Synthesis, biological activities, and molecular docking studies of triazolo[4,3-b]triazine derivatives as a novel class of α-glucosidase and α-amylase inhibitors.

In diabetes mellitus, amylase and glucosidase enzymes are the primary triggers. The main function of these enzymes is to break macromolecules into simple sugar units, which directly affect blood sugar levels by increasing blood permeability. To overcome this metabolic effect, there is a need for a potent and effective inhibitor capable of suppressing the enzymatic conversion of sugar macromolecules into their smaller units. Herein, we reported the discovery of a series of substituted triazolo[4,3-b][1,2,4]triazine derivatives as α-glucosidase and α-amylase inhibitors. All target compounds demonstrated significant inhibitory activities against α-glucosidase and α-amylase enzymes compared with acarbose as the positive control. The most potent compound 10k, 2-[(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)thio]-N-[4-(trifluoromethyl)phenyl]acetamide, demonstrated IC50 values of 31.87 and 24.64 nM against α-glucosidase and α-amylase enzymes, respectively. To study their mechanism of action, kinetic studies were also done, which determined the mode of inhibition of both enzymes. Molecular docking was used to confirm the binding interactions of the most active compounds.

Salivary bacterial community profile in normal-weight and obese adolescent patients prior to orthodontic treatment with fixed appliances.

OBJECTIVES: The aim of this study was to compare the intra-oral bacterial profile of normal-weight and obese adolescents prior to orthodontic treatment with fixed appliances. MATERIALS AND METHODS: Nineteen adolescent patients were recruited into two groups based upon body mass index (BMI) and classified as normal-weight or obese. Unstimulated whole mouth saliva was obtained for 5 minutes. Bacterial DNA extraction was performed from saliva, and 16S rRNA gene sequencing of the V1-2 variable regions was undertaken followed by analysis using the mothur pipeline. RESULTS: Saliva from a total of 19 adolescent patients with mean (SD) age 15.6 (1.8) years were divided into 10 normal-weight with mean BMI of 19.4 (2.2) kg/m2 and 9 obese with mean BMI of 30.2 (3.5) kg/m2 . A total of 156 783 sequences were obtained from the 19 samples with no significant differences in richness or diversity between sample groups by obesity status or gender (AMOVA). The bacterial community in both groups was dominated by bacterial genera characteristic of the human mouth, which included Streptococcus, Porphyromonas, Veillonella, Gemella, Prevotella, Fusobacterium and Rothia. CONCLUSION: There were no differences in alpha or beta diversity of oral bacterial communities between normal-weight and obese orthodontic patients. Obese adolescents attending for orthodontic treatment had a similar microflora to their normal-weight counterparts.

Synthesis of novel 2-acetamide-5-phenylthio-1,3,4-thiadiazole-containing phenyl urea derivatives as potential VEGFR-2 inhibitors.

A novel series of 2-acetamide-5-phenylthio-1,3,4-thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT-29, A431, and PC3, as well as normal HDF cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4-chloro-containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl-2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR-2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three-dimensional cell culture method using the hanging drop technique.

Serological, virological and molecular diagnosis of an outbreak of lumpy skin disease among cattle in Butana area, Eastern Sudan.

BACKGROUND: Lumpy skin disease (LSD) is a highly infectious disease of cattle caused by a virus of the Poxviridae family, genus Capripoxvirus. The disease has great economic effects on the global cattle industry. In this study, an outbreak of LSD among cattle which occurred in Nahr Atbara and Halfa El Jadida locations in Butana area, Kassala State in November, 2020 is described. METHODS: Lumpy skin disease virus (LSDV) antibody and nucleic acid were detected in specimens (n = 50) using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). RESULTS: The virus was isolated on the chorioallantoic membrane (CAM) of embryonated chicken eggs and identified by PCR. The number of animals at risk was 295 with a morbidity rate of 4.1% and a mortality rate of 2.4%. CONCLUSIONS: LSDV was diagnosed for the first time in the Butana region, Kassala State, Eastern Sudan in 2020.

Quinazolin-4(3H)-one based agents bearing thiadiazole-urea: Synthesis and evaluation of anti-proliferative and antiangiogenic activity.

A series of quinazolin-4(3H)-one based agents containing thiadiazole-urea were designed, synthesized, and biologically evaluated. The proliferation rate of PC3 cells was moderately reduced by compound 9f (IC50 = 17.7 µM)which was comparable with sorafenib (IC50 = 17.3 µM). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC50 = 6.1 µM). To test the potential of compounds in inducing apoptosis, Annexin V-FITC/propidium iodide double staining assay was used. After the treatment of HUVEC cells with 9f, they underwent apoptotic effects. A substantial effort was dedicated to gathering comprehensive data across CAM assay. These data showed that 9f moderately inhibits the growth of corresponding blood vessels. Finally, the outcomes of Western blotting proposed a mechanism of action, by which the phosphorylation of VEGFR-2 is inhibited by compounds 9f and 9y.

Prevalence of Antibodies to Simbu Serogroup Viruses in Cattle in Sudan.

The Simbu serogroup is one of the serogroups that belong to the Orthobunyavirus genus of the family Peribunyaviridae. Simbu serogroup viruses are transmitted mainly by Culicoides biting midges. Meager information is available on Simbu serogroup virus infection in ruminants in Sudan. Therefore, in this study, serological surveillance of Simbu serogroup viruses in cattle in seven states in Sudan was conducted during the period from May, 2015, to March, 2016, to shed some light on the prevalence of this group of viruses in our country. Using a cross-sectional design, 184 cattle sera were collected and tested by a commercial SBV ELISA kit which enables the detection of antibodies against various Simbu serogroup viruses. The results showed an overall 86.4% prevalence of antibodies to Simbu serogroup viruses in cattle in Sudan. Univariate analysis showed a significant association (p=0.007) between ELISA seropositivity and states where samples were collected. This study suggests that Simbu serogroup virus infection is present in cattle in Sudan. Further epizootiological investigations on Simbu serogroup viruses infection and virus species involved are warranted.

Corrugation of an unpaved road surface under vehicle weight.

Road corrugation refers to the formation of periodic, transverse ripples on unpaved road surfaces. It forms spontaneously on an initially flat surface under heavy traffic and can be considered to be a type of unstable growth phenomenon, possibly caused by the local volume contraction of the underlying soil due to a moving vehicle's weight. In the present work, we demonstrate a possible mechanism for road corrugation using experimental data of soil consolidation and numerical simulations. The results indicate that the vertical oscillation of moving vehicles, which is excited by the initial irregularities of the surface, plays a key role in the development of corrugation.

First report on molecular characterization and phylogenetic analysis of Reticuloendotheliosis virus in Sudan.

The reticuloendotheliosis virus (REV) group of retroviruses infects a wide range of avian species, including chickens, turkeys, ducks, geese, quail, and prairie chickens. The infection can result in immunosuppression, runting syndrome, high mortality, acute reticular cell neoplasia, or T- and/or B-cell lymphoma. One PCR positive chicken spleen sample obtained in a previous study in addition to one Marek's disease and three fowl pox (FP) vaccine samples were investigated in this study. A PCR assay was performed to detect the presence of REV provirus DNA in these samples. The results indicated the contamination of fowl pox virus and Marek's disease vaccines with REV. In addition, detection of integration of REV inside the genome of fowl pox vaccine was confirmed using primers corresponding to the FPV DNA regions flanking the REV integration site. Alignments of two sequences, one from the spleen tissue and the other from contaminated FP vaccine with REV, with other REV (env) gene sequences obtained from GenBank indicated their high similarity. Furthermore, phylogenetic analysis indicated that the partial part of (env) gene of our two isolates was closely related to variants from India, USA, Taiwan, and China. These results confirmed the contamination of commercial fowl pox and Marek's disease vaccines used in Sudan with REV. Phylogenetic analysis indicated that the partial part of (env) gene sequences from Sudan was closely related to variants from India, USA, Taiwan, and China.

Short-range propagation characteristics of airgun pulses during marine seismic reflection surveys.

Marine seismic reflection surveys use airguns to generate repetitive high energy sound signals to image the structure of the seafloor. To better mitigate against the impact of airgun pulses on marine mammals, safety criteria are defined to ensure marine mammals are not exposed to high levels of acoustic energy. Accurate prediction of the sound received levels away from the airguns is required for conducting effective marine mammal monitoring. In this study, measurements by a horizontal hydrophone array towed by the R/V Marcus G. Langseth behind a seismic source array have been used to characterize short-range propagation of airgun pulses and predict the acoustic energy radiated from a seismic source. Data from the Cascadia Open-Access Seismic Transects seismic reflection survey are used to train a linear regression (LR) and a random forest (RF) model to estimate sound exposure levels (SELs) in short ranges from the airguns. Results show that the LR model does not account for all the variance in data. However, the RF model is able to estimate the SELs with a high coefficient of determination and a low mean squared error. Results from the LR model show that the rate at which SELs decrease in deep water does not match either of the cylindrical or spherical spreading models. Simulations are undertaken to understand this inconsistency as well as the effect of hydrophone group-averaging on data recorded by a seismic hydrophone array.

Serological and molecular identification of Reticuloendotheliosis virus (REV) in chickens in Sudan.

BACKGROUND: Reticuloendotheliosis virus (REV) is a gammaretrovirus that belongs to the family of Retroviridae. The infection can result in immunosuppression, runting syndrome, high mortality, acute reticular cell neoplasia or T- and/ or B-cell lymphoma, in a variety of domestic and wild birds. The disease is widespread around the world. No related data have been reported in Sudan about the disease. The present study was conducted to determine the prevalence of REV antibodies and DNA in local and commercial breeds of chickens older than 20 weeks from June 2014 to February, 2017. METHODS: A total of 460 sera samples and 150 (50 liver and 100 spleen) tissue samples were collected from local and commercial breeds of chickens older than 20 weeks and screened for anti-REV antibodies in four states of Sudan using a commercial REV antibody ELISA test kit (IDEXX). Polymerase chain reaction (PCR) was performed to detect REV DNA in tissue samples in Khartoum State. RESULTS: The results revealed that the overall seroprevalence of REV was 74.6% among local and commercial chicken breeds, but in commercial it was 79.5% (190/239) and 69.2% in local breeds (153/221). One hundred and fifty tissue samples of chickens (50 liver, 100 spleen) were tested using PCR for detection of REV using primer sets of the conserved region in envelope glycoprotein (env) gene with a band length of 850 bp. Five out of 50 (10%) liver samples were RE provirus DNA positive detected by PCR, whereas 15 out of 100 (15%) spleen samples were PCR positive. Univariate analysis revealed there was a difference (p ≤ 0.05) between locality and breed of chickens and seropositivity to REV. CONCLUSIONS: The prevalence of the disease was high in Sudan and more studies are needed to evaluate the epidemiology and pathogenesis of the virus.

Acoustic localization of crows in pre-roost aggregations.

Crows are highly intelligent and social creatures. Each night during the non-breeding period, they gather on large pre-roost aggregations as they move towards their communal roost where they sleep. Crows make numerous and varied vocalizations on these pre-roost aggregations, but the purpose of these calls, and vocal communication in general, in these pre-roost aggregations is not fully understood. In this paper, an array of four microphones is used as a non-intrusive means to observe crow vocal behavior in pre-roost aggregations in the absence of human observers. By passively localizing animal vocalizations, the location of individuals can be monitored while simultaneously recording the acoustic structure and organization of their calls. Simulations and experiment are undertaken to study the performance of two time difference of arrival-based methods (hyperbolic location estimator and maximum likelihood estimator) for call localization. The effect of signal-to-noise ratio and uncertainty in measurement on the localization error is presented. By describing, modeling, and testing these techniques in this innovative context, the authors hope that researchers will employ the authors' approaches in future empirical studies to more fully understand crow vocal behavior.

Frequency-sum beamforming for passive cavitation imaging.

Beamforming includes a variety of spatial filtering techniques that may be used for determining sound source locations from near-field sensor array recordings. For this scenario, beamforming resolution depends on the acoustic frequency, array geometry, and target location. Random scattering in the medium between the source and the array may degrade beamforming resolution with higher frequencies being more susceptible to degradation. The performance of frequency-sum (FS) beamforming for reducing such sensitivity to mild scattering while increasing resolution is reported here. FS beamforming was used with a data-dependent [minimum variance (MV)] or data-independent (delay-and-sum, DAS) weight vector to produce higher frequency information from lower frequency signal components via a quadratic product of complex signal amplitudes. The current findings and comparisons are based on simulations and passive cavitation imaging experiments using 3 MHz and 6 MHz emissions recorded by a 128-element linear array. FS beamforming results are compared to conventional DAS and MV beamforming using four metrics: point spread function (PSF) size, axial and lateral contrast, and computation time. FS beamforming produces a smaller PSF than conventional DAS beamforming with less computation time than MV beamforming in free space and mild scattering environments. However, it may fail when multiple unknown sound sources are present.

Estimating the location of baleen whale calls using dual streamers to support mitigation procedures in seismic reflection surveys.

In order to mitigate against possible impacts of seismic surveys on baleen whales it is important to know as much as possible about the presence of whales within the vicinity of seismic operations. This study expands on previous work that analyzes single seismic streamer data to locate nearby calling baleen whales with a grid search method that utilizes the propagation angles and relative arrival times of received signals along the streamer. Three dimensional seismic reflection surveys use multiple towed hydrophone arrays for imaging the structure beneath the seafloor, providing an opportunity to significantly improve the uncertainty associated with streamer-generated call locations. All seismic surveys utilizing airguns conduct visual marine mammal monitoring surveys concurrent with the experiment, with powering-down of seismic source if a marine mammal is observed within the exposure zone. This study utilizes data from power-down periods of a seismic experiment conducted with two 8-km long seismic hydrophone arrays by the R/V Marcus G. Langseth near Alaska in summer 2011. Simulated and experiment data demonstrate that a single streamer can be utilized to resolve left-right ambiguity because the streamer is rarely perfectly straight in a field setting, but dual streamers provides significantly improved locations. Both methods represent a dramatic improvement over the existing Passive Acoustic Monitoring (PAM) system for detecting low frequency baleen whale calls, with ~60 calls detected utilizing the seismic streamers, zero of which were detected using the current R/V Langseth PAM system. Furthermore, this method has the potential to be utilized not only for improving mitigation processes, but also for studying baleen whale behavior within the vicinity of seismic operations.

Catastrophic cellular events leading to complex chromosomal rearrangements in the germline.

Although complex chromosomal rearrangements were thought to reflect the accumulation of DNA damage over time, recent studies have shown that such rearrangements frequently arise from 'all-at-once' catastrophic cellular events. These events, designated chromothripsis, chromoanasynthesis, and chromoanagenesis, were first documented in the cancer genome and subsequently observed in the germline. These events likely result from micronucleus-mediated chromosomal shattering and subsequent random reassembly of DNA fragments, although several other mechanisms have also been proposed. Typically, only one or a few chromosomes of paternal origin are affected per event. These events can produce intrachromosomal deletions, duplications, inversions, and translocations, as well as interchromosomal translocations. Germline complex rearrangements of autosomes often result in developmental delay and dysmorphic features, whereas X chromosomal rearrangements are usually associated with relatively mild clinical manifestations. The concept of these catastrophic events provides novel insights into the etiology of human genomic disorders. This review introduces the molecular characteristics and phenotypic outcomes of catastrophic cellular events in the germline.

Sound source localization technique using a seismic streamer and its extension for whale localization during seismic surveys.

Marine seismic surveys are under increasing scrutiny because of concern that they may disturb or otherwise harm marine mammals and impede their communications. Most of the energy from seismic surveys is low frequency, so concerns are particularly focused on baleen whales. Extensive mitigation efforts accompany seismic surveys, including visual and acoustic monitoring, but the possibility remains that not all animals in an area can be observed and located. One potential way to improve mitigation efforts is to utilize the seismic hydrophone streamer to detect and locate calling baleen whales. This study describes a method to localize low frequency sound sources with data recoded by a streamer. Beamforming is used to estimate the angle of arriving energy relative to sub-arrays of the streamer which constrains the horizontal propagation velocity to each sub-array for a given trial location. A grid search method is then used to minimize the time residual for relative arrival times along the streamer estimated by cross correlation. Results from both simulation and experiment are shown and data from the marine mammal observers and the passive acoustic monitoring conducted simultaneously with the seismic survey are used to verify the analysis.

Abrogation of protein phosphatase 6 promotes skin carcinogenesis induced by DMBA.

Somatic mutations in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) have been identified in malignant melanoma and are thought to function as a driver in B-raf- or N-ras-driven tumorigenesis. To assess the role of Ppp6c in carcinogenesis, we generated skin keratinocyte-specific Ppp6c conditional knockout mice and performed two-stage skin carcinogenesis analysis. Ppp6c deficiency induced papilloma formation with 7,12-dimethylbenz (a) anthracene (DMBA) only, and development of those papillomas was significantly accelerated compared with that seen following DMBA/TPA (12-O-tetradecanoylphorbol 13-acetate) treatment of wild-type mice. NF-κB activation either by tumor necrosis factor (TNF)-α or interleukin (IL)-1ß was enhanced in Ppp6c-deficient keratinocytes. Overall, we conclude that Ppp6c deficiency predisposes mice to skin carcinogenesis initiated by DMBA. This is the first report showing that such deficiency promotes tumor formation in mice.

Growth trends in medical specialists education in Iran; 1979 - 2013.

Over the past 35 years Iran had significant quantitative progress in postgraduate medical education; and growth in specialist's physician workforce supply. Health and medical education policy makers have struggled with many issues related to physician supply, such as determining the sufficient number of physicians workforce and the appropriate number to train; establishing new medical schools; the diversity of specialty programs; efforts to increase the supply of physicians in specialty level in remote and rural areas; and the growing number of female physicians and its impact on health services. After establishment of Ministry of Health and Medical Education (MoHME) in Iran, expansion of medical specialty education was a priority. Since then, great advances have been made in training of new specialty programs. Despite of these brilliant advances during the last decades in Iran, there has been no integrated and comprehensive documentation of previous and current growth trend, yet. To understand where Iranian physician supply and specialty training is headed, we examined the Iranian medical specialist's trends from 1979 to 2013 in a national study by support of Iranian academy of medicine. This paper documents the growth trend of medical specialist's workforce over the past 35 years. Examining the health manpower growth trends allow health and medical education policy makers to plan innovative strategies for the purposeful development of postgraduate medical education to ensure that in future there would be sufficient physicians supply, with the right skills, in the right places in response to population demands.

Synthesis and anti-cancer activity evaluation of new dimethoxylated chalcone and flavanone analogs.

A novel series of chalcones and flavanones discriminated by the presence of a 3,4-dimethoxyphenyl moiety in their structures were synthesized as anti-cancer agents. The cytotoxicity evaluation of the analogs against the MCF-7, MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cell lines demonstrated that the introduction of a halogen on the 3,4-dimethoxyphenyl part of both series and the attachment of a pyrrolidinylethoxy group on the C-7 position of the flavanone derivatives increased their activity. Indeed, 3-halogenated chalcones (1c and 1d) were more potent than the standard drug etoposide against all tested cell lines. Fluorescence microscopy and flow cytometry analyses confirmed that the anti-cancer effect of the most potent compounds 1c and 1d occurs via apoptosis induction.

Ranging bowhead whale calls in a shallow-water dispersive waveguide.

This paper presents the performance of three methods for estimating the range of broadband (50-500 Hz) bowhead whale calls in a nominally 55-m-deep waveguide: Conventional mode filtering (CMF), synthetic time reversal (STR), and triangulation. The first two methods use a linear vertical array to exploit dispersive propagation effects in the underwater sound channel. The triangulation technique used here, while requiring no knowledge about the propagation environment, relies on a distributed array of directional autonomous seafloor acoustics recorders (DASARs) arranged in triangular grid with 7 km spacing. This study uses simulations and acoustic data collected in 2010 from coastal waters near Kaktovik, Alaska. At that time, a 12-element vertical array, spanning the bottom 63% of the water column, was deployed alongside a distributed array of seven DASARs. The estimated call location-to-array ranges determined from CMF and STR are compared with DASAR triangulation results for 19 whale calls. The vertical-array ranging results are generally within ±10% of the DASAR results with the STR results providing slightly better agreement. The results also indicate that the vertical array can range calls over larger ranges and with greater precision than the particular distributed array discussed here, whenever the call locations are beyond the distributed array boundaries.