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Science Advances May 2023Genome-wide phenotypic screens in the budding yeast , enabled by its knockout collection, have produced the largest, richest, and most systematic phenotypic description...
Genome-wide phenotypic screens in the budding yeast , enabled by its knockout collection, have produced the largest, richest, and most systematic phenotypic description of any organism. However, integrative analyses of this rich data source have been virtually impossible because of the lack of a central data repository and consistent metadata annotations. Here, we describe the aggregation, harmonization, and analysis of ~14,500 yeast knockout screens, which we call Yeast Phenome. Using this unique dataset, we characterized two unknown genes ( and ) and showed that tryptophan starvation is a by-product of many chemical treatments. Furthermore, we uncovered an exponential relationship between phenotypic similarity and intergenic distance, which suggests that gene positions in both yeast and human genomes are optimized for function.
Topics: Humans; Saccharomyces cerevisiae
PubMed: 37235661
DOI: 10.1126/sciadv.adg5702 -
Clinical Therapeutics Oct 2013Parkinson's disease (PD) affects about 1% of the over 60 population and is characterized by a combination of motor symptoms (rest tremor, bradykinesia, rigidity,... (Review)
Review
BACKGROUND
Parkinson's disease (PD) affects about 1% of the over 60 population and is characterized by a combination of motor symptoms (rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait [FoG]) and non-motor symptoms (including psychiatric and cognitive disorders). Given that the loss of dopamine in the striatum is the main pathochemical hallmark of PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission and thus improving motor symptoms. However, the currently licensed medications have several major limitations. Firstly, dopaminergic medications modulate all the key steps in dopamine transmission other than the most powerful determinant of extracellular dopamine levels: the activity of the presynaptic dopamine transporter. Secondly, other monoaminergic neurotransmission systems (ie noradrenergic, cholinergic and glutamatergic systems are altered in PD and may be involved in a variety of motor and non-motor symptoms. Thirdly, today's randomized clinical trials are primarily designed to assess the efficacy and safety of treatments for motor fluctuations and dyskinesia. Fourthly, there is a need for disease- modifying treatments (DMTs) that slow disease progression and reduce the occurrence of the very disabling disorders seen in late-stage PD.
OBJECTIVE
To systematically review a number of putative pharmacological options for treating the main impairments in late-stage PD (ie gait disorders, cognitive disorders and behavioural disorders such as apathy).
METHODS
We searched the PubMed database up until July 2013 with logical combinations of the following search terms: "Parkinson's disease", "gait", "cognition", "apathy", "advanced stage", "modulation", "noradrenergic", "cholinergic", "glutamatergic" and "neurotransmission".
RESULTS
In patients undergoing subthalamic nucleus stimulation, the potentiation of noradrenergic and dopaminergic transmission by methylphenidate improves gait and FoG and may relieve apathy. However, the drug failed to improve cognition in this population. Potentiation of the cholinergic system by acetylcholinesterase inhibitors (which are licensed for use in dementia) may reduce pre-dementia apathy and falls. Modulation of the glutamatergic system by an N-methyl-D-aspartate receptor antagonist did not improve gait and dementia but may have reduced axial rigidity. A number of putative DMTs have been reported.
DISCUSSION
Novel therapeutic strategies should seek to reduce the appearance of the very disabling disorders observed in late-stage PD. Dopamine and/or noradrenaline transporter inhibitors, anticholinesterase inhibitors, Peroxisome-proliferator-activated-receptor-agonists and iron chelators should at least be investigated as putative DMTs by applying a delayed-start clinical trial paradigm to a large population
CONCLUSIONS
There is a need for more randomized clinical trials of treatments for late-stage PD.
Topics: Apathy; Cholinesterase Inhibitors; Clinical Trials as Topic; Deep Brain Stimulation; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drug Discovery; Gait; Humans; Iron Chelating Agents; Methylphenidate; Norepinephrine Plasma Membrane Transport Proteins; Parkinson Disease; Receptors, N-Methyl-D-Aspartate
PubMed: 24011636
DOI: 10.1016/j.clinthera.2013.08.011 -
The Journals of Gerontology. Series B,... Jan 2021This study compares estimates and determinants of within-individual changes in mobility across surveys of older U.S. adults.
OBJECTIVES
This study compares estimates and determinants of within-individual changes in mobility across surveys of older U.S. adults.
METHODS
Data come from the Health and Retirement Study (HRS) and the Midlife in the United States (MIDUS) study. Measures of mobility comprise self-reported level of difficulty with walking several blocks, going up several flights of stairs, lifting and carrying 10 pounds, and stooping. Predictors include sociodemographic characteristics and indicators of health and health behaviors. We pool the datasets and estimate weighted lagged dependent variable logistic regression models for each activity, assessing cross-study differences using interaction terms between a survey indicator and relevant variables.
RESULTS
Estimates of declines in mobility differ substantially across surveys for walking, lifting and carrying, and stooping, but there are no between-survey differences in the probability of (not) recovering from a limitation. With the exception of age, determinants of change are similar between studies. For lifting/carrying and stooping, the age-related increase in developing limitations is less steep at younger ages for HRS respondents than MIDUS respondents, but steeper at older ages.
DISCUSSION
To compare estimates of mobility change across surveys, mobility measures would need to be harmonized. Determinants of mobility change, however, are more comparable.
Topics: Adult; Age Factors; Aged; Aging; Cross-Sectional Studies; Female; Humans; Longitudinal Studies; Male; Middle Aged; Mobility Limitation; Motor Activity; Risk Factors; United States
PubMed: 31362309
DOI: 10.1093/geronb/gbz091 -
The Indian Journal of Medical Research Jan 2016Parkinson`s disease (PD) is the most common neurodegenerative disease and is characterized by tremor, rigidity and akinesia. Diagnosis is clinical in the majority of the... (Review)
Review
Parkinson`s disease (PD) is the most common neurodegenerative disease and is characterized by tremor, rigidity and akinesia. Diagnosis is clinical in the majority of the patients. Patients with PD may have stooped posture but some of them develop different types of postural and striatal deformities. Usually these deformities are more common in atypical parkinsonian disorders such as progressive supranuclear palsy and multisystem atrophy. But in many studies it has been highlighted that these may also be present in approximately one third of PD patients leading to severe disability. These include antecollis or dropped head, camptocormia, p0 isa syndrome, scoliosis, striatal hands and striatal toes. The pathogenesis of these deformities is a complex combination of central and peripheral influences such as rigidity, dystonia and degenerative skeletal changes. Duration of parkinsonism symptoms is an important risk factor and in majority of the patients these deformities are seen in advanced statge of the disease. The patients with such symptoms may initially respond to dopaminergic medications but if not intervened they may become fixed and difficult to treat. Pain and restriction of movement are most common clinical manifestations and these may mimick symptoms of musculoskeletal disorders like rheumatoid arthritis. Early diagnosis is important as the patients may respond to adjustment in dopaminergic medications. Recent advances such as deep brain stimulation (DBS) and ultrasound guided botulinum toxin injection are helpful in management of these deformities in patients with PD.
Topics: Brain; Congenital Abnormalities; Corpus Striatum; Humans; Parkinson Disease; Posture
PubMed: 26997007
DOI: 10.4103/0971-5916.178577 -
Journal of the American Society of... Jul 2014Renal epithelial cells must maintain distinct protein compositions in their apical and basolateral membranes in order to perform their transport functions. The creation... (Review)
Review
Renal epithelial cells must maintain distinct protein compositions in their apical and basolateral membranes in order to perform their transport functions. The creation of these polarized protein distributions depends on sorting signals that designate the trafficking route and site of ultimate functional residence for each protein. Segregation of newly synthesized apical and basolateral proteins into distinct carrier vesicles can occur at the trans-Golgi network, recycling endosomes, or a growing assortment of stations along the cellular trafficking pathway. The nature of the specific sorting signal and the mechanism through which it is interpreted can influence the route a protein takes through the cell. Cell type-specific variations in the targeting motifs of a protein, as are evident for Na,K-ATPase, demonstrate a remarkable capacity to adapt sorting pathways to different developmental states or physiologic requirements. This review summarizes our current understanding of apical and basolateral trafficking routes in polarized epithelial cells.
Topics: Cell Polarity; Endosomes; Epithelial Cells; Kidney; Protein Transport; Urothelium
PubMed: 24652803
DOI: 10.1681/ASN.2013080883 -
Journal of General Internal Medicine Apr 2022The long-term prevalence and risk factors for post-acute COVID-19 sequelae (PASC) are not well described and may have important implications for unvaccinated populations... (Observational Study)
Observational Study
BACKGROUND
The long-term prevalence and risk factors for post-acute COVID-19 sequelae (PASC) are not well described and may have important implications for unvaccinated populations and policy makers.
OBJECTIVE
To assess health status, persistent symptoms, and effort tolerance approximately 1 year after COVID-19 infection DESIGN: Retrospective observational cohort study using surveys and clinical data PARTICIPANTS: Survey respondents who were survivors of acute COVID-19 infection requiring Emergency Department presentation or hospitalization between March 3 and May 15, 2020.
MAIN MEASURE(S)
Self-reported health status, persistent symptoms, and effort tolerance KEY RESULTS: The 530 respondents (median time between hospital presentation and survey 332 days [IQR 325-344]) had mean age 59.2±16.3 years, 44.5% were female and 70.8% were non-White. Of these, 41.5% reported worse health compared to a year prior, 44.2% reported persistent symptoms, 36.2% reported limitations in lifting/carrying groceries, 35.5% reported limitations climbing one flight of stairs, 38.1% reported limitations bending/kneeling/stooping, and 22.1% reported limitations walking one block. Even those without high-risk comorbid conditions and those seen only in the Emergency Department (but not hospitalized) experienced significant deterioration in health, persistent symptoms, and limitations in effort tolerance. Women (adjusted relative risk ratio [aRRR] 1.26, 95% CI 1.01-1.56), those requiring mechanical ventilation (aRRR 1.48, 1.02-2.14), and people with HIV (aRRR 1.75, 1.14-2.69) were significantly more likely to report persistent symptoms. Age and other risk factors for more severe COVID-19 illness were not associated with increased risk of PASC.
CONCLUSIONS
PASC may be extraordinarily common 1 year after COVID-19, and these symptoms are sufficiently severe to impact the daily exercise tolerance of patients. PASC symptoms are broadly distributed, are not limited to one specific patient group, and appear to be unrelated to age. These data have implications for vaccine hesitant individuals, policy makers, and physicians managing the emerging longer-term yet unknown impact of the COVID-19 pandemic.
Topics: Adult; Aged; COVID-19; Female; Health Status; Humans; Middle Aged; Pandemics; Retrospective Studies; SARS-CoV-2
PubMed: 35075531
DOI: 10.1007/s11606-021-07379-z -
Archives of Physiotherapy Apr 2022Most of the studies evaluating lifting behavior only focus on very localized parameters such as lumbar spine flexion, while evaluations of whole-body strategies are...
BACKGROUND
Most of the studies evaluating lifting behavior only focus on very localized parameters such as lumbar spine flexion, while evaluations of whole-body strategies are largely lacking. To enable relatively simple evaluations of whole-body strategies, this study aimed at developing a novel index for quantifying the stoop-squat behavior, and to establish normative values of the index for healthy pain-free adults.
METHODS
A novel index, the Stoop-Squat-Index, was developed, which describes the proportion between trunk forward lean and lower extremity joint flexion, with possible values ranging from 0 (full squat lifting) to 100 (full stoop lifting). To enable the interpretation of the index in a real-life setting, normative values for lifting a moderately-weighted object (15-kg-box) with a full squat and a full stoop technique were established using motion capture data from 30 healthy pain-free individuals that underwent motion analysis of squat and stoop lifting in the context of a previously conducted study.
RESULTS
The results showed mean index values of lower than 30 and higher than 90 for the most relevant phases of the squat and stoop movements, respectively, with mean index values differing significantly from each other for the full duration of the lifting phases.
CONCLUSIONS
The main advantages of the index are that it is simple to calculate and can not only be derived from motion capture data but also from conventional video recordings, which enables large-scale in-field measurements with relatively low expenditure. When used in combination with lumbar spine flexion measurements, the index can contribute important information, which is necessary for comprehensively evaluating whole-body lifting strategies and to shed more light on the debate over the connection between lifting posture and back complaints.
PubMed: 35449120
DOI: 10.1186/s40945-022-00135-4 -
Neuron May 2016In this issue of Neuron, Oettl et al. (2016) show how oxytocin can boost processing of olfactory information in female rats by a top-downregulation from the anterior... (Review)
Review
In this issue of Neuron, Oettl et al. (2016) show how oxytocin can boost processing of olfactory information in female rats by a top-downregulation from the anterior olfactory nucleus onto the main olfactory bulb. As a result, interactions with juvenile conspecifics receive more attention and are longer memorized.
Topics: Animals; Humans; Memory; Neurons; Olfactory Bulb; Oxytocin; Smell
PubMed: 27151635
DOI: 10.1016/j.neuron.2016.04.033 -
Critical Reviews in Biomedical... 2021Industrial exoskeletons have been used to assist workers during occupational activities, such as overhead work, tool-use, mobility, stooping/squatting, and/or load... (Review)
Review
Industrial exoskeletons have been used to assist workers during occupational activities, such as overhead work, tool-use, mobility, stooping/squatting, and/or load carrying in various industries. Despite the promise of reducing the risk of work-related musculoskeletal disorders, there is a lack of sufficient evidence to support the safe and effective use of industrial exoskeletons. To assess the merits and residual risks of various types of exoskeletons in different work settings, more comprehensive evaluation procedures are needed. This review study aims to provide an overview of the existing viable and promising methods for evaluating the effectiveness of industrial exoskeletons. The different evaluation methods are organized into three categories-in vitro, in vivo, and in silico studies. The limitations and challenges in different types of evaluation approaches are also discussed. In summary, this review sheds light on choosing appropriate evaluation approaches and may help with decision-making during the development, evaluation, and application of industrial exoskeletons.
Topics: Exoskeleton Device; Humans
PubMed: 35695600
DOI: 10.1615/CritRevBiomedEng.2022041509 -
Health & Social Care in the Community Sep 2019In many integrated care programs, a comprehensive geriatric assessment (CGA) is conducted to identify older people's problems and care needs. Different ways for... (Review)
Review
In many integrated care programs, a comprehensive geriatric assessment (CGA) is conducted to identify older people's problems and care needs. Different ways for conducting a CGA are in place. However, it is still unclear which CGA instruments and procedures for conducting them are used in integrated care programs, and what distinguishes them from each other. Furthermore, it is yet unknown how and to what extent CGAs, as a component of integrated care programs, actually reflect the main principles of integrated care, being comprehensiveness, multidisciplinarity and person-centredness. Therefore, the objectives of this study were to: (a) describe and compare different CGA instruments and procedures conducted within integrated care programs for older people living at home, and (b) describe how the principles of integrated care were applied in these CGAs. A scoping review of the scientific literature on CGAs in the context of integrated care was conducted for the period 2006-2018. Data were extracted on main characteristics of the identified CGA instruments and procedures, and on how principles of integrated care were applied in these CGAs. Twenty-seven integrated care programs were included in this study, of which most were implemented in the Netherlands and the United States. Twenty-one different CGAs were identified, of which the EASYcare instrument, RAI-HC/RAI-CHA and GRACE tool were used in multiple programs. The majority of CGAs seemed to reflect comprehensiveness, multidisciplinarity and person-centredness, although the way and extent to which principles of integrated care were incorporated differed between the CGAs. This study highlights the high variability of CGA instruments and procedures used in integrated care programs. This overview of available CGAs and their characteristics may promote (inter-)national exchange of CGAs, which could enable researchers and professionals in choosing from the wide range of existing CGAs, thereby preventing them from unnecessarily reinventing the wheel.
Topics: Aged; Aged, 80 and over; Delivery of Health Care, Integrated; Female; Geriatric Assessment; Home Care Services; Humans; Male; Netherlands
PubMed: 31225946
DOI: 10.1111/hsc.12793