Physiological Tasks Research Articles

Amyloids: Friend or Foe?

Amyloidogenesis is the aggregation of soluble proteins into structurally conserved fibers. Amyloid fibers are distinguished by their resistance to proteinase K, tinctorial properties and beta-sheet-rich secondary structure. Amyloid formation is a hallmark of many human diseases including Alzheimer's, Huntington's and the prion diseases. Therefore, understanding amyloidogenesis will provide insights into the development of therapeutics that target these debilitating diseases. A new class of ;functional' amyloids promises a unique glimpse at how nature has harnessed the amyloid fiber to accomplish important physiological tasks. Functional amyloids are produced by organisms spanning all aspects of cellular life. Herein we review amyloidogenesis, with special attention focused on the similarities and differences between the best characterized disease-associated amyloidogenic protein amyloid-beta and the formation of several functional amyloids. The implications of studying functional amyloidogenesis and the strategies organisms employ to limit exposure to toxic intermediates will also be discussed.

Effects of modulators of TASK potassium channels on rat pulmonary artery tone

TWIK-related acid-sensitive potassium (TASK) channels have been implicated as having a role in maintaining and mediating the tone of pulmonary arteries by influencing the membrane potential of the smooth muscle cells. Inhibition of these channels would be expected to promote depolarization, calcium influx and contraction. The purpose of this study was to investigate the effects of TASK modulators on rat intrapulmonary artery tone. The modulators included pH, an important physiological TASK modulator, and drugs that inhibit TASK channels, such as bupivacaine, methanandamide and zinc. Small vessel myography was used to measure the tone of both conduit and resistance pulmonary arteries. Cumulative bupivacaine and methanandamide dose–response curves were compared with phenylephrine (a sympathomimetic vasoconstrictor). The effects of pH were investigated on vessel tone and responses to bupivacaine, methanandamide or zinc chloride. Bupivacaine and methanandamide (>10 µM) resulted in increased artery tone, with similar effects seen in conduit and resistance vessels. Zinc had no effect, possibly reflecting an inhibitory action on calcium channels. In the presence of endothelial blockers, methanandamide (100 µM) still resulted in an increase in artery tone, implying an action on smooth muscle. The application of nifedipine resulted in the inhibition of the response seen with bupivacaine (100 µM), implying that voltage-gated calcium entry was involved. Changing the pH from 7.3 to 8.3 resulted in vasoconstriction, and a relaxation was seen in acidic conditions. This is opposite to the result expected for TASK channel modulation, but may reflect the multiple effects of pH on smooth muscle. The contractions seen with bupivacaine and methanandamide were increased at pH 8.3 but inhibited at pH 6.3, consistent with an effect on TASK channels. Responses to bupivacaine and methanandamide were, however, very small, suggesting that currents produced by TASK channels may not be a major factor in contracting intrapulmonary arteries, but may still have a minor role.

Regulation of proteasome-mediated protein degradation during oxidative stress and aging

Protein degradation is a physiological process required to maintain cellular functions. There are distinct proteolytic systems for different physiological tasks under changing environmental and pathophysiological conditions. The proteasome is responsible for the removal of oxidatively damaged proteins in the cytosol and nucleus. It has been demonstrated that proteasomal degradation increases due to mild oxidation, whereas at higher oxidant levels proteasomal degradation decreases. Moreover, the proteasome itself is affected by oxidative stress to varying degrees. The ATP-stimulated 26S proteasome is sensitive to oxidative stress, whereas the 20S form seems to be resistant. Non-degradable protein aggregates and cross-linked proteins are able to bind to the proteasome, which makes the degradation of other misfolded and damaged proteins less efficient. Consequently, inhibition of the proteasome has dramatic effects on cellular aging processes and cell viability. It seems likely that during oxidative stress cells are able to keep the nuclear protein pool free of damage, while cytosolic proteins may accumulate. This is because of the high proteasome content in the nucleus, which protects the nucleus from the formation and accumulation of non-degradable proteins. In this review we highlight the regulation of the proteasome during oxidative stress and aging.

Adaptive functional divergence among triplicated alpha-globin genes in rodents.

The functional divergence of duplicated genes is thought to play an important role in the evolution of new developmental and physiological pathways, but the role of positive selection in driving this process remains controversial. The objective of this study was to test whether amino acid differences among triplicated alpha-globin paralogs of the Norway rat (Rattus norvegicus) and the deer mouse (Peromyscus maniculatus) are attributable to a relaxation of purifying selection or to a history of positive selection that has adapted the gene products to new or modified physiological tasks. In each rodent species, the two paralogs at the 5'-end of the alpha-globin gene cluster (HBA-T1 and HBA-T2) are evolving in concert and are therefore identical or nearly identical in sequence. However, in each case, the HBA-T1 and HBA-T2 paralogs are distinguished from the third paralog at the 3'-end of the gene cluster (HBA-T3) by multiple amino acid substitutions. An analysis of genomic sequence data from several rodent species revealed that the HBA-T3 genes of Rattus and Peromyscus originated via independent, lineage-specific duplication events. In the independently derived HBA-T3 genes of both species, a likelihood analysis based on a codon-substitution model revealed that accelerated rates of amino acid substitution are attributable to positive directional selection, not to a relaxation of purifying selection. As a result of functional divergence among the triplicated alpha-globin genes in Rattus and Peromyscus, the red blood cells of both rodent species contain a mixture of functionally distinct alpha-chain hemoglobin isoforms that are predicted to have different oxygen-binding affinities. In P. maniculatus, a species that is able to sustain physiological function under conditions of chronic hypoxia at high altitude, the coexpression of distinct hemoglobin isoforms with graded oxygen affinities is expected to broaden the permissible range of arterial oxygen tensions for pulmonary/tissue oxygen transport.

Genomic evidence for independent origins of β-like globin genes in monotremes and therian mammals

Phylogenetic reconstructions of the beta-globin gene family in vertebrates have revealed that developmentally regulated systems of hemoglobin synthesis have been reinvented multiple times in independent lineages. For example, the functional differentiation of embryonic and adult beta-like globin genes occurred independently in birds and mammals. In both taxa, the embryonic beta-globin gene is exclusively expressed in primitive erythroid cells derived from the yolk sac. However, the "epsilon-globin" gene in birds is not orthologous to the epsilon-globin gene in mammals, because they are independently derived from lineage-specific duplications of a proto beta-globin gene. Here, we report evidence that the early and late expressed beta-like globin genes in monotremes and therian mammals (marsupials and placental mammals) are the products of independent duplications of a proto beta-globin gene in each of these two lineages. Results of our analysis of genomic sequence data from a large number of vertebrate taxa, including sequence from the recently completed platypus genome, reveal that the epsilon- and beta-globin genes of therian mammals arose via duplication of a proto beta-globin gene after the therian/monotreme split. Our analysis of genomic sequence from the platypus also revealed the presence of a duplicate pair of beta-like globin genes that originated via duplication of a proto beta-globin gene in the monotreme lineage. This discovery provides evidence that, in different lineages of mammals, descendent copies of the same proto beta-globin gene may have been independently neofunctionalized to perform physiological tasks associated with oxygen uptake and storage during embryonic development.

A near‐infrared spectroscopy study of prefrontal cortex activation during a verbal fluency task and carbon dioxide inhalation in individuals with bipolar disorder

There is evidence of prefrontal cortex (PFC) dysfunction in patients with bipolar disorder (BP). Magnetic resonance and neuropathological studies show abnormalities of the brain microvasculature in patients with BP. However, the underlying biological mechanisms are not well understood. We investigated the relationship between activation of the PFC during a cognitive task and the vascular function in response to a physiological task in patients with BP. Fourteen euthymic patients with BP and 14 control subjects matched for age, sex, and education were recruited. We examined the response of the PFC during a verbal fluency task and during 5% CO(2) inhalation using a 24-channel near-infrared spectroscopy imaging system to measure alteration of oxygenated and deoxygenated hemoglobin. The BP patients showed a significantly lower level of PFC activation during the cognitive task compared to the healthy controls, but the task-performance of the BP patients was not significantly different from that of the controls. The vascular response of the BP patients to CO(2) was not significantly different from that of controls. This study suggests functional hypoactivation of the PFC during a cognitive load in patients with BP while they are in a euthymic state. The mechanism of this hypoactivation is different from that of vascular regulation in response to a physiological stimulus.

In Vitro Polymerization of a Functional Escherichia coli Amyloid Protein

Amyloid formation is characterized by the conversion of soluble proteins into biochemically and structurally distinct fibers. Although amyloid formation is traditionally associated with diseases such as Alzheimer disease, a number of biologically functional amyloids have recently been described. Curli are amyloid fibers produced by Escherichia coli that contribute to biofilm formation and other important physiological processes. We characterized the polymerization properties of the major curli subunit protein CsgA. CsgA polymerizes into an amyloid fiber in a sigmoidal kinetic fashion with a distinct lag, growth, and stationary phase. Adding sonicated preformed CsgA fibers to the polymerization reaction can significantly shorten the duration of the lag phase. We also demonstrate that the conversion of soluble CsgA into an insoluble fiber involves the transient formation of an intermediate similar to that characterized for several disease-associated amyloids. The CsgA core amyloid domain can be divided into five repeating units that share sequence and structural hallmarks. We show that peptides representing three of these repeating units are amyloidogenic in vitro. Although the defining characteristics of CsgA polymerization appear conserved with disease-associated amyloids, these proteins evolved in diverse systems and for different purposes. Therefore, amyloidogenesis appears to be an innate protein folding pathway that can be capitalized on to fulfill normal physiological tasks.

What makes physiology hard for students to learn? Results of a faculty survey

Teachers of physiology at all postsecondary levels were asked to participate in a survey about the possible sources of students' difficulty in learning physiology. Sixty-three physiology teachers responded to the 18-question survey; 35 of the respondents also responded to a request for written comments about this issue prior to taking the survey. Three categories of possible factors contributing to physiology being hard to learn were defined: 1) the nature of the discipline, 2) the way it is taught, and 3) what students bring to the task of learning physiology. Respondents thought that characteristics of the discipline (it requires causal reasoning, it uses graphs and mathematics, and it is highly integrative) and characteristics of students (they believe that learning and memorizing are the same thing, they cannot or will do attempt to integrate, and they compartmentalize) were significantly more important than any aspect of teaching in making physiology hard to learn. Recommendations are offered in this article to help students deal with the sources of difficulty that were identified.

Starting Physiology: Understanding Homeostasis

The life of a cell is heavily dependent on the composition and stability of the physical chemical characteristics of the surrounding external environment. Thermodynamically, the cell is an open system making a universe with the surrounding, which provides the substrates that the cell needs for

GABAB Receptor Isoforms Caught in Action at the Scene

The metabotropic GABAB receptors mediate slow synaptic inhibition and consist of heterodimers of GABAB1 and GABAB2 subunits. The only known molecular diversity of the GABAB receptors arises from the two GABAB1 isoforms, but its functional significance has been unclear. Two studies in this issue of Neuron now demonstrate that GABAB1a and GABAB1b show strategically distinct subcellular localization and physiological action.

Pathomechanik der thorakolumbalen Verletzung

Injuries of the thoracolumbar junction basically result from three mechanisms: compression, flexion/distraction and torsion. Compression and torsion lead mainly to bony injury patterns and flexion, distraction and lateral bending, mainly to ligamentous instabilities. The meaning of “instability” is clear, but when applied to the clinical status of thoracolumbar fractures instability can only be relative. In general, it seems helpful to define “instability” as loss of the ability of the spine to maintain its physiological tasks, such as the transfer of loads and moments, movement, and protection of neurological structures. Quantification of the instability of an individual thoracolumbar injury is not possible, radiologic criteria of instability allow more precise identification of bony and ligamentous instability. Radiomorphologic data are the basis of the evaluation. Native X-rays (a-p and lateral views) and computed tomography are necessary for ascertainment of all these parameters, and in some cases functional X-rays are essential.

Copper inHelix pomatia(Gastropoda) is regulated by one single cell type: differently responsive metal pools in rhogocytes

Like all other animal species, terrestrial pulmonate snails require Cu as an essential trace element. On the other hand, elevated amounts of Cu can exert toxic effects on snails. The homeostatic regulation of Cu must therefore be a pivotal goal of terrestrial pulmonates to survive. Upon administration of Cu, snails accumulate the metal nearly equally in most of their organs. Quantitative studies in connection with HPLC and electrospray ionization mass spectrometry reveal that a certain fraction of Cu in snails is bound to a Cu-metallothionein (Cu-MT) isoform that occurs in most organs at constant concentrations, irrespective of whether the animals had been exposed to physiological or elevated amounts of Cu. In situ hybridization demonstrates that at the cellular level, the Cu-binding MT isoform is exclusively expressed in the so-called pore cells (or rhogocytes), which can be found in all major snail organs. The number of pore cells with Cu-MT mRNA reaction products remains unaffected by Cu exposure. Rhogocytes also are major storage sites of Cu in a granular form, the metal quickly entering the snail tissues upon elevated exposure. The number of rhogocytes with granular Cu precipitations strongly increases upon Cu administration via food. Thus, whereas Cu-MT in the rhogocytes represents a stable pool of Cu that apparently serves physiological tasks, the granular Cu precipitations form a second, quickly inducible, and more easily available pool of the metal that serves Cu regulation by responding to superphysiological metal exposure.

Kontamination der Nahrungskette mit Cäsium-137 und Strontium-90 in der Schweiz

One task of the field physiology of nutrition is the monitoring of the quality of feedstuffs. Rations may consequently be prepared with unadulterated components. This review uses the example of contamination with the radionuclides caesium-137 und strontium-90 and shows how these two unwanted substances reach the end host via the food chain and how their untoward effects are expressed in animals and humans. The extent of the contamination with artificial radioactivity is followed with periodical measurements according to the program of the Division for Radiological Protection of the Swiss Federal Office of Public Health. The interpretation of the measurements and the directives of this division are designed to protect primarily human health, but also that of animals.

Proportional Assist Ventilation Reduces the Work of Breathing during Exercise at Moderate Altitude

Reducing the work of breathing (WOB) during exercise and thus the oxygen required solely for ventilation may be an option to increase the oxygen available for nonventilatory physiological tasks at altitude. This study evaluated whether pressure support ventilation (PSV) and proportional assist ventilation (PAV) may partially reduce WOB during exercise at altitude. Seven volunteers breathing with either PSV or PAV or without support (control) were examined for WOB, inspiratory pressure time product (iPTP), and (O(2)) before and during pedaling at 160 W for 4 min on an ergometer at an altitude of 2860 m, where barometric pressure and oxygen partial pressure are approximately 30% less than at sea level. PSV and PAV reduced WOB from 4.5 +/- 0.9 J/L(-1)/min(-1) during unsupported breathing to 3.7 +/- 0.4 (p < 0.05) and 3.2 +/- 0.7 (p < 0.01), respectively. iPTP was reduced during PAV (570 +/- 151 cm H(2)O/sec/min(-1), p < 0.01), but not during PSV (727 +/- 116, p = 0.58) compared with unsupported ventilation during exercise (763 +/- 90). During PSV and PAV breathing, higher arterial oxygen saturations (84 +/- 2%, p < 0.05, and 86 +/- 1%, p < 0.01, respectively) were observed compared with control (80 +/- 3%), indicating that PSV and PAV attenuated hypoxemia during exercise at altitude. Total body (O(2)), however, was not reduced during PSV or PAV. In conclusion, both PSV and PAV reduced the WOB during exercise at altitude, but only PAV reduces iPTP. Both modes reduce hypoxemia, which may be due to higher alveolar ventilation or decreased ventilation-perfusion heterogeneity compared to unsupported breathing.

Mechanism of rectification in inward-rectifier K+ channels.

Inward rectifiers are a class of K+ channels that can conduct much larger inward currents at membrane voltages negative to the K+ equilibrium potential than outward currents at voltages positive to it, even when K+ concentrations on both sides of the membrane are made equal. This conduction property, called inward rectification, enables inward rectifiers to perform many important physiological tasks. Rectification is not an inherent property of the channel protein itself, but reflects strong voltage dependence of channel block by intracellular cations such as Mg2+ and polyamines. This voltage dependence results primarily from the movement of K+ ions across the transmembrane electric field along the pore, which is energetically coupled to the blocker binding and unbinding. This mutual displacement mechanism between several K+ ions and a blocker explains the signature feature of inward rectifier K+ channels, namely, that at a given concentration of intracellular K+, their macroscopic conductance depends on the difference between membrane voltage and the K+ equilibrium potential rather than on membrane voltage itself.

Neurovascular coupling analyzed non-invasively in the human brain.

Most functional brain imaging methods detect neuronal activations indirectly through the accompanying neurovascular response. Here, we demonstrate that a novel methodological approach, the combination of DC-magnetoencephalography (DC-MEG) and near-infrared spectroscopy (NIRS), allows non-invasive assessment of the dynamics of neurovascular coupling in the human brain: detecting directly slow neuronal processes (with time constants of 30s), DC-MEG revealed, even in unaveraged recordings, sustained neuronal activations at pericentral hand cortices contralateral to repetitive finger movements; these were accompanied by the ensuing local vascular response showing similar dynamical features as quantified by simultaneously recorded NIRS. This non-invasive approach opens a new avenue for the understanding of neurovascular coupling during physiological tasks as well as in diseases involving slow neuronal depolarization shifts and alterations of blood flow, such as stroke or migraine.

Determinants of histamine recognition: implications for the design of antihistamines

Towards understanding how histamine, a vital neurotansmitter, can perform multiple physiological tasks, an analysis of the different proteins that bind histamine is reported here. Their structural comparison reveals conformational rigidity of histamine. Yet, flexibility in the modes of histamine binding has been observed, which appears to suit specific biological roles of the proteins. These results will be helpful in developing specific antihistamines and also in understanding the pharmacological and toxicological profiles of existing antihistamines.

The psychological puzzle presented by physiological acts

Physiological acts present the puzzle that we are unable to explain how we performed them, how we solved the technical difficulties involved in their execution. For instance, when we sing, we produce various musical notes by changing the shape of the larynx. The normal person does not even know what the larynx looks like, let alone its configurations corresponding to various notes and the combination of the 19 muscles acting on the larynx that has to be activated to bring about the required configuration. Some psychologists offer the explanation that the technical details are worked out by a computer-like mechanism. But how could a computer start controlled cell proliferation in the repair of an injury? Another idea (originally put forward by Leibniz around 1700) is the complex character of the mind. The mind may incorporate a multitude of personalities. Subordinate personalities, some, perhaps, specialising on various tasks, may carry out the orders of the commanding personality. Objection: most physiological tasks, for instance digestion or the fight against invading microorganisms, are completely unconscious. The ‘myself’ personality could not even issue commands regarding the repair of injuries or the fight against microorganisms. Proposed solution: At an early stage of evolution the body of a higher animal divides itself into three compartments, each specialising on a different task of life. The three parts correspond to the entoderm, mesoderm and ectoderm appearing at an early part of ontogenetic development. The task of the entoderm is metabolism, that of the mesoderm mainly the mechanical aspects of life, that of the ectoderm gathering information from and reacting to the outside world. Each of these is probably of a composite character. The myself personality is the equivalent of the ectoderm, not of the whole body. The technical details of its commands are worked out by subordinate personalities. So are the commands of the mesodermal and entodermal divisions. Dreams could be attempts of communication between the germ layers.

S100A13 and S100A6 exhibit distinct translocation pathways in endothelial cells.

S100 proteins have attracted great interest in recent years because of their cell- and tissue-specific expression and association with various human pathologies. Most S100 proteins are small acidic proteins with calcium-binding domains - the EF hands. It is thought that this group of proteins carry out their cellular functions by interacting with specific target proteins, an interaction that is mainly dependent on exposure of hydrophobic patches, which result from calcium binding. S100A13, one of the most recently identified members of the S100 family, is expressed in various tissues. Interestingly, hydrophobic exposure was not observed upon calcium binding to S100A13 even though the dimeric form displays two high- and two low- affinity sites for calcium. Here, we followed the translocation of S100A13 in response to an increase in intracellular calcium levels, as protein translocation has been implicated in assembly of signaling complexes and signaling cascades, and several other S100 proteins are involved in such events. Translocation of S100A13 was observed in endothelial cells in response to angiotensin II, and the process was dependent on the classic Golgi-ER pathway. By contrast, S100A6 translocation was found to be distinct and dependent on actin-stress fibers. These experiments suggest that different S100 proteins utilize distinct translocation pathways, which might lead them to certain subcellular compartments in order to perform their physiological tasks in the same cellular environment.

Complications in the Transition From Fetal to Neonatal Life

The transition from fetus to neonate is a time of significant physiologic adaptation. In addition to the normal physiologic tasks of transition, some neonates must also cope with underlying congenital abnormalities, birth injury, or disease. Careful assessment and astute nursing care are needed during the period of transition to ensure that the neonate who is experiencing problems with transition is recognized and appropriate interventions are initiated. This article examines the physiology of transition and discusses factors placing the neonate at risk of illness. A plan of care for neonates experiencing symptoms of underlying disease during transition is presented.