Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for ...effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady‐state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.
Dopamine neurons within the healthy human substantia nigra exhibit mild oxidative stress during aging, resulting from their unique biochemical properties and a number of age‐dependent biochemical changes specific to this neuronal population (grey). An exacerbation of these pathways, combined with additional environmental toxins and genetic mutations, worsens redox balance within nigral dopamine neurons in Parkinson's disease, causing excessive oxidative stress and dopamine neuron death (red).
The Class III receptor tyrosine kinase Flt3 and its ligand, the Flt3-ligand (FL), play an integral role in regulating the proliferation, differentiation, and survival of multipotent hematopoietic and ...lymphoid progenitors from which B cell precursors derive in bone marrow (BM). More recently, essential roles for Flt3 signaling in the regulation of peripheral B cell development and affinity maturation have come to light. Experimental findings derived from a multitude of mouse models have reinforced the importance of molecular and cellular regulation of Flt3 and FL in lymphohematopoiesis and adaptive immunity. Here, we provide a comprehensive review of the current state of the knowledge regarding molecular and cellular regulation of Flt3/FL and the roles of Flt3 signaling in hematopoietic stem cell (HSC) activation, lymphoid development, BM B lymphopoiesis, and peripheral B cell development. Cumulatively, the literature has reinforced the importance of Flt3 signaling in B cell development and function. However, it has also identified gaps in the knowledge regarding Flt3-dependent developmental-stage specific gene regulatory circuits essential for steady-state B lymphopoiesis that will be the focus of future studies.
Iron accumulation is a cardinal feature of degenerating regions in the Parkinson's disease brain. As a potent pro-oxidant, redox-active iron may be a key player in upstream mechanisms that ...precipitate cell death in this disorder. Although an elevation in brain iron levels is a normal feature of ageing, the increase is greater in Parkinson's disease; on the other hand, the effects of the disease are most marked in the nigrostriatal dopaminergic system. In this Update, we explain that neurodegeneration in the affected regions may result from the potent redox couple formed by iron and dopamine itself, and discuss the clinical implications of this molecular trait in this dynamic and rapidly moving area of Parkinson's disease research.
Matched field processing (MFP) compares the measures to the modeled pressure fields received at an array of sensors to localize a source in an ocean waveguide. Typically, there are only a few sources ...when compared to the number of candidate source locations or range-depth cells. We use sparse Bayesian learning (SBL) to learn a common sparsity profile corresponding to the location of present sources. SBL performance is compared to traditional processing in simulations and using experimental ocean acoustic data. Specifically, we localize a quiet source in the presence of a surface interferer in a shallow water environment. This multi-frequency scenario requires adaptive processing and includes modest environmental and sensor position mismatch in the MFP model. The noise process changes likely with time and is modeled as a non-stationary Gaussian process, meaning that the noise variance changes across snapshots. The adaptive SBL algorithm models the complex source amplitudes as random quantities, providing robustness to amplitude and phase errors in the model. This is demonstrated with experimental data, where SBL exhibits improved source localization performance when compared to the white noise gain constraint (-3 dB) and Bartlett processors.
This paper investigates the uncertainty in the impact of climate change on flood frequency in England, through the use of continuous simulation of river flows. Six different sources of uncertainty ...are discussed: future greenhouse gas emissions; Global Climate Model (GCM) structure; downscaling from GCMs (including Regional Climate Model structure); hydrological model structure; hydrological model parameters and the internal variability of the climate system (sampled by applying different GCM initial conditions). These sources of uncertainty are demonstrated (separately) for two example catchments in England, by propagation through to flood frequency impact. The results suggest that uncertainty from GCM structure is by far the largest source of uncertainty. However, this is due to the extremely large increases in winter rainfall predicted by one of the five GCMs used. Other sources of uncertainty become more significant if the results from this GCM are omitted, although uncertainty from sources relating to modelling of the future climate is generally still larger than that relating to emissions or hydrological modelling. It is also shown that understanding current and future natural variability is critical in assessing the importance of climate change impacts on hydrology.
Background Evidence is conflicting regarding the relationship between low maternal alcohol consumption and birth outcomes. This paper aimed to investigate the association between alcohol intake ...before and during pregnancy with birth weight and gestational age and to examine the effect of timing of exposure. Methods A prospective cohort in Leeds, UK, of 1303 pregnant women aged 18–45 years. Questionnaires assessed alcohol consumption before pregnancy and for the three trimesters separately. Categories of alcohol consumption were divided into ≤2 units/week and >2 units/week with a non-drinking category as referent. This was related to size at birth and preterm delivery, adjusting for confounders including salivary cotinine as a biomarker of smoking status. Results Nearly two-thirds of women before pregnancy and over half in the first trimester reported alcohol intakes above the Department of Health (UK) guidelines of ≤2 units/week. Associations with birth outcomes were strongest for intakes >2 units/week before pregnancy and in trimesters 1 and 2 compared to non-drinkers. Even women adhering to the guidelines in the first trimester were at significantly higher risk of having babies with lower birth weight, lower birth centile and preterm birth compared to non-drinkers, after adjusting for confounders (p<0.05). Conclusions We found the first trimester to be the period most sensitive to the effect of alcohol on the developing fetus. Women adhering to guidelines in this period were still at increased risk of adverse birth outcomes. Our findings suggest that women should be advised to abstain from alcohol when planning to conceive and throughout pregnancy.
Copper is a biometal essential for normal brain development and function, thus copper deficiency or excess results in central nervous system disease. Well-characterized disorders of disrupted copper ...homoeostasis with neuronal degeneration include Menkes disease and Wilson's disease but a large body of evidence also implicates disrupted copper pathways in other neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease and prion diseases. In this short review we critically evaluate the data regarding changes in systemic and brain copper levels in Parkinson's disease, where alterations in brain copper are associated with regional neuronal cell death and disease pathology. We review copper regulating mechanisms in the human brain and the effects of dysfunction within these systems. We then examine the evidence for a role for copper in pathogenic processes in Parkinson's disease and consider reports of diverse copper-modulating strategies in in vitro and in vivo models of this disorder. Copper-modulating therapies are currently advancing through clinical trials for Alzheimer's and Huntington's disease and may also hold promise as disease modifying agents in Parkinson's disease.
Face masks present a new challenge to face identification (here matching) and emotion recognition in Western cultures. Here, we present the results of three experiments that test the effect of masks, ...and also the effect of sunglasses (an occlusion that individuals tend to have more experienced with) on (i) familiar face matching, (ii) unfamiliar face matching and (iii) emotion categorization. Occlusion reduced accuracy in all three tasks, with most errors in the mask condition; however, there was little difference in performance for faces in masks compared with faces in sunglasses. Super-recognizers, people who are highly skilled at matching unconcealed faces, were impaired by occlusion, but at the group level, performed with higher accuracy than controls on all tasks. Results inform psychology theory with implications for everyday interactions, security and policing in a mask-wearing society.
Adjuvant hormonal therapy significantly improves long-term survival of breast cancer patients with hormone receptor-positive disease. Despite the proven clinical efficacy of tamoxifen and aromatase ...inhibitors, many breast cancer survivors either fail to take the correct dosage at the prescribed frequency (adherence) or discontinue therapy (persistence). This systematic review aims to: (1) determine the prevalence of adherence and persistence to adjuvant hormonal therapy among breast cancer survivors in clinical practice, and (2) identify correlates of adherence and persistence. We searched Medline, PubMed, PsycINFO, and CINAHL for studies that measured rates and/or correlates of adherence and/or persistence to adjuvant hormonal therapy. Studies were reviewed in a multi-step process: (1) the lead author screened titles and abstracts of all potentially eligible studies; (2) each coauthor reviewed a random 5 % sample of abstracts; and (3) two sets of coauthors each reviewed half of all “maybe” abstracts. Any disagreements were discussed until consensus was reached. Twenty-nine studies met inclusion criteria. Prevalence of adherence ranged from 41 to 72 % and discontinuation (i.e., nonpersistence) ranged from 31 to 73 %, measured at the end of 5 years of treatment. Extremes of age (older or younger), increasing out-of-pocket costs, follow-up care with a general practitioner (vs. oncologist), higher CYP2D6 activity, switching from one form of therapy to another, and treatment side effects were negatively associated with adherence and/or persistence. Taking more medications at baseline, referral to an oncologist, and earlier year at diagnosis were positively associated with adherence and/or persistence. Adherence and persistence to adjuvant hormonal therapy among breast cancer survivors is suboptimal. Many of the correlates of adherence and persistence studied to date are not modifiable. Our review reveals a critical need for further research on modifiable factors associated with adherence to adjuvant hormonal therapy, and the development of behavioral interventions to improve adherence in this population.
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