Matrix metalloproteinase-9: A magic drug target in neuropsychiatry?

Neuropsychiatric conditions represent a major medical and societal challenge. The etiology of these conditions is very complex and combines genetic and environmental factors. The latter, for example, excessive maternal or early postnatal inflammation, as well as various forms of psychotrauma, often act as triggers leading to mental illness after a prolonged latent period (sometimes years). Matrix metalloproteinase-9 (MMP-9) is an extracellularly and extrasynaptic operating protease that is markedly activated in response to the aforementioned environmental insults. MMP-9 has also been shown to play a pivotal role in the plasticity of excitatory synapses, which, in its aberrant form, has repeatedly been implicated in the etiology of mental illness. In this conceptual review, we evaluate the experimental and clinical evidence supporting the claim that MMP-9 is uniquely positioned to be considered a drug target for ameliorating the adverse effects of environmental insults on the development of a variety of neuropsychiatric conditions, such as schizophrenia, bipolar disorder, major depression, autism spectrum disorders, addiction, and epilepsy. We also identify specific challenges and bottlenecks hampering the translation of knowledge on MMP-9 into new clinical treatments for the conditions above and suggest ways to overcome these barriers.

Conduction system pacing, a European survey: insights from clinical practice.

AIMS: The field of conduction system pacing (CSP) is evolving, and our aim was to obtain a contemporary picture of European CSP practice. METHODS AND RESULTS: A survey was devised by a European CSP Expert Group and sent electronically to cardiologists utilizing CSP. A total of 284 physicians were invited to contribute of which 171 physicians (60.2%; 85% electrophysiologists) responded. Most (77%) had experience with both His-bundle pacing (HBP) and left bundle branch area pacing (LBBAP). Pacing indications ranked highest for CSP were atrioventricular block (irrespective of left ventricular ejection fraction) and when coronary sinus lead implantation failed. For patients with left bundle branch block (LBBB) and heart failure (HF), conventional biventricular pacing remained first-line treatment. For most indications, operators preferred LBBAP over HBP as a first-line approach. When HBP was attempted as an initial approach, reasons reported for transitioning to utilizing LBBAP were: (i) high threshold (reported as >2 V at 1 ms), (ii) failure to reverse bundle branch block, or (iii) > 30 min attempting to implant at His-bundle sites. Backup right ventricular lead use for HBP was low (median 20%) and predominated in pace-and-ablate scenarios. Twelve-lead electrocardiogram assessment was deemed highly important during follow-up. This, coupled with limitations from current capture management algorithms, limits remote monitoring for CSP patients. CONCLUSIONS: This survey provides a snapshot of CSP implementation in Europe. Currently, CSP is predominantly used for bradycardia indications. For HF patients with LBBB, most operators reserve CSP for biventricular implant failures. Left bundle branch area pacing ostensibly has practical advantages over HBP and is therefore preferred by many operators. Practical limitations remain, and large randomized clinical trial data are currently lacking.

Zeeman optical pumping of 87Rb atoms in a hollow-core photonic crystal fiber.

Preparation of an atomic ensemble in a particular Zeeman state is a critical step of many protocols for implementing quantum sensors and quantum memories. These devices can also benefit from optical fiber integration. In this work we describe experimental results supported by a theoretical model of single-beam optical pumping of 87Rb atoms within a hollow-core photonic crystal fiber. The observed 50% population increase in the pumped F = 2, mF = 2 Zeeman substate along with the depopulation of remaining Zeeman substates enabled us to achieve a threefold improvement in the relative population of the mF = 2 substate within the F = 2 manifold, with 60% of the F = 2 population residing in the mF = 2 dark sublevel. Based on theoretical model, we propose methods to further improve the pumping efficiency in alkali-filled hollow-core fibers.

Frameworks for implementation of policies promoting healthy nutrition and physically active lifestyle: systematic review.

BACKGROUND: Policy frameworks focusing on policy implementation may vary in terms of their scope, included constructs, relationships between the constructs, and context factors. Although multiple policy implementation frameworks exist, the overarching synthesis characterizing differences between the frameworks is missing. This study investigated frameworks guiding implementation of policies aiming at healthy nutrition, physical activity promotion, and a reduction of sedentary behavior. In particular, we aimed at examining the scope of the frameworks and the content of included constructs (e.g., referring to implementation processes, determinants, or implementation evaluation), the level at which these constructs operate (e.g., the individual level, the organizational/community level), relationships between the constructs, and the inclusion of equity factors. METHODS: A systematic review (the PROSPERO registration no. CRD42019133251) was conducted using 9 databases and 8 stakeholder websites. The content of 38 policy implementation frameworks was coded and analyzed. RESULTS: Across the frameworks, 47.4% (18 in 38) addressed three aims: description of the process, determinants, and the evaluation of implementation. The majority of frameworks (65.8%; 25 in 38) accounted for constructs from three levels: individual, organizational/community, and the system level. System-level constructs were included less often (76.3%; 29 in 38) than individual-level or organizational/community-level constructs (86.8% [33 in 38 frameworks] and 94.7% [36 in 38 frameworks] respectively). The majority of frameworks (84.2%, 32 in 38) included at least some sections that were solely of descriptive character (a list of unassociated constructs); 50.0% (19 in 38) included sections of prescriptive character (general steps of implementation); 60.5% (23 in 38) accounted for explanatory sections (assuming bi- or uni-directorial associations). The complex system approach was accounted for only in 21.1% (8 in 38) of frameworks. More than half (55.3%; 21 in 38) of frameworks did not account for any equity constructs (e.g., socioeconomic status, culture). CONCLUSIONS: The majority of policy implementation frameworks have two or three aims (combining processes, determinants and/or the evaluation of implementation), include multi-level constructs (although the system-level determinants are less frequently included than those from the individual- or organizational/community-level), combine sections of purely descriptive character with sections accounting for prescriptive and/or explanatory associations, and are likely to include a little or no equity constructs. REGISTRATION: PROSPERO, #CRD42019133251.

Clinical valuation of ST changes in a group of patients with ventricular arrhythmias: The inSighT Study.

BACKGROUND: The inSighT study was designed to determine the prevalence of ischemic changes as recorded by implantable cardioverter-defibrillator (ICD) ST deviations in intracardiac electrocardiograms (EGM) over the 24 h preceding malignant ventricular arrhythmias (VT/VF). METHODS: The study enrolled patients with known coronary artery disease (CAD) or high risk of future development of CAD implanted with an ICD equipped with an ST monitoring feature (Ellipse™/Fortify Assura™, St. Jude Medical). Device session records were collected at each in-clinic follow-up. EGM ST levels of the beats over the 15 minutes prior to VT/VF events were compared using a t test with those from a baseline period of 23-24 h prior to the VT/VF event. All events with p < .05 were visually inspected to confirm they were evaluable; additional criteria for exclusion from further analysis included inappropriate therapy, aberrant conduction, and occurrence of VT/VF within 24h prior to the current event. RESULTS: The study enrolled 481 ICD patients (64 ± 11 years, 83% male) in 14 countries and followed them for 15±5 months. A total of 165 confirmed VT/VF episodes were observed, of which 71 events (in 56 patients, 34% of all patients with VT/VF) were preceded by significant (p < .05) ST-segment changes unrelated to known non-ischemic causes. None of the analyzed demographic and clinical factors proved to be associated with greater odds of presenting with ST-segment changes prior to VT/VF episode. CONCLUSION: In this exploratory study, characteristic ST-segment changes, likely representative of ischemic events, were observed in 34% of all patients with VT/VF episodes.

Social, economic, political, and geographical context that counts: meta-review of implementation determinants for policies promoting healthy diet and physical activity.

BACKGROUND: This meta-review investigated the context-related implementation determinants from seven domains (geographical, epidemiological, sociocultural, economic, ethics-related, political, and legal) that were systematically indicated as occurring during the implementation of obesity prevention policies targeting a healthy diet and a physically active lifestyle. METHODS: Data from nine databases and documentation of nine major stakeholders were searched for the purpose of this preregistered meta-review (#CRD42019133341). Context-related determinants were considered strongly supported if they were indicated in ≥60% of the reviews/stakeholder documents. The ROBIS tool and the Methodological Quality Checklist-SP were used to assess the quality-related risk of bias. RESULTS: Published reviews (k = 25) and stakeholder documents that reviewed the evidence of policy implementation (k = 17) were included. Across documents, the following six determinants from three context domains received strong support: economic resources at the macro (66.7% of analyzed documents) and meso/micro levels (71.4%); sociocultural context determinants at the meso/micro level, references to knowledge/beliefs/abilities of target groups (69.0%) and implementers (73.8%); political context determinants (interrelated policies supported in 71.4% of analyzed reviews/documents; policies within organizations, 69.0%). CONCLUSIONS: These findings indicate that sociocultural, economic, and political contexts need to be accounted for when formulating plans for the implementation of a healthy diet and physical activity/sedentary behavior policies.

Structural and Biofunctional Insights into the Cyclo(Pro-Pro-Phe-Phe-) Scaffold from Experimental and In Silico Studies: Melanoma and Beyond.

Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-ß3homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-ß2homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank-none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-ß3homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O…H/H…O and C…H/H…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.

Antiviral Activity of a Cyclic Pro-Pro-ß3-HoPhe-Phe Tetrapeptide against HSV-1 and HAdV-5.

The core of Cyclolinopeptide A (CLA, cyclo(LIILVPPFF)), responsible for its high immunosuppressive activity, contains a Pro-Pro-Phe-Phe sequence. A newly synthesized cyclic tetrapeptide, cyclo(Pro-Pro-ß3-HoPhe-Phe) (denoted as 4B8M) bearing the active sequence of CLA, was recently shown to exhibit a wide array of anti-inflammatory properties in mouse models. In this investigation, we demonstrate that the peptide significantly inhibits the replication of human adenovirus C serotype 5 (HAdV-5) and Herpes simplex virus type-1 (HSV-1) in epithelial lung cell line A-549, applying Cidofovir and Acyclovir as reference drugs. Based on a previously established mechanism of its action, we propose that the peptide may inhibit virus replication by the induction of PGE2 acting via EP2/EP4 receptors in epithelial cells. In summary, we reveal a new, antiviral property of this anti-inflammatory peptide.

New Advances in Short Peptides: Looking Forward.

It is beyond doubt that short peptides hold significant promise in bio-medicine, as the most versatile molecules, both structurally and functionally [...].

[Wartosc prognostyczna wskazników elektrokardiograficznych zawalu prawej komory w ocenie wewnatrzszpitalnego przebiegu klinicznego u chorych z rozpoznanym zawalem sciany dolnej leczonych interwencyjnie]. / Wartosc prognostyczna wskazników elektrokardiograficznych zawalu prawej komory w ocenie wewnatrzszpitalnego przebiegu klinicznego u chorych z rozpoznanym zawalem sciany dolnej leczonych interwencyjnie.

Myocardial infarction (MI) of the right ventricle (RV) coexists in 20- 60% of patients with inferior MI. There are electrocardiographic indicators which are connected with RV MI, which may also predict unfavorable clinical outcome of in-hospital follow-up. AIM: The aim of the study was determination a value of seven electrocardiographic predictors of RV MI in prognosis of in-hospital complications in patients with inferior MI. MATERIALS AND METHODS: The analysis of hospital files of patients admitted with diagnosis of inferior MI with persistent ST elevation (STEMI) was retrospectively performed. A set of seven RV MI predictors (RVMIP) was assessed from the electrocardiographic tracings (ECG). Finally in group of 167 patients relation between each RVMIP and in-hospital complications was statistically evaluated. RESULTS: The most often RVMIP was an elevation of ST higher in III lead then in II and aVF (RVMIP-2; recorded in 61,7% patients). In total any RVMIP was found in ECG of 142 patients (85%). Patients who had more RVMIP were more prone for combined adverse cardiac event (CACE, which included artificial respirotherapy, lungs edema and cardiogenic shock) (p=0,012); ventricular arrhythmias (p<0,001) and second/third grade atrioventricular blocks (p=0,028). Advanced atrioventricular blocks were more often observed in patient with ST elevation in V1 and ST depression in aVL (OR=4,91, p=0,005; OR=4,67, p=0,006; respectively). On the other hand second/third grade atrioventricular blocks were also related to higher incidence of CACE, ventricular arrhythmias and atrial fibrillation (AF), respectively: OR=8,1, p<0,001; OR=7,19, p=0,001; OR=5,75, p=0,001). CONCLUSIONS: The more RVMIPs the higher risk of in-hospital complication in patients with inferior MI. The second/third grade atrioventricular blocks were recorded more often in patients with ST elevation in V1 and ST depression in aVL. Advanced atrioventricular conduction blocks were related to worse outcome of in-hospital followup. A detailed ECG analysis in admission still adds important contribution in determination of in-hospital risk of complications.

Effects of Modifications on the Immunosuppressive Properties of Cyclolinopeptide A and Its Analogs in Animal Experimental Models.

The consequences of manipulations in structure and amino acid composition of native cyclolinopeptide A (CLA) from linen seeds, and its linear precursor on their biological activities and mechanisms of action, are reviewed. The modifications included truncation of the peptide chain, replacement of amino acid residues with proteinogenic or non-proteinogenic ones, modifications of peptide bond, and others. The studies revealed changes in the immunosuppressive potency of these analogs investigated in a number of in vitro and in vivo experimental models, predominantly in rodents, as well as differences in their postulated mechanism of action. The modified peptides were compared with cyclosporine A and parent CLA. Some of the synthesized and investigated peptides show potential therapeutic usefulness.

Solid-Phase Synthesis of an Insect Pyrokinin Analog Incorporating an Imidazoline Ring as Isosteric Replacement of a trans Peptide Bond.

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).

A Global Review on Short Peptides: Frontiers and Perspectives.

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

On the Neutrosophic, Pythagorean and Some Other Novel Fuzzy Sets Theories Used in Decision Making: Invitation to Discuss.

In this short paper, a critical analysis of the Neutrosophic, Pythagorean and some other novel fuzzy sets theories foundations is provided, taking into account that they actively used for the solution of the decision-making problems. The shortcomings of these theories are exposed. It is stated that the independence hypothesis, which is a cornerstone of the Neutrosophic sets theory, is not in line with common sense and therefore leads to the paradoxical results in the asymptotic limits of this theory. It is shown that the Pythagorean sets theory possesses questionable foundations, the sense of which cannot be explained reasonably. Moreover, this theory does not completely solve the declared problem. Similarly, important methodological problems of other analyzed theories are revealed. To solve the interior problems of the Atanassov's intuitionistic fuzzy sets and to improve upon them, this being the reason most of the criticized novel sets theories were developed, an alternative approach based on extension of the intuitionistic fuzzy sets in the framework of the Dempster-Shafer theory is proposed. No propositions concerned with the improvement of the Cubic sets theory and Single-Valued Neutrosophic Offset theory were made, as their applicability was shown to be very dubious. In order to stimulate discussion, many statements are deliberately formulated in a hardline form.

A Fuzzy Multiple Criteria Decision Making Approach with a Complete User Friendly Computer Implementation.

The paper presents the generalization of the almost forty years of experience in the field of setting and solving the multiple criteria decision-making (MCDM) problems in various branches of a human activity under different types of uncertainties that inevitably accompany such problems. Based only on the pragmatic intentions, the authors avoid the detailed descriptions of the known methods for the decision-making, while instead focusing on the most frequently used mathematical tools and methodologies in the decision-making practice. Therefore, the paper may be classified as a special kind of illustrative review of the mathematical tools that are focused on applications and are the most used in the solutions of MCDM problems. As an illustrative example, a complete user-friendly computer implementation of such tools and methodology is presented with application to the simple "buying a cat" problem, which, however, possesses all the attributes of the hierarchical fuzzy MCDM task.

The use of evaluation methods for the overall assessment of health policy: potential and limitations.

BACKGROUND: The implementation of public policies requires special attention from public authorities to ensure their transparency, effectiveness and efficiency. For this reason, efforts to evaluate the abovementioned politics gained attention and importance. Similar processes, by their very nature, are also noticeable in the area of health policy, however, the nature of the solutions used raises questions about the extent to which they allow to capture the assessed phenomenon in a holistic way. The current approach to the problem of evaluating health policy shows a tendency to break down this phenomenon into components including policies, programs or projects. The purpose of this publication was to assess the main methodological approaches used in evaluation studies in terms of their usefulness and limitations in conducting overall assessment of health policy. MAIN BODY: The publication divides evaluation methods based on three main criteria identified in the literature-time, purpose and scope of evaluation. Methodological approaches to evaluation activities detailed on this basis are discussed from the point of view of their characteristics, usefulness and limitations in the creation of comprehensive health policy assessments. The growing awareness of the need for a different approach to evaluation, which was confirmed by the course of the discourse on evaluation in public health, was also pointed out. CONCLUSION: Given the complexity of the matter making up the health policy, attempts aimed at its overall assessment should be based on an approach integrating many approaches, while ensuring coordination of evaluation activities that should be subject to common assumptions.

Baseline intrinsic heart rate and response to ivabradine treatment in patients with inappropriate sinus tachycardia.

BACKGROUND: Treatment with ivabradine became a new therapeutic alternative for patients with inappropriate sinus tachycardia (IST). The aim was to determine a relation between intrinsic heart rate (IHR) and response to ivabradine treatment. METHODS: Twenty-seven patients (mean age 37 ± 11; 23 women) with symptomatic IST despite medical treatment were recruited into the study. Resting ECG, 24-hr ECG monitoring (24hECG), exercise treadmill test, and symptoms evaluation were performed initially and after 60 days on ivabradine. IHR was acquired at baseline after pharmacological autonomic blockade. RESULTS: Nineteen patients (70%) were classified as abnormal IHR group (AIHR) while eight showed normal IHR (NIHR). No significant differences in ECG parameters were found between NIHR and AIHR subgroups, while baseline exercise capacity was higher in AIHR patients (10.9 vs. 9.5 METs, p < .05). Ivabradine treatment resulted in significant reduction in resting heart rate, average 24hECG heart rate, improvement in exercise capacity and reduction of symptoms in both subgroups. Nevertheless, favorable influence of ivabradine was significantly more exaggerated in AIHR subgroup (HR 116 vs. 90 bpm, av. HR 98 vs. 79 bpm, 10.9 vs. 13.6 METS, EHRA score 3.1 vs. 1.1, p < .001 for all) than in NIHR patients (HR 112 vs. 98 bpm, av. HR 97 vs. 88 bpm, 9.5 vs. 11.1 METs, EHRA score 3.1 vs. 1.9; p < .05 for all). CONCLUSIONS: Intrinsic heart rate may be useful in predicting response to ivabradine in patients with IST. More intense response to ivabradine in patients with AIHR may be attributed to different pathophysiological mechanisms underlying IST in AIHR and NIHR groups.

Conventional and alternative preimplantation ECG screening for subcutaneous ICD in high risk hypertrophic cardiomyopathy patients.

INTRODUCTION: Patients with hypertrophic cardiomyopathy (HCM) relatively often fail preimplantation ECG screening for subcutaneous implantable cardioverter-defibrillator (S-ICD). We aimed to evaluate impact of conventional and alternative ECG electrodes placement on eligibility for S-ICD implantation in HCM patients at high risk of sudden cardiac death (SCD). We hypothesized that modified electrodes placement will influence QRS-T morphology and thus it will increase S-ICD eligibility in the screening process. MATERIAL AND METHODS: This study enrolled 17 HCM patients at high risk of SCD (5-year SCD risk above 5%) referred for an ICD implantation. ECG screening for S-ICD eligibility in horizontal and vertical position was performed in each patient, in two different screening electrodes configuration: conventional (recommended by manufacturer) and alternative (precordial electrodes shifted rightwards and lateral electrodes dorsally). We evaluated QRS and T waves amplitude as well as T wave index. Primary, secondary and alternate sensing vectors were assessed. RESULTS: Preimplantation ECG screening with alternative electrodes placement resulted in more sensing vectors that were screened successfully (77 vs. 88, p = 0.05). Modified screening combined with a standard one allowed more patients to qualify for S-ICD implantation (17/17 vs. 12/17, p = 0.04). Electrocardiographically, the alternative positioning of ECG electrodes resulted in significant decrease in absolute values of QRS complex and T waves amplitudes in almost all sensing vectors, which was responsible for successful screening. CONCLUSIONS: The use of alternative placement of screening electrodes may be a valuable method to increase eligibility for S-ICD implantation in HCM patients at high risk of SCD.

A Supramolecular Approach to Structure-Based Design with A Focus on Synthons Hierarchy in Ornithine-Derived Ligands: Review, Synthesis, Experimental and in Silico Studies.

The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life. Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by in silico docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely N-α,N-δ)-dibenzoyl-(α)-hydroxymethylornithine, 1. It was investigated by modern experimental and in silico methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=O…π intercontacts have been identified in 1. Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by H…O, O…H, C…H, Cl (Br, F)…H and O…O interactions. Additionally, π…π, C-H…π and N-O…π interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons (Long-Range Synthon Aufbau Module) were considered. The DFT optimization either in vacuo or in solutio yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore, in silico prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative 1 has the potential to be a new drug candidate. It has shown good in silico absorption and very low toxicity.

A Simple View on the Interval and Fuzzy Portfolio Selection Problems.

In this paper, first we show that the variance used in the Markowitz's mean-variance model for the portfolio selection with its numerous modifications often does not properly present the risk of portfolio. Therefore, we propose another treating of portfolio risk as the measure of possibility to earn unacceptable low profits of portfolio and a simple mathematical formalization of this measure. In a similar way, we treat the criterion of portfolio's return maximization as the measure of possibility to get a maximal profit. As the result, we formulate the portfolio selection problem as a bicriteria optimization task. Then, we study the properties of the developed approach using critical examples of portfolios with interval and fuzzy valued returns. The α-cuts representation of fuzzy returns was used. To validate the proposed method, we compare the results we got using it with those obtained with the use of fuzzy versions of seven widely reputed methods for portfolio selection. As in our approach we deal with the bicriteria task, the three most popular methods for local criteria aggregation are compared using the known example of fuzzy portfolio consist of five assets. It is shown that the results we got using our approach to the interval and fuzzy portfolio selection reflect better the essence of this task than those obtained by widely reputed traditional methods for portfolio selection in the fuzzy setting.