The brain-derived neurotrophic factor (BDNF) hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and that its restoration may underlie ...the therapeutic efficacy of antidepressant treatment. While this theory has received considerable experimental support, an increasing number of studies have generated evidence which is not only inconsistent, but also directly contradicts the hypothesis. This article provides a critical review of the clinical and preclinical studies which have been responsible for this controversy, outlining pharmacological, behavioural and genetic evidence which demonstrates the contrasting role of BDNF in regulating mood and antidepressant effects throughout the brain. I will also review key studies, both human and animal, which have investigated the association of a BDNF single-nucleotide polymorphism (Val66Met) with depression pathogenesis, and detail the number of inconsistencies which also afflict this novel area of BDNF research. The article will conclude by discussing why now is a critical time to reassess the original BDNF hypothesis of depression, and look towards the formation of new models that can provide a more valid account of the complex relationships between growth factors, mood disorders and their treatment.
Macromolecular crowding has a profound impact on reaction rates and the physical properties of the cell interior, but the mechanisms that regulate crowding are poorly understood. We developed ...genetically encoded multimeric nanoparticles (GEMs) to dissect these mechanisms. GEMs are homomultimeric scaffolds fused to a fluorescent protein that self-assemble into bright, stable particles of defined size and shape. By combining tracking of GEMs with genetic and pharmacological approaches, we discovered that the mTORC1 pathway can modulate the effective diffusion coefficient of particles ≥20 nm in diameter more than 2-fold by tuning ribosome concentration, without any discernable effect on the motion of molecules ≤5 nm. This change in ribosome concentration affected phase separation both in vitro and in vivo. Together, these results establish a role for mTORC1 in controlling both the mesoscale biophysical properties of the cytoplasm and biomolecular condensation.
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•GEMs enable high-throughput microrheology in unperturbed living cells•mTORC1 controls diffusion by tuning ribosome concentration•Diffusion can be accurately predicted as a function of ribosome concentration•Crowding of the cytoplasm by ribosomes increases phase separation
mTORC1 signaling controls phase transitions in the cytoplasm through its effects on molecular crowding.
Filopodia, dynamic membrane protrusions driven by polymerization of an actin filament core, can adhere to the extracellular matrix and experience both external and cell-generated pulling forces. The ...role of such forces in filopodia adhesion is however insufficiently understood. Here, we study filopodia induced by overexpression of myosin X, typical for cancer cells. The lifetime of such filopodia positively correlates with the presence of myosin IIA filaments at the filopodia bases. Application of pulling forces to the filopodia tips through attached fibronectin-coated laser-trapped beads results in sustained growth of the filopodia. Pharmacological inhibition or knockdown of myosin IIA abolishes the filopodia adhesion to the beads. Formin inhibitor SMIFH2, which causes detachment of actin filaments from formin molecules, produces similar effect. Thus, centripetal force generated by myosin IIA filaments at the base of filopodium and transmitted to the tip through actin core in a formin-dependent fashion is required for filopodia adhesion.
The complex life cycle of oncogenic human papillomavirus (HPV) initiates in undifferentiated basal epithelial keratinocytes where expression of the E6 and E7 oncogenes is restricted. Upon epithelial ...differentiation, E6/E7 transcription is increased through unknown mechanisms to drive cellular proliferation required to support virus replication. We report that the chromatin-organising CCCTC-binding factor (CTCF) promotes the formation of a chromatin loop in the HPV genome that epigenetically represses viral enhancer activity controlling E6/E7 expression. CTCF-dependent looping is dependent on the expression of the CTCF-associated Yin Yang 1 (YY1) transcription factor and polycomb repressor complex (PRC) recruitment, resulting in trimethylation of histone H3 at lysine 27. We show that viral oncogene up-regulation during cellular differentiation results from YY1 down-regulation, disruption of viral genome looping, and a loss of epigenetic repression of viral enhancer activity. Our data therefore reveal a key role for CTCF-YY1-dependent looping in the HPV life cycle and identify a regulatory mechanism that could be disrupted in HPV carcinogenesis.
This paper reports the first year results of field experiments to determine the survival times of pathogens in livestock manures during storage and following land application, using viable count ...methods.
E. coli O157,
Salmonella and
Campylobacter survived in stored slurries and dirty water for up to three months, with
Listeria surviving for up to three months. In contrast, all these pathogens survived for less than one month in solid manure heaps where temperatures greater than 55 °C were obtained. Following manure spreading to land,
E. coli O157,
Salmonella and
Campylobacter generally survived in the soil for up to one month after application to both the sandy arable and clay loam grassland soils, whereas
Listeria commonly survived for more than one month. These data are being used to develop guidelines on the management of manures to minimise the risks of pathogen transfer from animal manures to the human food chain.
Barth syndrome Clarke, Sarah L N; Bowron, Ann; Gonzalez, Iris L ...
Orphanet journal of rare diseases,
02/2013, Letnik:
8, Številka:
1
Journal Article
Recenzirano
Odprti dostop
First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased ...urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.
Research suggests that only 50% of patients with major depression respond to psychotherapy or pharmacological treatment, and relapse is common. Therefore, there is interest in elucidating factors ...that help predict clinical response. Cognitive impairment is a key feature of depression, which often persists beyond remission; thus, the aim of this systematic review was to determine whether baseline cognitive functioning can predict treatment outcomes in individuals with depression.
Studies examining cognitive predictors of treatment response in depression were identified using Pub Med and Web of Science databases. Given the heterogeneity of outcome measures, the variety of treatment protocols, and the differing ways in which data was presented and analyzed, a narrative rather than meta-analytic review technique was used.
39 studies met inclusion criteria. Findings in younger adult samples were inconclusive. There was some evidence for a predictive effect of executive function and to a lesser extent, psychomotor speed, on treatment response. There was no evidence of learning or memory being associated with treatment response. In older-aged samples, the evidence was much more consistent, suggesting that poor executive function predicts poor response to SSRIs.
Findings from the present review suggest that certain aspects of cognitive functioning, particularly executive function, may be useful in predicting treatment response in depression. This is certainly the case in elderly samples, with evidence suggesting that poor executive functioning predicts poor response to SSRIs. With further research, baseline cognitive functioning may serve as a factor which helps guide clinical decision making. Moreover, cognitive deficits may become targets for specific pharmacological or psychological treatments, with the hope of improving overall outcome.
Patients with severe grades of life-threatening brain injury are commonly characterized as having devastating brain injury (DBI), which we have defined as: ‘any neurological condition that is ...assessed at the time of hospital admission as an immediate threat to life or incompatible with good functional recovery AND where early limitation or withdrawal of therapy is being considered’. The outcome in patients with DBI is often death or severe disability, and as a consequence rapid withdrawal of life sustaining therapies is commonly contemplated or undertaken. However, accurate prognostication in life-threatening brain injury is difficult, particularly at an early stage. Evidence from controlled studies to guide decision-making is limited, and there is a risk of a ‘self-fulfilling prophecy’, with early prognostication leading to early withdrawal of life sustaining therapies and death. The Joint Professional Standards committee of the Faculty of Intensive Care Medicine and the Intensive Care Society convened a consensus group with representation from stakeholder professional organizations to develop clear professional guidance in this area. It recognized that the weak evidence base makes GRADE guidelines difficult to justify. We have made 12 practical, pragmatic recommendations to help clinicians deliver safe, effective, equitable, and justifiable care within resource constrained healthcare systems. In the situation where patient-centred outcomes are recognized to be unacceptable, regardless of the extent of neurological improvement, then early transition to palliative care is appropriate. These recommendations are intended to apply where the primary pathology is DBI, rather than where DBI has compounded a progressive and irreversible deterioration in other life-threatening comorbidities.
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