dots, and in turn the excitonic optical spectra. We also show that the artifact-free modeling of crystal phase quantum dots should incorporate any additional potentials on equal footing with the electron-hole interaction. In this paper, we discuss a reliable theoretical framework that can be applied to investigate the electronic and optical properties of InP-based crystal phase quantum dots. The importance of accurate excitonic calculations for such systems is highlighted in view of their potential applications in nanowire photonics, yet further research is necessary for bringing theory and experiment in agreement.

Structural elucidation of substrate-bound aminoglycoside acetyltransferase (3)-IIIa.

Canonical aminoglycosides are a large group of antibiotics, where the part of chemical diversity stems from the substitution of the neamine ring system on positions 5 and 6. Certain aminoglycoside modifying enzymes can modify a broad range of 4,5- and 4,6-disubstituted aminoglycosides, with some as many as 15. This study presents the structural and kinetic results describing a promiscuous aminoglycoside acetyltransferase AAC(3)-IIIa. This enzyme has been crystallized in ternary complex with coenzyme A and 4,5- and 4,6-disubstituted aminoglycosides. We have followed up this work with kinetic characterization utilizing a panel of diverse aminoglycosides, including a next-generation aminoglycoside, plazomicin. Lastly, we observed an alternative binding mode of gentamicin in the aminoglycoside binding site, which was proven to be a crystallographic artifact based on mutagenesis.

The Role of Endoscopic Ultrasound-guided Transmural Approach in the Management of Biliary Obstructions.

BACKGROUND: Transpapillary biliary drainage in endoscopic retrograde cholangiopancreatography (ERCP) is an established method for treatment of patients with benign and malignant biliary obstruction. However, attempts to gain access to the biliary tract through the major duodenal papilla during ERCP have been unsuccessful in some patients. This study aims to determine the role of endoscopic ultrasonography (EUS)-guided transmural approach in biliary endotherapy in case of failed ERCP. MATERIALS AND METHODS: A prospective analysis of the treatment outcomes of all 896 patients with obstructive jaundice secondary to biliary obstruction, who underwent endoscopic treatment in the years 2016-2021 at our institution. RESULTS: Effective drainage of bile ducts through the major duodenal papilla during ERCP was achieved in 772/896 (86.16%) patients with biliary obstruction. In 124/896 (13.84%) patients [92 males, 32 females; mean age 63.52 (46 to 89) y] ERCP failed and EUS-guided transmural approach was performed. Benign biliary obstruction was identified in 17/124 (13.71%) patients; the remaining 107/124 (86.29%) were diagnosed with malignant biliary obstruction. EUS-guided endoscopic transpapillary biliary tract stenting with transmural access was performed in 21/124 (16.94%) patients; the remaining 103/124 (83.06%) required extra-anatomic transmural anastomosis of the bile ducts to the gastrointestinal tract. Technical success was achieved in 121/124 (97.58%) patients, while clinical success was achieved in 112/124 (90.32%). Complications were reported in 15/124 (12.1%) patients; with early complications in 12 and late complications in 3. CONCLUSIONS: Various methods of EUS-guided transmural access to bile ducts improves endotherapy outcomes of patients with biliary obstruction. Endoscopic transmural access is highly effective and associated with an acceptable number of complications.

Escitalopram alters the hypothalamic OX system but does not affect its up-regulation induced by early-life stress in adult rats.

We hypothesized that there is a relationship between the orexinergic system (OX) alterations and changes elicited by escitalopram or venlafaxine in adult rats subjected to maternal separation (MS). This animal model of childhood adversity induces long-lasting consequences in adult physiology and behavior. Male Wistar rats from the control and MS groups were injected with escitalopram or venlafaxine (10 mg/kg) IP from postnatal day (PND) 69-89. Adult rats were subjected to behavioral assessment, estimation of hypothalamic-pituitary-adrenal (HPA) axis activity and analysis of the OX system (quantitative PCR and immunohistochemistry) in the hypothalamus and amygdala. MS caused anxiety- and depressive-like behavior, endocrine stress-related response, and up-regulation of the OX system in the hypothalamus. Escitalopram, but not venlafaxine, increased the activity of hypothalamic OX system in the control rats and both drugs had no effect on OXs in the MS group. The disturbed signaling of the OX pathway may be significant for harmful long-term consequences of early-life stress. Our data show that the normal brain and brain altered by MS respond differently to escitalopram. Presumably, anti-anxiety and antidepressant effects of this drug do not depend on the activity of hypothalamic OX system.

Reductive Modification of Carbon Nitride Structure by Metals-The Influence on Structure and Photocatalytic Hydrogen Evolution.

Pt, Ru, and Ir were introduced onto the surface of graphitic carbon nitride (g-C3N4) using the wet impregnation method. A reduction of these photocatalysts with hydrogen causes several changes, such as a significant increase in the specific surface area, a C/N atomic ratio, a number of defects in the crystalline structure of g-C3N4, and the contribution of nitrogen bound to the amino and imino groups. According to the X-ray photoelectron spectroscopy results, a transition layer is formed at the g-C3N4/metal nanoparticle interphase, which contains metal at a positive degree of oxidation bonded to nitrogen. These structural changes significantly enhanced the photocatalytic activity in the production of hydrogen through the water-splitting reaction. The activity of the platinum photocatalyst was 24 times greater than that of pristine g-C3N4. Moreover, the enhanced activity was attributed to significantly better separation of photogenerated electron-hole pairs on metal nanoparticles and structural distortions of g-C3N4.

Neuropeptides as regulators of the hypothalamus-pituitary-gonadal (HPG) axis activity and their putative roles in stress-induced fertility disorders.

Neuropeptides being regulators of the hypothalamus-pituitary-adrenal (HPA) axis activity, also affect the function of the hypothalamus-pituitary-gonadal (HPG) axis by regulating gonadotrophin-releasing hormone (GnRH) secretion from hypothalamic neurons. Here, we review the available data on how neuropeptides affect HPG axis activity directly or indirectly via their influence on the HPA axis. The putative role of neuropeptides in stress-induced infertility, such as polycystic ovary syndrome, is also described. This review discusses both well-known neuropeptides (i.e., kisspeptin, Kp; oxytocin, OT; arginine-vasopressin, AVP) and more recently discovered peptides (i.e., relaxin-3, RLN-3; nesfatin-1, NEFA; phoenixin, PNX; spexin, SPX). For the first time, we present an up-to-date review of all published data regarding interactions between the aforementioned neuropeptide systems. The reviewed literature suggest new pathophysiological mechanisms leading to fertility disturbances that are induced by stress.

Investigation of the Strength of Plastic Parts Improved with Selective Induction Heating.

The use of selective induction heating of molding surfaces allows for better filling of molding cavities and has a positive effect on the properties of molded products. This is particularly important in the production of parts that include flexible hinges, which are thin plastic layers connecting two or more parts of the product. By using hinges, it is possible to expand the use of injection molding products and their capabilities. They are widely used in the production of parts for the electrical engineering industry and for packaging Fast Moving Consumer Goods (FMCG). The use of hinges also entails specific reductions in wall thickness. Increases in the shear rate can be expected, which can lead to the degradation of polymers and deterioration of mechanical properties of materials. This paper investigates injection molded flexible hinge parts manufactured with selective induction heating to improve their properties. To verify the efficiency of reduction of material degradation due to high shear rates, open/close tests of elastic hinges were performed. The linear relation between the number of cycles the hinges can withstand, mold temperature and injection time was identified, where mold temperature was the more significant factor.

Design and Simulation Study of the Induction Heated Injection Mold with Sliders.

In order to increase the quality of the products manufactured by injection molding, RTC technology can be used to achieve higher mold temperatures. As a result, the path of the injected melt can be extended, allowing the production of parts with more complex shapes and greater length. Induction heating allows heating only selected forming surfaces of the mold which increases the speed and efficiency of the process. This paper presents the concept of a detachable inductor integrated with sliders to enable the application of this technology in an injection mold with sliders, along with the theoretical model used to perform the tests. First, the effect of the magnetic concentrator shape on the process was analyzed. This was followed by a simulation study of the influence of process parameters: heating time, frequency, and electric current. An extensive analysis of the test results of the temperature distribution on the insert allowed for the selection of parameter sets that would enable obtaining the desired surface temperature without a major increase in process time. The results of simulation studies confirm the possible applications and present the range of parameters for obtaining the optimal process.

Applying and improving AlphaFold at CASP14.

We describe the operation and improvement of AlphaFold, the system that was entered by the team AlphaFold2 to the "human" category in the 14th Critical Assessment of Protein Structure Prediction (CASP14). The AlphaFold system entered in CASP14 is entirely different to the one entered in CASP13. It used a novel end-to-end deep neural network trained to produce protein structures from amino acid sequence, multiple sequence alignments, and homologous proteins. In the assessors' ranking by summed z scores (>2.0), AlphaFold scored 244.0 compared to 90.8 by the next best group. The predictions made by AlphaFold had a median domain GDT_TS of 92.4; this is the first time that this level of average accuracy has been achieved during CASP, especially on the more difficult Free Modeling targets, and represents a significant improvement in the state of the art in protein structure prediction. We reported how AlphaFold was run as a human team during CASP14 and improved such that it now achieves an equivalent level of performance without intervention, opening the door to highly accurate large-scale structure prediction.

Serious Complications of EUS-Guided Hepaticoesophagostomy due to Transmural Stent Migration.

Thoracic complications, such as biliopleural fistula and bile leaking into the right pleural cavity, are serious adverse events of transmural endoscopic ultrasound- (EUS-) guided biliary drainage involving EUS-guided hepaticoesophagostomy (EUS-HES). In this article, the authors present endoscopic treatment of biliopleural fistula as a serious thoracic complication of EUS-HES. The authors highlight key components of EUS-guided transmural biliary drainage and their experience with particular emphasis on endoscopic treatment of thoracic complications.

Studies of New Iridium Catalysts Supported on Modified Silicalite-1-Their Structure and Hydrogenating Properties.

This paper investigates the catalytic properties of the iridium catalysts supported on modified silicalite-1. Post-synthesis modification of silicalite-1, with solutions of ammonium compounds (NH4F and NH4OH), appeared to be an efficient method to generate the acidic sites in starting support. The modification of support led not only to changes in its acidity but also its porosity-formation of additional micro- and mesopores. The novel materials were used as supports for iridium. The iridium catalysts (1 wt.% Ir) were characterized by N2 adsorption/desorption measurements, temperature-programmed reduction with hydrogen (TPR-H2), H2 chemisorption, transmission electron microscopy (TEM), temperature-programmed desorption of ammonia (TPD-NH3), X-ray photoelectron spectroscopy (XPS) and tested in the hydrogenation of toluene reaction. The catalytic activity of iridium supported on silicalite-1 treated with NH4OH (higher porosity of support, better dispersion of active phase) was much higher than that of Ir supported on unmodified and modified with NH4F silicalite-1.

A prolonged steroid therapy may be beneficial in some patients after the COVID-19 pneumonia.

INTRODUCTION: This report introduces two cases presenting absorption of considerable radiological changes in the course of the coronavirus pneumonia in patients treated with prolonged oral steroids.CASES: The first case concerns a male receiving steroids only during hospitalisation in the Infectious Disease Hospital. After discharge, the patient experienced increasing dyspnoea resulting in hospitalisation in our Department of Lung Diseases. HRCT revealed progression of a bilateral, middle, and basal ground-glass opacity when compared to the examination performed at the early stage of the disease. The supplementary oxygen therapy and steroids were administered, followed by extended prednisone consumption up to 2 months after discharge. Follow-up HRCT revealed an almost complete absorption of the ground-glass opacity. The second case concerns a male treated with steroids only during hospitalisation in the Infectious Disease Hospital. Chest CT revealed widespread bilateral ground-glass opacities with consolidations. After discharge with no treatment, he suffered from severe dyspnoea and exercise intolerance, resulting in hospitalisation on the 7th day of home stay. Since then, a continued steroid treatment was administered resulting in a clinical, spirometric, and radiological improvement.CONCLUSIONS: Based on these observations, patients after the COVID-pneumonia may derive benefits from a prolonged steroid treatment. Therefore, this class of medications should be considered in SARS-CoV-2 patients, especially in patients with persistent radiological changes and dyspnoea requiring the supplementary oxygen therapy. However, randomised controlled trials are required to establish guidelines for the steroid treatment in this group of patients.