ModFOLD8: accurate global and local quality estimates for 3D protein models.

Methods for estimating the quality of 3D models of proteins are vital tools for driving the acceptance and utility of predicted tertiary structures by the wider bioscience community. Here we describe the significant major updates to ModFOLD, which has maintained its position as a leading server for the prediction of global and local quality of 3D protein models, over the past decade (>20 000 unique external users). ModFOLD8 is the latest version of the server, which combines the strengths of multiple pure-single and quasi-single model methods. Improvements have been made to the web server interface and there has been successive increases in prediction accuracy, which were achieved through integration of newly developed scoring methods and advanced deep learning-based residue contact predictions. Each version of the ModFOLD server has been independently blind tested in the biennial CASP experiments, as well as being continuously evaluated via the CAMEO project. In CASP13 and CASP14, the ModFOLD7 and ModFOLD8 variants ranked among the top 10 quality estimation methods according to almost every official analysis. Prior to CASP14, ModFOLD8 was also applied for the evaluation of SARS-CoV-2 protein models as part of CASP Commons 2020 initiative. The ModFOLD8 server is freely available at: https://www.reading.ac.uk/bioinf/ModFOLD/.

Retreatment of XP-endo Shaper and R-Endo files in curved root canals.

OBJECTIVES: To compare the retreatment efficiency of XP-endo Shaper and R-Endo files in curved root canals using ImageJ software. METHODS: Forty extracted mandibular first molars with curved mesial canals (25°-35°) were chosen. Access cavities, preparation and obturation of root canals were performed. Roots were randomly distributed into two groups corresponding to the retreatment files used. Group 1 retreated with XP-endo Shaper file, and group 2 retreated with R-Endo files. Each root was sectioned and photographed. ImageJ software was used to estimate the percentage of residual filling material that existed on the three root canal segments. Mann-Whitney U and the Kruskal-Wallis tests were used to compare the percentages of residual filling material between the teeth segments (P < .05). RESULTS: The R-Endo group showed a significantly higher median percentage of residual filling material than the XP-endo Shaper group. In both groups, the coronal segments had the highest median of the residual filling material, followed by the middle and apical segments. CONCLUSION: XP-endo Shaper is significantly more effective than R-Endo in removing root canal filling materials in the coronal, middle, and apical segments.

The Incidence of Retrograde Peri-Implantitis in a Single University Dental Hospital Training Center: A Retrospective Analysis.

Background and objective: Retrograde peri-implantitis (RPI) is a periapical radiolucent lesion developed around the implant apex. This study aimed to investigate the Incidence of RPI in a single university dental hospital training center. Materials and Methods: All records of patients who received single Implants between 2016-2020 were screened. For cases that met inclusion criteria, clinical and radiographic data were analyzed. Results: A total of 215 were included and categorized as follows, Category A: implants were placed next to endodontically treated teeth (n = 58, 27%); category B, implants placed at the sites with previous endodontic involvement within 6 months of tooth extraction (n = 25, 11.6%); Category AB: implants placed at sites that fulfill the criteria of groups A and B (n = 18, 8.4%); and Category C: Implants that were placed next to vital teeth and at a site with no previous endodontic treatment or a site that was allowed to heal for more than six (n = 114, 53%). Categories A, B and AB served as the endodontically involved (EI) group, while category C served as non- endodontically involved (NEI) group. Only two sites (0.9%) were confirmed as RPI, both from group A (3.4%). Comparing all groups studied showed no statistically significant difference in RPI incidence. Conclusions: The incidence of RPI is low; however, endodontically treated teeth with periapical lesions (PALs) next to an implant site could contribute to RPI.

Chemical Review of Gorgostane-Type Steroids Isolated from Marine Organisms and Their 13C-NMR Spectroscopic Data Characteristics.

Gorgostane steroids are isolated from marine organisms and consist of 30 carbon atoms with a characteristic cyclopropane moiety. From the pioneering results to the end of 2021, isolation, biosynthesis, and structural elucidation using 13C-NMR will be used. Overall, 75 compounds are categorized into five major groups: gorgost-5-ene, 5,6-epoxygorgostane, 5,6-dihydroxygorgostane, 9,11-secogorgostane, and 23-demethylgorgostane, in addition to miscellaneous gorgostane. The structural diversity, selectivity for marine organisms, and biological effects of gorgostane steroids have generated considerable interest in the field of drug discovery research.

A Comprehensive In Silico Study of New Metabolites from Heteroxenia fuscescens with SARS-CoV-2 Inhibitory Activity.

Chemical investigation of the total extract of the Egyptian soft coral Heteroxenia fuscescens, led to the isolation of eight compounds, including two new metabolites, sesquiterpene fusceterpene A (1) and a sterol fuscesterol A (4), along with six known compounds. The structures of 1-8 were elucidated via intensive studies of their 1D, 2D-NMR, and HR-MS analyses, as well as a comparison of their spectral data with those mentioned in the literature. Subsequent comprehensive in-silico-based investigations against almost all viral proteins, including those of the new variants, e.g., Omicron, revealed the most probable target for these isolated compounds, which was found to be Mpro. Additionally, the dynamic modes of interaction of the putatively active compounds were highlighted, depending on 50-ns-long MDS. In conclusion, the structural information provided in the current investigation highlights the antiviral potential of H. fuscescens metabolites with 3ß,5α,6ß-trihydroxy steroids with different nuclei against SARS-CoV-2, including newly widespread variants.

Biosynthesis, Characterization, and Wound-Healing Activity of Phenytoin-Loaded Copper Nanoparticles.

Wound-healing is a very complex and evolutionary process that involves a great variety of dynamic steps. Although different pharmaceutical agents have been developed to hasten the wound-healing process, the existing agents are still far from optimal. The present work aimed to prepare and evaluate the wound-healing efficacy of phenytoin-loaded copper nanoparticles (PHT-loaded CuNPs). CuNPs were biosynthesized using licorice aqueous extract. The prepared CuNPs were loaded with PHT by adsorption, characterized, and evaluated for wound-healing efficiency. Results showed that both plain and PHT-loaded CuNPs were monodisperse and exhibited a cubic and hexagonal morphology. The mechanism by which PHT was adsorbed on the surface of CuNPs was best fit by the Langmuir model with a maximum loaded monolayer capacity of 181 mg/g. The kinetic study revealed that the adsorption reaction followed the pseudo-second order while the thermodynamic parameters indicated that the adsorption process was physical in nature and endothermic, and occurred spontaneously. Moreover, the in vivo wound-healing activity of PHT-loaded CuNP impregnated hydroxypropylmethyl cellulose (HPMC) gel was carried out using an excisional wound model in rats. Data showed that PHT-loaded CuNPs accelerated epidermal regeneration and stimulated granulation and tissue formation in treated rats compared to controls. Additionally, quantitative real-time polymerase chain reaction (RT-PCR) analysis showed that lesions treated with PHT-loaded CuNPs were associated with a marked increase in the expression of dermal procollagen type I and a decrease in the expression of the inflammatory JAK3 compared to control samples. In conclusion, PHT-loaded CuNPs are a promising platform for effective and rapid wound-healing.

Spectrum of medulloblastoma subtypes and frequency of MYC amplification; Experience from a tertiary care center in Saudi Arabia.

OBJECTIVE: To clarify the spectrum of morphological and molecular subtypes of medulloblastoma (MBL), in addition to MYC and MYCN amplification statuses in a cohort of Saudi patients. The latter was correlated with patient outcome. METHODS: We conducted a retrospective cohort study of 57 patients with MBL, diagnosed at the central laboratory of King Abdulaziz Medical City in Riyadh, Saudi Arabia, between 2006 and 2019. Molecular analysis for MYC and MYCN amplification was performed for the 19 most recently diagnosed patients. RESULTS: Classic MBL was the most prevalent histologic subtype and MBL with extensive nodularity was the rarest. The non-WNT/non-SHH molecular subgroup was the most common while the WNT-activated was the least common. Among 19 patients analyzed, MYC and MYCN amplifications were discovered in 2 (10.5%) and 1 (5.3%) cases, respectively, using interphase fluorescence in-situ hybridization. The 2 MYC amplified cases belonged to the large cell/anaplastic subtype and had the worst outcomes. CONCLUSION: The MYC amplification corresponded with poor prognosis, the large cell/anaplastic variant of MBL, and the non-WNT/non-SHH molecular subtype.

Utilizing mixer torque rheometer in the prediction of optimal wet massing parameters for pellet formulation by extrusion/spheronization.

In this study, we aimed to optimize theophylline pellet formulations using a two-factor three-level full-factorial design (32) by monitoring the concentration of two pellet excipients, polyvinyl pyrrolidone K30 (PVP) binder solution (X1) and the hydrophilic excipient mannitol (X2). Their impact on pellet characteristics (responses) were evaluated. Increasing PVP concentration in the binder solution resulted in an increase in the wet mass torque value. The effect of mannitol, however, was antagonistic. Moreover, the pellet particle size was significantly influenced by the level of mannitol, PVP solution, and quadratic effect of mannitol. Mannitol significantly antagonized the pellet particle size. Furthermore, increased mannitol concentrations significantly enhanced drug dissolution rate from the pellets, whereas PVP concentration in the binder solution significantly reduced the drug dissolution rate. In conclusion, wet granulations can be controlled by monitoring the composition of the binder solution and pellet composition.

Prevalence and Associated Risk Factors of Gestational Diabetes Mellitus at a University Hospital in Saudi Arabia.

OBJECTIVES: We aimed to find out the prevalence and associated risk factors of GDM among females who attended antenatal clinic at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia (SA). METHODS: This retrospective study was carried out from 25th September 2016 till 20th December 2016, at the Endocrine Clinic, Faculty of Medicine, KAUH, Jeddah, SA. A total of 5000 women attended antenatal clinic and 637 women were referred to the endocrine clinic for GDM. The data of only 103 GDM was included in the study because only these patients' complete data was available. The electronic record of 93 pregnant age and BMI matched females, not having GDM were selected as a control group. RESULTS: The prevalence of GDM was 12.75% (637/5000). Parity was associated with GDM (X2=16.82, P=.001) and GDM was significantly higher in multigravida while no association of GDM was found with working status, place of living, hypertension, family history of DM and BMI. Logistic regression analysis revealed that grand multigravida female had the lower risk of GDM as compared to multi, primi and nulligravida while age, working status, place of living, hypertension, family history of DM and BMI were not found significant risk factors for GDM. In GDM group, according to nationality, 68(66%) women were Saudi while 35(34%) were expatriates' (Yemeni 11.2%, Egyptians 3.9%, Indians 3.9%, Pakistanis 2.9%, Sudanese 2.9%, Syrians 2.9% and others). CONCLUSIONS: The prevalence of GDM was 12.75% and it was not associated with working status, place of living, hypertension, family history of diabetes and BMI.

Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin and Mammary Papilla (Nipple).

PURPOSE: Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast. METHODS: Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. RESULTS: Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment. CONCLUSIONS: The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

Influence of Hydroalcoholic Vehicle on In Vitro Transport of 4-Hydroxy Tamoxifen Through the Mammary Papilla (Nipple).

Majority of breast cancers originate from epithelial cells in the duct and lobules in the breast. Current systemic treatments for breast cancer are associated with significant systemic side effects, thus warranting localized drug delivery approaches. The aim of this study was to investigate the influence of hydroalcoholic vehicle on topical delivery of 4-hydroxy tamoxifen (4-HT) through the mammary papilla (nipple). The in vitro permeability of 4-HT through porcine mammary papilla was studied using different hydroalcoholic vehicles (0, 33.33, and 66.66% alcohol). Nile red was used as a model lipophilic dye to characterize the drug transport pathway in the mammary papilla. The penetration of 4-HT through the mammary papilla increased with increase in alcohol concentration in the vehicle. The solubility of 4-HT was enhanced by increasing alcohol concentration in the vehicle. On the other hand, the epidermis/vehicle partition coefficient decreased with increase in alcohol concentration. The mammary papilla served as a depot and slowly released 4-HT into the receptor medium. Highest drug penetration was observed with saturated drug solution in 66.66% alcohol, and 4-HT levels were comparable to IC50 value of 4-HT. Results from this study demonstrate the possibility of using mammary papilla as a potential route for direct delivery of 4-HT to the breast.

Transpapillary (Nipple) Delivery of Macromolecules to the Breast: Proof of Concept Study.

Localized drug delivery to the breast can maximize drug concentration at the target site and minimize systemic drug distribution. To this end, the study explored the feasibility of delivering macromolecules to the breast through mammary papilla (nipple). The in vitro penetration of model macromolecules (inulin, dextran, ovalbumin, and bovine serum albumin) varying in molecular weight from 5 to 67 kDa was studied using excised porcine and human mammary papilla. The penetration of macromolecules decreased with increase in molecular weight. The penetration of the macromolecules was significantly higher through the mammary papilla in comparison to breast skin. In vitro penetration of the macromolecules was similar in human and porcine mammary papilla. Iontophoresis was used to enhance the transport of bovine serum albumin (BSA) through the mammary papilla. The flux and cumulative amount permeated was increased by 2- to 4-fold by iontophoresis. The macromolecules were transported through the ducts and the surrounding connective tissue in the mammary papilla. Overall, the results from this study for the first time demonstrate the feasibility of delivering macromolecules through the mammary papilla. These findings have implications for developing safe and effective localized therapeutic approaches for breast cancer.

HEALTH AWARENESS AMONG FEMALE UNDERGRADUATE MEDICAL STUDENTS IN SAUDI ARABIA.

This study was conducted to assess the level of health awareness (HA) among students attending three undergraduate programs in the Colleges of Applied Medical Sciences (CAMS) in Riyadh, Saudi Arabia (SA). A modified self-reported survey was utilized to measure HA demonstrating four domains: Nutrition (NU), Personal Health (PH), Physical Exercise (PE), and Body Build (BB). The questionnaire was distributed to 302 female students attending the first semester of the academic year 2014-2015 BS degree in Radiology Sciences (RS), Clinical Laboratory (CL), and Health Education (HE) departments. Bloom's taxonomy was utilized to describe the three cognitive levels. Synthesizing, creating, and evaluating were grouped to represent high level indicators; applying cognitive skills only revealed an intermediate level; while memorizing and listing demonstrated low levels. In a 5-point Likert scale, the overall mean (M) of HA among CAMS students was 3.82 with the highest among students attending HE (M = 3.89). The domain of PH ranked first with a high average (M = 4.30). There were significant differences (α = 0.05), in the level of HA in PH and BB domains, among students in terms of program specialty only, but no such significant differences were found for other characteristics. The study recommended incorporating health promotion concepts within teaching curricula and conducting health and education campaigns by health education institutions.

[Managing late-effects after allogeneic stem cell transplantation in children: recommendations from the SFGM-TC]. / Prise en charge des séquelles après greffe de cellules souches hématopoïétiques chez l'enfant : recommandations de la SFGM-TC.

In this report, we address the issue of late-effects after allogeneic stem cell transplantation in children. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

Isolation of two new cucurbitane-type triterpenoids from Kedrostis gijef.

Two new cucurbitane-type triterpenoids (2,3), together with two known compounds (1,4), were isolated from the aerial parts of Kedrostis gijef. The structure of all compounds was elucidated based on NMR, HRESIMS analyses, and by comparison with the literature. Additionally, the cytotoxic activity against HeLa, Caco-2, and SH-SY5Y cell lines was determined using MTT colorimetric assay.

Characterizing a design space for a twin-screw wet granulation process: A case study of extended-release tablets.

Twin-screw wet granulation is an emerging continuous manufacturing technology for solid oral dosage forms. This technology has been successfully employed for the commercial manufacture of immediate-released tablets. However, the higher polymer content in extended-release (ER) formulations may present challenges in developing and operating within a desired design space. The work described here used a systematic approach for defining the optimum design space by understanding the effects of the screw design, operating parameters, and their interactions on the critical characteristics of granules and ER tablets. The impacts of screw speed, powder feeding rate, and the number of kneading (KEs) and sizing elements on granules and tablets characteristics were investigated by employing a definitive screening design. A semi-mechanistic model was used to calculate the residence time distribution parameters and validated using the tracers. The results showed that an increase in screw speed decreased the mean residence time of the material within the barrel, while an increase in the powder feeding rate or number of KEs did the opposite and increased the barrel residence time. Screw design and operating parameters affected the flow and bulk characteristics of granules. The screw speed was the most significant factor impacting the tablet's breaking strength. The dissolution profiles revealed that granule characteristics mainly influenced the early phase of drug release. This study demonstrated that a simultaneous optimization of both operating and screw design parameters was beneficial in producing ER granules and tablets of desired performance characteristics while mitigating any failure risks, such as swelling during processing.

Assessment of health risks associated with heavy metal contamination in selected fish and crustacean species from Temsah Lake, Suez Canal.

Marine pollution caused by heavy metals has emerged as a significant environmental concern, garnering increased attention in recent years. The accumulation of heavy metals in the tissues of marine organisms poses substantial threats to both marine ecosystems and human populations that rely on seafood as a primary food source. Fish and crustaceans are effective biomonitors for assessing heavy metal contamination in aquatic environments. In this study, we determined the concentrations of several heavy metals, including cadmium (Cd), lead (Pb), nickel (Ni), mercury (Hg), and tin (Sn), in four fish species (Mugil cephalus, Mugil capito, L. aurata, and Morone labrax) and five crustacean species (S. rivulatus, Cerastoderma glaucum, Paratapes undulatus, R. decussatus, Callinectes sapidus, and Metapenaeus Stebbingi) from Temsah Lake during both winter and summer seasons. To evaluate the potential ecological and health risks associated with consuming these fish and crustacean species, we calculated the metal pollution index (MPI), weekly intake (EWI), target hazard quotient (THQ), and carcinogenic risk (CR) values. The results revealed a noticeable increase in metal levels during the summer compared to winter in the studied samples. Moreover, the concentration of heavy metals in the muscles of the species generally exceeded those in the liver and gills. The MPI values indicated that Morone labrax exhibited the highest values during winter, while L. aurata showed the highest values during summer. Mugil cephalus demonstrated the lowest MPI values in both seasons. The EWI values for the studied metals were found to be lower than the corresponding tolerable weekly intake (TWI) values. Additionally, under average exposure conditions, the THQ and HI data were generally below one for most study species in the area. The calculated CR values for investigated metals in the studied species indicated acceptable carcinogenic risk levels. Therefore, this suggests that consuming studied species within Temsah lake does not present any potential health hazards for consumers.

Antiviral activity of sulphated specialized metabolites from sea urchin Clypeaster humilis: in vitro and in silico studies.

Chemical investigations of the sea urchin Clypeaster humilis has led to separation of twelve compounds including one new sulfonic acid derivative (7R) tridec-1-en-7-yl hydrogen sulphate (1), first isolated from natural source, pyridine-3-yl methane sulfonate (2), and first isolated from marine organisms, boldine (12), in addition to nine known compounds (3-11), which were isolated for the first time from the genus Clypeaster. Their structures were elucidated based on spectroscopic analyses (1D and 2D NMR), HR-ESI-MS as well as comparison with the previously reported data. The antiviral activity of the crude extract and sulphated compounds were evaluated using MTT colorimetric assay against Coxsackie B4 virus. The crude extract and compound 1 showed very potent antiviral activity with a percentage of inhibition equal to 89.7 ± 0.53% and 86.1 ± 0.92%, respectively. Results of the molecular docking analysis of the isolated compounds within Coxsackie Virus B4 (COX-B4) X-ray crystal structure and quantum chemical calculation for three sulphated compounds are in a consistent adaptation with the in vitro antiviral results. The pharmacokinetic properties (ADME) of isolated compounds were determined.

Light microscopical and parasitological analyses revealed the beneficial effects of silver nanoparticles and various myrrh extracts against Trichinella spiralis infection in mice.

Trichinella spiralis infection is a food-borne zoonotic disease caused by nematodes that dwell in the tissues, presenting a significant public health concern. This study aimed to evaluate the effectiveness of different treatments including silver nanoparticles (AgNPs), myrrh biosynthesized AgNPs "AgNPs synthesized using plant-based green technologies", myrrh extract, and myrrh essential oil, as alternative treatments against T. spiralis infection. Parasitological, histopathological, and cytotoxicity assessments were conducted to investigate the effects of various concentrations of these treatments in reducing the populations of adult worms and larvae during both the intestinal and muscular phases of T. spiralis-infected mice. The results showed that the highest antihelminthic efficacy against the intestinal phase of T. spiralis was achieved by myrrh extract (86.66%), followed closely by AgNPs (84.96%) and myrrh AgNPs (82.51%) at higher concentrations (800 mg/kg for myrrh extract, 40 µg/mL for AgNPs, and 40 µg/mL for myrrh AgNPs). While the group treated with myrrh essential oil showed the lowest percentage of adult reduction (78.14%). However, all treatments demonstrated comparable effects in reducing the larvae population in the muscle phase. Histopathological examination of the tissues revealed compelling evidence of the effectiveness of AgNPs, particularly when prepared with myrrh. Additionally, a comprehensive assessment of the cytotoxicity of AgNPs indicated low toxicity levels. This study supports that AgNPs synthesized using plant-based green technologies hold therapeutic potential for the treatment of T. spiralis infection. These findings present a promising avenue for the development of novel antiparasitic drugs that are both effective and safe. RESEARCH HIGHLIGHTS: Myrrh extract has the highest antihelminthic efficacy against the intestinal phase of T. spiralis. Histopathological examination of the tissues revealed compelling evidence of the effectiveness of AgNPs, particularly when prepared with myrrh. During intestinal phase of T. spiralis, varying levels of nanoparticle precipitation were detected in the liver, brain, lung, and intestine. During the muscular phase, the highest amount of AgNPs precipitation was detected in the liver, followed by the brain, and lung.