Ageing, Drosophila melanogaster and Epigenetics.

Ageing is a phenomenon where the accumulation of all the stresses that alter the functions of living organisms, halter them from maintaining their physiological balance and eventually lead to death. The emergence of epigenetic tremendously contributed to the knowledge of ageing. Epigenetic changes in cells or tissues like deoxyribonucleic acid (DNA) methylation, modification of histone proteins, transcriptional modification and also the involvement of non-coding DNA has been documented to be associated with ageing. In order to study ageing, scientists have taken advantage of several potential organisms to aid them in their study. Drosophila melanogaster has been an essential model in establishing current understanding of the mechanism of ageing as they possess several advantages over other competitors like having homologues to more than 75% of human disease genes, having 50% of Drosophila genes are homologues to human genes and most importantly they are genetically amenable. Here, we would like to summarise the extant knowledge about ageing and epigenetic process and the role of Drosophila as an ideal model to study epigenetics in association with ageing process.

Drosophila melanogaster: Deciphering Alzheimer's Disease.

Alzheimer's disease (AD) is the most widespread neurodegenerative disorder worldwide. Its pathogenesis involves two hallmarks: aggregation of amyloid beta (Aß) and occurrence of neurofibrillary tangles (NFTs). The mechanism behind the disease is still unknown. This has prompted the use of animal models to mirror the disease. The fruit fly, Drosophila melanogaster has garnered considerable attention as an organism to recapitulate human disorders. With the ability to monopolise a multitude of traditional and novel genetic tools, Drosophila is ideal for studying not only cellular aspects but also physiological and behavioural traits of human neurodegenerative diseases. Here, we discuss the use of the Drosophila model in understanding AD pathology and the insights gained in discovering drug therapies for AD.

Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo.

Increased neuron and astrocyte activity triggers increased brain blood flow, but controversy exists over whether stimulation-induced changes in astrocyte activity are rapid and widespread enough to contribute to brain blood flow control. Here, we provide evidence for stimulus-evoked Ca(2+) elevations with rapid onset and short duration in a large proportion of cortical astrocytes in the adult mouse somatosensory cortex. Our improved detection of the fast Ca(2+) signals is due to a signal-enhancing analysis of the Ca(2+) activity. The rapid stimulation-evoked Ca(2+) increases identified in astrocyte somas, processes, and end-feet preceded local vasodilatation. Fast Ca(2+) responses in both neurons and astrocytes correlated with synaptic activity, but only the astrocytic responses correlated with the hemodynamic shifts. These data establish that a large proportion of cortical astrocytes have brief Ca(2+) responses with a rapid onset in vivo, fast enough to initiate hemodynamic responses or influence synaptic activity.

Are there roles for brain cell senescence in aging and neurodegenerative disorders?

The term cellular senescence was introduced more than five decades ago to describe the state of growth arrest observed in aging cells. Since this initial discovery, the phenotypes associated with cellular senescence have expanded beyond growth arrest to include alterations in cellular metabolism, secreted cytokines, epigenetic regulation and protein expression. Recently, senescence has been shown to play an important role in vivo not only in relation to aging, but also during embryonic development. Thus, cellular senescence serves different purposes and comprises a wide range of distinct phenotypes across multiple cell types. Whether all cell types, including post-mitotic neurons, are capable of entering into a senescent state remains unclear. In this review we examine recent data that suggest that cellular senescence plays a role in brain aging and, notably, may not be limited to glia but also neurons. We suggest that there is a high level of similarity between some of the pathological changes that occur in the brain in Alzheimer's and Parkinson's diseases and those phenotypes observed in cellular senescence, leading us to propose that neurons and glia can exhibit hallmarks of senescence previously documented in peripheral tissues.

Pancytopenia in a Patient with Grave's Disease.

Pancytopenia can rarely complicate Grave's disease. It can be due to uncontrolled thyrotoxicosis or as a result of rare side effect of antithyroid medication. Pernicious anemia leading to Vitamin B12 deficiency is another rare associated cause. We report a case of a patient with Grave's disease and undiagnosed pernicious anemia whom was assumed to have antithyroid drug induced pancytopenia. Failure to recognize this rare association of pernicious anemia as a cause of pancytopenia had resulted in delay in treatment and neurological complication in our patient.

p-Coumaric acid attenuates the effects of Aß42 in vitro and in a Drosophila Alzheimer's disease model.

Alzheimer's disease (AD) is the most common neurodegenerative condition in civilizations worldwide. The distinctive occurrence of amyloid-beta (Aß) accumulation into insoluble fibrils is part of the disease pathophysiology with Aß42 being the most toxic and aggressive Aß species. The polyphenol, p-Coumaric acid (pCA), has been known to boost a number of therapeutic benefits. Here, pCA's potential to counteract the negative effects of Aß42 was investigated. First, pCA was confirmed to reduce Aß42 fibrillation using an in vitro activity assay. The compound was next examined on Aß42-exposed PC12 neuronal cells and was found to significantly decrease Aß42-induced cell mortality. pCA was then examined using an AD Drosophila melanogaster model. Feeding of pCA partially reversed the rough eye phenotype, significantly lengthened AD Drosophila's lifespan, and significantly enhanced the majority of the AD Drosophila's mobility in a sex-dependent manner. The findings of this study suggest that pCA may have therapeutic benefits for AD.

Behavioural Effects and RNA-seq Analysis of Aß42-Mediated Toxicity in a Drosophila Alzheimer's Disease Model.

Alzheimer's disease (AD) is the most common neurological ailment worldwide. Its process comprises the unique aggregation of extracellular senile plaques composed of amyloid-beta (Aß) in the brain. Aß42 is the most neurotoxic and aggressive of the Aß42 isomers released in the brain. Despite much research on AD, the complete pathophysiology of this disease remains unknown. Technical and ethical constraints place limits on experiments utilizing human subjects. Thus, animal models were used to replicate human diseases. The Drosophila melanogaster is an excellent model for studying both physiological and behavioural aspects of human neurodegenerative illnesses. Here, the negative effects of Aß42-expression on a Drosophila AD model were investigated through three behavioural assays followed by RNA-seq. The RNA-seq data was verified using qPCR. AD Drosophila expressing human Aß42 exhibited degenerated eye structures, shortened lifespan, and declined mobility function compared to the wild-type Control. RNA-seq revealed 1496 genes that were differentially expressed from the Aß42-expressing samples against the control. Among the pathways that were identified from the differentially expressed genes include carbon metabolism, oxidative phosphorylation, antimicrobial peptides, and longevity-regulating pathways. While AD is a complicated neurological condition whose aetiology is influenced by a number of factors, it is hoped that the current data will be sufficient to give a general picture of how Aß42 influences the disease pathology. The discovery of molecular connections from the current Drosophila AD model offers fresh perspectives on the usage of this Drosophila which could aid in the discovery of new anti-AD medications.

3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-Carbonyl]Amino]Propanoic Acid (THICAPA) Is Protective Against Aß42-Induced Toxicity In Vitro and in an Alzheimer's Disease Drosophila.

Alzheimer's disease (AD) is the most prevalent type of dementia globally. The accumulation of amyloid-beta (Aß) extracellular senile plaques in the brain is one of the hallmark mechanisms found in AD. Aß42 is the most damaging and aggressively aggregating Aß isomer produced in the brain. Although Aß42 has been extensively researched as a crucial peptide connected to the development of the characteristic amyloid fibrils in AD, the specifics of its pathophysiology are still unknown. Therefore, the main objective was to identify novel compounds that could potentially mitigate the negative effects of Aß42. 3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carbonyl]amino]propanoic acid (THICAPA) was identified as a ligand for Aß42 and for reducing fibrillary Aß42 aggregation. THICAPA also improved cell viability when administered to PC12 neuronal cells that were exposed to Aß42. Additionally, this compound diminished Aß42 toxicity in the current AD Drosophila model by rescuing the rough eye phenotype, prolonging the life span, and enhancing motor functions. Through next-generation RNA-sequencing, immune response pathways were downregulated in response to THICAPA treatment. Thus, this study suggests THICAPA as a possible disease-modifying treatment for AD.

Patient Characteristics, Disease Burden, Treatment Patterns and Outcomes in Patients with Acromegaly: Real-World Evidence from the Malaysian Acromegaly Registry.

Objective: This study aims to report the demographic features of patients with acromegaly, the disease burden, and the corresponding treatment patterns and outcomes in Malaysia. Methodology: This is a retrospective study that included patients from the Malaysian Acromegaly registry who were diagnosed with acromegaly from 1970 onwards. Data collected included patient demographics, clinical manifestations of acromegaly, biochemical results and imaging findings. Information regarding treatment modalities and their outcomes was also obtained. Results: Registry data was collected from 2013 to 2016 and included 140 patients with acromegaly from 12 participating hospitals. Median disease duration was 5.5 years (range 1.0 - 41.0 years). Most patients had macroadenoma (67%), while 15% were diagnosed with microadenoma. Hypertension (49.3%), diabetes (37.1%) and hypopituitarism (27.9%) were the most common co-morbidities for patients with acromegaly. Majority of patients had surgical intervention as primary treatment (65.9%) while 20.7% were treated medically, mainly with dopamine agonists (18.5%). Most patients had inadequate disease control after first-line treatment regardless of treatment modality (79.4%). Conclusion: This registry study provides epidemiological data on patients with acromegaly in Malaysia and serves as an initial step for further population-based studies.

Microalgal Biomass as Feedstock for Bacterial Production of PHA: Advances and Future Prospects.

The search for biodegradable plastics has become the focus in combating the global plastic pollution crisis. Polyhydroxyalkanoates (PHAs) are renewable substitutes to petroleum-based plastics with the ability to completely mineralize in soil, compost, and marine environments. The preferred choice of PHA synthesis is from bacteria or archaea. However, microbial production of PHAs faces a major drawback due to high production costs attributed to the high price of organic substrates as compared to synthetic plastics. As such, microalgal biomass presents a low-cost solution as feedstock for PHA synthesis. Photoautotrophic microalgae are ubiquitous in our ecosystem and thrive from utilizing easily accessible light, carbon dioxide and inorganic nutrients. Biomass production from microalgae offers advantages that include high yields, effective carbon dioxide capture, efficient treatment of effluents and the usage of infertile land. Nevertheless, the success of large-scale PHA synthesis using microalgal biomass faces constraints that encompass the entire flow of the microalgal biomass production, i.e., from molecular aspects of the microalgae to cultivation conditions to harvesting and drying microalgal biomass along with the conversion of the biomass into PHA. This review discusses approaches such as optimization of growth conditions, improvement of the microalgal biomass manufacturing technologies as well as the genetic engineering of both microalgae and PHA-producing bacteria with the purpose of refining PHA production from microalgal biomass.

Aggressive giant prolactinoma: a case report.

BACKGROUND: Managing treatment-resistant aggressive giant prolactinoma can be challenging, as the diagnosis is often complex, and treatment beyond dopamine agonists, surgery, and radiotherapy is limited. CASE PRESENTATION: A 21-year-old Malay woman first presented to our hospital at the age of 16 years with 1-year history of reduced vision and 2 years of amenorrhea. Her baseline prolactin level was 255,894 µIU/mL with secondary hypogonadism, and pituitary magnetic resonance imaging revealed a giant prolactinoma (2.8 × 3.2 × 4.2 cm3) with suprasellar extension and optic chiasmal compression. She was initially treated with cabergoline, and reductions in the prolactin level and tumor mass were achieved, leading to vision improvement and resumption of normal menstruation. However, she developed recurrent tumor growth and hyperprolactinemia, causing relapse of symptoms, and she needed surgery. Eventually, despite three tumor debulking surgeries and escalation of cabergoline doses up to 1 mg/day, her tumor progressed with aggressive characteristics. Following a multidisciplinary meeting, the patient is initiated on temozolomide therapy after considering the long-term side effects of radiotherapy in her case. CONCLUSION: This case highlights the importance of early identification of treatment-resistant prolactinoma and the need for a multidisciplinary approach in managing aggressive prolactinoma in young patients, particularly regarding timely implementation of temozolomide therapy.

Collision of Two Tumors: A Case Report of a Lung Adenocarcinoma With Metastasis to a Pituitary Adenoma.

A collision tumor involving metastasis to a pituitary adenoma is rare. We describe a case of a 68-year-old Bidayuh woman with underlying treatment-responsive lung adenocarcinoma, who presented with mass effect, panhypopituitarism and polyuria. Her initial imaging study reported pituitary macroadenoma, and she was treated with hormone replacement therapy. She then underwent transsphenoidal tumor debulking surgery with subsequent histopathological findings of a collision tumor of an adenocarcinoma with metastasis to a non-functioning pituitary adenoma.

Closing the Type 1 Diabetes gap in South-East Asia through government partnership working with non-government organisations.

This will be the first publication of Type 1 diabetes(T1D) outcomes in five low-middle-income countries (LMICs)-Laos, Malaysia, Vietnam, Cambodia and Myanmar in the Southeast Asia (SEA) region. The information obtained has been possible due to partnership programmes of non-government organisationAction4Diabetes (A4D) with defined local hospitalsthrough a Memorandum of Understandingsigned with the governments in SEAthat guarantees ongoing supplies of free insulin, blood glucose meter supplies, HbA1c tests and hospital emergency funds. PARTICIPANTS: Between 2020 and 2021, 383 children and young people with T1D who were active in the A4D supported programmes were reviewed including information on health coverage, multidisciplinary team management, diabetic ketoacidosis (DKA) on admission and insulin regimen. RESULTS: Mean HbA1c between 2020 and 2021 for patients in these LMICs arereported for the first time. The average glycaemic index in the five SEAcountries reviewed between 2020 and 2021 were high at 83 mmol/mol (9.7%). CONCLUSIONS: Government partnership working with non-government organisationsto support T1D from diagnosis to adulthood are the first steps to closing thegaps in many LMICs. Further epidemiological studies are needed to identify the glycaemic outcomes and DKA rates on admission for many of these countries.

Behavioral factors associated with SARS-CoV-2 infection.

OBJECTIVE: To study the association between behavioural factors and incidence rates of SARS-CoV-2 infection. DESIGN: Case-control web-based questionnaire study. SETTING: Questionnaire data were collected in the Capital Region of Denmark in December 2020 when limited restrictions were in place, while the number of daily SARS-CoV-2 cases increased rapidly. PARTICIPANTS: 8913 cases of laboratory-confirmed SARS-CoV-2 infection were compared with two groups of controls: (1) 34 063 individuals with a negative SARS-CoV-2 test from the same date (negative controls, NCs) and 2) 25 989 individuals who had never been tested for a SARS-CoV-2 infection (untested controls, UC). Controls were matched on sex, age, test date and municipality. EXPOSURE: Activities during the 14 days prior to being tested positive for SARS-CoV-2 or during the same period for matched controls and precautions taken during the entire pandemic. MAIN OUTCOMES AND MEASURES: SARS-CoV-2 infection incidence rate ratios (IRR). RESULTS: Response rate was 41.4% (n=93 121). Using public transportation, grocery shopping (IRR: NC: 0.52; UC: 0.63) and outdoor sports activities (NC: 0.75; UC: 0.96) were not associated with increased rate of SARS-CoV-2 infection. Most precautions, for example, using hand sanitizer (NC: 0.79; UC: 0.98), physical distancing (NC: 0.79; UC: 0.82) and avoiding handshakes (NC: 0.74; UC: 0.77), were associated with a lower rate of infection. Activities associated with many close contacts, especially indoors, increased rate of infection. Except for working from home, all types of occupation were linked to increased rate of infection. CONCLUSIONS: In a community setting with moderate restrictions, activities such as using public transportation and grocery shopping with the relevant precautions were not associated with an increased rate of SARS-CoV-2 infection. Exposures and activities where safety measures are difficult to maintain might be important risk factors for infection. These findings may help public health authorities tailor their strategies for limiting the spread of SARS-CoV-2.

Ethyl caffeate ameliorated amyloid-beta42 protein-associated toxicity in PC12 cells and Drosophila melanogaster.

AIM: Alzheimer's disease (AD) is the most pervasive neurodegenerative disorder in societies globally. Till now, the mechanism behind this disease is still equivocal. Amyloid-beta42 protein (Aß42), the most toxic and aggressive Aß species, is the main focus of this study. The naturally occurring ethyl caffeate (EC) is associated with various medicinal properties. Here, EC was tested for its protective properties against Aß42's toxic effects. METHODS: As treatment of Aß42 has been shown to cause neuronal cell death, EC was first screened with Aß42-incubated PC12 neuronal cells. Next, the compound was tested on the Drosophila melanogaster AD model using the rough eye phenotype assay, lifespan assay and negative geotaxis assay. RESULTS: EC ameliorated PC12 cells from cell death linked to Aß42 exposure. Using Drosophila expressing human Aß42, feeding of EC was able to partially rescue the rough eye phenotype, lengthen the lifespan of AD Drosophila and enhanced the mobility of middle-aged AD Drosophila. CONCLUSION: Overall, the results of this study showed that EC might possess therapeutic properties for AD. Geriatr Gerontol Int 2021; 21: 1125-1130.

Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen water extract (DWE), obtained from the Salvia miltiorrhiza Bunge (Family Lamiaceae) root, is usually employed in Chinese traditional medicine as treatment to cardiovascular ailments and cerebrovascular diseases. Intriguingly, the extract was also found to contain vast beneficial properties in Alzheimer's disease (AD) treatment. AIM OF THE STUDY: Alzheimer's disease is the most significant type of neurodegenerative disorder plaguing societies globally. Its pathogenesis encompasses the hallmark aggregation of amyloid-beta (Aß). Of all the Aß oligomers formed in the brain, Aß42 is the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to attenuate Aß42's toxic effects. METHODS: The composition of DWE was determined via Ultra-Performance Liquid Chromatography (UPLC). DWE, SalA and SalB were first verified for their capability to diminish Aß42 fibrillation using an in vitro activity assay. Since Aß42 aggregation results in neuronal degeneration, the potential Aß42 inhibitors were next evaluated on Aß42-exposed PC12 neuronal cells. The Drosophila melanogaster AD model was then employed to determine the effects of DWE, SalA and SalB. RESULTS: DWE, SalA and SalB were shown to be able to reduce fibrillation of Aß42. When tested on PC12 neuronal cells, DWE, SalA and SalB ameliorated cells from cell death associated with Aß42 exposure. Next, DWE and its components were tested on the Drosophila melanogaster AD model and their rescue effects were further characterized. The UPLC analysis showed that SalA and SalB were present in the brains and bodies of Drosophila after DWE feeding. When human Aß42 was expressed, the AD Drosophila exhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of AD Drosophila and improved most of the mobility of AD Drosophila. CONCLUSION: Collectively, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases.

The Effect of DPP4 Inhibitor on Glycemic Variability in Patients with Type 2 Diabetes treated with twice-daily Premixed Human Insulin.

OBJECTIVE: To evaluate the effect of adding DPP4 inhibitor (DPP4-i) on glycemic variability (GV) in patients with type 2 diabetes mellitus (T2DM) treated with premixed human insulin (MHI). METHODOLOGY: We conducted a prospective study in patients with T2DM on twice-daily MHI with or without metformin therapy. Blinded continuous glucose monitoring was performed at baseline and following 6 weeks of Vildagliptin therapy. RESULTS: Twelve patients with mean (SD) age of 55.8 (13.1) years and duration of disease of 14.0 (6.6) years were recruited. The addition of Vildagliptin significantly reduced GV indices (mmol/L): SD from 2.73 (IQR 2.12-3.66) to 2.11 (1.76-2.55), p=0.015; mean amplitude of glycemic excursions (MAGE) 6.94(2.61) to 5.72 (1.87), p=0.018 and CV 34.05 (8.76) to 28.19 (5.36), p=0.010. In addition, % time in range (3.9-10 mmol/l) improved from 61.17 (20.50) to 79.67 (15.33)%, p=0.001; % time above range reduced from 32.92 (23.99) to 18.50 (15.62)%, p=0.016; with reduction in AUC for hyperglycemia from 1.24 (1.31) to 0.47 (0.71) mmol/day, p=0.015. Hypoglycemic events were infrequent and the reduction in time below range and AUC for hypoglycemia did not reach statistical significance. CONCLUSION: The addition of DPP4-I to commonly prescribed twice-daily MHI in patients with T2DM improves GV and warrants further exploration.

Unusual presentation of pheochromocytoma with ischemic sigmoid colitis and stenosis.

A 45-year-old woman with poorly controlled hypertension and diabetes mellitus presented with left iliac fossa pain, constipation alternating with diarrhea, and weight loss. She had been diagnosed with idiopathic cardiomyopathy five years previously. Echocardiogram had shown a left ventricular ejection fraction (LVEF) of 35%; coronary angiogram was normal. Colonoscopy revealed sigmoid colitis with stenosis. Abdominal computed tomography revealed a 5 cm right adrenal tumor. Twenty-four hour urinary free catecholamines and fractionated metanephrine excretion values were elevated, confirming pheochromocytoma. Her colitis resolved after one month of adrenergic blockade. Repeat echocardiogram showed improvement of LVEF to 65%. After laparoscopic right adrenalectomy, the patient's hypertension resolved, and diabetic control improved. Timely management avoided further morbidity and potential mortality in our patient.

Global hydro-environmental sub-basin and river reach characteristics at high spatial resolution.

The HydroATLAS database provides a standardized compendium of descriptive hydro-environmental information for all watersheds and rivers of the world at high spatial resolution. Version 1.0 of HydroATLAS offers data for 56 variables, partitioned into 281 individual attributes and organized in six categories: hydrology; physiography; climate; land cover & use; soils & geology; and anthropogenic influences. HydroATLAS derives the hydro-environmental characteristics by aggregating and reformatting original data from well-established global digital maps, and by accumulating them along the drainage network from headwaters to ocean outlets. The attributes are linked to hierarchically nested sub-basins at multiple scales, as well as to individual river reaches, both extracted from the global HydroSHEDS database at 15 arc-second (~500 m) resolution. The sub-basin and river reach information is offered in two companion datasets: BasinATLAS and RiverATLAS. The standardized format of HydroATLAS ensures easy applicability while the inherent topological information supports basic network functionality such as identifying up- and downstream connections. HydroATLAS is fully compatible with other products of the overarching HydroSHEDS project enabling versatile hydro-ecological assessments for a broad user community.

Renin dependent hypertension caused by accessory renal arteries.

BACKGROUND: Hypokalemia in the presence of hypertension is often attributed to primary hyperaldosteronism as a cause of secondary hypertension, however secondary hyperaldosteronism may present similarly. Accessory renal arteries are variants in the vascular anatomy which are often thought to be innocuous but in some circumstances can cause renovascular hypertension leading to secondary hyperaldosteronism. CASE PRESENTATION: We report 2 cases of hypertension with secondary hyperaldosteronism associated with accessory renal arteries. Both patients presented with hypokalemia and further investigations revealed hyperaldosteronism with unsuppressed renin levels. Imaging studies showed the presence of accessory renal artery. CONCLUSION: Accessory renal arteries are a potential cause renovascular hypertension which can be detected via CT angiography or magnetic resonance angiography. Hormonal evaluation should be undertaken to determine whether its presence contributes to hypertension in the patient as targeted treatment such as aldosterone antagonist can be initiated. Surgical intervention or renal denervation may be considered in resistant cases.