Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of ...Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patient-reported Outcome Measures in Spine Surgery McCormick, John D; Werner, Brian C; Shimer, Adam L
Journal of the American Academy of Orthopaedic Surgeons,
02/2013, Letnik:
21, Številka:
2
Journal Article
Recenzirano
The ultimate goals of intervention for spinal pathology are to improve the patient's quality of life, restore function, and relieve pain. Traditional clinician-based assessments typically fall short ...of adequately addressing these important outcomes because these assessments are inherently biased and may not describe patients' perception of their state of health. Patient-reported outcome measures have been developed to obtain quantitative data regarding general health quality, function, and pain. These data can aid the clinician in stratifying the severity of the disorder to formulate an appropriate treatment plan. This information also can be followed over time to assess treatment efficacy. Patient-reported outcome measures have become increasingly important with increased scrutiny of quality of care. Given the increasing importance and use of patient-reported outcome measures, knowledge regarding proper implementation of these tools is essential for accurate assessment of general health quality, function, and pain.
Prolactin is an important regulator of multiple biological functions in vertebrates, and has been viewed as essential to ion uptake as well as reduction in ion and water permeability of ...osmoregulatory surfaces in freshwater and euryhaline fish. Prolactin-releasing peptide seems to stimulate prolactin expression in the pituitary and peripheral organs during freshwater adaptation. Growth hormone, a member of the same family of hormones as prolactin, promotes acclimation to seawater in several teleost fish, at least in part through the action of insulin-like growth factor I. In branchial epithelia, development and differentiation of the seawater-type chloride cell (and their underlying biochemistry) is regulated by GH, IGF-I, and cortisol, whereas the freshwater-type chloride cell is regulated by prolactin and cortisol. In the epithelia of gastrointestinal tract, prolactin induces cell proliferation during freshwater adaptation, whereas cortisol stimulates both cell proliferation and apoptosis. We propose that control of salinity acclimation in teleosts by prolactin and growth hormone primarily involves regulation of cell proliferation, apoptosis, and differentiation (the latter including upregulation of specific ion transporters), and that there is an important interaction of these hormones with corticosteroids.
Gill Na(+)/K(+)-ATPase (NKA) in teleost fishes is involved in ion regulation in both freshwater and seawater. We have developed and validated rabbit polyclonal antibodies specific to the NKA alpha1a ...and alpha1b protein isoforms of Atlantic salmon (Salmo salar Linnaeus), and used western blots and immunohistochemistry to characterize their size, abundance and localization. The relative molecular mass of NKA alpha1a is slightly less than that for NKA beta1b. The abundance of gill NKA alpha1a was high in freshwater and became nearly undetectable after seawater acclimation. NKA alpha1b was present in small amounts in freshwater and increased 13-fold after seawater acclimation. Both NKA isoforms were detected only in chloride cells. NKA alpha1a was located in both filamental and lamellar chloride cells in freshwater, whereas in seawater it was present only as a faint background in filamental chloride cells. In freshwater, NKA alpha1b was found in a small number of filamental chloride cells, and after seawater acclimation it was found in all chloride cells on the filament and lamellae. Double simultaneous immunofluorescence indicated that NKA alpha1a and alpha1b are located in different chloride cells in freshwater. In many chloride cells in seawater, NKA alpha1b was present in greater amounts in the subapical region than elsewhere in the cell. The combined patterns in abundance and immunolocalization of these two isoforms can explain the salinity-related changes in total NKA and chloride cell abundance. The results indicate that there is a freshwater and a seawater isoform of NKA alpha-subunit in the gills of Atlantic salmon and that they are present in distinct chloride cells.
As the primary link between environmental change and physiological response, the neuroendocrine system is a critical part of osmoregulatory adaptations. Cortisol has been viewed as ‘the’ ...seawater-adapting hormone in fish and prolactin as ‘the’ fresh water adapting hormone. Recent evidence indicates that the growth hormone/insulin-like growth factor I axis is also important in seawater adaptation in several teleosts of widely differing evolutionary lineages. In salmonids, growth hormone acts in synergy with cortisol to increase seawater tolerance, at least partly through the upregulation of gill cortisol receptors. Cortisol under some conditions may promote ion uptake and interacts with prolactin during acclimation to fresh water. The osmoregulatory actions of growth hormone and prolactin are antagonistic. In some species, thyroid hormones support the action of growth hormone and cortisol in promoting seawater acclimation. Although a broad generalization that holds for all teleosts is unlikely, our current understanding indicates that growth hormone promotes acclimation to seawater, prolactin promotes acclimation to fresh water, and cortisol interacts with both of these hormones thus having a dual osmoregulatory function.
Smolting in Atlantic salmon Salmo salar is a critical life‐history stage that is preparatory for downstream migration and entry to seawater that is regulated by abiotic variables including ...photoperiod and temperature. The present study was undertaken to determine the interaction of temperature and salinity on salinity tolerance, gill osmoregulatory proteins and cellular and endocrine stress in S. salar smolts. Fish were exposed to rapid changes in temperature (from 14 to 17, 20 and 24°C) in fresh water (FW) and seawater (SW), with and without prior acclimation and sampled after 2 and 8 days. Fish exposed simultaneously to SW and 24°C experienced 100% mortality, whereas no mortality occurred in any of the other groups. The highest temperature also resulted in poor ion regulation in SW with or without prior SW acclimation, whereas no substantial effect was observed in FW. Gill Na+–K+‐ATPase (NKA) activity increased in SW fish compared to FW fish and decreased with high temperature in both FW and SW. Gill Nkaα1a abundance was high in FW and Nkaα1b and Na+–K+‐2Cl‐ cotransporter high in SW, but all three were lower at the highest temperature. Gill Hsp70 levels were elevated in FW and SW at the highest temperature and increased with increasing temperature 2 days following direct transfer to SW. Plasma cortisol levels were elevated in SW at the highest temperature. Our results indicate that there is an important interaction of salinity and elevated temperature on osmoregulatory performance and the cellular stress response in S. salar, with an apparent threshold for osmoregulatory failure in SW above 20°C.
The endocrine system mediates many of the physiological responses to the homeostatic and acclimation demands of salt and water transport. Many of the hormones involved in the control of salt and ...water transport are common to all vertebrates, although their precise function and target tissues have changed during evolution. Arginine vasopressin (vasotocin), angiotensin II, natriuretic peptides, vasoactive intestinal peptide, urotensin II, insulin and non-genomic actions of corticosteroids are involved in acute (minutes and hours) alterations in ion and water transport. This rapid alteration in transport is primarily the result changes in behavior, blood flow to osmoregulatory organs, and membrane insertion or activation (e.g., phosphorylation) of existing transport proteins, ion and water channels, contransporters and pumps. Corticosteroids (through genomic actions), prolactin, growth hormone, and insulin-like growth factor I primarily control long-term (several hours to days) changes in transport capacity that are the result of synthesis of new transport proteins, cell proliferation, and differentiation. In addition to the important task of establishing broad evolutionary patterns in hormones involved in ion regulation, comparative endocrinology can determine species and population level differences in signaling pathways that may be critical for adaptation to extreme or rapidly changing environments.
It is unknown whether and how osmoregulation is controlled by corticosteroid signaling in the phylogenetically basal vertebrate group Agnatha, including lampreys and hagfishes. It is known that a ...truncated steroid biosynthetic pathway in lampreys produces two predominant circulating corticosteroids, 11-deoxycortisol (S) and 11-deoxycorticosterone (DOC). Furthermore, lampreys express only a single, ancestral corticosteroid receptor (CR). Whether S and/or DOC interact with the CR to control osmoregulation in lampreys is still unknown. We examined the role of the endogenous corticosteroids in vivo and ex vivo in sea lamprey (Petromyzon marinus) during the critical metamorphic period during which sea lamprey increase osmoregulatory capacity and acquire seawater (SW) tolerance. We demonstrate in vivo that increases in circulating S and gill CR abundance are associated with increases in osmoregulatory capacity during metamorphosis. We further show that in vivo and ex vivo treatment with S increases activity and expression of gill active ion transporters and improves SW tolerance, and that only S (and not DOC) has regulatory control over active ion transport in the gills. Lastly, we show that the lamprey CR expresses an ancestral, spironolactone-as-agonist structural motif and that spironolactone treatment in vivo increases osmoregulatory capacity. Together, these results demonstrate that S is an osmoregulatory hormone in lamprey and that receptor-mediated discriminative corticosteroid regulation of hydromineral balance is an evolutionarily basal trait among vertebrates.
Background
Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the USA. Many with CVD or cardiovascular risk factors (CVRFs) lacked insurance coverage and access to care ...before enactment of the Affordable Care Act (ACA).
Objective
To assess the effect of the ACA on insurance coverage, access to care, and racial/ethnic disparities among non-elderly adults with CVD or CVRFs.
Design
Quasi-experimental policy intervention.
Participants
Nationally representative, non-institutionalized sample of 1,014,450 adults aged 18 to 64 years with CVD or at least 2 established CVRFs in the pre-ACA (2012–2013) and post-ACA (2015–2016) periods.
Intervention
Implementation of ACA provisions on 1 January 2014.
Main Measures
Insurance coverage, having a check-up, having a personal physician, and not having to forgo a needed physician visit because of cost.
Key Results
Following ACA implementation, insurance coverage increased by 6.9 percentage points (95% CI, 6.6 to 7.2), not having to forgo a physician visit increased by 3.6 percentage points (CI, 3.3 to 3.9), having a check-up increased by 2.1 percentage points (CI, 1.8 to 2.6), and having a personal physician increased by 1 percentage point (0.6 to 1.3); changes were approximately doubled for those with lower incomes (< $35,000/year). Changes in coverage varied substantially by state and all outcomes improved more in Medicaid expansion states. Although racial/ethnic minorities had greater improvements in some outcomes, approximately 13% black and 29% Hispanic adults continued to lack coverage and access to care post-ACA.
Conclusion
The ACA increased coverage and access for adults with CVD or multiple CVRFs; substantial gaps remain, particularly for minorities and those in Medicaid non-expansion states.
The highly interconnected networks of the mammalian forebrain can generate a wide variety of synchronized activities, including those underlying epileptic seizures, which often appear as a ...transformation of otherwise normal brain rhythms. The cerebral cortex and hippocampus are particularly prone to the generation of the large, synchronized bursts of activity underlying many forms of seizures owing to strong recurrent excitatory connections, the presence of intrinsically burst-generating neurons, ephaptic interactions among closely spaced neurons, and synaptic plasticity. The simplest form of epileptiform activity in these structures is the interictal spike, a synchronized burst of action potentials generated by recurrent excitation, followed by a period of hyperpolarization, in a localized pool of pyramidal neurons. Seizures can also be generated in response to a loss of balance between excitatory and inhibitory influences and can take the form of either tonic depolarizations or repetitive, rhythmic burst discharges, either as clonic or spike-wave activity, again mediated both by intrinsic membrane properties and synaptic interactions. The interaction of the cerebral cortex and the thalamus, in conjunction with intrathalamic communication, can also generate spike waves similar to those occurring during human absence seizure discharges. Although epileptic syndromes and their causes are diverse, the cellular mechanisms of seizure generation appear to fall into only two categories: rhythmic or tonic "runaway" excitation or the synchronized and rhythmic interplay between excitatory and inhibitory neurons and membrane conductances.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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