Evaluation of pharmacological rescue of melanocortin-4 receptor nonsense mutations by aminoglycoside

This research was funded by the Deutsche Forschungsgemeinschaft (DFG) (German Research Foundation) through SFB1423, project number 421152132, subprojects B02 to H.B. and P.K., A01 and Z03 to P.S., and C03 to P.A., and project numbers 430971019, 430970922 and KU 2673/6-1 to P.K., and by the European Union’s Horizon 2020 MSCA Program under grant agreement 956314 (ALLODD) to P.S.The melanocortin-4 receptor (MC4R) is critical for central satiety regulation, therefore presenting a potent target for pharmacological obesity treatment. Melanocortin-4 receptor mutations prevalently cause monogenetic obesity. A possibility of overcoming stop mutations is aminoglycoside-mediated translational readthrough. Promising results were achieved in COS-7 cells, but data for human cell systems are still missing, so uncertainty surrounds this potential treatment. In transfected HEK-293 cells, we tested whether translational readthrough by aminoglycoside Geneticin combined with high-affinity ligand setmelanotide, which is effective in proopiomelanocortin or leptin receptor deficiency patients, is a treatment option for affected patients. Five MC4R nonsense mutants (W16X, Y35X_D37V, E61X, W258X, Q307X) were investigated. Confocal microscopy and cell surface expression assays revealed the importance of the mutations' position within the MC4R. N-terminal mutants were marginally expressed independent of Geneticin treatment, whereas mutants with nonsense mutations in transmembrane helix 6 or helix 8 showed wild-type-like expression. For functional analysis, Gs and Gq/11 signaling were measured. N-terminal mutants (W16X, Y35X_D37V) showed no cAMP formation after challenge with alpha-MSH or setmelanotide, irrespective of Geneticin treatment. Similarly, Gs activation was almost impossible in W258X and Q307X with wild-type-like cell surface expression. Results for Gq/11 signaling were comparable. Based on our data, this approach improbably represents a therapeutic option.Publisher PDFPeer reviewe

Correlation Between Lund-Mackay Ct Scores Before and after Surgery for Nasal Polyposis, An Evaluation of Medical and Surgical Treatment in Nasal Polyposis

Objective: To determine the efficacy of functional endoscopic sinus surgery on treating nasal polyps in terms of improvement in the Lund-MacKay score. Study Design: Quasi-experimental study. Place and Duration of Study: Department of ENT, Combined Military Hospital, Rawalpindi Pakistan, Jul 2021 to Jan 2022. Methodology: Seventy patients suffering from chronic rhino-sinusitis were included in this study. All patients were assessed before and three weeks after treatment using the Lund-MacKay computed tomography score. Group-A patients received management with a hybrid therapy using functional endoscopic sinus surgery and drug therapy, while Group-B patients received conservative management alone. Results: The majority of the patients in our sample were males 43(61.4%), a mean duration of complaints of 6.47±1.91 months.Hybrid therapy showed a significantly higher improvement in relieving nasal obstruction when compared to conservative management alone (p=0.033). Conservative management appeared to be more effective in relieving nasal discharge and headache, although this did not approach statistical significance (p=0.11 and 0.43, respectively). Facial pain and olfactory function showed a greater improvement with hybrid therapy, which was not statistically significant (p=0.097 and 0.131, respectively).The Lund-MacKay computed tomography scores with conservative and hybrid therapy were 13.91±4.11 and 11.17±4.17 at the end of treatment (p=0.007), demonstrating that hybrid therapy was superior. Conclusion: Functional Endoscopic Sinus Surgery combined with limited medical therapy is superior to pure medical therapy in terms of improvement in Lund-MacKay CT scores and relief in symptoms of nasal obstruction

The Prevalence, Severity and the Contributive Organizational Factors of Burnout Syndrome among Pakistani Physiotherapists

Background: This is fast age where many underlying health issues go unaddressed in race of progress such as Burnout. This state of mental illness due to chronic stress that may be comprised of emotional exhaustion, personal accomplishment and depersonalization. This is thought to be associated with occupation and organizational parameters. This can put physiotherapist compromised health, social and family life, dealing with patients and low performance at work. Objective: To determine burnout level and its severity among physical therapists and associated organizational factors Material and method: Cross sectional survey was conducted in sample of convenience comprising 120 physiotherapists. The participants were of both gender and age above 25 years. The data was collected by using Maslach Burnout Inventory Scale and data analysis was executed using SPSS version 20. Continuous variables including age, total scores were analyzed for mean and standard deviation, while frequency percentages were calculated against categorical variables. Results: Results of the study demonstrated that mean+SD score for emotional exhaustion was 16.55+ 5.07, mean+SD score for personal accomplishment was 44.73+1.54 and mean+SD score for depersonalization was 0.75+0.93. Conclusion: The study concluded that physiotherapists demonstrated mild to moderate level of burnout. Burnout symptoms apparently found significantly associated with high working hours, private sector, female gender and less physical activity.           &nbsp

Novel Concepts of Soft Multi Rough Sets with MCGDM for the Selection of Humanoid Robot

This paper comes out with a fascinating fusion of soft sets, multisets and rough sets. We introduce novel concepts of soft multi rough sets (SMR-Sets) and soft multi approximation spaces. We present some fundamental properties of SMR-approximations and their related examples. We also discuss the variation between some properties of Pawlak approximation space, soft approximation spaces and the same properties of soft multi approximation spaces. Furthermore, we present two different algorithms based on soft multi rough set with an application to multi-criteria group decision-making (MCGDM) for the selection of humanoid robot

Floristic Indices, Nutrients Accumulation and Nutrients Uptake Ratios of Some Medicinal Plants Along the Altitudinal Gradients of Sand Dunes in Thal Desert of Pakistan

Background: In deserts, precipitation causes unequal distribution of nutrients along altitude of dunes. This can influence the nutrients uptake and distribution of plant species. Objective: The objective of the studies was to explore the concentration and uptake ratios of various ions in soil of Thal desert along with finding some floristic indices of medicinal plants endemic to the desert. The sites were selected in district Muzaffar Garth (Pakistan). Methods: Sand dunes for the studies were selected as being of almost equal heights and with typical vegetations type. Plants and their samples were selected and collected in replicates and data were analyzed statistically.  Soils samples were brought to laboratory for determination of electrical conductivity, nutrients, organic matter and bi-carbonates. The relationship with uptake was drawn after analysis of samples. Results: In the upper most altitude EC, nitrogen and sodium contents were the most in quantity. While the contents of bicarbonate, phosphorus and organic matter were maximum in lower most altitude of dunes. Regarding the nutrient’s status, maximum potassium concentration (125.70mg/g) was in Aerva javanica leaves. Maximum potassium uptake and accumulation percentage (311.26%) Aerva javanica stem. Maximum phosphorus concentration (5.41mg/g) in Haloxylone stockii bark. Maximum phosphorus uptake and accumulation percentage (253.65%) Aerva javanica flower. Maximum sodium concentration (13.51mg/g) was in Haloxylone stockii stem. Maximum sodium uptake and accumulation percentage (93.81%) was in Crotollaria  burhia   stem. As regard the floristic indices, at the most top 1st altitude zone of sand dune, maximum frequency was of Caligonum polygonoides, Aerva javanica, Crotollaria burhia and Symbopogon jawarancusa. In 2nd altitude, maximum frequency was of Haloxylone stocksii, Caligonum polygonoides, Aerva javanica and Crotollaria burhia. In altitude 3, maximum frequency was of Aerva javanica and Fogonia arabica. Similarly, in altitude 1, maximum density was of Symbopogon jawarancusa. In altitude zone 2, maximum density was of Crotollaria burhia and in 3rd altitude zone, maximum density was of Aesphodalus tenuifolius. Conclusion: It is concluded that altitudinal variations of soil physio-chemical properties were found in sand dunes. Also, vegetation varied along soil physical and chemical properties

IoT applications and challenges in smart cities and services

Abstract Internet of Things (IoT) is a revolutionary and novel platform where a smart network connects to the large number of electronic devices via internet through available communication systems for reliable and real time connectivity, sensing thus acquiring data from sensors, computing and actuating devices. A review of the current status of IoT features, architecture, communication infrastructure and applications is presented here. Number of IoT applications and challenges in the development of smart cities are covered about this innovative technological platform in this review along with communication protocols characteristics and applications. IoT aided smart city services, health applications, transport applications and smart grid improvements are also discussed. Many challenges and issues related to security, communication, applications and system architecture along with future directions of IoT technology are elaborated in detail

DEAE-Dextran Coated AgNPs: A Highly Blendable Nanofiller Enhances Compressive Strength of Dental Resin Composites

Micro-crack formation and resultant bacterial infiltration are major causes of secondary caries formation in dental resin-based composite restorations. Improving dental resin composites’ mechanical and biological properties using highly bendable nanoparticles (NPs) can resolve this issue. This study aims to develop novel Diethylaminoethyl (DEAE)-Dextran silver nanoparticles (AgNPs) and subsequently modify composite resins with these NPs to enhance their mechanical and antibacterial properties. DEAE-Dextran AgNPs were successfully synthesized using a chemical reduction method that was confirmed with the help of ultraviolet-visible (UV-Vis) spectroscopy, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), Zeta potential, and energy-dispersive X-ray spectroscopy (EDS). Antibacterial activity of a composite disc with DEAE-Dextran AgNPs was tested against Streptococcus mutans, Enterococcus faecalis, and oral microcosm. The composite discs prepared with DEAE-Dextran AgNPs exhibited excellent antibacterial activity compared with composite resin reinforced by simple AgNPs (p p < 0.05). Moreover, unlike AgNPs, DEAE-Dextran AgNPs were found to be less hemolytic. The results establish strong ground applications for DEAE-Dextran-modified dental composite resins in restorative dental applications

MOF derived novel zero-valent iron @ graphitic carbon-based nanoreactors for selective reduction of hazardous 4-nitrophenol

Fabrication of stable and efficient zerovalent non-noble metal-based nanostructured catalyst has emerged as the hot area of research for wastewater treatment due to their low cost and facile natural source availability. In this work, the rationally controlled calcination of iron-terephthalate MOF has produced the magnetically active zero-valent iron-based nanostructured catalyst. Unlike other synthesis approaches, MOF’s temperature-controlled calcination has offered highly effective and stable metallic iron nanoparticles encapsulated in few-layered porous graphitic carbons. The developed nanostructured catalyst was applied for room temperature conversion of hazardous 4-Nitrophenol (4-NiP) to a value-added industrial intermediate 4-Aminophenol (4-AP) by exploiting sodium borohydride as a hydrogen donor agent. The synthesized zerovalent iron-based nanostructured catalysts were thoroughly investigated and characterized by powder X-ray diffraction (pXRD), infrared and Raman spectroscopy, thermogravimetric analysis (TGA), energy dispersive X-Rays (EDS), X-ray photoelectron (XPS) spectroscopy, and transmission electron microscopy (TEM). The UV–Vis spectroscopy was used for the monitoring of the conversion of the 4-NiP into 4-AP. The conversion analysis result has shown that the MOF-based precursors’ calcination temperature has played a critical role in the potency of the catalyst for converting the 4-NiP into 4-AP. The outer porous architecture provided the facile adsorption and desorption of the 4-NiP on the active nanostructured metallic iron catalyst. The maximum degradation of 4-NiP into 4-AP has taken place in a short time of 3 ​min at a rate constant of 0.0149 s−1. In terms of economic perspective and high catalytic efficiency, the developed low coast nanostructured catalyst is the right choice over the reported noble metal-based catalyst for the room temperature conversion of 4NiP to a value-added product

Evaluation of pharmacological rescue of melanocortin-4 receptor nonsense mutations by aminoglycoside

The melanocortin-4 receptor (MC4R) is critical for central satiety regulation, therefore presenting a potent target for pharmacological obesity treatment. Melanocortin-4 receptor mutations prevalently cause monogenetic obesity. A possibility of overcoming stop mutations is aminoglycoside-mediated translational readthrough. Promising results were achieved in COS-7 cells, but data for human cell systems are still missing, so uncertainty surrounds this potential treatment. In transfected HEK-293 cells, we tested whether translational readthrough by aminoglycoside Geneticin combined with high-affinity ligand setmelanotide, which is effective in proopiomelanocortin or leptin receptor deficiency patients, is a treatment option for affected patients. Five MC4R nonsense mutants (W16X, Y35X_D37V, E61X, W258X, Q307X) were investigated. Confocal microscopy and cell surface expression assays revealed the importance of the mutations' position within the MC4R. N-terminal mutants were marginally expressed independent of Geneticin treatment, whereas mutants with nonsense mutations in transmembrane helix 6 or helix 8 showed wild-type-like expression. For functional analysis, Gs and Gq/11 signaling were measured. N-terminal mutants (W16X, Y35X_D37V) showed no cAMP formation after challenge with alpha-MSH or setmelanotide, irrespective of Geneticin treatment. Similarly, Gs activation was almost impossible in W258X and Q307X with wild-type-like cell surface expression. Results for Gq/11 signaling were comparable. Based on our data, this approach improbably represents a therapeutic option.</p