AI-Driven De Novo Design and Molecular Modeling for Discovery of Small-Molecule Compounds as Potential Drug Candidates Targeting SARS-CoV-2 Main Protease.

Over the past three years, significant progress has been made in the development of novel promising drug candidates against COVID-19. However, SARS-CoV-2 mutations resulting in the emergence of new viral strains that can be resistant to the drugs used currently in the clinic necessitate the development of novel potent and broad therapeutic agents targeting different vulnerable spots of the viral proteins. In this study, two deep learning generative models were developed and used in combination with molecular modeling tools for de novo design of small molecule compounds that can inhibit the catalytic activity of SARS-CoV-2 main protease (Mpro), an enzyme critically important for mediating viral replication and transcription. As a result, the seven best scoring compounds that exhibited low values of binding free energy comparable with those calculated for two potent inhibitors of Mpro, via the same computational protocol, were selected as the most probable inhibitors of the enzyme catalytic site. In light of the data obtained, the identified compounds are assumed to present promising scaffolds for the development of new potent and broad-spectrum drugs inhibiting SARS-CoV-2 Mpro, an attractive therapeutic target for anti-COVID-19 agents.

Five-year yield variation in N-nitrosonornicotine and (4-methylnitrosoamino)-1-(3-pyridyl)-1-butanone from the smoke of commercial cigarette brands on the Japanese market.

This study reports on variation in the yields of N-nitrosonornicotine (NNN) and (4-methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) from the mainstream smoke of cigarette brands and describes factors affecting this variation. Yields of NNN and NNK from smoke and tobacco filler, which is blended and cut tobacco filled in a cigarette tube, together with cigarette design parameters, were measured for 11 commercial cigarette brands, which were available in Japan from 2009 to 2013. The ranges of the relative standard deviations (RSDs) for NNN from the smoke of each brand were 5.0%-29.9% under International Organization for Standardization (ISO) and 6.3%-26.3% under Health Canada Intense (HCI) smoking regime. When these RSDs were compared with those of tar, nicotine, and carbon monoxide yields in each brand, they were found to be much higher for all of the brands under the HCI, and higher for most of the brands under the ISO smoking regime. In addition, the RSDs of NNN and NNK in smoke were mostly higher than those of KY3R4F which was manufactured in a single batch. It was identified that variation in NNN yields from tobacco filler mainly contribute to variation in NNN yields from smoke.

Estimation of mouth level exposure to smoke constituents of cigarettes with different tar levels using filter analysis.

A nicotine part-filter method can be applied to estimate smokers' mouth level exposure (MLE) to smoke constituents. The objectives of this study were (1) to generate calibration curves for 47 smoke constituents, (2) to estimate MLE to selected smoke constituents using Japanese smokers of commercially available cigarettes covering a wide range of International Organization for Standardization tar yields (1-21mg/cigarette), and (3) to investigate relationships between MLE estimates and various machine-smoking yields. Five cigarette brands were machine-smoked under 7 different smoking regimes and smoke constituents and nicotine content in part-filters were measured. Calibration curves were then generated. Spent cigarette filters were collected from a target of 50 smokers for each of the 15 brands and a total of 780 filters were obtained. Nicotine content in part-filters was then measured and MLE to each smoke constituent was estimated. Strong correlations were identified between nicotine content in part-filters and 41 out of the 47 smoke constituent yields. Estimates of MLE to acetaldehyde, acrolein, 1,3-butadiene, benzene, benzo[a]pyrene, carbon monoxide, and tar showed significant negative correlations with corresponding constituent yields per mg nicotine under the Health Canada Intense smoking regime, whereas significant positive correlations were observed for N-nitrosonornicotine and (4-methylnitrosoamino)-1-(3-pyridyl)-1-butanone.

Evaluation of functional relationships for predicting mainstream smoke constituent machine yields for conventional cigarettes from the Japanese market.

The objective of this study was to predict mainstream smoke constituent yields for conventional filter cigarette brands on sale in Japan between 2004 and 2005. Mainstream smoke was generated under ISO machine smoking conditions. Developed functional relationships indicate the validity of benchmarking even for a market which is characterized by a diversity of tobacco blend types. Smoke yields were in general well predicted by linear regression with "tar" (R2>or=0.7). Blend-type-sensitive analytes like tobacco-specific nitrosamines showed improved prediction relationships after blend stratification or regressing against nitric oxide (NO, R(2)>0.7). Relationships calculated from 83 exploratory brands were validated with a subset of 23 validation brands. Seventy-five to one-hundred percent of the validation brand yields were inside the 95% prediction intervals. The mean-relative prediction error over all analytes was 24% after stratification. Smoke constituents yields analyzed in 2002 from 96 Japanese market products were well predicted and indicate the model validity over time. Similar relationships were observed when comparing American blended filter cigarette yields from Japan and worldwide markets. Consistent with reported results from previous benchmark studies and market surveys mainstream smoke constituent yields are well predictable when "tar" (and NO) yields are known.

Serum Th1 and Th2 profile cytokine level changes in patients with Graves' ophthalmopathy treated with corticosteroids.

The aim of this study was to estimate the influence of corticosteroids on Th1 and Th2 serum cytokine balance in patients with GO: IFNgamma, TNFalpha, IL-4 and IL-10. Further, we tested the hypothesis of an up-regulation of Th2 immune response during successful treatment with corticosteroids to explain their beneficial effect in Graves' ophthalmopathy. Serum cytokines were detected in three groups of subjects: 20 patients with Graves' disease without ophthalmopathy (Gd), 16 patients with clinical symptoms of ophthalmopathy (GO) (CAS over 3 points, last consultation record for GO less than a year old) and 16 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methylprednisolone (MP) (2 series, 3 g each time) and subsequent treatment with oral prednisone (60 mg per day) in a tapering schedule. The serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of treatment with prednisone and at the end of corticosteroid therapy. The levels of IFNgamma, TNFalpha, IL-4 and IL-10 in the serum were determined using ELISA. Statistical significance was estimated by the Mann-Whitney U-test. Our findings show a deviation to systemic Th2 profile cytokines in Graves' disease. In patients with GO, we found a significantly increased serum IL-10 concentration. In corticosteroid-responsive patients, the balance of serum cytokines IL-4/IFNgamma, IL-4/TNFalpha, IL-10/IFNgamma and IL-10/TNFalpha increased and remained upregulated until the end of the study. In non-responders, the balance of serum cytokines studied increased after methylprednisolone but declined markedly during continuation of the therapy with prednisone. In summary, our results show that efficient corticosteroid therapy may be related to its influence on Th2/Th1 profile cytokine balance. The upregulation of serum IL-4 and IL-10 during successful treatment with corticosteroids indicate the possibility of using these cytokines as predictors of the beneficial effect of corticosteroids in Graves' ophthalmopathy.

Serum L-selectin and ICAM-1 in patients with Graves' ophthalmopathy during treatment with corticosteroids.

UNLABELLED: Circulating forms of L-selectin were found to be elevated in several autoimmune diseases. ICAM-1 has been suggested a predictor of the onset of GO. The aim of the study was an estimation of serum L-selectin and ICAM-1 in patients with Graves' disease with ophthalmopathy during treatment with corticosteroids to assess their potential as a guideline of immunosuppressive therapy. We detected serum L-selectin and ICAM-1 in three groups of subjects: 20 patients with Graves' disease without ophthalmopathy (Gd), 17 patients with clinical symptoms of ophthalmopathy (CAS> or =3, anamnesis of GO> or =1 year) and 24 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methyloprednisolone (MP) and subsequent treatment with oral prednisone (P). The serum samples were collected 24 h before MP, 24 h after MP, 12+/-2 days of treatment with prednisone and after the end of the corticosteroid therapy. The levels of soluble L-selectin and ICAM-1 in the serum were determined by the ELISA method. The statistical significance was estimated by the Mann-Whitney U-test. Serum L-selectin and ICAM-1 were significantly increased in patients with GO (respectively 1182+/-222 and 438+/-68 ng/ml) and in patients with Graves' disease without ophthalmopathy (respectively: 1168+/-130 and 343+/-109) in relation to the controls. After MP treatment in corticosteroid-responsive patients (improvement in CAS < or =1) serum concentration of L-selectin and ICAM-1 decreased significantly and gradually increased during subsequent treatment with prednisone. In corticosteroid-responsive patients serum L-selectin was significantly higher before MP administration and after P treatment in relation to corticosteroid-resistant subjects. CONCLUSIONS: 1. Serum L-selectin and ICAM-1 were elevated in patients with active GO 2. Methyloprednisolone decreased levels of the studied adhesion molecules in corticosteroid-responsive patients with GO 3. Lack of clinical results in corticosteroid therapy in patients with a low starting L-selectin level would suggest the possibility of serum L-selectin estimation as a prognostic for immunotherapy efficacy.

Psychological effect of the Nagasaki atomic bombing on survivors after half a century.

In 1997 a mental health survey using a 30-item General Health Questionnaire (GHQ-30) and an interview survey of an atomic bombing experience were conducted in survivors of the Nagasaki atomic bombing. Overall psychological distress measured on the basis of the GHQ-30 was greater in the atomic bombing survivors than in the controls. As for the contents of psychological distress, those concerning emotion such as anxiety and depression were milder in survivors than in the controls, but those related to social activities such as apathy, disturbance of human relations, loss of enjoyment of living were more severe. Furthermore, recurring and distressing recollection of the experience of the atomic bombing, suspicion over the relationship between the atomic bombing and an unhealthy physical condition, and the experience of witnessing death or severe injury of close relatives due to the atomic bombing were significantly related to the degree of psychological distress of the survivors.

Serum pro- and anti-inflammatory cytokines in patients with Graves' disease with ophthalmopathy during treatment with glucocorticoids.

UNLABELLED: The aim of the study was to estimate serum pro-inflammatory cytokines concentration: TNF alpha and IL-6 as well as anti-inflammatory cytokine levels: IL-10 and IL-1ra in patients with Graves' disease and ophthalmopathy before and during glucocorticoid therapy. Serum cytokines were detected in three groups of subjects: 20 patients with Graves' disease without ophthalmopathy (GD), 17 patients with clinical symptoms of ophthalmopathy (GO) (CAS > or = 3, anamnesis of GO > or = 1 yr) and 24 healthy volunteers. Glucocorticoid therapy consisted of intravenous infusions of methyloprednisolone (MP) (2 series, 3 grams each time) and subsequent treatment with oral prednisone (60 mg per day) in a tapering schedule. The serum samples were collected 24 hours before MP, 24 hours after MP, 12 +/- 2 days of treatment with prednisone and at the end of glucocorticoid therapy. The levels of TNF alpha, IL-6, IL-10 and IL-1ra in the serum were determined by the ELISA method. The statistical significance was estimated by the Mann-Whitney U-test. Serum IL-6 level was increased in patients with GO in comparison to the controls and did not change significantly after immunosuppressive treatment. We did not find any significant differences of serum TNF alpha between the studied groups and glucocorticoids did not change its level significantly. Serum IL-10 was elevated significantly both in patients with GD and GO in comparison to the control group. IL-10 levels increased significantly after glucocorticoids. IL-1ra level was significantly higher in patients with GO. In the GO group we found an increase of IL-1ra after MP treatment and its gradual decline during prednisone therapy. CONCLUSIONS: 1. The production of both: pro- and anti-inflammatory cytokines is increased in infiltrative Graves' ophthalmopathy 2. Efficient glucocorticoid therapy may be related to its influence on anti-inflammatory cytokines: IL-10 and IL-1ra.

[Physiology and pathology of tear film in the course of dry eye syndrome]. / Fizjologia i patologia filmu lzowego w przebiegu zespolu suchego oka.

Due to the grow-up of number of patients suffering from signs of dry-eye syndrome we are obligated to investigate physiology and pathology of tear film. Data obtained from patients with Sjögren Syndrome and other types of lacrimal dysfunction shows that the expectations for break-up in dry-eye treatment strategy are very high. In our review we are presenting contemporary views concerning tear film production and tear deficiency with special look at the treatment possibilities.

[Incidence of cataract and risk factors in Northeastern Poland]. / Wystepowanie zacmy i czynniki jej ryzyka w pólnocno-wschodnim regionie Polski.

PURPOSE: Retrospective analysis of the incidence and risk factors of senile and pre-senile cataract in patients from North-East Region of Poland, operated on cataract in the years 1986-1995. MATERIAL AND METHODS: In the analysed decade, 6038 patients were operated on cataract in the Ophthalmology Department of the Clinical Hospital and Ophthalmology Department of the District Hospital in Bialystok. There were 2603 males and 3435 females, mean age amounted to 69 +/- 11 years. 44% of the patients came from rural communities (560.000 inhabitants in the region), whereas 56% of the patients were of urban province (796.000 inhabitants). Statistical analysis was performed on such variables like age, gender, place of residence, cataract history and presence of concomitant diseases: arterial hypertension, diabetes, lung and joints disorders, intestinal diseases. RESULTS AND CONCLUSIONS: Residence in rural communities increases the risk of cataract, although the condition in this environment tends to develop in older age. Gender distribution of the patients does not differ from male/female ratio in the population of the region, so both genders are exposed to similar risk of cataract. Females contract cataract in older age, on average about 3 years later than males. Age is the most important risk factor of cataract; 52% of the patients are older than 70, 43% are in the age of 51-70 years. Mean value of duration of cataract history before operation decreased during the analysed 10 years from 3.8 years in 1986 to 2.2 years in 1995. In 14% of patients cataract coexisted with arterial hypertension, in 8% with diabetes, and in 15% with other diseases. During the analysed 10 years period the number of patients with cataract increased in the same degree in all examined communities. The mean age of patients operated on cataract decreased in this period by 2 years in spite of increasing number of patients older than 75 years. This result can be explained by the fact that the disease tends now to develop earlier and by concomitant decreasing of the time between onset of the disease and decision for operation.

[Sensory vision tests in neuro-ophthalmology]. / Sensoryczne testy wzrokowe w neurookulistyce.

Contemporary views on assessment of visual function were presented. The tests feature high sensitivity and possibility of quantitative evaluation of visual abnormality.

Operation for chronic dislocation of the radial head in children. Reduction by osteotomy of the ulna.

Nine children with chronic post-traumatic dislocation of the head of the radius were treated by an osteotomy of the ulna with over-correction of the angular deformity and with elongation of the bone. Satisfactory results were obtained in eight cases, the only poor outcome following a three-year delay between the initial injury and the reposition. The interosseous membrane of the forearm appeared to be the most important structure in maintaining the corrected position of the radial head.

[50-year experience with the surgical treatment of goiter in the Transcarpathian region]. / Piatidesiatiletnii opyt khirurgicheskogo lecheniia zoba v Zakarpat'e.

The article generalizes experience with the surgical treatment of 1988 patients with different diseases of the thyroid gland. Indications for the surgical treatment, special preoperative management, choosing the anesthesia, methods and technique of the operation are discussed.

[Patient rehabilitation following the surgical treatment of gastric and duodenal peptic ulcer]. / Reabilitatsiia bol'nykh posle khirurgicheskogo lecheniia iazvennoi bolezni zheludka i dvenadtsatiperstnoi kishki.

On the basis of observation of the ulcer disease of the stomach and duodenum in 970 patients given the restorative treatment in rehabilitation hospitals after being discharged from the surgical hospital the authors recommend the earlier rehabilitative treatment since it gives more rapid reestablishment of their working capacity.