Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of microglia by retroviral infection correlates with transient clearance of prions from the brain but does not change incubation time

Prion diseases are fatal transmissible diseases, where conversion of the endogenous prion protein (PrPC) into a misfolded isoform (PrPSc) leads to neurodegeneration. Microglia, the immune cells of the brain, are activated in neurodegenerative disorders including prion diseases; however, their impact on prion disease pathophysiology is unclear with both beneficial PrPSc‐clearing and detrimental potentially neurotoxic effects. Moreover, monocytes entering the brain from the periphery during disease course might add to disease pathophysiology. Here, the degree of microglia activation in the brain of prion infected mice with and without an additional intraperitoneal retrovirus infection was studied. Peripheral murine retrovirus infection leads to activation of parenchymal microglia without recruitment of monocytes. This activation correlated with transient clearance or delay in accumulation of infectious prions specifically from the brain at early time points in the diseases course. Microglia expression profiling showed upregulation of genes involved in protein degradation coinciding with prion clearance. This enforces a concept where microglia act beneficial in prion disease if adequately activated. Once microglia activation has ceased, prion disease reemerges leading to disease kinetics undistinguishable from the situation in prion‐only infected mice. This might be caused by the loss of microglial homeostatic function at clinical prion disease.
Multiple sclerosis animal models: a clinical and histopathological perspective

There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, that is, damage to axons, synapses and nerve cell bodies. While we are equipped with appropriate therapeutic options to prevent immune‐cell driven relapses, effective therapeutic options to prevent the progressing neurodegeneration are still missing. In this review article, we will discuss to what extent pathology of the progressive disease stage can be modeled in MS animal models. While acute and relapsing–remitting forms of experimental autoimmune encephalomyelitis (EAE), which are T cell dependent, are aptly suited to model relapsing‐remitting phases of MS, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Besides EAE, the cuprizone model is rapidly gaining popularity to study the formation and progression of demyelinating CNS lesions without T cell involvement. Here, we discuss these two non‐popular MS models. It is our aim to point out the pathological hallmarks of MS, and discuss which pathological aspects of the disease can be best studied in the various animal models available.
A brain in flame; do inflammasomes and pyroptosis influence stroke pathology?

Stroke is one of the leading causes of death and disability worldwide. Inflammation plays a key role across the time course of stroke, from onset to the post‐injury reparative phase days to months later. Several regulatory molecules are implicated in inflammation, but the most established inflammatory mediator of acute brain injury is the cytokine interleukin‐1. Interleukin‐1 is regulated by large, macromolecular complexes called inflammasomes, which play a central role in cytokine release and cell death. In this review we highlight recent advances in inflammasome research and propose key roles for inflammasome components in the progression of stroke damage.
Role of curcumin in health and disease

Abstract Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. In recent years, considerable interest has been focused on curcumin due to its use to treat a wide variety of disorders without any side effects. It is one of the major curcuminoids of turmeric, which impart its characteristic yellow colour. It was used in ancient times on the Indian subcontinent to treat various illnesses such as rheumatism, bodyache, skin diseases, intestinal worms, diarrhoea, intermittent fevers, hepatic disorders, biliousness, urinary discharges, dyspepsia, inflammations, constipation, leukoderma, amenorrhea, and colic. Curcumin has the potential to treat a wide variety of inflammatory diseases including cancer, diabetes, cardiovascular diseases, arthritis, Alzheimer's disease, psoriasis, etc, through modulation of numerous molecular targets. This article reviews the use of curcumin for the chemoprevention and treatment of various diseases.
Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities

Astroblastoma is a rare and controversial glioma with variable clinical behavior. The diagnosis currently rests on histologic findings of a circumscribed glioma with astroblastomatous pseudorosettes and vascular hyalinization. Immunohistochemical studies have suggested different oncogenic drivers, such as BRAF p.V600E, but very few cases have been studied using genome‐wide methodologies. Recent genomic profiling identified a subset of CNS embryonal tumors with astroblastoma‐like morphology that harbored MN1 gene fusions, termed “CNS high‐grade neuroepithelial tumors with MN1 alteration” (CNS‐HGNET‐MN1). To further characterize the genetic alterations that drive astroblastomas, we performed targeted next‐generation sequencing (NGS) of 500 cancer‐associated genes in a series of eight cases. We correlated these findings with break‐apart fluorescence in situ hybridization (FISH) analysis of the MN1 locus and genome‐wide DNA methylation profiling. Four cases showed MN1 alteration by FISH, including two pediatric cases that lacked other pathogenic alterations, and two adult cases that harbored other cancer‐associated gene mutations or copy number alterations (eg, CDKN2A/B homozygous deletion, TP53, ATM and TERT promoter mutations). Three of these cases grouped with the CNS‐HGNET‐MN1 entity by methylation profiling. Two of four MN1 intact cases by FISH showed genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH‐wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS and TERT promoter mutations) and these cases had an aggressive clinical course. Two clinically indolent cases remained unclassifiable despite multimodal molecular analysis. We conclude that astroblastoma histology is not specific for any entity including CNS‐HGNET‐MN1, and that additional genetic characterization should be considered for astroblastomas, as a number of these tumors likely contain a methylation profile or genetic alterations that suggest classification as other tumor entities. Our heterogeneous molecular findings help to explain the clinical unpredictability of astroblastoma.
Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor

Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such ‘superagonism’ has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a ‘superagonist’.
TRPV1 and SP: key elements for sepsis outcome?

Sensory neurons play important roles in many disorders, including inflammatory diseases, such as sepsis. Sepsis is a potentially lethal systemic inflammatory reaction to a local bacterial infection, affecting thousands of patients annually. Although associated with a high mortality rate, sepsis outcome depends on the severity of systemic inflammation, which can be directly influenced by several factors, including the immune response of the patient. Currently, there is a lack of effective drugs to treat sepsis, and thus there is a need to develop new drugs to improve sepsis outcome. Several mediators involved in the formation of sepsis have now been identified, but the mechanisms underlying the pathology remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) receptor and the neuropeptide substance P (SP) have recently been demonstrated as important targets for sepsis and are located on sensory neurones and non‐neuronal cells. Herein, we highlight and review the importance of sensory neurones for the modulation of sepsis, with specific focus on recent findings relating to TRPV1 and SP, with their distinct abilities to alter the transition from local to systemic inflammation and also modify the overall sepsis outcome. We also emphasize the protective role of TRPV1 in this context.
Ketoconazole: From an antimycotic to a drug for prostate cancer

The observation in a few patients that gynecomastia developed during an antifungal therapy with 200 mg ketoconazole daily set the stage for a totally new application for this drug. By administering 400 mg ketoconazole orally, every 8 hr, serum testosterone levels in or close to the castrate range were obtained within 1 day in prostate cancer patients. In addition, the adrenal androgens androstenedione and dihydroepiandrosterone were dramatically reduced. The effect was due to an interaction with cytochrome P450‐dependent enzymes active in the sex steroid‐synthesizing organs. Clinical improvement and a lowering of acid phosphatase were achieved within the first few days in previously untreated patients, and long‐term objective responses were obtained. A remarkable subjective and objective response to ketoconazole high dose was noticed in several patients who no longer responded to previous hormonal manipulations. Tolerance to the therapy was acceptable. Long‐term side effects were mainly related to the mechanism of action. Hepatotoxicity was rare. In some cases, gastric intolerance interfered with the therapy. The observation during antifungal therapy of a very rare side effect, namely, gynecomastia, has thus opened up new perspectives for patients afflicted with one of the main male cancers.
Factors Associated with Late Initiation of Antenatal Care among Pregnant Women Attending Antenatal Clinic at Public Health Centers in Kembata Tembaro Zone, Southern Ethiopia

The purpose of this study was to identify those factors associated with late initiation of antenatal care among pregnant women attending antenatal clinics in public health centers in Kembata Tembaro Zone, Ethiopia. A facility based cross-sectional study with supplement of qualitative data was carried out to collect data from 401 pregnant women who were attending antenatal care service at five randomly selected governmental health centres in Kembata Tembaro Zone from March 10 to May 8, 2012 . Pretested and structured questionnaire was used to collect the data and data were entered onto a computer using Epi-info 3.5. 1 statistical program then exported to SPSS Windows version 16.0 for further analysis. Binary descriptive statistics and multiple variable regressions were done.This study showed that prevalence of late entry to antenatal care was 68.6%. The mean timing was 5.5±1.8 months. Multivariate analysis revealed that age, maternal education, family income, parity, previous utilization of antenatal care and type of pregnancy remained significant factors influencing late booking. The findings of this study showed that most women book antenatal care late. This seems to be because antenatal care is viewed primarily as curative rather than preventive in the study population. Public enlightenment, health education coupled with women empowerment would be helpful in reducing the problem. In addition to that incorporation of the benefits of early booking in the routine antenatal care education.
Activation of adenosine A2A receptor reduces osteoclast formation via PKA‐ and ERK1/2‐mediated suppression of NFκB nuclear translocation

We previously reported that adenosine, acting at adenosine A2A receptors (A2AR), inhibits osteoclast (OC) differentiation in vitro (A2AR activation OC formation reduces by half) and in vivo. For a better understanding how adenosine A2AR stimulation regulates OC differentiation, we dissected the signalling pathways involved in A2AR signalling.
Nitrite in organ protection

In the last decade, the nitrate‐nitrite‐nitric oxide pathway has emerged to therapeutical importance. Modulation of endogenous nitrate and nitrite levels with the subsequent S‐nitros(yl)ation of the downstream signalling cascade open the way for novel cytoprotective strategies. In the following, we summarize the actual literature and give a short overview on the potential of nitrite in organ protection.
Evaluation of Bone Tissue After Cafeteria-Diet-Induced Obesity and Periodontitis in Rats

Background: The purpose of this paper was to evaluate the influence of obesity on alveolar bone tissue, either associated with ligature-induced periodontal disease, or not. The possible association between obesity and periodontitis is mainly related to the production of inflammatory cytokines. Methods: Twenty-four male Wistar rats were divided into the following groups: control group (CON); ligature group (LIG) with periodontitis by ligature was induced in the 24th week; obese group (OBESE) received cafeteria diet; obese and ligature group (OBESE + LIG) received cafeteria diet and periodontitis by ligature was induced in the 24th week. Results: The number of osteocytes in the alveolar bone region and the distance from the cementoenamel junction to the alveolar crest were assessed, and descriptive analysis of tissues was performed. The results showed that both obesity and periodontitis led to decreased number of osteocytes (P < 0.01), and increased distance from the cementoenamel junction to the alveolar crest (P < 0.01). Conclusions: In addition, inflammatory characteristics and bone reabsorption in the periodontal tissue were found. It could be concluded that both periodontitis and obesity, in isolation, resulted in a reduction of alveolar bone mass; however, it was more intense when associated with bone loss, demonstrating that obesity contributed to bone loss in periodontitis. J Endocrinol Metab. 2015;5(1-2):172-178 doi: http://dx.doi. org/10.14740/jem248w
Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart

Mitochondrially bound hexokinase II (mtHKII) has long been known to confer cancer cells with their resilience against cell death. More recently, mtHKII has emerged as a powerful protector against cardiac cell death. mtHKII protects against ischaemia‐reperfusion (IR) injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end‐effectors through which ischaemic preconditioning protects against myocardial IR injury. Mechanisms of mtHKII cardioprotection against reperfusion injury entail the maintenance of regulated outer mitochondrial membrane (OMM) permeability during ischaemia and reperfusion resulting in stabilization of mitochondrial membrane potential, the prevention of OMM breakage and cytochrome C release, and reduced reactive oxygen species production. Increasing mtHK may also have important metabolic consequences, such as improvement of glucose‐induced insulin release, prevention of acidosis through enhanced coupling of glycolysis and glucose oxidation, and inhibition of fatty acid oxidation. Deficiencies in expression and distorted cellular signalling of HKII may contribute to the altered sensitivity of diabetes to cardiac ischaemic diseases. The interaction of HKII with the mitochondrion constitutes a powerful endogenous molecular mechanism to protect against cell death in almost all cell types examined (neurons, tumours, kidney, lung, skeletal muscle, heart). The challenge now is to harness mtHKII in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischaemic preconditioning, metformin administration and miR‐155/miR‐144 manipulations are potential means of doing just that.
Parsing the players: 2‐arachidonoylglycerol synthesis and degradation in the CNS

The endogenous cannabinoid signalling system, composed of endogenous cannabinoids, cannabinoid receptors and the enzymes that synthesize and degrade the endogenous cannabinoids, is much more complex than initially conceptualized. 2‐Arachidonoylglycerol (2‐AG) is the most abundant endocannabinoid and plays a major role in CNS development and synaptic plasticity. Over the past decade, many key players in 2‐AG synthesis and degradation have been identified and characterized. Most 2‐AG is synthesized from membrane phospholipids via sequential activation of a phospholipase Cβ and a diacylglycerol lipase, although other pathways may contribute in specialized settings. 2‐AG breakdown is more complicated with at least eight different enzymes participating. These enzymes can either degrade 2‐AG into its components, arachidonic acid and glycerol, or transform 2‐AG into highly bioactive signal molecules. The implications of the precise temporal and spatial control of the expression and function of these pleiotropic metabolizing enzymes have only recently come to be appreciated. In this review, we will focus on the primary organization of the synthetic and degradative pathways of 2‐AG and then discuss more recent findings and their implications, with an eye towards the biological and therapeutic implications of manipulating 2‐AG synthesis and metabolism.
Risks of financial abuse of older people with dementia: findings from a survey of UK voluntary sector dementia community services staff

Purpose – Financial abuse of people with dementia is of rising concern to family carers, the voluntary sector and professionals. Little is known about preventative and early response practice among community services staff. The purpose of this paper is to investigate voluntary sector staff's views of the risks of managing money when a person has a dementia and explore ways that individuals may be protected from the risks of financial abuse. Design/methodology/approach – An online survey of staff of local Alzheimer's Society groups across England was conducted in 2011 and was completed by 86 respondents. Open-ended responses supplemented survey questions. Statistical analysis and content analysis identified emergent findings. Findings – Most respondents said their people with dementia experienced problems with money management, with almost half the respondents reporting encountering cases of financial abuse over the past year. Most were alert to warning signs and vulnerabilities and offered suggestions rel.
Metformin and male reproduction: effects on Sertoli cell metabolism

Metformin is commonly used to treat type 2 diabetes (T2D). While new clinical applications have been ascribed to metformin, including treatment of anovulatory infertility, its effects on male reproduction have not been investigated. The Sertoli cell (SC) is crucial for germ cell development, exerting metabolic control of spermatogenesis, therefore, we investigated the effects of metformin on SC metabolism.
Regulatory role of the cannabinoid CB2 receptor in stress‐induced neuroinflammation in mice

Stress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress‐related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress‐responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB2 receptors in stress‐induced excitotoxicity and neuroinflammation.
Heteromers of μ‐δ opioid receptors: new pharmacology and novel therapeutic possibilities

Several studies suggest that heteromerization between μ (MOP) and δ (DOP) opioid receptors modulates the signalling properties of the individual receptors. For example, whereas activation of MOP receptors by an agonist induces G protein‐mediated signalling, the same agonist induces β‐arrestin‐mediated signalling in the context of the MOP‐DOP receptor heteromer. Moreover, heteromer‐mediated signalling is allosterically modulated by a combination of MOP and DOP receptor ligands. This has implications in analgesia given that morphine‐induced antinociception can be potentiated by DOP receptor ligands. Recently reagents selectively targeting the MOP‐DOP receptor heteromer such as bivalent ligands, antibodies or membrane permeable peptides have been generated; these reagents are enabling studies to elucidate the contribution of endogenously expressed heteromers to analgesia as well as to the development of side‐effects associated with chronic opioid use. Recent advances in drug screening technology have led to the identification of a MOP‐DOP receptor heteromer‐biased agonist that activates both G protein‐mediated and β‐arrestin‐mediated signalling. Moreover, this heteromer‐biased agonist exhibits potent antinociceptive activity but with reduced side‐effects, suggesting that ligands targeting the MOP‐DOP receptor heteromer form a basis for the development of novel therapeutics for the treatment of pain. In this review, we summarize findings regarding the biological and functional characteristics of the MOP‐DOP receptor heteromer and the in vitro and in vivo properties of heteromer‐selective ligands.
β‐Arrestin‐2 knockout prevents development of cellular μ‐opioid receptor tolerance but does not affect opioid‐withdrawal‐related adaptations in single PAG neurons

Tolerance to the behavioural effects of morphine is blunted in β‐arrestin‐2 knockout mice, but opioid withdrawal is largely unaffected. The cellular mechanisms of tolerance have been studied in some neurons from β‐arrestin‐2 knockouts, but tolerance and withdrawal mechanisms have not been examined at the cellular level in periaqueductal grey (PAG) neurons, which are crucial for central tolerance and withdrawal phenomena.
Diversity and antimicrobial activities of the fungal endophyte community associated with the traditional Brazilian medicinal plant Solanum cernuum Vell. (Solanaceae).

The diversity and antimicrobial activity of endophytic fungi associated with the Brazilian medicinal plant Solanum cernuum Vell. were studied during summer and winter seasons. A total of 246 fungal isolates were obtained, including 225 filamentous fungi and 21 yeasts. They were identified by morphological, physiological, and molecular methods. Fifty-five different taxa represented by the phyla Ascomycota (33 taxa), Basidiomycota (21 taxa), and Zygomycota (one taxon) were identified. The most abundant taxa were closely related to Arthrobotrys foliicola , Colletotrichum gloeosporioides , Coprinellus radians , Glomerella acutata , Diatrypella frostii , Phoma glomerata , Mucor sp. , Phlebia subserialis , Phoma moricola , Phanerochaete sordida , and Colletotrichum sp. A total of 265 fungal extracts were screened and 64 (26.01%) displayed antimicrobial activities. Among these extracts, 18 (28.12%) presented antibacterial and antifungal activities, 42 (65.62%) displayed selective antibacterial activity, and four (6.25%) exhibited only antifungal activity. The best values of minimum inhibitory concentration were obtained from extracts of Cryptococcus rajasthanensis , Glomerella acutata, Leptosphaeria sp. , and Phoma glomerata ranging from 7.8 to 15.62 µg/mL. This study is the first survey of the endophytic fungi community associated with S. cernuum, and our results show that they can represent a promising source of bioactive compounds.