Search

To monitor for drug-related cardiac arrhythmias, psychiatrists regularly perform and interpret 12-lead (12L) and, increasingly often, six-lead (6L) electrocardiograms (ECGs). It is not known how training on this complex skill is updated or how well psychiatrists can interpret relevant arrhythmias on either device.

Abstract Four yeast strains were isolated from the gut of stingless bee, collected in Churdhar, Himachal Pradesh, India. Physiological characterization, morphological examination, and sequence analysis of small subunit ribosomal RNA (18S rRNA) genes, internal transcribed spacer (ITS) region, and D1/D2 domain of the large subunit rRNA gene revealed that the four strains isolated from the gut of stingless bee belonged to the Debaryomyces clade. Strain CIG-23HT showed sequence divergence of 7.5% from Debaryomyces nepalensis JCM 2095T, 7.8% from Debaryomyces udenii JCM 7855T, and Debaryomyces coudertii JCM 2387T in the D1/D2 domain. In the ITS region sequences, strain CIG-23HT showed a 15% sequence divergence from Debaryomyces nepalensis JCM 2095T and Debaryomyces coudertii JCM 2387T. In 18S rRNA gene sequence, the strain CIG-23HT showed 1.14% sequence divergence from Debaryomyces nepalensis JCM 2095 and and Debaryomyces coudertii JCM 2387, and 0.83% sequence divergence from Debaryomyces hansenii NRRL Y-7426. Strain CIG-23HT can utilize more carbon sources than closely related species. The findings suggest that strain CIG-23HT is a novel species of the genus Debaryomyces, and we propose to name it as Debaryomyces apis f.a., sp. nov. The holotype is CBS 16297T, and the isotypes are MTCC 12914T and KCTC 37024T. The MycoBank number of Debaryomyces apis f.a., sp. nov. is MB836065. Additionally, a method using cresol red and Bromothymol blue pH indicator dyes was developed to screen for lipase producers, which is more sensitive and efficient than the currently used phenol red and rhodamine B dye-based screening methods, and avoids the problem of less differentiable zone of hydrolysis.

Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats.

— Landslides are short-lived phenomena but can cause extraordinary changes in the landscape, destroying life and property. Mitigation and management of natural disasters are important issues. Recognising this, the United Nations in the year 2004 made gout “Learning from today’s disaster for tomorrow’s hazards”(UNISDR website). The Nadugani Hill is situated in SE of Panthalur taluk, Nilgiris District. The ghat section is 6.5 km in length. The region has moderate climatic conditions. The average rainfall in this ghat section is 3500mm. In this ghat section, two major activities, like tea plantation and heavy truck movement, lead to slope instability during heavy monsoon season. The study mainly aimed to use terrain factors and identify land susceptibility zonation. In this context, a detailed investigation was carried out using geomorphology, parent rock weathering, structural mapping, runoff and anthropogenic activities. The ghat section is covered by a thick Reserve Forest, a tea plantation and a smaller area enclosed by settlement. Hornblende biotitic gneiss and patches of charnockite in some places cover the study area. The gneissic rocks are highly fissile in nature. NE - SW fault controls the drainage systems, contributing to landslides. The structural data delineated from IRS-RS2, L-IV data and the lineaments are oriented in NE - SW. Morphology is one of the prime factors that cause which is landslides. Satellite imageries identify structural and fracture valleys in this study area. The thematic maps were converted into a digital format using ARC Map (10.2v) software. GIS-based Decision Support System provides advanced models of a system to identify land susceptibility zonation. Based on the analysis, the study area has been categorized into low, moderate, high and very high classes.

Dina Keumala Sari,1 Suresh Mani,2 Muhammad Fadli,3 Riyadh Ihksan,4 Yetty Machrina,5 Nurfida Khairina Arrasyid,6 Kamal Basri Siregar,7 Agung Sunarno8 1Department of Nutrition, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 2Department of Physiotherapy, Faculty of Applied Medical Science, Lovely Professional University, Phagwara, Punjab, India; 3Medical Education and Professional Program, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 4Department of Science and Technology, North Sumatra Branch-National Sport Committee, Medan, Indonesia; 5Department of Physiology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 6Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 7Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 8Department of Sport, Faculty of Sport Science, Universitas Medan Area, Medan, IndonesiaCorrespondence: Dina Keumala Sari, Email dina@usu.ac.idBackground: Difficulties in exercising have occurred for the entire world’s population during this COVID-19 pandemic, especially in the second wave at the end of 2021. Most worrying is the lack of physical activity in young adults, as lack of exercise will increase the risk of noncommunicable diseases in the future. The youth such as university student can be agents of change, to increase physical activity, from sedentary to sport life. This study aimed to determine the relationship between knowledge, attitudes, and actions of university students and the correlation between the related variables.Methods: This study is a cross-sectional observational study involving 458 Asian university students based on Asian and African nationalities. This research was conducted from December 2021 to January 2022, during the second wave of the COVID-19 pandemic in Asia. The variables studied were the knowledge, attitudes, and actions of university students with regard to sports, and the statistical test used was the Chi-squared test.Results: The results showed that the research subjects were mainly from Indonesia and India (95.8%), there were more women than men (69.9% vs 30.1%), the most common age range was 18– 20 years (61.4%), and 45.4% had a normal body mass index. In total, 48.3% had high knowledge, 93.4% had a positive attitude, and 34.7% had good practice. There was a significant relationship between knowledge and attitude (p=0.002) but not with action.Conclusion: This study found that good knowledge was associated with a good attitude, but due to the COVID-19 pandemic with activity restrictions on university students, there was no relationship with action.Keywords: athlete, exercise, physical activity, understand, youth

Kah Min Yap,1 Mahendran Sekar,1 Shivkanya Fuloria,2 Yuan Seng Wu,3,4 Siew Hua Gan,5 Nur Najihah Izzati Mat Rani,6 Vetriselvan Subramaniyan,7 Chandrakant Kokare,8 Pei Teng Lum,1 M Yasmin Begum,9 Shankar Mani,10 Dhanalekshmi Unnikrishnan Meenakshi,11 Kathiresan V Sathasivam,12 Neeraj Kumar Fuloria2 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 2Faculty of Pharmacy, AIMST University, Kedah, 08100, Malaysia; 3Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 4Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 5School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia; 6Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 7Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia; 8Department of Pharmaceutics, Sinhgad Technical Education Society’s, Sinhgad Institute of Pharmacy, Narhe, Pune, 411041, India; 9Department of Pharmaceutics, College of Pharmacy, King Khalid University (KKU), Asir-Abha, 61421, Saudi Arabia; 10Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, Karnataka, 571418, India; 11College of Pharmacy, National University of Science and Technology, Muscat, 130, Oman; 12Faculty of Applied Sciences, AIMST University, Kedah, 08100, MalaysiaCorrespondence: Neeraj Kumar Fuloria; Shivkanya FuloriaFaculty of Pharmacy, AIMST University, Kedah, 08100, MalaysiaTel +60 16 4037685; +60 14 3034057Email neerajkumar@aimst.edu.my; shivkanya_fuloria@aimst.edu.myAbstract: Despite recent advances in the diagnosis and treatment of breast cancer (BC), it remains a global health issue affecting millions of women annually. Poor prognosis in BC patients is often linked to drug resistance as well as the lack of effective therapeutic options for metastatic and triple-negative BC. In response to these unmet needs, extensive research efforts have been devoted to exploring the anti-BC potentials of natural products owing to their multi-target mechanisms of action and good safety profiles. Various medicinal plant extracts/essential oils and natural bioactive compounds have demonstrated anti-cancer activities in preclinical BC models. Despite the promising preclinical results, however, the clinical translation of natural products has often been hindered by their poor stability, aqueous solubility and bioavailability. There have been attempts to overcome these limitations, particularly via the use of nano-based drug delivery systems (NDDSs). This review highlights the tumour targeting mechanisms of NDDSs, the advantages and disadvantages of the major classes of NDDSs and their current clinical status in BC treatment. Besides, it also discusses the proposed anti-BC mechanisms and nanoformulations of nine medicinal plants’ extracts/essential oils and nine natural bioactive compounds; selected via the screening of various scientific databases, including PubMed, Scopus and Google Scholar, based on the following keywords: “Natural Product AND Nanoparticle AND Breast Cancer”. Overall, these nanoformulations exhibit improved anti-cancer efficacy against preclinical BC models, with some demonstrating biocompatibility with normal cell lines and mouse models. Further clinical studies are, however, warranted to ascertain their efficacy and biocompatibility in humans.Keywords: breast cancer, drug delivery, molecular mechanisms, nanoparticles, natural products, phytomedicine

Mohd Nasarudin Watroly,1 Mahendran Sekar,1 Shivkanya Fuloria,2 Siew Hua Gan,3 Srikanth Jeyabalan,4 Yuan Seng Wu,5,6 Vetriselvan Subramaniyan,7 Kathiresan V Sathasivam,8 Subban Ravi,9 Nur Najihah Izzati Mat Rani,10 Pei Teng Lum,1 Jaishree Vaijanathappa,11 Dhanalekshmi Unnikrishnan Meenakshi,12 Shankar Mani,13 Neeraj Kumar Fuloria2 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 2Faculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Kedah, 08100, Malaysia; 3School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia; 4Department of Pharmacology, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research (DU), Chennai, Tamil Nadu, 600116, India; 5Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 6Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 7Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia; 8Faculty of Applied Science & Centre of Excellence for Biomaterials Engineering, AIMST University, Kedah, 08100, Malaysia; 9Department of Chemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 640 021, India; 10Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 11Department of Pharmaceutical Chemistry, School of Life Sciences, JSS Academy of Higher Education and Research Mauritius, Vacoas, Mauritius; 12College of Pharmacy, National University of Science and Technology, Muscat, 130, Oman; 13Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, Karnataka, 571418, IndiaCorrespondence: Neeraj Kumar Fuloria; Shivkanya FuloriaFaculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Kedah, 08100, MalaysiaTel +60 16 4037685; +60 14 3034057Email neerajkumar@aimst.edu.my; shivkanya_fuloria@aimst.edu.myAbstract: Anthraquinones (AQs) are found in a variety of consumer products, including foods, nutritional supplements, drugs, and traditional medicines, and have a wide range of pharmacological actions. Rubiadin, a 1,3-dihydroxy-2-methyl anthraquinone, primarily originates from Rubia cordifolia Linn (Rubiaceae). It was first discovered in 1981 and has been reported for many biological activities. However, no review has been reported so far to create awareness about this molecule and its role in future drug discovery. Therefore, the present review aimed to provide comprehensive evidence of Rubiadin’s phytochemistry, biosynthesis, physicochemical properties, biological properties and therapeutic potential. Relevant literature was gathered from numerous scientific databases including PubMed, ScienceDirect, Scopus and Google Scholar between 1981 and up-to-date. The distribution of Rubiadin in numerous medicinal plants, as well as its method of isolation, synthesis, characterisation, physiochemical properties and possible biosynthesis pathways, was extensively covered in this review. Following a rigorous screening and tabulating, a thorough description of Rubiadin’s biological properties was gathered, which were based on scientific evidences. Rubiadin fits all five of Lipinski’s rule for drug-likeness properties. Then, the in depth physiochemical characteristics of Rubiadin were investigated. The simple technique for Rubiadin’s isolation from R. cordifolia and the procedure of synthesis was described. Rubiadin is also biosynthesized via the polyketide and chorismate/o-succinylbenzoic acid pathways. Rubiadin is a powerful molecule with anticancer, antiosteoporotic, hepatoprotective, neuroprotective, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antimalarial, antifungal, and antiviral properties. The mechanism of action for the majority of the pharmacological actions reported, however, is unknown. In addition to this review, an in silico molecular docking study was performed against proteins with PDB IDs: 3AOX, 6OLX, 6OSP, and 6SDC to support the anticancer properties of Rubiadin. The toxicity profile, pharmacokinetics and possible structural modifications were also described. Rubiadin was also proven to have the highest binding affinity to the targeted proteins in an in silico study; thus, we believe it may be a potential anticancer molecule. In order to present Rubiadin as a novel candidate for future therapeutic development, advanced studies on preclinical, clinical trials, bioavailability, permeability and administration of safe doses are necessary.Keywords: Rubiadin, Rubia cordifolia, biosynthesis, physicochemical properties, anticancer, pharmacology

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.

Sarcoidosis, a chronic granulomatous disease of unknown cause, has been linked to several environmental risk factors, among which are some that may favor carbon nanotube formation. Using gene array data, we initially observed that bronchoalveolar lavage (BAL) cells from sarcoidosis patients displayed elevated mRNA of the transcription factor, Twist1, among many M1-associated genes compared to healthy controls. Based on this observation we hypothesized that Twist1 mRNA and protein expression might become elevated in alveolar macrophages from animals bearing granulomas induced by carbon nanotube instillation. To address this hypothesis, wild-type and macrophage-specific peroxisome proliferator-activated receptor gamma (PPARγ) knock out mice were given oropharyngeal instillation of multiwall carbon nanotubes (MWCNT). BAL cells obtained 60 days later exhibited significantly elevated Twist1 mRNA expression in granuloma-bearing wild-type or PPARγ knock out alveolar macrophages compared to sham controls. Overall, Twist1 expression levels in PPARγ knock out mice were higher than those of wild-type. Concurrently, BAL cells obtained from sarcoidosis patients and healthy controls validated gene array data: qPCR and protein analysis showed significantly elevated Twist1 in sarcoidosis compared to healthy controls. In vitro studies of alveolar macrophages from healthy controls indicated that Twist1 was inducible by classical (M1) macrophage activation stimuli (LPS, TNFα) but not by IL-4, an inducer of alternative (M2) macrophage activation. Findings suggest that Twist1 represents a PPARγ-sensitive alveolar macrophage M1 biomarker which is induced by inflammatory granulomatous disease in the MWCNT model and in human sarcoidosis.

Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, is caused by toxic RNAs produced from the mutant DM protein kinase (DMPK) gene. DM1 is characterized by progressive muscle wasting and weakness. Therapeutic strategies have mainly focused on targeting the toxic RNA. Previously, we found that fibroblast growth factor-inducible 14 (Fn14), the receptor for TWEAK, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and that blocking TWEAK/Fn14 signaling improves muscle function and histology. Here, we studied the effect of Tweak deficiency in a RNA toxicity mouse model. The genetic deletion of Tweak in these mice significantly reduced muscle damage and improved muscle function. In contrast, administration of TWEAK in the RNA toxicity mice impaired functional outcomes and worsened muscle histopathology. These studies show that signaling via TWEAK is deleterious to muscle in RNA toxicity and support the demonstrated utility of anti-TWEAK therapeutics.

Myotonic dystrophy type 1(DM1) is the prototype for diseases caused by RNA toxicity. RNAs from the mutant allele contain an expanded (CUG)n tract within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The toxic RNAs affect the function of RNA binding proteins leading to sequestration of muscleblind-like (MBNL) proteins and increased levels of CELF1 (CUGBP, Elav-like family member 1). The mechanism for increased CELF1 is not very clear. One favored proposition is hyper-phosphorylation of CELF1 by Protein Kinase C alpha (PKCα) leading to increased CELF1 stability. However, most of the evidence supporting a role for PKC-α relies on pharmacological inhibition of PKC. To further investigate the role of PKCs in the pathogenesis of RNA toxicity, we generated transgenic mice with RNA toxicity that lacked both the PKCα and PKCβ isoforms. We find that these mice show similar disease progression as mice wildtype for the PKC isoforms. Additionally, the expression of CELF1 is also not affected by deficiency of PKCα and PKCβ in these RNA toxicity mice. These data suggest that disease phenotypes of these RNA toxicity mice are independent of PKCα and PKCβ.

Surfactant accumulates in alveolar macrophages of granulocyte-macrophage colony-stimulating factor (GM-CSF) knockout (KO) mice and pulmonary alveolar proteinosis (PAP) patients with a functional loss of GM-CSF resulting from neutralizing anti–GM-CSF antibody. Alveolar macrophages from PAP patients and GM-CSF KO mice are de­ficient in peroxisome proliferator-activated receptor-γ (PPARγ) and ATP-binding cassette (ABC) lipid transporter ABCG1. Previous studies have demonstrated that GM-CSF induces PPARγ. We therefore hypothesized that PPARγ promotes surfactant catabolism through regulation of ABCG1. To address this hypothesis, macrophage-specific PPARγ (MacPPARγ) knockout mice were utilized. MacPPARγ KO mice develop foamy, lipid-engorged Oil Red O positive alveolar macrophages. Lipid analyses revealed significant increases in the cholesterol and phospholipid contents of MacPPARγ KO alveolar macrophages and extracellular bronchoalveolar lavage (BAL)–derived fluids. MacPPARγ KO alveolar macrophages showed decreased expression of ABCG1 and a deficiency in ABCG1-mediated cholesterol efflux to HDL. Lipid metabolism may also be regulated by liver X receptor (LXR)–ABCA1 pathways. Interestingly, ABCA1 and LXRβ expression were elevated, indicating that this pathway is not sufficient to prevent surfactant accumulation in alveolar macrophages. These results suggest that PPARγ mediates a critical role in surfactant homeostasis through the regulation of ABCG1.

Background and Aim: The role of caretakers at day-care centers has become more imperative in promoting oral health care in children since many new mothers opt to work outside their homes, leaving their children at day-care centers. The aim of this study is to assess the knowledge, attitude and practice of oral health promoting factors among secondary caretakers of children attending day-care centers. Settings and Design: This was a cross-sectional exploratory study conducted among secondary caretakers in Kubang Kerian, Malaysia. Materials and Methods: Thirty-four caretakers fulfilling the inclusion and exclusion criteria participated in the study. The data were collected using a self-administered questionnaire addressing various aspects of knowledge, attitude and practice of oral health in children. Analysis was done using SPSS version 12.0. Results: The knowledge of factors causing dental caries was found to be good among majority of the caretakers, but the concepts of transmissibility of caries and effect of hidden sugars were not evident. Seventy one percent did not know that frequent bottle feeding could cause tooth decay. Attitudes seemed to be governed by the cultural practices of the region rather than the knowledge obtained. The knowledge was not translated to practice adequately. Giving sweetened liquid in bottles was practiced by 53% of the caretakers. Conclusion: Implementation of nursery-based oral health promotion programs for secondary caretakers is needed to counteract early childhood caries.

Patients with pulmonary alveolar proteinosis (PAP) display impaired surfactant clearance, foamy, lipid-filled alveolar macrophages, and increased cholesterol metabolites within the lung. Neutralizing autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) are also present, resulting in virtual GM-CSF deficiency. We investigated ABCG1 and ABCA1 expression in alveolar macrophages of PAP patients and GM-CSF knockout (KO) mice, which exhibit PAP-like pulmonary pathology and increased pulmonary cholesterol. Alveolar macrophages from both sources displayed a striking similarity in transporter gene dysregulation, consisting of deficient ABCG1 accompanied by highly increased ABCA1. Peroxisome proliferator-activated receptor γ (PPARγ), a known regulator of both transporters, was deficient, as reported previously. In contrast, the liver X receptor α, which also upregulates both transporters, was highly increased. GM-CSF treatment increased ABCG1 expression in macrophages in vitro and in PAP patients in vivo. Overexpression of PPARγ by lentivirus-PPARγ transduction of primary alveolar macrophages, or activation by rosiglitazone, also increased ABCG1 expression. These results suggest that ABCG1 deficiency in PAP and GM-CSF KO alveolar macrophages is attributable to the absence of a GM-CSF-mediated PPARγ pathway. These findings document the existence of ABCG1 deficiency in human lung disease and highlight a critical role for ABCG1 in surfactant homeostasis.

The conversion of cholesterol into the more polar metabolites 27-hydroxycholesterol (27-OH) and cholestenoic acid by the cytochrome P450 sterol 27-hydroxylase is a cholesterol-removal mechanism used by almost all cells. Most of the cholestenoic acid present in the circulation originates from the lung, and it has been suggested that sterol 27-hydroxylase is of particular importance for cholesterol homeostasis in this organ. As an example of pulmonary cholesterol accumulation, a known disorder of surfactant homeostasis, pulmonary alveolar proteinosis (PAP), was studied. Analysis of bronchoalveolar lavage fluid from PAP patients revealed a significant accumulation of the cholesterol metabolites cholestenoic acid and 27-OH. This pattern was recapitulated in serum, with a significant increase in the levels of both cholestenoic acid (P = 0.003) and 27-OH (P = 0.017) in PAP patients compared with healthy controls. Analysis of PAP alveolar macrophages did not reveal a significant change in mRNA expression levels of either sterol 27-hydroxylase or the cholesterol-esterifying enzyme acyl-CoA:cholesterol acyltransferase-1.These results are consistent with the contention that substrate availability, rather than enzyme expression, is the key factor in regulating the production of cholestenoic acid by the lung and that serum cholestenoic acid may be a marker of pulmonary cholesterol homeostasis.

Förster Resonance Energy Transfer (FRET) microscopy is a powerful tool used to identify molecular interactions in live or fixed cells using a non-radiative transfer of energy from a donor fluorophore in the excited state to an acceptor fluorophore in close proximity. FRET can be a very sensitive tool to study protein-protein and/or protein-nucleic acids interactions. RNA toxicity is implicated in a number of disorders; especially those associated with expanded repeat sequences, such as myotonic dystrophy. Myotonic dystrophy (DM1) is caused by a (CTG)n repeat expansion in the 3' UTR of the DMPK gene which results in nuclear retention of mutant DMPK transcripts in RNA foci. This results in toxic gain-of-function effects mediated through altered functions of RNA-binding proteins (e.g. MBNL1, hnRNPH, CUGBP1). In this study we demonstrate the potential of a new acceptor photobleaching assay to measure FRET (AP-FRET) between RNA and protein. We chose to focus on the interaction between MBNL1 and mutant DMPK mRNA in cells from DM1 patients due to the strong microscopic evidence of their co-localization. Using this technique we have direct evidence of intracellular interaction between MBNL1 and the DMPK RNA. Furthermore using the AP-FRET assay and MBNL1 mutants, we show that all four zinc-finger motifs in MBNL1 are crucial for MBNL1-RNA foci interactions. The data derived using this new assay provides compelling evidence for the interaction between RNA binding proteins and RNA foci, and mechanistic insights into MBNL1-RNA foci interaction demonstrating the power of AP-FRET in examining RNA-Protein interactions in DM1.

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. It is caused by an expanded (CTG)n tract in the 3' UTR of the Dystrophia Myotonica Protein Kinase (DMPK) gene. This causes nuclear retention of the mutant mRNA into ribonuclear foci and sequestration of interacting RNA-binding proteins (such as muscleblind-like 1 (MBNL1)). More severe congenital and childhood-onset forms of the disease exist but are less understood than the adult disease, due in part to the lack of adequate animal models. To address this, we utilized transgenic mice over-expressing the DMPK 3' UTR as part of an inducible RNA transcript to model early-onset myotonic dystrophy. In mice in which transgene expression was induced during embryogenesis, we found that by two weeks after birth, mice reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, muscle weakness, histopathology and mRNA splicing defects. Notably, these defects were more severe than in adult mice induced for an equivalent period of exposure to RNA toxicity. Additionally, the utility of the model was tested by over-expressing MBNL1, a key therapeutic strategy being actively pursued for treating the disease phenotypes associated with DM1. Significantly, increased MBNL1 in skeletal muscle partially corrected myotonia and splicing defects present in these mice, demonstrating the responsiveness of the model to relevant therapeutic interventions. Furthermore, these results also represent the first murine model for early-onset DM1 and provide a tool to investigate the effects of RNA toxicity at various stages of development.

A ruminant's digestion depends on microbial degradation of feed rather than endogenous enzyme degradation as in most monogastric animals. The study was conducted to assess the effects of Lactic Acid Bacteria (LAB) strains administered as direct-fed microbials on weight gain and ruminai pH of Damara and Meatmaster sheep breeds. Sixty-four Damara and Meatmaster sheep breeds [Damara males (36.6 [+ or -] 8.3 kg); Damara females (28.9 [+ or -] 6.9 kg); Meatmaster males (24.6 [+ or -]3.4 kg); Meat master females (21.5 [+ or -] 3.1 kg)] were subjected to a 30-day trial and divided into five treatment groups as follows: pellets with no antibiotic and no probiotics administered (Tl); pellets with no antibiotics, only Lactobacillus rhamnosus SCH administered (T2); pellets with no antibiotics, only Lactobacillus rhamnosus AF3G administered (T3); pellets with no antibiotics, with the combination of Lactobacillus rhamnosus SCH and Lactobacillus rhamnosus AF3G, administered (T4); pellets fortified with antibiotic and no probiotic administered (T5). The animals were fed on commercial pellets fortified with or without antibiotics. Animals were each weighed, and rumen fluids were collected using a stomach tube, and pH was read immediately, before and at the end of the trials. Data obtained were subjected to analysis of variance using SPSS version 4.0. The results showed that the effect of treatment, sex and some of their interactive effects were significant (p Key words: Sheep breeds, Lactic Acid Bacteria, Weight gain, Rumen fluid pH, INTRODUCTION Sheep production is one of the most significant commercial livestock production activities in South Africa, especially in the arid, pastoral areas. The fat-tailed sheep are an important animal genetic [...]

Aims: This study aims to achieve an electrochemical deposition of Sr- and Zn-doped hydroxyapatite coating on stainless steel mini-implants and verify it by Fourier transform infrared spectroscopy (FTIR). Materials and methods: Synthesis of the powder: Zinc-Sr hydroxyapatite nanoparticles were synthesised in this work using a sonochemical-mediated hydrothermal technique. Electrochemical deposition of the coating: The coating was applied electrochemically onto commercially available stainless steel miniplates measuring 2 mm in thickness and screws measuring 2 x 8 mm. The coated implants were analysed for their functional groups using Fourier transform infrared spectroscopy (FTIR) covering a frequency range of 4000-400 cm-1. Results: The chemical nature and functional groups involved in the successful production of Zn-Sr/HAP were predominantly elucidated by FT-IR spectroscopy investigations. In FTIR, the coated stainless-steel plates showed 3 peaks at 1024.85, 601.02, and 561.26. The coated stainless-steel screws showed 2 peaks at 1028.43 and 563.23. Conclusion: Zinc and strontiumdoped hydroxyapatite coating can be done on stainless steel miniplates using electrochemical deposition. [ABSTRACT FROM AUTHOR]

Background: Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring. Aims: To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK. Method: We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment. Results: We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally. Conclusions: Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly. [ABSTRACT FROM AUTHOR]

Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats. [ABSTRACT FROM AUTHOR]