Interaction Sites Research Articles

Iterative Development of an Interactive Website to Support Shared Decision-Making in Metastatic Breast Cancer.

Recent treatment advances have resulted in significantly increased survival times following metastatic breast cancer (MBC) diagnosis. Novel treatment approaches-and their related side effects-have changed the landscape of MBC treatment decision-making. We developed a prototype of an online educational tool to prepare patients with MBC for shared decision-making with their oncologists. We describe the five phases of tool development: (1) in-depth, semi-structured qualitative interviews and (2) feedback on storyboards of initial content with patients with MBC and oncology providers. This was followed by three phases of iterative feedback with patients in which they responded to (3) initial, non-navigable website content and (4) a beta version of the full website. In the final phase (5), patients newly diagnosed with MBC (N = 6) used the website prototype for 1week and completed surveys assessing acceptability, feasibility, treatment knowledge, preparation for decision-making, and self-efficacy for decision-making. Participants in Phase 1 characterized a cyclical process of MBC treatment decision-making and identified key information needs. Website content and structure was iteratively developed in Phases 2-4. Most participants in Phase 5 (n = 4) accessed the website 2-5 times. All participants who accessed the website at least once (n = 5) felt they learned new information from the website prototype and would recommend it to others newly-diagnosed with MBC. After using the website prototype, participants reported high preparation and self-efficacy for decision-making. This multiphase, iterative process resulted in a prototype intervention designed to support decision-making for MBC patients.

Co-design and usability of an interactive web-based fertility decision aid for transgender youth and young adults.

To develop a patient- and family-centered Aid For Fertility-Related Medical Decisions (AFFRMED) interactive website targeted for transgender and nonbinary (TNB) youth/young adults and their parents to facilitate shared decision-making about fertility preservation interventions through user-centered participatory design. TNB youth/young adults interested in or currently receiving pubertal suppression or gender-affirming hormone treatment and parents of eligible TNB youth/young adults were recruited to participate in a series of iterative human-centered co-design sessions to develop an initial AFFRMED prototype. Subsequently, TNB youth/young adults and parents of TNB youth/young adults were recruited for usability testing interviews, involving measures of usability (i.e., After Scenario Questionnaire, Net Promotor Score, System Usability Scale). Twenty-seven participants completed 18 iterative co-design sessions and provided feedback on 10 versions of AFFRMED (16 TNB youth/young adults and 11 parents). Nine TNB youth/young adults and six parents completed individual usability testing interviews. Overall, participants rated AFFRMED highly on measures of acceptability, appropriateness, usability, and satisfaction. However, scores varied by treatment cohort, with TNB youth interested in or currently receiving pubertal suppression treatment reporting the lowest usability scores. We co-created a youth- and family-centered fertility decision aid prototype that provides education and decision support in an online, interactive format. Future directions include testing the efficacy of the decision aid in improving fertility and fertility preservation knowledge, decisional self-efficacy, and decision satisfaction.

Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan.

In this study, we report the mutational profiles, pathogenicity, and their association with different clinicopathologic and sociogenetic factors in patients with Pashtun ethnicity for the first time. A total of 19 FFPE blocks of invasive ductal carcinoma (IDC) from the Breast Cancer (BC) tissue and 6 normal FFPE blocks were analyzed by whole-exome sequencing (WES). Various somatic and germline mutations were identified in cancer-related genes, i.e., ATM, CHEK2, PALB2, and XRCC2. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The ATM gene exhibited the maximum number of mutations (11/18), followed by CHEK2 (3/18), PALB2 (3/18), and XRCC2 (1/18). Except one frameshift deletion, all other 17 mutations were nonsynonymous single-nucleotide variants (SNVs). SIFT prediction revealed 7/18 (38.8%) mutations as deleterious. PolyPhen-2 and MutationTaster identified 5/18 (27.7%) mutations as probably damaging and 10/18 (55.5%) mutations as disease-causing, respectively. Mutations like PALB2 p.Q559R (6/19; 31.5%), XRCC2 p.R188H (5/19; 26.31%), and ATM p.D1853N (4/19; 21.05%) were recurrent mutations and proposed to have a biomarker potential. The protein network prediction was performed using GeneMANIA and STRING. ISPRED-SEQ indicated three interaction site mutations which were further used for molecular dynamic simulation. An average increase in the radius of gyration was observed in all three mutated proteins revealing their perturbed folding behavior. Obtained SNVs were further correlated with various parameters related to the clinicopathological status of the tumors. Three mutation positions (ATM p. D1853N, CHEK2 p.M314I, and PALB2 p.T1029S) were found to be highly conserved. Finally, the wild- and mutant-type proteins were screened for two drugs: elagolix (DrugBank ID: DB11979) and LTS0102038 (a triterpenoid, isolated from the anticancer medicinal plant Fagonia indica). Comparatively, a higher number of interactions were noted for normal ATM with both compounds, as compared to mutants.

Neuroprotective amyloid β N-terminal peptides differentially alter human α7- and α7β2-nicotinic acetylcholine (nACh) receptor single-channel properties.

Oligomeric amyloid β 1-42 (oAβ1-42) exhibits agonist-like action at human α7- and α7β2-containing nicotinic receptors. The N-terminal amyloid β1-15 fragment (N-Aβ fragment) modulates presynaptic calcium and enhances hippocampal-based synaptic plasticity via α7-containing nicotinic receptors. Further, the N-Aβ fragment and its core sequence, the N-amyloid-beta core hexapeptide (N-Aβcore), protect against oAβ1-42-associated synapto- and neurotoxicity. Here, we investigated how oAβ1-42, the N-Aβ fragment, and the N-Aβcore regulate the single-channel properties of α7- and α7β2-nicotinic receptors. Single-channel recordings measured the impact of acetylcholine, oAβ1-42, the N-Aβ fragment, and the N-Aβcore on the unitary properties of human α7- and α7β2-containing nicotinic receptors expressed in nicotinic-null SH-EP1 cells. Molecular dynamics simulations identified potential sites of interaction between the N-Aβ fragment and orthosteric α7+/α7- and α7+/β2- nicotinic receptor binding interfaces. The N-Aβ fragment and N-Aβcore induced α7- and α7β2-nicotinic receptor single-channel openings. Relative to acetylcholine, oAβ1-42 preferentially enhanced α7β2-nicotinic receptor single-channel open probability and open-dwell times. Co-application with the N-Aβcore neutralized these effects. Further, administration of the N-Aβ fragment alone, or in combination with acetylcholine or oAβ1-42, selectively enhanced α7-nicotinic receptor open probability and open-dwell times (compared to acetylcholine or oAβ1-42). Amyloid-beta peptides demonstrate functional diversity in regulating α7- and α7β2-nicotinic receptor function, with implications for a wide range of nicotinic receptor-mediated functions in Alzheimer's disease. The effects of these peptides on α7- and/or α7β2-nicotinic receptors revealed complex interactions with these subtypes, providing novel insights into the neuroprotective actions of amyloid β-derived fragments against the toxic effects of oAβ1-42.

Responsive Organic Fluorescent Aggregates Based on Ion‐π Interactions Away from Fluorescent Conjugated Groups

Responsive organic luminescent aggregates have a wide range of application fields, but currently there is still a lack of reasonable molecular design strategies. Introducing ion‐π interactions into molecules can effectively alter their luminescent properties. However, current research typically focuses on ion localization at luminescent conjugated groups with the strong interaction forces. In this work, we introduce the flexible alkoxy chain spacers between fluorescent conjugated groups and ion‐π interaction sites, and then adjust the fluorescence performance of the molecule by changing the strength of ion‐π interactions. Bromine ion‐based molecules with strong ion‐π interactions exhibit high and stable fluorescence quantum yields in crystals and amorphous powders under the external stimuli. Hexafluorophosphate ion‐based molecules with weak ion‐π interactions have the high fluorescence quantum yield in crystals and very low fluorescence quantum yield in amorphous powders, showing variable fluorescence intensities under external stimuli. This demonstrates a new class of responsive organic luminescent solid‐state materials.

Target prediction and potential application of dihydroartemisinin on hepatocarcinoma treatment.

With high incidence of hepatocarcinoma and limited effective treatments, most patients suffer in pain. Antitumor drugs are single-targeted, toxicity, causing adverse side effects and resistance. Dihydroartemisinin (DHA) inhibits tumor through multiple mechanisms effectively. This study explores and evaluates safety and potential mechanism of DHA towards human hepatocarcinoma based on network pharmacology in a comprehensive way. Adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of DHA were evaluated with pkCSM, SwissADME, and ADMETlab. Potential targets of DHA were obtained from SwissTargetPrediction, Drugbank, TargetNET, and PharmMapper. Target gene of hepatocarcinoma was obtained from OMIM, GeneCards, and DisGeNET. Overlapping targets and hub genes were identified and analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway. Molecular docking was utilized to investigate the interactions sites and hydrogen bonds. Cell counting kit-8 (CCK8), wound healing, invasion, and migration assays on HepG2 and SNU387 cell proved DHA inhibits malignant biological features of hepatocarcinoma cell. DHA is safe and desirable for clinical application. A total of 131 overlapping targets were identified. Biofunction analysis showed targets were involved in kinase activity, protein phosphorylation, intracellular reception, signal transduction, transcriptome dysregulation, PPAR pathway, and JAK-STAT signaling axis. Top 9 hub genes were obtained using MCC (Maximal Clique Centrality) algorithm, namely CDK1, CCNA2, CCNB1, CCNB2, KIF11, CHEK1, TYMS, AURKA, and TOP2A. Molecular docking suggests that all hub genes form a stable interaction with DHA for optimal binding energy were all less than - 5kcal/mol. Dihydroartemisinin might be a potent and safe anticarcinogen based on its biological safety and effective therapeutic effect.

Responsive Organic Fluorescent Aggregates Based on Ion-π Interactions Away from Fluorescent Conjugated Groups.

Responsive organic luminescent aggregates have a wide range of application fields, but currently there is still a lack of reasonable molecular design strategies. Introducing ion-π interactions into molecules can effectively alter their luminescent properties. However, current research typically focuses on ion localization at luminescent conjugated groups with the strong interaction forces. In this work, we introduce the flexible alkoxy chain spacers between fluorescent conjugated groups and ion-π interaction sites, and then adjust the fluorescence performance of the molecule by changing the strength of ion-π interactions. Bromine ion-based molecules with strong ion-π interactions exhibit high and stable fluorescence quantum yields in crystals and amorphous powders under the external stimuli. Hexafluorophosphate ion-based molecules with weak ion-π interactions have the high fluorescence quantum yield in crystals and very low fluorescence quantum yield in amorphous powders, showing variable fluorescence intensities under external stimuli. This demonstrates a new class of responsive organic luminescent solid-state materials.

Topology Prediction of Gas-Separating Metal-Organic Frameworks with Low Symmetry Vertices.

Topology serves as a blueprint for the construction of reticular structures such as metal-organic frameworks, especially for those based on building blocks with highly symmetrical shapes. However, it remains a challenge to predict the topology of the frameworks from less symmetrical units, because their corresponding vertex figures are largely deformed from the perfect geometries with no "default" net embedding. Furthermore, vertices involving flexible units may have multiple shape choices, and the competition among their designated topologies makes the structure prediction in large uncertainty. Herein, the deformation index is proposed to characterize the symmetry loss of the vertex figure by comparing it with its ideal geometry. The mathematical index is employed to predict the shapes of two in situ formed Co-based metalloligands (pseudo-tetrahedron and pseudo-square), which further dictate the framework topology (flu and scu) when they are joined with the [Zr6O8]-based cuboid units. The two frameworks with very similar constituents provide an ideal platform to investigate how the pore shapes and interconnectivity influence the gas separation. The net with cylindrical channels outperforms the other with discreate cages in C3H8/C2H6/CH4 separation, benefiting from the facile accessibility of its interaction sites to the guests imposed by the specific framework topology.

MR2CPPIS: Accurate prediction of protein–protein interaction sites based on multi-scale Res2Net with coordinate attention mechanism

Proteins play a vital role in various biological processes and achieve their functions through protein–protein interactions (PPIs). Thus, accurate identification of PPI sites is essential. Traditional biological methods for identifying PPIs are costly, labor-intensive, and time-consuming. The development of computational prediction methods for PPI sites offers promising alternatives. Most known deep learning (DL) methods employ layer-wise multi-scale CNNs to extract features from protein sequences. But, these methods usually neglect the spatial positions and hierarchical information embedded within protein sequences, which are actually crucial for PPI site prediction. In this paper, we propose MR2CPPIS, a novel sequence-based DL model that utilizes the multi-scale Res2Net with coordinate attention mechanism to exploit multi-scale features and enhance PPI site prediction capability. We leverage the multi-scale Res2Net to expand the receptive field for each network layer, thus capturing multi-scale information of protein sequences at a granular level. To further explore the local contextual features of each target residue, we employ a coordinate attention block to characterize the precise spatial position information, enabling the network to effectively extract long-range dependencies. We evaluate our MR2CPPIS on three public benchmark datasets (Dset 72, Dset 186, and PDBset 164), achieving state-of-the-art performance. The source codes are available at https://github.com/YyinGong/MR2CPPIS.

Analyzing a series of ligands against malaria through the application of molecular docking, molecular quantum similarity, and reactivity indices

Background The primary goal of this research is to underscore the significance of molecular docking in the context of malaria drug discovery. Molecular docking plays a crucial role in comprehending the interactions between prospective drugs and the target proteins found in Plasmodium parasites. The study delves into the docking interactions of various compounds, emphasizing the necessity of stabilizing the active site to formulate potent and selective drugs. Methods The research focuses on highlighting compound-specific interactions with residues, stressing the importance of stabilizing the active site to design drugs tailored to specific target proteins. Inhibiting the function of these target proteins disrupts the life cycle of the malaria parasite. Quantum Similarity Analysis, utilizing Overlap and Coulomb operators, is employed to identify electronic similarities. The resulting quantum similarity values guide subsequent chemical reactivity analysis. Global reactivity indices such as chemical potential, hardness, softness, and electrophilicity contribute to drug design by showcasing compound-specific indices that underscore the significance of stability and electrophilicity. Fukui functions are utilized to visualize regions for stabilization, providing insights crucial for potential malaria treatment. Results The enhancement of drug-target binding affinity is observed through stabilizing interactions in the active site. Understanding electrophilicity at the active site emerges as a critical factor in drug design and selectivity. The rational manipulation of electrophilic interactions holds promise for developing potent and selective drugs against malaria. Consequently, the integration of molecular docking, quantum similarity analysis, and chemical reactivity indices offers a comprehensive approach to malaria drug discovery. Conclusions The study identifies potential lead compounds, emphasizing the crucial role of stabilizing the active site. Additionally, it sheds light on electronic considerations vital for the design of effective and resistance-resistant drugs. The insights provided by Fukui functions into regions susceptible to -H bond formation make these compounds promising candidates for malaria treatment.

Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis.

BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial channel protein VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy.

Ex vivo analysis of cortical microarchitecture of the distal clavicle: implications for surgical management of fractures.

Cortical thickness and porosity are two main determinants of cortical bone strength. Thus, mapping variations in these parameters across the full width of the distal end of the clavicle may be helpful for better understanding the basis of distal clavicle fractures and for selecting optimal surgical treatment. Distal ends of 11 clavicles (6 men, 5 women; age: 81.9 ± 15.1years) were scanned by micro-computed tomography at 10-µm resolution. We first analyzed cortical thickness and porosity of each 500-μm-wide area across the superior surface of distal clavicle at the level of conoid tubercle in an antero-posterior direction. This level was chosen for detailed evaluation because previous studies have demonstrated its superior microarchitecture relative to the rest of the distal clavicle. Subsequently, we divided the full width of distal clavicle to three subregions (anterior, middle, and posterior) and analyzed cortical porosity, pore diameter, pore separation, and cortical thickness. We found the largest number of low-thickness and high-porosity areas in the anterior subregion. Cortical porosity, pore diameter, pore separation, and cortical thickness varied significantly among the three subregions (p < 0.001 p = 0.016, p = 0.001, p < 0.001, respectively). Cortex of the anterior subregion was more porous than that of the middle subregion (p < 0.001) and more porous and thinner than that of the posterior subregion (p < 0.001, p = 0.030, respectively). Interaction of site and sex revealed higher porosity of the anterior subregion in women (p < 0.001). The anterior subregion had larger pores than the middle subregion (p = 0.019), whereas the middle subregion had greater pore separation compared with the anterior (p = 0.002) and posterior subregions (p = 0.006). In general, compared with men, women had thinner (p < 0.001) and more porous cortex (p = 0.03) with larger cortical pores (p < 0.001). Due to high cortical porosity and low thickness, the anterior conoid subregion exhibits poor bone microarchitecture, particularly in women, which may be considered in clinical practice. Level IV.

Thresholds and mechanisms of human magnetophosphene perception induced by low frequency sinusoidal magnetic fields

BackgroundVirtually everyone is exposed to power-frequency MF (50/60 Hz), inducing in our body electric fields and currents, potentially modulating brain function. MF-induced electric fields within the central nervous system can generate flickering visual perceptions (magnetophosphenes), which form the basis of international MF exposure guidelines and recommendations protecting workers and the general public. However, magnetophosphene perception thresholds were estimated 40 years ago in a small, unreplicated study with significant uncertainties and leaving open the question of the involved interaction site. MethodsWe used a stimulation modality termed transcranial alternating magnetic stimulation (tAMS), delivering in situ sinusoidal electric fields comparable to transcranial alternating current stimulation (tACS). Magnetophosphene perception was quantified in 81 volunteers exposed to MF (eye or occipital exposure) between 0 and 50 mT at frequencies of 20, 50, 60 and 100 Hz. ResultsReliable magnetophosphene perception was induced with tAMS without any scalp sensation, a major advantage as compared to tACS. Frequency-dependent thresholds were quantified using binary logistic regressions hence allowing to establish condition dependent probabilities of perception. Results support an interaction between induced current density and retinal rod cells. ConclusionBeyond fundamental and immediate implications for international safety guidelines, and for identifying the interaction site underlying phosphene perception (ubiquitous in tACS experiments), our results support exploring the potential of tAMS for the differential diagnosis of retinal disorders and neuromodulation therapy.

Heterogeneous nucleation of polyethylene crystals on binary hexagonal nanoplatelets

Crystal nucleating agents offer an effective strategy for controlling the morphology, dimensional stability and rate of solidification of polymers during processing. Molecular dynamics (MD) simulation can shed light on nucleation behavior at the nanoscopic length and time scales over which nucleation occurs. In this work, crystal nucleation of a polyethylene oligomer, n-pentacontane, on three graphene-like substrates, hexagonal boron nitride (hBN), molybdenum disulfide (MoS2), and tungsten disulfide (WS2), was simulated, and the thermodynamic efficiencies of these substrates as nucleating agents were determined. Experimental measurements of heterogeneous nucleation of a high-density polyethylene on nanoparticles of these three graphene-like materials were performed using the method of dispersed microdroplets in an immiscible polystyrene matrix. Qualitative agreement between simulations and experiments was observed for trends in nucleation rate, J, and interfacial free energy difference, Δσ, with JhBN>JMoS2>JWS2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$J_{\ ext{hBN}} > J_{\ ext{MoS}_{2}} > J_{\ ext{WS}_{2}}$$\\end{document}. The simulations are then used to gain additional insight into the mechanisms of nucleation. Epitaxy is confirmed in all systems, with small mismatches in lattice spacing being accommodated by strain in the oligomer crystal. However, epitaxy alone is insufficient to explain the observed trends. The strength of interaction between the nucleating agent and the polyethylene oligomer is found to be the strongest predictor of nucleating agent efficiency. The strength of interaction is in turn related to the density of interaction sites at the interface: hBN has the highest density, and thus the fastest nucleation rate.

Identification of heparin interaction sites on thrombin-activatable fibrinolysis inhibitor that modulate plasmin-mediated activation, thermal stability, and antifibrinolytic potential

BackgroundThrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that provides a molecular link between coagulation and fibrinolysis. Studies have shown that the presence of glycosaminoglycans accelerates TAFI activation by plasmin and stabilizes activated TAFI (TAFIa). ObjectivesWe aimed to define the elements of TAFI structure that allow these effects. MethodsBased on crystallographic studies and homology to heparin-binding proteins, we performed mutagenesis of surface-exposed charged residues on TAFI that putatively constitute heparin-binding sites. We determined heparin binding, kinetics of activation by plasmin in the presence or absence of heparin, thermal stability, and antifibrinolytic potential of each variant. ResultsMutagenesis of Lys211 and Lys212 did not impair heparin binding but affected the ability of TAFI to be activated by plasmin. Mutagenesis of Lys306 and His308 did not impair heparin binding, but mutation of His308 had a severe negative effect on TAFI/TAFIa function. Mutation of Arg320 and Lys324 in combination markedly decreased heparin binding but had no effect on heparin-mediated acceleration of TAFI activation by plasmin while somewhat decreasing TAFIa stabilization by heparin. Mutagenesis of Lys327 and Arg330 decreased (but did not eliminate) heparin binding while decreasing the ability of heparin to accelerate plasmin-mediated TAFI activation, stabilize TAFIa, and increase the antifibrinolytic ability of TAFIa. A quadruple mutant of Arg320, Lys324, Lys327, and Arg330 completely lost heparin-binding ability and stabilization of the enzyme by heparin. ConclusionBasic residues in the dynamic flap of TAFIa define a functionally relevant heparin-binding site, but additional heparin-binding sites may be present on TAFI.

In silico modelling of proteins encoded by important genes of flavonoid biosynthesis pathway in Gymnema sylvestre R. Br.

Understanding the proteins and metabolites produced by plants aids in developing superior planting materials. Gymnema sylvestre, a significant medicinal plant containing beneficial compounds such as oleanane, dammarane, flavonoids and gymnemic acids, exhibiting antioxidant and antidiabetic properties, making it a promising alternative treatment for Type 2 diabetes with minimal side effects. Transcriptomics in G. sylvestre yielded Coding DNA Sequences (CDS) for 12 key genes of flavonoid biosynthesis. Translated protein sequences of those 12 genes underwent characterization using protPARAM and i-TASSER. In silico protein modelling found similarities to validated enzymes, suggesting functional potential of the studied proteins. The study enlightens the first comprehensive insight into key proteins involved in G. sylvestre's flavonoid biosynthesis pathway. GsCHS (G. sylvestre chalcone synthase), a key enzyme in flavonoid biosynthesis, corroborated its phylogenetic proximity to Vincetoxicum mongolicum's CHS. Protein docking analysis delineated the distinctive features of GsCHS from cpCHS1 of Cyclosorus parasiticus, particularly in its substrate binding pockets and interactive sites crucial for synthesizing essential flavonoids.

Comparison of Greek and Portuguese Hospital Websites Using HSWAI v1.1

Every country should aim to strengthen the efficiency, accessibility and quality of its health system. To achieve this goal, the digital transformation of hospitals, which are the main pillars of any health system, is necessary. Patients and potential users of health services use the websites of healthcare institutions to find and access information about their health problems in health services. Greece has two hundred and forty-five(245) public and private hospi- tals. Using the HSWAI tool of the United Nations Universi- ty in Portugal – Operating Unit on Policy Driven Electronic Governance, the websites of the aforementioned hospitals were evaluated. The results of the evaluation were used to compare with the corresponding results in a survey con- ducted in Portugal with the same tool. The current paper deals with the comparison of the overall values according to HSWAI between the hospitals of Greece and Portugal as countries with a European character and both with a simi- lar profile (population, economy, health spending etc). Specifically, comparison was made of overall HSWAI values of Greek and Portuguese hospitals. Also, a comparison was carried out of HSWAI values of Greek and Portuguese hos- pitals in the four Criterions of the tool such as “Content”, «Services», «Community Interaction» and «Technology Features». From the comparison came up that in three cri- teria Portuguese hospitals have better performance and Greek hospitals are ahead only in Criterion «Technology Features». In conclusion, Portuguese hospitals have more complete, better quality and more interactive websites than Greek ones.

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

AbstractCalcium‐sensing receptor (CaSR), a family C G‐protein‐coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L‐Trp and L‐Phe), small peptides, anions (e.g., HCO3− and PO43−), and pH. CaSR‐mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein–protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+‐dependent cellular physiological processes and in CaSR‐dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G‐protein‐coupled receptors.

Structural basis of closed groove scrambling by a TMEM16 protein.

Activation of Ca2+-dependent TMEM16 scramblases induces phosphatidylserine externalization, a key step in multiple signaling processes. Current models suggest that the TMEM16s scramble lipids by deforming the membrane near a hydrophilic groove and that Ca2+ dependence arises from the different association of lipids with an open or closed groove. However, the molecular rearrangements underlying groove opening and how lipids reorganize outside the closed groove remain unknown. Here we directly visualize how lipids associate at the closed groove of Ca2+-bound fungal nhTMEM16 in nanodiscs using cryo-EM. Functional experiments pinpoint lipid-protein interaction sites critical for closed groove scrambling. Structural and functional analyses suggest groove opening entails the sequential appearance of two π-helical turns in the groove-lining TM6 helix and identify critical rearrangements. Finally, we show that the choice of scaffold protein and lipids affects the conformations of nhTMEM16 and their distribution, highlighting a key role of these factors in cryo-EM structure determination.

Hydroxide Ion Conduction through Viologen-Based Covalent Organic Frameworks (vCOFs): An Approach toward the Advancement.

Alkaline fuel cells rely on the movement of hydroxide anions (OH-) for their operation, yet these anions face challenges in efficient conduction due to their limited diffusion coefficient and substantial mass compared to proton (H+) transport. Within the covalent organic framework structure, ordered channels offer a promising solution for the OH- ion transport. Herein, we synthesized a cationic covalent organic framework (vTAPA) via the solvothermal-assisted Zincke reaction. vTAPA showcases excellent stability in harsh basic solution (12 M) and a wide range of pH. This framework facilitates OH- conduction through its one-dimensional network through the anion exchange process. We employed various tertiary ammonium salts (tetramethyl, tetraethyl, and tetrabutyl ammonium hydroxide) to exchange trapped anionic chloride ions inside the vTAPA structure with OH- ions. The density functional theory (DFT) study exhibited that the anion exchange process is very favorable, as the vTAPA framework offers preferable interaction sites for OH- ions. The impact of steric hindrance from these tertiary ammonium salts on the OH- conduction performance was extensively investigated. Butyl@vTAPA exhibited a high OH- ion conductivity of 1.05 × 10-4 S cm-1 at 90 °C under 98% relative humidity (RH). Our uniquely designed cationic covalent organic frameworks (COF) created a platform for a preferential transport network of hydroxide ions, and this is the first report of directly used COFs for hydroxide ion conduction without any vigorous postsynthetic modification.