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Background/objective: The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance., Methods: Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service., Results: We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance., Conclusion: Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found., (© 2024. The Author(s).)

Transiently associating amines with therapeutic agents through the formation of ion-pairs has been established both in vitro and in vivo as an effective means to systemically direct drug delivery to the lung via the polyamine transport system (PTS). However, there remains a need to better understand the structural traits required for effective PTS uptake of drug ion-pairs. This study aimed to use a structurally related series of amine counterions to investigate how they influenced the stability of theophylline ion-pairs and their active uptake in A549 cells. Using ethylamine (mono-amine), ethylenediamine (di-amine), spermidine (tri-amine) and spermine (tetra-amine) as counterions the ion-pair affinity was shown to increase as the number of protonated amine groups in the counterion structure increased. The mono and diamines generated a single hydrogen bond and the weakest ion-pair affinities (pK FTIR : 1.32 ± 0.04 and 1.43 ± 0.02) whereas the polyamines produced two hydrogen bonds and thus the strongest ion-pair affinities (pK FTIR : 1.93 ± 0.05 and 1.96 ± 0.04). In A549 cells depleted of endogenous polyamines using α-difluoromethylornithine (DFMO), the spermine-theophylline uptake was significantly increased (p < 0.05) compared to non-amine depleted cells and this evidenced the active PTS sequestering of the ion-pair. The mono-amine and di-amine failed to enhance theophylline uptake in these A549 cells, but the tri-amine and tetra-amine both almost doubled the theophylline uptake into the cells when compared to the uptake of free drug. As the data indicated that polyamines with at least 3 amines were required to form ion-pairs that could enhance A549 cell uptake, it suggested that at least two amines were required to physically stabilise the ion-pair and one to interact with the PTS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Herein we report the synthesis and characterization of electro-conductive chitosan-gelatin-agar (Cs-Gel-Agar) based PEDOT: PSS hydrogels for tissue engineering. Cs-Gel-Agar porous hydrogels with 0-2.0% ( v / v ) PEDOT: PSS were fabricated using a thermal reverse casting method where low melting agarose served as the pore template. Sample characterizations were performed by means of scanning electron microscopy (SEM), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray diffraction analysis (XRD) and electrochemical impedance spectroscopy (EIS). Our results showed enhanced electrical conductivity of the cs-gel-agar hydrogels when mixed with DMSO-doped PEDOT: PSS wherein the optimum mixing ratio was observed at 1% ( v / v ) with a conductivity value of 3.35 × 10 -4 S cm -1 . However, increasing the PEDOT: PSS content up to 1.5 % ( v / v ) resulted in reduced conductivity to 3.28 × 10 -4 S cm -1 . We conducted in vitro stability tests on the porous hydrogels using phosphate-buffered saline (PBS) solution and investigated the hydrogels' performances through physical observations and ATR-FTIR characterization. The present study provides promising preliminary data on the potential use of Cs-Gel-Agar-based PEDOT: PSS hydrogel for tissue engineering, and these, hence, warrant further investigation to assess their capability as biocompatible scaffolds.

Background: Nasopharyngeal carcinoma (NPC) is endemic in Southern Chinese and Southeast Asian populations. Geographical and ethnic clustering of the cancer is due to genetic, environmental, and lifestyle risk factors. This case-control study aimed to identify or confirm both genetic and non-genetic risk factors for NPC in one of the endemic countries, Malaysia., Materials and Method: A panel of 768 single-nucleotide polymorphisms (SNPs) previously associated with various cancers and known non-genetic risk factors for NPC were selected and analyzed for their associations with NPC in a case-control study., Results: Statistical analysis identified 40 SNPs associated with NPC risk in our population, including 5 documented previously by genome-wide association studies (GWAS) and other case-control studies; the associations of the remaining 35 SNPs with NPC were novel. In addition, consistent with previous studies, exposure to occupational hazards, overconsumption of salt-cured foods, red meat, as well as low intake of fruits and vegetables were also associated with NPC risk., Conclusions: In short, this study confirmed and/or identified genetic, environmental and dietary risk factors associated with NPC susceptibility in a Southeast Asian population.

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs; as novel solvents for improving the solubility of drugs in carriers; as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs; and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structureactivity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs. [ABSTRACT FROM AUTHOR]

This study aimed to study the habitat preferences and daylight behaviour of the Irrawaddy dolphin (Orcaella brevirostris) and the Indo-Pacific finless porpoise (Neophocaena phocaenoides) off the west coast of Penang Island, Malaysia. Between February 2019 and April 2021, 87 boat-based surveys were undertaken using predetermined survey routes. Species occurrence, behaviour, and habitat use were recorded. Irrawaddy dolphins (n = 52 sightings) were recorded with a mean group size of 3.6 (SE = 0.4) and finless porpoises (n = 35 sightings) with a mean group size of 2.5 (SE = 0.2). Both species were found between 0.4 km and 7.9 km from the shore. Encounter rate for Irrawaddy dolphins was 0.19 sightings per effort hour and 1.4 sightings per 100 km while for finless porpoises it was 0.13 sightings per effort hour and 0.9 sightings per 100 km. A higher coefficient of area use (AU> 1.5%) for Irrawaddy dolphins occurred at the estuarine areas off Sungai [=River] Pinang and Sungai Burung while higher coefficient of area use for finless porpoises was seen near Teluk [=Bay] Kampi and Sungai Pinang. In terms of activity budget, milling behaviour was the most recorded behaviour for both Irrawaddy dolphin and finless porpoise at 36.4% and 51.6% respectively. Resting behaviour for both the Irrawaddy dolphin and the finless porpoise was recorded for the first time off west Penang. The information obtained for habitat use and behaviour would contribute towards better management of Penang marine areas and conservation strategies for the Irrawaddy dolphin and the finless porpoise. [ABSTRACT FROM AUTHOR]

Objective: Nasopharyngeal carcinoma (NPC) is a common malignant tumour in Southeast Asia, especially in southern China. ABO blood groups have been proven to play an important role in many cancers. However, it is still controversial whether the ABO blood group has a definite relationship to susceptibility to NPC and the prognosis of NPC patients. This meta-analysis was performed to elucidate the correlation between ABO blood group and NPC to provide more data for clinical practice. Methods: A systematic search was performed of the Chinese National Knowledge Infrastructure (CNKI), Wanfang, Web of Science, EMBASE, and PubMed databases up to December 31, 2020. Stata 11.0 statistical software was used for this meta-analysis. Results: According to the inclusion and exclusion criteria, a total of 6 studies including 6938 patients with NPC were selected. Blood group O was relevant to Chinese NPC patients, and patients with blood group O had a significantly lower incidence of NPC, while blood group A had no correlation with susceptibility to NPC. There was no difference in the 3-year overall survival (OS), locoregional relapse-free survival (LRRFS) or distant metastasis-free survival (DMFS) rates between patients with blood group O and those with non-O blood groups; worse 5-year OS, LRRFS and DMFS rates were found in patients with blood group O, whereas blood group A was not related to prognosis. Conclusion: Blood group O in Chinese patients with NPC seems to be a protective factor for morbidity. However, once patients with blood group O are diagnosed with NPC, this blood group often indicates unfavourable OS, LRRFS and DMFS rates. It is recommended that more attention should be paid to the influence of blood group factor on patients in the treatment of NPC. [ABSTRACT FROM AUTHOR]

A ring oscillator is an important circuit used to evaluate the performance limits of any digital technology. The advantages of Graphene field effect transistor (GFET) over current CMOS technologies make it a prominent candidate for future high-performance electronics. In this paper, a GFET model is implemented in Verilog-A, and GFET design and analysis of a ring oscillator are performed using advanced design system (ADS) tool. By using GFET ring oscillator, the designed circuit is simulated using a 0.18 µm GFET process in ADS environment. The results show that the power consumption is 9.98 mW, while the VCO generates 24.12 GHz at 1 V. The effect of Graphene channel length variations on the frequency span, power dissipation and phase noise of GFET ring oscillators are studied. The main performance characteristics of the ring oscillator are compared with CMOS technology. It is shown that a GFET ring oscillator gives a higher oscillation frequency and has more power dissipation. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is one of the most common malignant head and neck cancers in southern China. Although the local and regional control of NPC has been considerably improved, patients with advanced disease still suffer from poor prognosis. Statins inhibit the mevalonate pathway and play antiproliferative and proapoptotic roles in a number of cancer cells. However, the effects and molecular mechanism of statins in NPC treatment remain unclear. In this study, the cell viability of NPC cell line, C666-1, after simvastatin exposure was determined using the alamarBlue Cell Viability Assay. Cell apoptosis in C666-1 treated with simvastatin was assessed by flow cytometry and TUNEL assay. The expression levels of cell cycle regulatory proteins were determined using western blotting. Simvastatin markedly decreased cell viability in a concentration-dependent manner, increased caspase 3 activity and induced apoptosis in C666-1 cells. Simvastatin induced Bim expression by regulating phosphorylation of transcriptional factor c-Jun. Simvastatin treatment induced cell cycle arrest in the G1 phase in C666-1 cells by inhibiting the expression of cyclin D1 and cyclin-dependent kinase 4, and enhancing p27 expression. Simvastatin treatment inhibited protein kinase B and extracellular signal regulated kinase 1/2 activation. In conclusion, the results of the present study reveal the possible molecular mechanism of simvastatin-induced anti-tumor effects in C666-1 and suggest that simvastatin is a potential chemotherapy agent in NPC treatment. [ABSTRACT FROM AUTHOR]

Dysregulation of the cell cycle and the resulting aberrant cellular proliferation has been highlighted as a hallmark of cancer. Certain traditional Chinese medicines can inhibit cancer growth by inducing cell cycle arrest. In this study we explore the effect of Hedyotis diffusae Herba-Andrographis Herba on the cell cycle of nasopharyngeal carcinoma (NPC). Hedyotis diffusae Herba-Andrographis Herba-containing serum was prepared and then added to the cell culture medium. BrdU, comet, and FUCCI assays, western blot analysis and flow cytometry analysis revealed that Hedyotis diffusae Herba-Andrographis Herba treatment significantly alters cell proliferation, DNA damage, and cell cycle distribution. Xenograft mouse model experiments were performed, confirming these in vitro findings in vivo. Treatment with Hedyotis diffusae Herba-Andrographis Herba inhibited cell proliferation, promoted DNA damage, and arrested NPC cells progression from G1 to S phase. Further examination of the underlying molecular mechanisms revealed that treatment with Hedyotis diffusae Herba-Andrographis Herba increased the expression of p53 and p21, while reducing that of CCND1, Phospho-Rb, E2F1, γH2AX, and Ki-67 both in vivo and in vitro. Conversely, the inhibition of p53 and p21 could abolish the promoting effect of Hedyotis diffusae Herba-Andrographis Herba on the NPC cell cycle arrest at the G1 phase, contributing to the proliferation of NPC cells. Hedyotis diffusae Herba-Andrographis Herba suppressed the tumor growth in vivo. Overall, these findings suggest that Hedyotis Diffusae Herba-Andrographis prevent the progression of NPC by inducing NPC cell cycle arrest at the G1 phase through a p53/p21-dependent mechanism, providing a novel potential therapeutic treatment against NPC., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Viral, dietary and genetic factors have been implicated in nasopharyngeal carcinoma (NPC), however, the molecular mechanism underlying its pathogenesis remains to be fully elucidated. MicroRNAs (miRNAs) have been reported to be important in NPC tumorigenesis, with a previous miRNA microarray study showing the downregulation of miRNA (miR)-429 in NPC cells. However, the possible mechanisms of action of miR-429 have not been examined. In the present study, the expression profiles of miR-429 were detected using reverse transcription-quantitative polymerase chain reaction analysis in CNE-1 and CNE-2 cells, which are two generally used NPC cells with different degrees of differentiation. Subsequently, cell proliferation, invasion and migration were analyzed in miR-429-overexpressing CNE-2 cells, and the modulatory function of miR-429 was also investigated using two target genes, zinc finger E-Box-binding homeobox 1 (ZEB1) and CRK-like (CRKL), by transfection with miR-429 mimic or anti-miR-429. Significant changes in the expression of miR-429 were detected, particularly in low-differentiated CNE-2 cells, with higher levels of epidemicity and malignancy. Additional results revealed that miR-429 inhibited the invasion and migration of the CNE-2 cells, whereas no significant effect on cell growth was observed. In addition, the mRNA and protein expression levels of the two target genes, ZEB1 and CRKL, were negatively regulated by miR-429, demonstrated through gain-of-function and loss-of-function investigations, indicating that these two functional downstream targets may be involved in the inhibitory effects of miR-429 on NPC migration and invasion. miR-429 may act as a negative regulatory factor of NPC tumorigenesis, involving the functions of its downstream targets, ZEB1 and CRKL. The results suggested miR-429 as a potential candidate for miRNA-based prognosis or therapy against NPC. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx, and is extremely common in southern regions of China. Although the standard combination of radiotherapy and chemotherapy has improved the efficiency in patients with NPC, relapse and early metastasis are still the common causes of mortality. Cancer stem-like cells (CSCs) or tumor initial cells are hypothesized to be involved in cancer metastasis and recurrence. Over the past decade, increasing numbers of studies have been carried out to identify CSCs from human NPC cells and tissues. The present paper will summarize the investigations on nasopharyngeal CSCs, including isolation, characteristics, and therapeutic approaches. Although there are still numerous challenges to translate basic research into clinical applications, understanding the molecular details of CSCs is essential for developing effective strategies to prevent the recurrence and metastasis of NPC. [ABSTRACT FROM AUTHOR]