Decoding ALS: from genes to mechanism Taylor, J Paul; Brown, Jr, Robert H; Cleveland, Don W
Nature (London),
2016-Nov-10, 2016-11-10, 20161110, Volume:
539, Issue:
7628
Journal Article
Peer reviewed
Open access
Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ...ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Amyotrophic Lateral Sclerosis Brown, Robert H; Al-Chalabi, Ammar
The New England journal of medicine,
07/2017, Volume:
377, Issue:
2
Journal Article
Peer reviewed
Open access
Progress has been made in understanding the genetic defects and the pathophysiology of this crippling motor neuron disease (commonly called Lou Gehrig’s disease). However, this information has not ...yet led to a successful intervention that alters the course of the disease.
Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a ...motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable.
The severity of urban heat islands (UHIs) is increasing due to global and urban climate change. The damage caused by UHIs is also increasing. To establish a plan to improve the deteriorating thermal ...environment in cities due to UHIs and to minimize the damage, further research is needed to accurately estimate and analyze the intensity and magnitude of UHIs. This systematic literature review (SLR) is an in-depth review of 51 studies obtained through a five-step filtering process focusing on their analysis of the spatial extent of UHIs, the UHI concept that was used for UHI estimation, and the UHI estimation and analysis methods. This SLR confirmed the need for accurate UHI intensity and magnitude estimation and analysis to reset the existing UHI classification based on the variety of vertical and horizontal ranges where UHIs occur. The results also indicated that the existing UHI energy concepts for estimating UHIs need to be modified and developed to reflect the three-dimensional physical form of the city. Finally, this SLR clarifies the need to develop an optimized analysis method for UHI research. The review results of this SLR will inform future studies and be the cornerstone for establishing policies and plans that can accurately predict and respond to the damage caused by UHIs.
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•Review intensity, magnitude estimation, and analysis of UHIs using an SLR framework.•Lack of general protocols to establish UHI classification criteria to efficiently estimate and analyze UHIs.•Need to develop a UHI estimation and analysis model considering a 3-D form of a city.•Need for further research to develop a model focusing on the intensity and magnitude of UHIs
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Intracranial saccular or berry aneurysms are common, occurring in about 1–2% of the population. Unruptured intracranial aneurysms are increasingly being detected as cross-sectional imaging ...techniques are used more frequently in clinical practice. Once an unruptured intracranial aneurysm is detected, decisions regarding optimum management are made on the basis of careful comparison of the short-term and long-term risks of aneurysmal rupture with the risk associated with the intervention, whether that be surgical clipping or endovascular management. Several factors need to be carefully considered, including aneurysm size and location, the patient's family history and medical history, and the availability of an interventional option that has an acceptable risk. The patient's knowledge that they have an unruptured intracranial aneurysm can lead to substantial stress and anxiety, and their perspective regarding treatment, after hearing an unbiased appraisal of the rupture risks and the risk of interventional treatment, is of the utmost importance. Controversy remains regarding optimum management, and thorough assessments of the risks and benefits of contemporary management options, specific to aneurysm size, location, and many other aneurysm and patient factors, are needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Syngas from gasification of carbonaceous feedstocks is used for power production and synthesis of fuels and commodity chemicals. Impurities in gasification feedstocks, especially sulfur, nitrogen, ...chlorine, and ash, often find their way into syngas and can interfere with downstream applications. Incomplete gasification can also produce undesirable products in the raw syngas in the form of tar and particulate char. This paper reviews the technologies for removing contaminants from raw syngas. These technologies are classified according to the gas temperature exiting the cleanup device: hot (T > 300 °C), cold (T < ∼100 °C), and warm gas cleaning regimes. Cold gas cleanup uses relatively mature techniques that are highly effective although they often generate waste water streams and may suffer from energy inefficiencies. The majority of these techniques are based on using wet scrubbers. Hot gas cleaning technologies are attractive because they avoid cooling and reheating the gas stream. Many of these are still under development given the technical difficulties caused by extreme environments. Warm gas cleaning technologies include traditional particulate removal devices along with new approaches for removing tar and chlorine.
► A comprehensive review of cleaning methods for syngas is presented. ► The source of each contaminant group and issues they cause are discussed. ► Contaminants include: particulate matter, tar, sulfur, nitrogen, alkali, chlorine. ► Cleaning processes include hot, cold, and intermediate temperature methods.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
7.
Adult primary central nervous system vasculitis Salvarani, Carlo, Dr; Brown, Robert D, Prof; Hunder, Gene G, Prof
The Lancet (British edition),
08/2012, Volume:
380, Issue:
9843
Journal Article
Peer reviewed
Primary CNS vasculitis is an uncommon disorder of unknown cause that is restricted to brain and spinal cord. The median age of onset is 50 years. The neurological manifestations are diverse, but ...generally consist of headache, altered cognition, focal weakness, or stroke. Serological markers of inflammation are usually normal. Cerebrospinal fluid is abnormal in about 80–90% of patients. Diagnosis is unlikely in the presence of a normal MRI of the brain. Biopsy of CNS tissue showing vasculitis is the only definitive test; however, angiography has often been used for diagnosis even though it has only moderate sensitivity and specificity. The size of the affected vessels varies and determines outcome and response to treatment. Early recognition is important because treatment with corticosteroids with or without cytotoxic drugs can often prevent serious outcomes. The differential diagnosis includes reversible cerebral vasoconstriction syndromes and secondary cerebral vasculitis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a ...conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by ...clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1(+/+) stem cell line do not display the hyperexcitability phenotype. SOD1(A4V/+) ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Genetics of Amyotrophic Lateral Sclerosis Ghasemi, Mehdi; Brown, Jr, Robert H
Cold Spring Harbor perspectives in medicine,
05/2018, Volume:
8, Issue:
5
Journal Article
Peer reviewed
Open access
Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disorder of motor neurons that overlaps clinically with frontotemporal dementia (FTD). Investigations of the 10% of ...ALS cases that are transmitted as dominant traits have revealed numerous gene mutations and variants that either cause these disorders or influence their clinical phenotype. The evolving understanding of the genetic architecture of ALS has illuminated broad themes in the molecular pathophysiology of both familial and sporadic ALS and FTD. These central themes encompass disturbances of protein homeostasis, alterations in the biology of RNA binding proteins, and defects in cytoskeletal dynamics, as well as numerous downstream pathophysiological events. Together, these findings from ALS genetics provide new insight into therapies that target genetically distinct subsets of ALS and FTD.
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