Oxidative phosphorylation provides most of the ATP that higher animals and plants use to support life and is responsible for setting and maintaining metabolic homeostasis. The pathway incorporates ...three consecutive near equilibrium steps for moving reducing equivalents between the intramitochondrial NAD+/NADH pool to molecular oxygen, with irreversible reduction of oxygen to bound peroxide at cytochrome c oxidase determining the net flux. Net flux (oxygen consumption rate) is determined by demand for ATP, with feedback by the energy state (ATP/ADPPi) regulating the pathway. This feedback affects the reversible steps equally and independently, resulting in the rate being coupled to (ATP/ADPPi)3. With increasing energy state, oxygen consumption decreases rapidly until a threshold is reached, above which there is little further decrease. In most cells, ATP and Pi are much higher than ADP and change in ADP is primarily responsible for the change in energy state. As a result, the rate of ATP synthesis, plotted against ADP, remains low until ADP reaches about 30 μm and then increases rapidly with further increase in ADP. The dependencies on energy state and ADP near the threshold can be fitted by the Hill equation with a Hill coefficients of about −2.6 and 4.2, respectively. The homeostatic set point for metabolism is determined by the threshold, which can be modulated by the PO2 and intramitochondrial NAD+/NADH. The ability of oxidative phosphorylation to precisely set and maintain metabolic homeostasis is consistent with it being permissive of, and essential to, development of higher plants and animals.
Integration of oxidative phosphorylation into cellular metabolism made possible the evolutionary development of higher organisms. Progressive improvements in control of oxidative phosphorylation supported the increasing demands of specialized tissues, in particular muscles and neurons. One of these improvements, replacing arginine kinase with creatine kinase, was permissive of the evolutionary development of vertebrates.
Genetic information is constantly being attacked by intrinsic and extrinsic damaging agents, such as reactive oxygen species, atmospheric radiation, environmental chemicals, and chemotherapeutics. If ...DNA modifications persist, they can adversely affect the polymerization of DNA or RNA, leading to replication fork collapse or transcription arrest, or can serve as mutagenic templates during nucleic acid synthesis reactions. To combat the deleterious consequences of DNA damage, organisms have developed complex repair networks that remove chemical modifications or aberrant base arrangements and restore the genome to its original state. Not surprisingly, inherited or sporadic defects in DNA repair mechanisms can give rise to cellular outcomes that underlie disease and aging, such as transformation, apoptosis, and senescence. In the review here, we discuss several genetic disorders linked to DNA repair defects, attempting to draw correlations between the nature of the accumulating DNA damage and the pathological endpoints, namely cancer, neurological disease, and premature aging.
Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological ...protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs.
Neurodegenerative diseases (NDDs) are a heterogeneous group of disorders characterized by progressive loss of neurons in the central or peripheral nervous system. This review highlights the eight key hallmarks of NDDs and presents a hallmark-based framework for unifying and categorizing NDDs, for stratifying NDD patients, and for designing personalized therapeutic strategies.
The genetic material of all organisms is susceptible to modification. In some instances, these changes are programmed, such as the formation of DNA double strand breaks during meiotic recombination ...to generate gamete variety or class switch recombination to create antibody diversity. However, in most cases, genomic damage is potentially harmful to the health of the organism, contributing to disease and aging by promoting deleterious cellular outcomes. A proportion of DNA modifications are caused by exogenous agents, both physical (namely ultraviolet sunlight and ionizing radiation) and chemical (such as benzopyrene, alkylating agents, platinum compounds and psoralens), which can produce numerous forms of DNA damage, including a range of “simple” and helix-distorting base lesions, abasic sites, crosslinks and various types of phosphodiester strand breaks. More significant in terms of frequency are endogenous mechanisms of modification, which include hydrolytic disintegration of DNA chemical bonds, attack by reactive oxygen species and other byproducts of normal cellular metabolism, or incomplete or necessary enzymatic reactions (such as topoisomerases or repair nucleases). Both exogenous and endogenous mechanisms are associated with a high risk of single strand breakage, either produced directly or generated as intermediates of DNA repair. This review will focus upon the creation, consequences and resolution of single strand breaks, with a particular focus on two major coordinating repair proteins: poly(ADP-ribose) polymerase 1 (PARP1) and X-ray repair cross-complementing protein 1 (XRCC1).
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•Overview of the types and consequences of prominent forms of endogenous DNA damage.•Detailed description of the structure, biochemistry and biology of PARP1 and XRCC1.•Comprehensive summary of the molecular choreography of single strand break repair.•Introduction of the link between defects in single strand break repair and neurological disease.
We report the discovery of a tandem catalytic process to reduce energy demanding substrates, using the Ir(ppy)2(dtb-bpy)+ (1 + ) photocatalyst. The immediate products of photoinitiated electron ...transfer (PET) between 1 + and triethylamine (TEA) undergo subsequent reactions to generate a previously unknown, highly reducing species (2). Formation of 2 occurs via reduction and semisaturation of the ancillary dtb-bpy ligand, where the TEA radical cation serves as an effective hydrogen atom donor, confirmed by nuclear magnetic resonance, mass spectrometry, and deuterium labeling experiments. Steady-state and time-resolved luminescence and absorption studies reveal that upon irradiation, 2 undergoes electron transfer or proton-coupled electron transfer (PCET) with a representative acceptor (N-(diphenylmethylene)-1-phenylmethanamine; S). Turnover of this new photocatalytic cycle occurs along with the reformation of 1 + . We rationalize our observations by proposing the first example of a mechanistic pathway where two distinct yet interconnected photoredox cycles provide access to an extended reduction potential window capable of engaging a wide range of energy demanding and synthetically relevant organic substrates including aryl halides.
There is evidence that HIV prevention programs for sex workers, especially female sex workers, are cost-effective in several contexts, including many western countries, Thailand, India, the ...Democratic Republic of Congo, Kenya, and Zimbabwe. The evidence that sex worker HIV prevention programs work must not inspire complacency but rather a renewed effort to expand, intensify, and maximize their impact. The PLOS Collection "Focus on Delivery and Scale: Achieving HIV Impact with Sex Workers" highlights major challenges to scaling-up sex worker HIV prevention programs, noting the following: sex worker HIV prevention programs are insufficiently guided by understanding of epidemic transmission dynamics, situation analyses, and programmatic mapping; sex worker HIV and sexually transmitted infection services receive limited domestic financing in many countries; many sex worker HIV prevention programs are inadequately codified to ensure consistency and quality; and many sex worker HIV prevention programs have not evolved adequately to address informal sex workers, male and transgender sex workers, and mobile- and internet-based sex workers. Based on the wider collection of papers, this article presents three major clusters of recommendations: (i) HIV programs focused on sex workers should be prioritized, developed, and implemented based on robust evidence; (ii) national political will and increased funding are needed to increase coverage of effective sex worker HIV prevention programs in low and middle income countries; and (iii) comprehensive, integrated, and rapidly evolving HIV programs are needed to ensure equitable access to health services for individuals involved in all forms of sex work.
As a key utility service that more than 2 billion people are currently lacking, solid waste management (SWM) is a crosscutting issue that can be directly linked to 12 out of the 17 UN Sustainable ...Development Goals (SDGs). Distinguishing between physical components and governance aspects of SWM, this research focuses on governance issues concerning basic solid waste collection services and controlled disposal, thus addressing the ‘How’ and the ‘Who’ dimensions of a SWM system. As a form of transdisciplinary research, the findings from the literature on governance issues in SWM were iteratively subjected to several rounds of commentary by a large group of stakeholders from six continents, within the authors’ work for the United Nations Environment Programme (UNEP)’s 2015 Global Waste Management Outlook. The study identifies a combination of complementary instruments required for extending collection to all and bringing disposal under control. While municipalities have a legal responsibility for providing services to their citizens, various service providers can contribute to an effective SWM system. Appropriate forms of funding are essential to secure financial sustainability of the services under the local conditions of affordability and willingness to pay. As new services require behavioural change on the part of citizens and municipal waste departments alike, communication and exchange with other stakeholders function as enabling and supporting factors. The significance of capacity development is highlighted.
Area-based prevention studies often produce results that can be represented in a 2-by-2 table of counts. For example, a table may show the crime counts during a 12-month period prior to the ...intervention compared to a 12-month period during the intervention for a treatment and control area or areas. Studies of this type have used either Cohen’s
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or the odds ratio as an effect size index. The former is unsuitable and the latter is a misnomer when used on data of this type. Based on the quasi-Poisson regression model, an incident rate ratio and relative incident rate ratio effect size and associated overdispersion parameter are developed and advocated as the preferred effect size for count-based outcomes in impact evaluations and meta-analyses of such studies.
•A review of the contribution of the different DNA repair mechanisms in dividing and non-dividing cells is provided.•The most recent findings on the molecular mechanisms of DNA repair in ...proliferating and terminally differentiated brain cells are described.•The relationship between a deficiency in a particular DNA repair pathway and human disease, with an emphasis on neuropathologies, is reviewed.
DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within which they operate. For example, the human body is composed of non-dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye toward how these pathways may regulate the development of neurological disease.
Enzymatic hydrolysis of cellulose by microorganisms is a key step in the global carbon cycle. Despite its abundance only a small percentage of microorganisms can degrade cellulose, probably because ...it is present in recalcitrant cell walls. There are at least five distinct mechanisms used by different microorganisms to degrade cellulose all of which involve cellulases. Cellulolytic organisms and cellulases are extremely diverse possibly because their natural substrates, plant cell walls, are very diverse. At this time the microbial ecology of cellulose degradation in any environment is still not clearly understood even though there is a great deal of information available about the bovine rumen. Two major problems that limit our understanding of this area are the vast diversity of organisms present in most cellulose degrading environments and the inability to culture most of them.
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