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.

Highly accurate protein structure prediction with AlphaFold.

Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort1-4, the structures of around 100,000 unique proteins have been determined5, but this represents a small fraction of the billions of known protein sequences6,7. Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence-the structure prediction component of the 'protein folding problem'8-has been an important open research problem for more than 50 years9. Despite recent progress10-14, existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14)15, demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.

Highly accurate protein structure prediction for the human proteome.

Protein structures can provide invaluable information, both for reasoning about biological processes and for enabling interventions such as structure-based drug development or targeted mutagenesis. After decades of effort, 17% of the total residues in human protein sequences are covered by an experimentally determined structure1. Here we markedly expand the structural coverage of the proteome by applying the state-of-the-art machine learning method, AlphaFold2, at a scale that covers almost the entire human proteome (98.5% of human proteins). The resulting dataset covers 58% of residues with a confident prediction, of which a subset (36% of all residues) have very high confidence. We introduce several metrics developed by building on the AlphaFold model and use them to interpret the dataset, identifying strong multi-domain predictions as well as regions that are likely to be disordered. Finally, we provide some case studies to illustrate how high-quality predictions could be used to generate biological hypotheses. We are making our predictions freely available to the community and anticipate that routine large-scale and high-accuracy structure prediction will become an important tool that will allow new questions to be addressed from a structural perspective.

A clinically applicable approach to continuous prediction of future acute kidney injury.

The early prediction of deterioration could have an important role in supporting healthcare professionals, as an estimated 11% of deaths in hospital follow a failure to promptly recognize and treat deteriorating patients1. To achieve this goal requires predictions of patient risk that are continuously updated and accurate, and delivered at an individual level with sufficient context and enough time to act. Here we develop a deep learning approach for the continuous risk prediction of future deterioration in patients, building on recent work that models adverse events from electronic health records2-17 and using acute kidney injury-a common and potentially life-threatening condition18-as an exemplar. Our model was developed on a large, longitudinal dataset of electronic health records that cover diverse clinical environments, comprising 703,782 adult patients across 172 inpatient and 1,062 outpatient sites. Our model predicts 55.8% of all inpatient episodes of acute kidney injury, and 90.2% of all acute kidney injuries that required subsequent administration of dialysis, with a lead time of up to 48 h and a ratio of 2 false alerts for every true alert. In addition to predicting future acute kidney injury, our model provides confidence assessments and a list of the clinical features that are most salient to each prediction, alongside predicted future trajectories for clinically relevant blood tests9. Although the recognition and prompt treatment of acute kidney injury is known to be challenging, our approach may offer opportunities for identifying patients at risk within a time window that enables early treatment.

Acute Stress Affects the Relaxin/Insulin-Like Family Peptide Receptor 3 mRNA Expression in Brain of Pubertal Male Wistar Rats.

The current literature suggests that relaxin-3/relaxin/insulin-like family peptide receptor 3 (RLN-3/RXFP-3) system is involved in the pathophysiology of affective disorders because the results of anatomical and pharmacological studies have shown that the RLN-3 signaling pathway plays a role in modulating the stress response, anxiety, arousal, depression-like behavior, and neuroendocrine homeostasis. The risk of developing mental illnesses in adulthood is increased by exposure to stress in early periods of life. The available data indicate that puberty is especially characterized by the development of the neural system and emotionality and is a "stress-sensitive" period. The presented study assessed the short-term changes in the expression of RLN-3 and RXFP-3 mRNA in the stress-dependent brain regions in male pubertal Wistar rats that had been subjected to acute stress. Three stressors were applied from 42 to 44 postnatal days (first day: a single forced swim; second day: stress on an elevated platform that was repeated three times; third day: restraint stress three times). Anxiety (open field, elevated plus maze test) and anhedonic-like behavior (sucrose preference test) were estimated during these tests. The corticosterone (CORT) levels and blood morphology were estimated. We found that the RXFP-3 mRNA expression decreased in the brainstem, whereas it increased in the hypothalamus 72 h after acute stress. These molecular changes were accompanied by the increased levels of CORT and anxiety-like behavior detected in the open field test that had been conducted earlier, that is, 24 h after the stress procedure. These findings shed new light on the neurochemical changes that are involved in the compensatory response to adverse events in pubertal male rats and support other data that suggest a regulatory interplay between the RLN-3 pathway and the hypothalamus-pituitary-adrenal axis activity in the mechanisms of anxiety-like behavior.

Modification of Silica with Sucrose and Ammonium Fluoride Agents: A Facile Route to Prepare Supports of Iridium Catalysts for Hydrogenation Reaction.

Mesoporous silica materials were synthesized using inexpensive and environmentally friendly sucrose as a porogeneous agent. It was found that the presence of sucrose and the products of its chemical transformation during synthesis (e.g., furfural polymer) significantly affected the structure of the obtained porous silica. The influence of synthesis conditions (pH, temperature, time) on the textural properties of the final materials was determined. Samples obtained in an acidic medium, at pH = 1, and treated at room temperature, yielded products with a large surface area and a narrow pore size distribution in the range of 2-5 nm, while the synthesis at pH = 8 allowed for the formation of mesoporous systems with pores in the range of 14-20 nm. To generate acidity, the silicas were modified with an ammonium fluoride solution and then used as supports for iridium catalysts in a hydrogenation reaction, with toluene as a model hydrocarbon. The influence of parameters such as specific surface area, support acidity, and iridium dispersion on catalytic activity was determined. It was shown that modification with sucrose improved the porous structure, and NH4F modification generated acidity. These parameters favored better reducibility and dispersion of the active phase, resulting in higher activity of the catalysts in the studied hydrogenation reaction.

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.

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.

Outcomes and limitations of endoscopic ultrasound-guided hepaticogastrostomy in malignant biliary obstruction.

BACKGROUND: Transpapillary biliary drainage in ERCP is an established method for symptomatic treatment of patients with unresectable malignant biliary obstruction. Percutaneous transhepatic biliary drainage frequently remains the treatment of choice when the transpapillary approach proves ineffective. Recently, EUS-guided extra-anatomical anastomoses of bile ducts to the gastrointestinal tract have been reported as an alternative to percutaneous biliary drainage. To assess the usefulness of extra-anatomical intrahepatic biliary duct anastomoses to the gastrointestinal tract as endotherapy for unresectable malignant biliary obstruction and to determine factors affecting the efficacy of treatment. METHODS: A prospective analysis of the treatment results of all patients with unresectable biliary obstruction treated with EUS-guided hepaticogastrostomy at our institution in the years 2016-2019. RESULTS: Transmural intrahepatic biliary drainage (EUS-guided hepaticogastrostomy) was performed due to the ineffectiveness of ERCP in 53 patients (38 males, 15 females; mean age 74.66 [56-89] years) with unresectable biliary obstruction. Technical success of EUS-guided hepaticogastrostomy was achieved in 52/53 (98.11%) patients. Complications of endoscopic treatment were observed in 10/53 (18.87%) patients. Clinical success of EUS-guided hepaticogastrostomy was achieved in 46/53 (86.79%) patients. Bismuth type II-IV cholangiocarcinoma, hepatic metastases, ascites, suppurative cholangitis, and high blood bilirubin levels exceeding 30 mg/dL were independent factors for increased complications and inefficacy of EUS-guided hepaticogastrostomy. CONCLUSIONS: In the event of transpapillary biliary drainage proving ineffective, extra-anatomical anastomoses of intrahepatic bile ducts to the gastrointestinal tract provide an effective method for the treatment of patients with malignant biliary obstruction.

Dynamer and Metallodynamer Interconversion: An Alternative View to Metal Ion Complexation.

A bifunctional molecule containing both a bidentate binding site for metal ions and an aminopyrimidine H-bond donor-acceptor site has been synthesized, and its properties, in its free and coordinated forms, have been established in solution and in the solid state by analytical and spectroscopic methods as well as by X-ray structure determinations. Structural characterization has shown that it forms a one-dimensional H-bonded polymeric assembly in the solid state, while spectroscopic measurements indicate that it also aggregates in solution. The reaction of a simple Fe(II) salt with this assembly results in the emergence of two geometrical isomers of the complex: [FeL3](BF4)2·9H2O-C1 (meridional, mer) and [FeL3]2(SiF6)(BF4)2·12H2O-C2 (facial, fac). While, complex C1 in the solid state generates a one-dimensional H-bonded polymer involving just two ligands on each Fe center, with the chirality of the complex units alternating along the polymer chain, the structure of complex C2 shows NH···N interactions seen in both the ligand and mer complex (C1) structures to be completely absent. Physicochemical properties of the free and complexed ligand differ substantially.

Measurement of grouped intracellular solute osmotic virial coefficients.

Models of cellular osmotic behaviour depend on thermodynamic solution theories to calculate chemical potentials in the solutions inside and outside the cell. These solutions are generally thermodynamically non-ideal under cryobiological conditions. The molality-based Elliott et al. form of the multi-solute osmotic virial equation is a solution theory which has been demonstrated to provide accurate predictions in cryobiological solutions, accounting for the non-ideality of these solutions using solute-specific thermodynamic parameters called osmotic virial coefficients. However, this solution theory requires as inputs the exact concentration of every solute in the solution being modeled, which poses a problem for the cytoplasm, where such detailed information is rarely available. This problem can be overcome by using a grouped solute approach for modeling the cytoplasm, where all the non-permeating intracellular solutes are treated as a single non-permeating "grouped" intracellular solute. We have recently shown (Zielinski et al., J Physical Chemistry B, 2017) that such a grouped solute approach is theoretically valid when used with the Elliott et al. model, and Ross-Rodriguez et al. (Biopreservation and Biobanking, 2012) have previously developed a method for measuring the cell type-specific osmotic virial coefficients of the grouped intracellular solute. However, the Ross-Rodriguez et al. method suffers from a lack of precision, which-as we demonstrate in this work-can severely impact the accuracy of osmotic model predictions under certain conditions. Thus, we herein develop a novel method for measuring grouped intracellular solute osmotic virial coefficients which yields more precise values than the existing method and then apply this new method to measure these coefficients for human umbilical vein endothelial cells.

Influence of Gaseous Pollutants on COPD Exacerbations in Patients with Cardiovascular Comorbidities.

Exacerbations of chronic obstructive pulmonary disease (COPD) are a serious public health issue. Ambient pollution and meteorological factors are considered among precipitating factors. There are few data concerning the impact of ambient pollutants other than particulates on COPD exacerbations. Among gaseous pollutants four main groups of substances are primarily monitored: nitrogen oxides (NOx), sulphur dioxide (SO2), carbon monoxide (CO), and ozone (O3). In this study, 12,889 hospitalizations in the years 2006-2014 due to exacerbations of COPD in patients having a co-existing cardiovascular pathology were retrospectively analyzed. Cardiovascular disease was ruled out as the underlying reason of hospitalization. Data concerning the then accompanying gaseous pollutants and weather conditions were collected. The findings were that the impact of SO2 content was significantly associated with the relative risk (RR) of COPD exacerbation when the exposure took place at least 30 days or longer before hospital admission (RR 1.04-1.05; p < 0.05). In contrast, risk of COPD exacerbation rose when a shortening of the time lag between exposure to NOx and hospital admission was considered (RR 1.02-1.04; p < 0.05). O3 exposure was associated with a lower risk irrespective of the length of exposure/exacerbation lag (RR 0.77-0.90; p < 0.05). There were insignificant associations observed for CO. In conclusion, the study demonstrates a salient influence of a co-existing cardiovascular malady on the appearance of COPD-related respiratory exacerbations when the pollutant SO2 and NOx contents rose. In contrast, higher O3 content was associated with a lower risk of COPD exacerbation.

Photon Cascade from a Single Crystal Phase Nanowire Quantum Dot.

We report the first comprehensive experimental and theoretical study of the optical properties of single crystal phase quantum dots in InP nanowires. Crystal phase quantum dots are defined by a transition in the crystallographic lattice between zinc blende and wurtzite segments and therefore offer unprecedented potential to be controlled with atomic layer accuracy without random alloying. We show for the first time that crystal phase quantum dots are a source of pure single-photons and cascaded photon-pairs from type II transitions with excellent optical properties in terms of intensity and line width. We notice that the emission spectra consist often of two peaks close in energy, which we explain with a comprehensive theory showing that the symmetry of the system plays a crucial role for the hole levels forming hybridized orbitals. Our results state that crystal phase quantum dots have promising quantum optical properties for single photon application and quantum optics.

Hydrodechlorination of Tetrachloromethane over Palladium Catalysts Supported on Mixed MgF2-MgO Carriers.

Pd/MgO, Pd/MgF2 and Pd/MgO-MgF2 catalysts were investigated in the reaction of CCl4 hydrodechlorination. All the catalysts deactivated in time on stream, but the degree of deactivation varied from catalyst to catalyst. The MgF2-supported palladium with relatively large metal particles appeared the best catalyst, characterized by good activity and selectivity to C2-C5 hydrocarbons. Investigation of post-reaction catalyst samples allowed to find several details associated with the working state of hydrodechlorination catalysts. The role of support acidity was quite complex. On the one hand, a definite, although not very high Lewis acidity of MgF2 is beneficial for shaping high activity of palladium catalysts. The MgO-MgF2 support characterized by stronger Lewis acidity than MgF2 contributes to very good catalytic activity for a relatively long reaction period (~5 h) but subsequent neutralization of stronger acid centers (by coking) eliminates them from the catalyst. On the other hand, the role of acidity evolution, which takes place when basic supports (like MgO) are chlorided during HdCl reactions, is difficult to assess because different events associated with distribution of chlorided support species, leading to partial or even full blocking of the surface of palladium, which plays the role of active component in HdCl reactions.

Musculosceletal tuberculosis with involvement of tendon sheaths and formation of synovial cyst.

Due to an increasing amount of patients on immunosuppressive treatment, the number of tuberculosis (TB) of atypical course and extrapulmonary tuberculosis cases increase. Locomotor system is a place of every fifth case of extrapulmonary TB. Because of lack of characteristic symptoms, as well as rare co-occurrence of active lung lesions in radiological imaging, proper diagnosis is hard to establish. We present a case of patient on immunosuppressive therapy due to myositis, in whom we diagnosed musculoskeletal tuberculosis in form of involvement of tendon sheath and formation of synovial cyst.

Pulmonary lesions in the course of gastric cancer--two cases of Bard's syndrome.

The Bard's syndrome is a medical condition related to miliary dissemination of gastric cancer to the lungs. Difficulties in diagnosis are associated with the need of differentiation between numerous diseases, which may manifest as disseminated lesions in the lung parenchyma on chest X-ray. Despite the advanced proliferative process, primary focus of neoplasm frequently remains subclinical. Metastatic lesions cause many symptoms in the respiratory system, suggesting primary pulmonary pathology. The Bard's syndrome should be always taken into account in differential diagnosis of disseminated lesions, particularly due to prevalence of gastric cancer. The study presents two cases of patients with disseminated pulmonary lesions, corresponding to gastric cancer metastases on radiological imaging.

Aspergilloma in atypical localisation in severe asthma patient - case report.

Pulmonary aspergillosis is a condition caused by the fungi Aspergillus. The form of disease depends on the immunological condition of the host organism and other concomitant illnesses that influence the pulmonary tissue. Asthmatic patients, in particular with the severe form of disease, who require the use of systemic glucocorticoids, are predisposed to develop allergic bronchopulmonary aspergillosis. Development of aspergilloma in the lung is preceded by the formation of pathological cavity in the course of another illness. The study reports a case of a severe asthma patient who developed aspergilloma in atypical localisation, without the presence of predisposing anatomical changes and illnesses.

Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase.

In order to explore the interactions of bisphosphonate ligands with the active site and an allosteric pocket of the human farnesyl pyrophosphate synthase (hFPPS), substituted indole and azabenzimidazole bisphosphonates were designed as chameleon ligands. NMR and crystallographic studies revealed that these compounds can occupy both sub-pockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg(2+) ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feed-back regulatory role for this enzyme.

Comment on "Determination of the quaternary phase diagram of the water-ethylene glycol-sucrose-NaCl system and a comparison between two theoretical methods for synthetic phase diagrams" Cryobiology 61 (2010) 52-57.

Recently, measurements of a considerable portion of the phase diagram for the quaternary system water-ethylene glycol-sucrose-NaCl were published (Han et al., 2010). In that article, the data were used to evaluate the accuracy of two non-ideal multi-solute solution theories: the Elliott et al. form of the multi-solute osmotic virial equation and the Kleinhans and Mazur freezing point summation model. Based on this evaluation, it was concluded that the freezing point summation model provides more accurate predictions for the water-ethylene glycol-sucrose-NaCl system than the multi-solute osmotic virial equation. However, this analysis suffered from a number of issues, notably including the use of inconsistent solute-specific coefficients for the multi-solute osmotic virial equation. Herein, we reanalyse the data using a recently-updated and consistent set of solute-specific coefficients (Zielinski et al., 2014). Our results indicate that the two models have very similar performance, and, in fact, the multi-solute osmotic virial equation can provide more accurate predictions than the freezing point summation model depending on the concentration units used.

Occurrence of alert pathogens in patients hospitalised in the department of lung diseases.

INTRODUCTION: Infections caused by multiple drug-resistant pathogens represent an increasingly often encountered challenge in clinical practice. The problem particularly applies to patients with chronic lung diseases resulting in multiple hospitalisations. The aim of this paper was to analyse the incidence of alert pathogens isolated from patients hospitalised in the department of lung diseases, who were divided into three groups: patients qualified for lung transplantation, patients treated for neoplastic diseases and patients with chronic lung diseases. MATERIALS AND METHODS: Analysis involved microbiological test results of 3950 samples obtained from 3521 patients divided into: 200 patients being qualified for lung transplantation, 1292 patients treated for neoplastic diseases and 2029 patients with chronic lung diseases. RESULTS: Infection with alert pathogen was found in 155 of 3521 patients (4.4%). Most often isolated infectious agent was P. aeruginosa, which accounted for 27% of infections. Other pathogens were as follows A. baumanii ESBL(-) (13%), S. pneumoniae (12%), E. cloacae ESBL(+) (10%), K. pneumoniae ESBL(+) (10%), S. aureus MRSA (8%), E. faecalis (7%), E. coli ESBL(+) (6%), S. maltophilia ESBL(+) (5%) and E. kobei ESBL(+) (2%). Alert pathogens were found in 31 (15%) of 200 patients being qualified for lung transplantation, 89 (4.4%) of 2029 patients with chronic lung diseases and 35 (2.7%) of 1292 patients treated for neoplastic diseases. Difference between infection frequency in patients being qualified for lung transplantation and the remaining groups was statistically significant (p < 0.01). P. aeruginosa infection was the most frequent in all groups. It constituted 35% in patients being qualified for lung transplantation, 29% in patients treated for neoplastic diseases and 22% in patients with chronic lung diseases. CONCLUSIONS: Infections caused by alert pathogens were found in more than 4% of patients hospitalised in the department of lung diseases between 2007 and 2011. Their frequency was significantly higher in patients being qualified for lung transplantation than in other analysed groups. In all examined groups the most frequently isolated bacteria was P. aeruginosa (27% of all isolates).