Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies.

We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.

First Report of the Root-Knot Nematode Meloidogyne luci on Tomato in Serbia.

Root-knot nematode (RKN) Meloidogyne luci Carneiro, Correa, Almeida, Gomes, Deimi, Castagnone-Sereno, and Karssen, 2014 was described from Brazil, Chile and Iran, parasitizing in various crops (Carneiro et al. 2014). It was later also described from Slovenia, Italy, Greece, Portugal, Turkey and Guatemala (review in Geric Stare et al. 2017). It is considered an extremely damaging pest as it has a wide host range and infects numerous higher plants, including monocotyledons and dicotyledons as well as herbaceous and woody plants. This species was included in the European Plant Protection Organisation Alert List of harmful organisms. In Europe, M. luci has been detected in both greenhouse and field agricultural production (review in Geric Stare et al. 2017). Furthermore, M. luci has been shown to survive winter in the field under continental and sub-Mediterranean climatic conditions (Strajnar et al. 2011). In August 2021, an official survey for quarantine RKN in Serbia (Province Vojvodina) revealed in a greenhouse in the village of Lugovo (43043'32,562; 19008'55,168), near Sombor, yellowing, stunning and extensive root galls on tomato (Solanum lycopersicum L.) cultivar Diva F1 caused by an unknown Meloidogyne sp. (Fig. 1). As correct identification is essential for effective pest management program, the next step was to identify the nematode species. Morphological characterization performed on freshly isolated females revealed perineal patterns similar to M. incognita (Kofoid and White, 1919) Chitwood, 1949. The shape was oval to squarish with the dorsal arch rounded to moderately high and without shoulders. The dorsal striae were wavy and continuous. The ventral striae were smooth and the lateral lines were weakly demarcated. The perivulval region was without striae (Fig. 2). The female stylet was robust with well-developed knobs and the stylet cone slightly curved dorsally. Although morphological characters was very variable, the nematode was suspected as M. luci based on comparison with originally described M. luci and M. luci populations from Slovenia, Greece and Turkey. Identification was achieved with subsequent species-specific PCR and sequence analysis. The nematode was determined to belong to the tropical RKN group and the M. ethiopica group using two PCR reactions as described by Geric Stare et al. (2019) (Figs. 3 and 4). Identification was confirmed by species-specific PCR of M. luci as described by Maleita et al. (2021), and a band of approximately 770 bp was obtained (Fig. 5). In addition, the identification was confirmed by sequence analyses. The region of mtDNA was amplified with primers C2F3 and 1108 (Powers and Harris 1993), cloned, sequenced (acc. no. OQ211107), and compared to other Meloidogyne spp. sequences from the Genbank. The determined sequence is 100% identical to an unidentified Meloidogyne sp. from Serbia, while the next highest scores are sequences of M. luci from Slovenia, Greece and Iran, all of which have 99.94% sequence identity. In phylogenetic tree, all M. luci sequences including the sequence from Serbia belong to a single clade. Egg masses isolated from infected tomato roots were used to establish a nematode culture in greenhouse and they caused typical root galls on cultivar Maraton of tomato. The galling index assessed 110 days-post-inoculation was in the range 4-5 according to the scoring scheme (1-10) for field evaluation of RKN infestations (Zeck 1971). To our knowledge, this is the first report of M. luci in Serbia. The authors hypothesize that climate change and higher temperatures could lead to much greater spread and damage to various agricultural crops in the field by M. luci in the future. National surveillance program for RKN in Serbia continued in 2022 and 2023. A management program to control the spread and damage from M. luci will be implemented in Serbia in 2023. Acknowledgments: This work was financially supported by the Serbian Plant Protection Directorate of MAFWM in the frame of Program of Measures in Plant Health in 2021, the Slovenian Research Agency in the frame of Research Programme Agrobiodiversity (P4-0072) and the Ministry of Agriculture, Forestry and Food of the Republic of Slovenia in the frame of Expert work in the field of plant protection (C2337).

Deep Learning Based SWIR Object Detection in Long-Range Surveillance Systems: An Automated Cross-Spectral Approach.

SWIR imaging bears considerable advantages over visible-light (color) and thermal images in certain challenging propagation conditions. Thus, the SWIR imaging channel is frequently used in multi-spectral imaging systems (MSIS) for long-range surveillance in combination with color and thermal imaging to improve the probability of correct operation in various day, night and climate conditions. Integration of deep-learning (DL)-based real-time object detection in MSIS enables an increase in efficient utilization for complex long-range surveillance solutions such as border or critical assets control. Unfortunately, a lack of datasets for DL-based object detection models training for the SWIR channel limits their performance. To overcome this, by using the MSIS setting we propose a new cross-spectral automatic data annotation methodology for SWIR channel training dataset creation, in which the visible-light channel provides a source for detecting object types and bounding boxes which are then transformed to the SWIR channel. A mathematical image transformation that overcomes differences between the SWIR and color channel and their image distortion effects for various magnifications are explained in detail. With the proposed cross-spectral methodology, the goal of the paper is to improve object detection in SWIR images captured in challenging outdoor scenes. Experimental tests for two object types (cars and persons) using a state-of-the-art YOLOX model demonstrate that retraining with the proposed automatic cross-spectrally created SWIR image dataset significantly improves average detection precision. We achieved excellent improvements in detection performance in various variants of the YOLOX model (nano, tiny and x).

DIRECTION: a machine learning framework for predicting and characterizing DNA methylation and hydroxymethylation in mammalian genomes.

MOTIVATION: 5-Methylcytosine and 5-Hydroxymethylcytosine in DNA are major epigenetic modifications known to significantly alter mammalian gene expression. High-throughput assays to detect these modifications are expensive, labor-intensive, unfeasible in some contexts and leave a portion of the genome unqueried. Hence, we devised a novel, supervised, integrative learning framework to perform whole-genome methylation and hydroxymethylation predictions in CpG dinucleotides. Our framework can also perform imputation of missing or low quality data in existing sequencing datasets. Additionally, we developed infrastructure to perform in silico, high-throughput hypotheses testing on such predicted methylation or hydroxymethylation maps. RESULTS: We test our approach on H1 human embryonic stem cells and H1-derived neural progenitor cells. Our predictive model is comparable in accuracy to other state-of-the-art DNA methylation prediction algorithms. We are the first to predict hydroxymethylation in silico with high whole-genome accuracy, paving the way for large-scale reconstruction of hydroxymethylation maps in mammalian model systems. We designed a novel, beam-search driven feature selection algorithm to identify the most discriminative predictor variables, and developed a platform for performing integrative analysis and reconstruction of the epigenome. Our toolkit DIRECTION provides predictions at single nucleotide resolution and identifies relevant features based on resource availability. This offers enhanced biological interpretability of results potentially leading to a better understanding of epigenetic gene regulation. AVAILABILITY AND IMPLEMENTATION: http://www.pradiptaray.com/direction, under CC-by-SA license. CONTACTS: pradiptaray@gmail.com or mchen@utdallas.edu or michael.zhang@utdallas.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Disulfiram moderately restores impaired hepatic redox status of rats subchronically exposed to cadmium.

Examination of cadmium (Cd) toxicity and disulfiram (DSF) effect on liver was focused on oxidative stress (OS), bioelements status, morphological and functional changes. Male Wistar rats were intraperitoneally treated with 1 mg CdCl2/kg BW/day; orally with 178.5 mg DSF/kg BW/day for 1, 3, 10 and 21 days; and co-exposed from 22nd to 42nd day. The co-exposure nearly restored previously suppressed total superoxide dismutase (SOD), catalase (CAT) and increased glutathione peroxidase (GPx) activities; increased previously reduced glutathione reductase (GR) and total glutathione-S-transferase (GST) activities; reduced previously increased superoxide anion radical (O2·-) and malondialdehyde (MDA) levels; increased zinc (Zn) and iron (Fe), and decreased copper (Cu) (yet above control value), while magnesium (Mg) was not affected; and decreased serum alanine aminotransferases (ALT) levels. Histopathological examination showed signs of inflammation process as previously demonstrated by exposure to Cd. Overall, we ascertained partial liver redox status improvement, compared with the formerly Cd-induced impact.

Epidermotropic B-Cell Lymphoma: A Unique Subset of CXCR3-Positive Marginal Zone Lymphoma.

BACKGROUND: Epidermotropic B-cell lymphoma is a very rare entity that has primarily been reported in the literature as anecdotal case reports. The majority of the reported cases exhibit a diffuse skin rash affecting middle-aged to older adults with a male predominance. The exact mechanism of marginal zone B-cell localization to the epidermis is unclear. MATERIAL AND METHODS: To describe a very rare subset of cutaneous B-cell lymphoma and explore potential pathogenetic mechanisms for the epidermotropic tendency, the hospital database and literature review was conducted to isolate cases of epidermotropic B-cell lymphoma. Routine hematoxylin and eosin stain followed by selective phenotypic studies. RESULTS: Two of the cases were encountered in the hospital database, whereas 5 cases have been previously reported; material was requested on previously reported cases and was received on 3 of them. In one of the 2 cases encountered in our database, the patient presented with a progressive skin rash over 7 months resembling pityriasis rosea. Subsequent to a diagnosis of B-cell lymphoma, further staging revealed bone marrow involvement. The other patient, an elderly female, presented with isolated nodules. The biopsies of both cases showed areas of superficial band-like lymphocytic infiltration with large monocytoid appearance and an epidermotropic pattern of lymphocyte migration into the epidermis. Neoplastic cells were extensively positive for CD20, CD79a, and BCL-2 and negative for CD10 and BCL-6. Of interest, a similar pityriasis rosea-like presentation was encountered in the cases reported in the literature. All patients were elderly males with established bone marrow, peripheral blood, and spleen involvement several months to years after the initial cutaneous presentation in 3 of them. None of the patients to date have died of lymphoma. CXCR3 epidermotropic B cells were detected in both our cases and in 3 of the 3 previously published cases. CONCLUSIONS: Epidermotropic B-cell lymphoma represents a subset of marginal zone lymphoma characterized by a papulosquamous rash most frequently resembling pityriasis rosea, occurring almost exclusively in older males. We speculate that aberrant expression of CXCR3 in marginal zone lymphoma of the skin is associated with migration of lymphoma cells to the epidermis and could lead to an epidermotropic pattern given the known role of CXCR3 expression in neoplastic T cells in the localization of mycosis fungoides to the epidermis. There is a tendency toward bone marrow, spleen, and peripheral blood involvement.

[Drug Treatment of Chronic Venous Diesease]. / Medikamentöse Behandlung chronischer Venenerkrankungen.

Chronic venous disease (CVD) affects at least 15-25 % of the general population incurring not only high morbidity but also considerable economical burden. The mainstay of modern treatment of CVD are endovenous therapeutic procedures and compression therapy. As far as the pathogenesis of CVD is being gradually unraveled the interest in drugs able to impact the process is growing. Here we have presented an overview of a majority of oral preparations used so far to treat CVD including venous leg ulcers. After several decades of clinical use a few flavonoid preparations, in the first place micronized purified flavonoid fraction, collected enough evidence to recommend them as a short-term adjunct treatment of CVD. However, other compounds are also promising in this regards. Yet, we need more larger and longer-term clinical trials to more precisely define effects, cost-effectiveness and, above all, capacity for prophylactic application of the drugs. Learning more about basis of CVD will help design new drugs directed at specific aspects of the disease process.

Widespread dermatophytosis in a healthy adolescent: the first report of multidrug-resistant Trichophyton indotineae infection in the UAE.

A multidrug-resistant dermatophyte species recently arose in India, first described as terbinafine-resistant Trichophyton interdigitale and soon given a separate name: T. indotineae. Thanks to its treatment recalcitrance, person-to-person spread, and frequent travel, before long it was identified in many countries on all continents. We describe here the case of a boy with widespread, extremely pruritic, inflammatory dermatophytosis affecting his face, neck, trunk, and extremities, unsuccessfully treated for months with oral terbinafine and fluconazole and a range of topical antimycotics. Qualitative polymerase chain reaction of skin scrapings from his lesions identified a T. interdigitale complex fungus, highly probably T. indotineae due to conspecificity and antifungal resistance. Oral itraconazole, administered over 8 weeks, cleared the infection. Because the patient had not traveled outside the United Arab Emirates for months before the infection became obvious, it must have been acquired from a local source.

Safety and effectiveness of indirect radiofrequency ablation (closure FAST) of incompetent great saphenous veins with Type I aneurysms: Long-term results radiofrequency ablation for saphenous aneurysms.

BACKGROUND: Assess the safety and effectiveness of indirect radiofrequency ablation (RFA, Closure FAST) for the treatment of incompetent great saphenous veins (GSVs) with type 1 aneurysms. METHODS: This was a retrospective analysis performed in three centers (2007-2021). All patients presenting with saphenous aneurysms close to the junction (within 2 cm) were included. They were treated with RFA. Phlebectomies and/or sclerotherapy were performed during the same treatment session. Duplex ultrasound (DUS) was performed early after the procedure and then, more than a year later. RESULTS: Eight patients (11 limbs) were included between June 2007 and May 2021 with a median diameter of the GSV aneurysm 21 mm (IQR 17.2-23.4). No severe adverse events occurred apart from one endovenous heat-induced thrombosis (EHIT) class III (9.1%). After more than a year (mean 7.2 ± 4.2, median 8 years), none of the aneurysms was present on DUS and the truncal obliteration rate was 100%. CONCLUSION: RFA appears to be a safe and effective treatment for patients presenting with incompetent saphenous veins with the type 1 aneurysm.

Eruptive facial lentiginosis-like repigmentation in a patient with longstanding generalized vitiligo without a detectable trigger.

Spontaneous appearance of hyperpigmented macules on chronic vitiligo lesions is a very rare phenomenon, which is described as eruptive lentiginosis. We describe the case of a patient with chronic non-segmental generalized vitiligo who presented with a sudden onset of hyperpigmented macules on depigmented areas of the face. A biopsy showed pigmented basal keratinocytes in the interfollicular epidermis, and immunohisochemistry with anti-SOX10 antibodies showed nuclei of single melanocytes. This case shows that even long-standing depigmented vitiligo lesions may contain functional melanocytes or their precursors.

COVID-19 susceptibility and severity risks in a cross-sectional survey of over 500 000 US adults.

OBJECTIVES: The enormous toll of the COVID-19 pandemic has heightened the urgency of collecting and analysing population-scale datasets in real time to monitor and better understand the evolving pandemic. The objectives of this study were to examine the relationship of risk factors to COVID-19 susceptibility and severity and to develop risk models to accurately predict COVID-19 outcomes using rapidly obtained self-reported data. DESIGN: A cross-sectional study. SETTING: AncestryDNA customers in the USA who consented to research. PARTICIPANTS: The AncestryDNA COVID-19 Study collected self-reported survey data on symptoms, outcomes, risk factors and exposures for over 563 000 adult individuals in the USA in just under 4 months, including over 4700 COVID-19 cases as measured by a self-reported positive test. RESULTS: We replicated previously reported associations between several risk factors and COVID-19 susceptibility and severity outcomes, and additionally found that differences in known exposures accounted for many of the susceptibility associations. A notable exception was elevated susceptibility for men even after adjusting for known exposures and age (adjusted OR=1.36, 95% CI=1.19 to 1.55). We also demonstrated that self-reported data can be used to build accurate risk models to predict individualised COVID-19 susceptibility (area under the curve (AUC)=0.84) and severity outcomes including hospitalisation and critical illness (AUC=0.87 and 0.90, respectively). The risk models achieved robust discriminative performance across different age, sex and genetic ancestry groups within the study. CONCLUSIONS: The results highlight the value of self-reported epidemiological data to rapidly provide public health insights into the evolving COVID-19 pandemic.

Expanded COVID-19 phenotype definitions reveal distinct patterns of genetic association and protective effects.

Multiple COVID-19 genome-wide association studies (GWASs) have identified reproducible genetic associations indicating that there is a genetic component to susceptibility and severity risk. To complement these studies, we collected deep coronavirus disease 2019 (COVID-19) phenotype data from a survey of 736,723 AncestryDNA research participants. With these data, we defined eight phenotypes related to COVID-19 outcomes: four phenotypes that align with previously studied COVID-19 definitions and four 'expanded' phenotypes that focus on susceptibility given exposure, mild clinical manifestations and an aggregate score of symptom severity. We performed a replication analysis of 12 previously reported COVID-19 genetic associations with all eight phenotypes in a trans-ancestry meta-analysis of AncestryDNA research participants. In this analysis, we show distinct patterns of association at the 12 loci with the eight outcomes that we assessed. We also performed a genome-wide discovery analysis of all eight phenotypes, which did not yield new genome-wide significant loci but did suggest that three of the four 'expanded' COVID-19 phenotypes have enhanced power to capture protective genetic associations relative to the previously studied phenotypes. Thus, we conclude that continued large-scale ascertainment of deep COVID-19 phenotype data would likely represent a boon for COVID-19 therapeutic target identification.

Rapid dermoscopic evolution of a Spitz nevus in an adult masquerading as melanoma.

Spitz nevi in adults should be closely monitored. Dermoscopy is the preferred method of in vivo imaging of melanocytic nevi and may provide clues for high-risk lesions. However, there is not a perfect match between the dermoscopic image of an individual nevus, the evolution of its change, and its histopathology. We present a case of a rapidly (over months) changing and growing nevus in an adult patient with dermoscopy suggesting a melanoma but eventually with a histology of a Spitz nevus with an accompanying immune reaction.

Drug-induced pruritic micropapular eruption: anastrozole, a commonly used aromatase inhibitor.

Anastrozole, a selective nonsteroidal aromatase inhibitor is widely used as an adjuvant therapy for postmenopausal women with early hormone-sensitive breast cancer. There are few reports on cutaneous side effects of anastrozole. It may induce subacute cutaneous lupus erythematosus, erythema nodosum, cutaneous vasculitis, and nondescript skin eruptions. A 68-year-old woman was prescribed anastrozole after surgical removal of her breast cancer and adjuvant radiation therapy. Two months later she experienced a generalized pruritic micropapular eruption. History, clinical presentation, histology and inadvertent re-exposure to the drug confirmed that anastrozole triggered the exanthem. Pruritic micropapular eruption is a typical pattern for a drug hypersensitivity reaction. Anastrozole should be added to the list of medications able to induce not only non-specific eruptions but the type of exanthem typically triggered by drugs.

Initial healing rates as predictive factors of venous ulcer healing: the use of a laser-based three-dimensional ulcer measurement.

There is a need for practical methods to predict the healing time of venous leg ulcers. In a prospective cohort study of 81 patients with venous leg ulcers, we used a recently described laser-based three-dimensional measurement of the ulcers at days 0 and 28 to estimate the predictive power of horizontal (HIHR) and vertical initial healing rates (VIHR) for wound healing by week 24. The rates were calculated by Gilman's equation [(A(1)-A(2))/((p(1)+p(2))/2)((0-4))] and by its modification [(V(1)-V(2))/((A(1)+A(2))/2)((0-4))], respectively. The influence of risk factors on both the initial healing rates was also studied. The HIHR and VIHR are important predictors of healing at 24 weeks. They are not influenced by age, ulcer duration, initial ulcer area, and insufficient sapheno-femoral junction, and/or calf perforating veins. Together with ulcer duration, they are independent predictors of the 24-week healing (the area under ROC curve equals to 0.9). VIHR gives us additional information and significantly improves the prediction of 24-week healing.

Periodontal disease in children and adolescents with type 1 diabetes in Serbia.

BACKGROUND: The purpose of this study was to evaluate periodontal health in young patients with type 1 diabetes mellitus in Serbia. METHODS: Periodontal disease was clinically assessed and compared in 187 children and adolescents (6 to 18 years of age) with type 1 diabetes mellitus and 178 control subjects without diabetes. RESULTS: Children and adolescents with type 1 diabetes mellitus had significantly more plaque, gingival inflammation, and periodontal destruction than control subjects. The main risk factors for periodontitis were diabetes (odds ratio [OR] = 2.78; 95% confidence interval [CI]: 1.42 to 5.44), bleeding/plaque ratio (OR = 1.25; 95% CI: 1.06 to 1.48), and age (OR = 1.10; 95% CI: 1.01 to 1.21). In case subjects, the number of teeth affected by periodontal destruction was associated with mean hemoglobin A1c (regression coefficient 0.17; P = 0.026), duration of diabetes (regression coefficient 0.19; P = 0.021), and bleeding/plaque ratio (regression coefficient 0.17; P = 0.021). CONCLUSIONS: Compared to children and adolescents without diabetes, periodontal disease is more prevalent and widespread in children and adolescents with type 1 diabetes mellitus and depends on the duration of disease, metabolic control, and the severity of gingival inflammation. Gingival inflammation in young patients with diabetes is more evident and more often results in periodontal destruction.

Cervical fluid cytokines in pregnant women: Relation to vaginal wet mount findings and polymorphonuclear leukocyte counts.

OBJECTIVE: The purpose of the study was to measure and compare concentrations of IFN-gamma, IL-8, IL-10 and IL-12 in cervical fluids of pregnant women with normal and pathologic microscopic findings of vaginal wet mount. STUDY DESIGN: Vaginal samples were obtained from 100 pregnant women (22-32 weeks of gestation) without signs and symptoms of preterm labour (PTL), selected on the basis of the microscopic examination of vaginal wet mounts. Cytokine (IFN-gamma, IL-8, IL-10 and IL-12) concentrations were measured in cervical fluids by an enzyme-linked immunosorbent assay. RESULTS: The cytokines were found in cervical fluids of the majority of pregnant women, with IFN-gamma and IL-8 detected in all samples. Concentrations of IL-8 were significantly higher in pregnant women with pathologic findings on vaginal wet mount, including elevated polymorphonuclear (PMN) cell counts. CONCLUSION: A significant correlation between microscopic findings and cervical fluid IL-8 concentrations may make vaginal wet mount microscopy a useful tool for identification of patients with cervicovaginal inflammation, which is considered a risk factor for spontaneous preterm delivery.

Contact sensitivity in patients with venous leg ulcers in Serbia: comparison with contact dermatitis patients and relationship to ulcer duration.

BACKGROUND: Contact hypersensitivity is a common occurrence in patients with chronic venous leg ulcers (CVLU) with allergen profiles depending upon the local treatment policies. OBJECTIVE: This study was to determine the frequency of contact sensitivity, prevalence of individual allergens, polyvalent sensitization, and/or their relationship to ulcers duration in the population of CVLU and contact dermatitis patients in Serbia. PATIENTS: 75 patients with CVLU and 82 patients with clinically suspected contact dermatitis were prospectively included in the study. The patients were patch tested with a series of 21 standard and 22 supplemental allergens. RESULTS: 73% (n = 55) of CVLU and 52% (n = 43) of control subjects had 1 or more positive patch test results (P < 0.01). Polysensitization was found in 53% of patients and 21% of controls (P < 0.01). CVLU patients run 2.5 and 4.3 higher risk for contact sensitization and polysensitization, respectively. The most common allergens were Balsam of Peru (21.3%), carba mix (18.7%), fusidic acid (17.3%), colophony (13.3%), paraben mix (12%), chloramphenicol (12%), silver nitrate (12%), and neomycin (10.7%). Polivalent sensitization and higher mean number of allergens were associated with ulcer duration >5 years. CONCLUSIONS: The results confirm a high rate of contact (poly)sensitization in patients with CVLU and local variability in allergen prevalence.