APOE and Alzheimer's disease: Pathologic clues from transgenic Drosophila melanogaster.

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Apolipoprotein E4 (ApoE4) is the main genetic risk factor in the development of late-onset AD. However, the exact mechanism underlying ApoE4-mediated neurodegeneration remains unclear. We utilized Drosophila melanogaster to examine the neurotoxic effects of various human APOE isoforms when expressed specifically in glial and neural cells. We assessed impacts on mitochondrial dynamics, ER stress, lipid metabolism, and bio-metal ion concentrations in the central nervous system (CNS) of the transgenic flies. Dachshund antibody staining revealed a reduction in the number of Kenyon cells. Behavioral investigations including ethanol tolerance and learning and memory performance demonstrated neuronal dysfunction in APOE4-expressing larvae and adult flies. Transcription level of marf and drp-1 were found to be elevated in APOE4 flies, while atf4, atf6, and xbp-1 s showed down regulation. Enhanced concentrations of triglyceride and cholesterol in the CNS were observed in APOE4 transgenic flies, with especially pronounced effects upon glial-specific expression of the gene. Spectrophotometry of brain homogenate revealed enhanced Fe++ and Zn++ ion levels in conjunction with diminished Cu++ levels upon APOE4 expression. To explore therapeutic strategies, we subjected the flies to heat-shock treatment, aiming to activate heat-shock proteins (HSPs) and assess their potential to mitigate the neurotoxic effects of APOE isoforms. The results showed potential therapeutic benefits for APOE4-expressing flies, hinting at an ability to attenuate memory deterioration. Overall, our findings suggest that APOE4 can alter lipid metabolism, bio metal ion homeostasis, and disrupt the harmonious fission-fusion balance of neuronal and glial mitochondria, ultimately inducing ER stress. These alterations mirror the main clinical manifestations of AD in patients. Therefore, our work underscores the suitability of Drosophila as a fertile model for probing the pathological roles of APOE and furthering our understanding of diverse isoform-specific functions.

Bioengineering vascularized liver tissue for biomedical research and application.

The liver performs a wide range of biological functions that are essential to body homeostasis. Damage to liver tissue can result in reduced organ function, and if chronic in nature can lead to organ scarring and progressive disease. Currently, donor liver transplantation is the only longterm treatment for end-stage liver disease. However, orthotopic organ transplantation suffers from several drawbacks that include organ scarcity and lifelong immunosuppression. Therefore, new therapeutic strategies are required. One promising strategy is the engineering of implantable and vascularized liver tissue. This resource could also be used to build the next generation of liver tissue models to better understand human health, disease and aging in vitro. This article reviews recent progress in the field of liver tissue bioengineering, including microfluidic-based systems, bio-printed vascularized tissue, liver spheroids and organoid models, and the induction of angiogenesis in vivo.

Modulation of social and depression behaviors in cholestatic and drug-dependent mice: possible role of opioid receptors.

Objectives: Social behavior, a set of motivating activities critical for survival, is disturbed in cholestasis conditions and many substance abusers as well as psychiatric disorders. The documented loss of social interest in cholestatic patients may be associated with depressive symptoms. Interestingly, the endogenous opioid system is involved in the modulation of depression. Methods in this research: , we assessed the effect of cholestasis and drug dependence on social and depression behaviors using the Three-Chamber Paradigm Test, Forced Swim Test (FST), and Tail Suspension Test (TST) as well as Open Field Test (OFT) in male NMRI mice. Results: The results indicated that alone administration of morphine and tramadol, as well as co-administration of them, increased social motivation and novelty but decreased depression in bile duct ligated mice. Whereas, alone administration of naloxone (a µ-opioid receptor antagonist) and co-administration of it along with morphine and tramadol decreased social motivation and novelty while enhanced depression in the sham-operated and bile duct ligated mice. These administrations of drugs did not change locomotor activity compared to the control group. Conclusion: In conclusion, it appears that (i) both cholestasis and drug dependence impaired social motivation behavior, as well as induced depression-like behavior in the bile duct, ligated mice, (ii) alone administration of morphine and tramadol as well as co-treatment of them may protect against cholestasis and drug dependence induced abnormal behaviors, (iii) µ-opioid receptors play an important role in modulation of social motivation and depression behaviors in mice.

Enhanced anxiolytic and analgesic effectiveness or a better safety profile of morphine and tramadol combination in cholestatic and addicted mice.

The involvement of the opioidergic system on anxiolytic and antinociceptive responses induced by cholestasis was investigated in cholestatic and addicted mice. Elevated plus-maze and tail-flick devices were used to assess anxiety and pain levels, respectively. The data indicated that induction of cholestasis and injection of opioid drugs including morphine and tramadol enhanced %OAT and %OAE but naloxone reduced %OAT and %OAE in the sham-operated and bile duct ligation (BDL) mice. Induction of cholestasis and addiction to morphine and tramadol prolonged tail-flick latency, which was reversed by naloxone. Coadministration of morphine and tramadol enhanced anxiolytic and analgesic effects in the sham-operated and BDL mice. It seems (a) cholestasis and addiction affect anxiety and pain behaviors, (b) µ-opioid receptors play a key role in anxiolytic and analgesic effects induced by cholestasis, and (c) cotreatment with morphine and tramadol augmented the effectiveness of them for induction of anxiolytic and analgesic effects both in cholestatic and addicted mice.

Policy options for strengthening evidence-informed health policy-making in Iran: overall SASHA project findings.

BACKGROUND: The institutionalization of evidence-informed health policy-making (EIHP) is complex and complicated. It is complex because it has many players and is complicated because its institutionalization will require many changes that will be challenging to make. Like many other issues, strengthening EIHP needs a road map, which should consider challenges and address them through effective, harmonized and contextualized strategies. This study aims to develop a road map for enhancing EIHP in Iran based on steps of planning. METHODS: This study consisted of three phases: (1) identifying barriers to EIHP, (2) recognizing interventions and (3) measuring the use of evidence in Iran's health policy-making. A set of activities was established for conducting these, including foresight, systematic review and policy dialogue, to identify the current and potential barriers for the first phase. For the second phase, an evidence synthesis was performed through a scoping review, by searching the websites of benchmark institutions which had good examples of EIHP practices in order to extract and identify interventions, and through eight policy dialogues and two broad opinion polls to contextualize the list of interventions. Simultaneously, two qualitative-quantitative studies were conducted to design and use a tool for assessing EIHP in the third phase. RESULTS: We identified 97 barriers to EIHP and categorized them into three groups, including 35 barriers on the "generation of evidence" (push side), 41 on the "use of evidence" (pull side) and 21 on the "interaction between these two" (exchange side). The list of 41 interventions identified through evidence synthesis and eight policy dialogues was reduced to 32 interventions after two expert opinion polling rounds. These interventions were classified into four main strategies for strengthening (1) the education and training system (6 interventions), (2) the incentives programmes (7 interventions), (3) the structure of policy support organizations (4 interventions) and (4) the enabling processes to support EIHP (15 interventions). CONCLUSION: The policy options developed in the study provide a comprehensive framework to chart a path for strengthening the country's EIHP considering both global practices and the context of Iran. It is recommended that operational plans be prepared for road map interventions, and the necessary resources provided for their implementation. The implementation of the road map will require attention to the principles of good governance, with a focus on transparency and accountability. Video abstract.

Proposing a novel unsupervised stack ensemble of deep and conventional image segmentation (SEDCIS) method for localizing vitiligo lesions in skin images.

BACKGROUND: Vitiligo is an acquired pigmentary skin disorder characterized by depigmented macules and patches which brings many challenges for the patients suffering from. For vitiligo severity assessment, several scoring methods have been proposed based on morphometry and colorimetry. But, all methods suffer from much inter- and intra-observer variations for estimating the depigmented area. For all mentioned assessment methods of vitiligo disorder, accurate segmentation of the skin images for lesion detection and localization is required. The image segmentation for localizing vitiligo skin lesions has many challenges because of illumination variation, different shapes and sizes of vitiligo lesions, vague lesion boundaries and skin hairs and vignette effects. The manual image segmentation is a tedious and time-consuming task. Therefore, using automatic image segmentation methods for lesion detection is necessarily required. MATERIALS AND METHODS: In this study, a novel unsupervised stack ensemble of deep and conventional image segmentation (SEDCIS) methods is proposed for localizing vitiligo lesions in skin images. Unsupervised segmentation methods do not require prior manual segmentation of vitiligo lesions which is a tedious and time-consuming task with intra- and inter-observer variations. RESULTS: Our collected dataset includes 877 images taken from 21 patients with the resolution of 5760*3840 pixels suffering from vitiligo disorder. Experimental results show that SEDCIS outperforms the compared methods with accuracy of 97%, sensitivity of 98%, specificity of 96%, area overlapping of 94%, and Dice index of 97%. CONCLUSION: The proposed method can segment vitiligo lesions with highly reasonable performance and can be used for assessing the vitiligo lesion surface.

Possible involvement of the opioidergic system in the modulation of body temperature, jumping behavior and memory process in cholestatic and addicted mice.

Cholestasis is related to an increased plasma level of endogenous opioid levels. Naloxone-induced withdrawal syndrome has been reported in a mouse model of cholestasis. Moreover, studies revealed that the memory process is affected by cholestasis. Thus, we aimed at determining whether pharmacological manipulation of the opioidergic system is involved in signs of cholestasis disease such as hypothermia and withdrawal behaviors such as jumping behavior as well as memory process in mice. Cholestasis was induced by bile duct resection in mice and physical dependence was induced by administration of morphine and/or tramadol three times daily (8, 12 and 16 h) at the doses of 25, 50 and 75 mg/kg during three consecutive days. The memory process was assessed by a step-down passive avoidance test. Our results indicated that cholestatic mice showed hypothermia whereas cholestatic- and drug dependent mice indicated hyperthermia. Moreover, administration of morphine (50 mg/kg) and/or tramadol (50 mg/kg) on the 4th day, 2 h before naloxone injection significantly decreased latency to first jumping but increased the number of jumping and rearing behavior as well as locomotor activity in BDL-vs. sham-operated mice. In addition, the latency time of the step-down test decreased in BDL-vs. sham-operated group, showing impairment of memory in BDL mice. The results of this study support the evidence that (1) the opioidergic system involved in thermoregulation of cholestasis mice, (2) µ-opioid receptors play an important role in withdrawal behaviors, and (3) memory process is affected by cholestasis and addiction in mice.

Potential Prophylactic and Therapeutic Effects of Respiratory Physiotherapy for COVID-19.

New coronavirus disease 2019 (COVID-19) has succeeded in surprising the world with infecting more than 12 million people and claiming 560,000 lives in only six months. COVID-19 is associated with a spectrum of respiratory symptoms, especially dyspnea. Patients who progress to severe or critical condition display peripheral and posterior lung lesions bilaterally. These patients require admission to the intensive care unit (ICU); therefore, they are prone to ICU-related complications during disease and after recovery. Respiratory physiotherapy techniques, in particular, active techniques, might help the improvement of airway clearance and lung capacity in addition to the reduction of breathing effort during the active disease. In parallel, it might lead to the prevention of disabilities, resulting from infection and extended hospitalization in patients who recovered from COVID-19. This supports physiotherapy both as a prophylactic and therapeutic strategy for COVID-19.

Persian adaptation of a questionnaire of environmental risk factors in multiple sclerosis (EnvIMS-Q).

BACKGROUND: It seems that gene-environment interaction play most important role in Multiple Sclerosis development. Increasing the incidence and prevalence of MS during the recent decades in the low prevalence area such as Iran is explained better by environment factors. Environmental Risk Factors in Multiple Sclerosis (the 'EnvIMS-Q') is a 6-page self-administered questionnaire for case control studies. OBJECTIVES: the objectives of study are validation and adaptation of the EnvIMS-Q' then development of a Persian version for case control studies in Persian population. METHODS: This questionnaire translated literally and in culturally relevant form, then content validation process was done by three groups' experts. According to giving rating to each item, each section and the whole instrument, we calculated their content validation indexes and also added some new questions and a new section to EnvIMS-Q. Finally, we analyzed repeatability of the answers within a 4 weeks interval. RESULTS: Relevancy and clarity indexes of all items were more than 80%. Scale relevancy index equaled 99% and scale clarity index equaled 97%. Repeatability of most items was acceptable. CONCLUSIONS: the use of standardized validated questionnaires will assist the researchers to perform local studies on the role of environmental factors on the basis of reliable data.