Changes in the fragile X mental retardation 1 gene (FMR1) have been associated with specific phenotypes, most specifically those of fragile X syndrome (FXS), fragile X tremor/ataxia syndrome (FXTAS), and fragile X primary ovarian insufficiency (FXPOI). Evidence of increased risk for additional medical, psychiatric, and cognitive features and conditions is now known to exist for individuals with a premutation, although some features have been more thoroughly studied than others. This review highlights the literature on medical, reproductive, cognitive, and psychiatric features, primarily in females, that have been suggested to be associated with changes in the FMR1 gene. Based on this review, each feature is evaluated with regard to the strength of evidence of association with the premutation. Areas of need for additional focused research and possible intervention strategies are suggested.
For most cells, a sudden decrease in external osmolarity results in fast water influx that can burst the cell. To survive, cells rely on the passive response of mechanosensitive channels, which open under increased membrane tension and allow the release of cytoplasmic solutes and water. Although the gating and the molecular structure of mechanosensitive channels found in Escherichia coli have been extensively studied, the overall dynamics of the whole cellular response remain poorly understood. Here, we characterize E. coli's passive response to a sudden hypoosmotic shock (downshock) on a single-cell level. We show that initial fast volume expansion is followed by a slow volume recovery that can end below the initial value. Similar response patterns were observed at downshocks of a wide range of magnitudes. Although wild-type cells adapted to osmotic downshocks and resumed growing, cells of a double-mutant (ΔmscL, ΔmscS) strain expanded, but failed to fully recover, often lysing or not resuming growth at high osmotic downshocks. We propose a theoretical model to explain our observations by simulating mechanosensitive channels opening, and subsequent solute efflux and water flux. The model illustrates how solute efflux, driven by mechanical pressure and solute chemical potential, competes with water influx to reduce cellular osmotic pressure and allow volume recovery. Our work highlights the vital role of mechanosensation in bacterial survival.osmotic downshock | bacterial mechanosensing | single-cell imaging B iology offers an array of intriguing mechanical solutions, both active and passive, often exceeding what is currently possible with man-made methods. Understanding how biological systems achieve different functionalities under mechanical stimuli can inform new, thus-far-unexplored design principles. One such passive control system is the bacterial response to sudden decreases in external osmolarities.A Gram-negative cell's fluid cytoplasm is separated from the external environment by the inner membrane, the periplasmic space, and the outer membrane. Ordinarily, the total solute concentration within the cytoplasm is higher than that of the environment, resulting in a positive osmotic pressure on the cell wall (termed turgor pressure) (1). Escherichia coli is able to respond to both increases and decreases in external concentrations. An increase in external osmolarity (hyperosmotic shock or upshock) results in water efflux from the cell interior, causing cellular volume to shrink and osmotic pressure to drop to zero (2). E. coli responds by actively accumulating specific solutes (osmolytes), such as potassium, proline, and glycine-betaine (2). Accumulation of osmolytes in the cell's cytoplasm causes reentry of water, cell volume increase, and recovery of osmotic pressure (3, 4). A downward shift in external osmolarity (termed hypoosmotic shock or downshock) causes fast water influx into the cell's cytoplasm. As a result, the osmotic pressure increases and the cell expands in a nonlinear fashion (5,6
Cognitive event-related brain potential (ERP) studies of decision-making and attention, language, and memory impairments in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are reviewed. Circumscribed lesions of the medial temporal lobe (MTL), as may be the case in individuals with amnestic MCI, generally produce altered plasticity of the late positive P600 component, with relative sparing of earlier sensory ERP components. However, as the neuropathology of AD extends to neocortical association areas, abnormalities of the P300 and N400 (and perhaps even P50) become more common. Critically, ERP studies of individuals at risk for AD may reveal neurophysiological changes prior to clinical deficits, which could advance the early detection and diagnosis of “presymptomatic AD”.
The alarmone nucleotides guanosine tetraphosphate and pentaphosphate, commonly referred to as (p)ppGpp, regulate bacterial responses to nutritional and other stresses. There is evidence for potential existence of a third alarmone, guanosine-5′-monophosphate-3′-diphosphate (pGpp), with less-clear functions. Here, we demonstrate the presence of pGpp in bacterial cells, and perform a comprehensive screening to identify proteins that interact respectively with pGpp, ppGpp and pppGpp in Bacillus species. Both ppGpp and pppGpp interact with proteins involved in inhibition of purine nucleotide biosynthesis and with GTPases that control ribosome assembly or activity. By contrast, pGpp interacts with purine biosynthesis proteins but not with the GTPases. In addition, we show that hydrolase NahA (also known as YvcI) efficiently produces pGpp by hydrolyzing (p)ppGpp, thus modulating alarmone composition and function. Deletion of nahA leads to reduction of pGpp levels, increased (p)ppGpp levels, slower growth recovery from nutrient downshift, and loss of competitive fitness. Our results support the existence and physiological relevance of pGpp as a third alarmone, with functions that can be distinct from those of (p)ppGpp.
Only a subset of mild cognitive impairment (MCI) patients progress to develop a form of dementia. A prominent feature of Alzheimer's disease (AD) is a progressive decline in language. We investigated if subtle anomalies in EEG activity of MCI patients during a word comprehension task could provide insight into the likelihood of conversion to AD. We studied 25 amnestic MCI patients, a subset of whom developed AD within 3-years, and 11 elderly controls. In the task, auditory category descriptions (e.g., ‘a type of wood’) were followed by a single visual target word either semantically congruent (i.e., oak) or incongruent with the preceding category. We found that the MCI convertors group (i.e. patients that would go on to convert to AD in 3-years) had a diminished early posterior-parietal theta (3–5 Hz) activity induced by first presentation of the target word (i.e., access to lexico-syntactic properties of the word), compared to MCI non-convertors and controls. Moreover, MCI convertors exhibited oscillatory signatures for processing the semantically congruent words that were different from non-convertors and controls. MCI convertors thus showed basic anomalies for lexical and meaning processing. In addition, both MCI groups showed anomalous oscillatory signatures for the verbal learning/memory of repeated words: later alpha suppression (9–11 Hz), which followed first presentation of the target word, was attenuated for the second and third repetition in controls, but not in either MCI group. Our findings suggest that a subtle breakdown in the brain network subserving language comprehension can be foretelling of conversion to AD.
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