Induction of cryptic antifungal pulicatin derivatives from <i>Pantoea agglomerans</i> by microbial co-culture

Microbial co-culture or mixed fermentation proved to be an efficient strategy to expand chemical diversity by the induction of cryptic biosynthetic pathways, and in many cases led to the production of new antimicrobial agents. In the current study, we report a rare example of the induction of silent/cryptic bacterial biosynthetic pathway by the co-culture of Durum wheat plant roots-associated bacterium Pantoea aggolomerans and date palm leaves-derived fungus Penicillium citrinum. The initial co-culture indicated a clear fungal growth inhibition which was confirmed by the promising antifungal activity of the co-culture total extract against Pc. LC-HRMS chemical profiling demonstrated a huge suppression in the production of secondary metabolites (SMs) of axenic cultures of both species with the emergence of new metabolites which were dereplicated as a series of siderophores. Large-scale co-culture fermentation led to the isolation of two new pulicatin derivatives together with six known metabolites which were characterised using HRESIMS and NMR analyses. During the in vitro antimicrobial evaluation of the isolated compounds, pulicatin H (2) exhibited the strongest antifungal activity against Pc, followed by aeruginaldehyde (1) and pulicatin F (4), hence explaining the initial growth suppression of Pc in the co-culture environment

Gamma-Ray Protection Properties of Bismuth-Silicate Glasses Against Some Diagnostic Nuclear Medicine Radioisotopes: A Comprehensive Study

This study aimed to perform an investigation for the potential implementation of bismuth silicate glasses as novel shield equipment instead of ordinary shields in nuclear medicine facilities. Accordingly, a group of Bi2O3 reinforced silicate glass system were investigated and compared with ordinary shields in terms of their gamma-ray attenuation properties in diagnostic nuclear medicine radioisotope energies emitted from99mTc,111 In,67Ga,123 I,131 I,81mKr,201Tl,133Xe. Mass attenuation coefficient (µm) results for glass samples were calculated comparatively with the XCOM program and MCNPX code. The gamma-ray attenuation parameters such as half value layer (HVL), tenth value layer (TVL), mean free path (MFP), effective atomic number (Zeff ) were obtained in the diagnostic gamma ray energy range from 75 to 336 keV. To confirm the attenuation performance of superior sample, obtained results were extensively compared with ordinary shielding materials. According to the results obtained, BISI6 glass sample with the highest Bi2O3 additive has an excellent gamma-ray protection. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Funding: This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program

Cardiac myosin binding protein C phosphorylation in cardiac disease

Perturbations in sarcomeric function may in part underlie systolic and diastolic dysfunction of the failing heart. Sarcomeric dysfunction has been ascribed to changes in phosphorylation status of sarcomeric proteins caused by an altered balance between intracellular kinases and phosphatases during the development of cardiac disease. In the present review we discuss changes in phosphorylation of the thick filament protein myosin binding protein C (cMyBP-C) reported in failing myocardium, with emphasis on phosphorylation changes observed in familial hypertrophic cardiomyopathy caused by mutations in MYBPC3. Moreover, we will discuss assays which allow to distinguish between functional consequences of mutant sarcomeric proteins and (mal)adaptive changes in sarcomeric protein phosphorylation

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities

Parental obesity and risk factors for cardiovascular disease among their offspring in mid-life: findings from the 1958 British Birth Cohort Study

Background:Few studies have investigated whether parental adiposity is associated with offspring cardiovascular health or the underlying pathways. Studying these associations may help to illuminate the paradox of increasing prevalence of obesity and declining trends in cardiovascular disease (CVD) mortality, which may be partially explained by beneficial adaptations to an obesogenic environment among people exposed to such environments from younger ages.Objective:To investigate associations between parental body mass index (BMI) and risk factors for CVD among their offspring in mid-life and to test whether associations of offspring BMI with CVD risk factors were modified by parental BMI.Methods:Data from parents and offspring in the 1958 British birth cohort were used (N=9328). Parental BMI was assessed when offspring were aged 11 years; offspring BMI, waist circumference and CVD risk factors (lipid levels, blood pressure, glycosylated haemoglobin (HbA1c) and inflammatory and haemostatic markers) were measured at 44-45 years.Results:Higher parental BMI was associated with less favourable levels of offspring risk factors for CVD. Most associations were maintained after adjustment for offspring lifestyle and socioeconomic factors but were largely abolished or reversed after adjustment for offspring adiposity. For some CVD risk factors, there was evidence of effect modification; the association between higher BMI and an adverse lipid profile among offspring was weaker if maternal BMI had been higher. Conversely, offspring BMI was more strongly associated with HbA1c if parental BMI had been higher.Conclusions:Intergenerational influences may be important in conferring the effect of high BMI on CVD risk among offspring

A systematic review of recent clinical practice guidelines on the diagnosis, assessment and management of hypertension.

BACKGROUND: Despite the availability of clinical practice guidelines (CPGs), optimal hypertension control is not achieved in many parts of the world; one of the challenges is the volume of guidelines on this topic and their variable quality. To systematically review the quality, methodology, and consistency of recommendations of recently-developed national CPGs on the diagnosis, assessment and the management of hypertension. METHODOLOGY/PRINCIPAL FINDINGS: MEDLINE, EMBASE, guidelines' websites and Google were searched for CPGs written in English on the general management of hypertension in any clinical setting published between January 2006 and September 2011. Four raters independently appraised each CPG using the AGREE-II instrument and 2 reviewers independently extracted the data. Conflicts were resolved by discussion or the involvement of an additional reviewer. Eleven CPGs were identified. The overall quality ranged from 2.5 to 6 out of 7 on the AGREE-II tool. The highest scores were for "clarity of presentation" (44.4%-88.9%) and the lowest were for "rigour of development" (8.3%-30% for 9 CGPs). None of them clearly reported being newly developed or adapted. Only one reported having a patient representative in its development team. Systematic reviews were not consistently used and only 2 up-to-date Cochrane reviews were cited. Two CPGs graded some recommendations and related that to levels (but not quality) of evidence. The CPGs' recommendations on assessment and non-pharmacological management were fairly consistent. Guidelines varied in the selection of first-line treatment, adjustment of therapy and drug combinations. Important specific aspects of care (e.g. resistant hypertension) were ignored by 6/11 CPGs. The CPGs varied in methodological quality, suggesting that their implementation might not result in less variation of care or in better health-related outcomes. CONCLUSIONS/SIGNIFICANCE: More efforts are needed to promote the realistic approach of localization or local adaptation of existing high-quality CPGs to the national context

Effect of nanostructured lipid carriers on transdermal delivery of tenoxicam in irradiated rats

Transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) is an effective route of drug administration, as it directs the drug to the inflamed site with reduced incidence of systemic adverse effects such as gastric hemorrhage and ulcers. Tenoxicam (TNX) is a member of NSAIDs that are marketed only as oral tablets due to very poor absorption through the skin. The current study intended to formulate and characterize a hydrogel loaded with nanostructured lipid carriers (NLCs) to enhance the transdermal delivery of TNX. Six formulations of TNX were formulated by slight modifications of high shear homogenization and ultrasonication method. The selected formula was characterized for their particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), in-vitro drug release and ex-vivo skin permeation studies. Moreover, the effectiveness of the developed formula was studied in-vivo using carrageenan-induced paw edema and hyperalgesia model in irradiated rats. Formula F4 was chosen from six formulations, as the average diameter was 679.4 ± 51.3 nm, PDI value of about 0.02, zeta potential of −4.24 mV, EE of 92.36%, globules nanoparticles without aggregations and absence of interactions in the developed formula. Additionally, the in-vivo study showed the efficacy of formula F4 (TNX-NLCs hydrogel) equivalent to oral TNX in reducing the exaggerated inflammatory response induced by carrageenan after irradiation. In conclusion, the present findings suggest that TNX-NLCs hydrogel could be a potential transdermal drug delivery system alternative to the oral formulation for the treatment of various inflammatory conditions

Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses

Tetrasubstituted 2-acetylthiophene derivative 5 was synthesized and then condensed with various nitrogen nucleophiles such as 5-amino-1,2,4-triazole, 2-aminobenzimidazole, aniline or p-chloroaniline to afford the corresponding iminothiophene derivatives 6–8a,b. Condensation of thiophene 5 with malononitrile as carbon nucleophile afforded compound 9, which underwent nucleophilic addition with DMF-DMA to afford compound 10. The newly synthesized products were characterized by elemental analysis, IR, MS, 1H-13C-NMR and CHN analysis and then evaluated for their antimicrobial activity. Results of the in vitro antibacterial activity showed that thiophene derivative 7 was found to be more potent than the standard drug gentamicin against Pseudomonas aeruginosa. Some of these compounds showed potential antimicrobial activities. Molecular docking and Osiris/Molinspiration analyses show the crucial role and impact of substituents on bioactivity and indicate the unfavorable structural parameters in actual drug design: more substitution with electronic donor group doesn’t guarantee more effective bioactivity. This study should greatly help in an intelligent and a controlled pharmacomodulation of antibiotics

Physical interventions to interrupt or reduce the spread of respiratory viruses: a cochrane review

BackgroundViral epidemics or pandemics of acute respiratory infections like influenza or severe acute respiratory syndrome pose a world-wide threat. Antiviral drugs and vaccinations may be insufficient to prevent catastrophe.ObjectivesTo systematically review the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses.Search strategyWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2); MEDLINE (1966 to May 2009); OLDMEDLINE (1950 to 1965); EMBASE (1990 to May 2009); and CINAHL (1982 to May 2009).Selection criteriaWe scanned 2958 titles, excluded 2790 and retrieved the full papers of 168 trials, to include 59 papers of 60 studies. We included any physical interventions (isolation, quarantine, social distancing, barriers, personal protection and hygiene) to prevent transmission of respiratory viruses. We included the following study designs: randomised controlled trials (RCTs), cohorts, case controls, cross-over, before-after, and time series studies.Data collection and analysisWe used a standardised form to assess trial eligibility. RCTs were assessed by: randomisation method; allocation generation; concealment; blinding; and follow up. Non-RCTs were assessed for the presence of potential confounders, and classified into low, medium, and high risks of bias.Main resultsThe risk of bias for the four RCTs, and most cluster RCTs, was high. The observational studies were of mixed quality. Only case-control data were sufficiently homogeneous to allow meta-analysis. The highest quality cluster RCTs suggest respiratory virus spread can be prevented by hygienic measures, such as handwashing, especially around younger children. Additional benefit from reduced transmission from children to other household members is broadly supported in results of other study designs, where the potential for confounding is greater. Six case-control studies suggested that implementing barriers to transmission, isolation, and hygienic measures are effective at containing respiratory virus epidemics. We found limited evidence that N95 respirators were superior to simple surgical masks, but were more expensive, uncomfortable, and caused skin irritation. The incremental effect of adding virucidals or antiseptics to normal handwashing to decrease respiratory disease remains uncertain. Global measures, such as screening at entry ports, were not properly evaluated. There was limited evidence that social distancing was effective especially if related to the risk of exposure.Authors' conclusionsMany simple and probably low-cost interventions would be useful for reducing the transmission of epidemic respiratory viruses. Routine long-term implementation of some of the measures assessed might be difficult without the threat of a looming epidemic