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1.
Zinkernagel RM 《Cellular and molecular life sciences : CMLS》2012,69(10):1635-1640
So-called ‘immunological memory’ is, in my view, a typical example where a field of enquiry, i.e. to understand long-term
protection to survive reexposure to infection, has been overtaken by ‘l’art pour l’art’ of ‘basic immunology’. The aim of
this critical review is to point out some key differences between academic text book-defined immunological memory and protective
immunity as viewed from a co-evolutionary point of view, both from the host and the infectious agents. A key conclusion is
that ‘immunological memory’ of course exists, but only in particular experimental laboratory models measuring ‘quicker and
better’ responses after an earlier immunization. These often do correlate with, but are not the key mechanisms of, protection.
Protection depends on pre-existing neutralizing antibodies or pre-activated T cells at the time of infection—as documented
by the importance of maternal antibodies around birth for survival of the offspring. Importantly, both high levels of antibodies
and of activated T cells are antigen driven. This conclusion has serious implications for our thinking about vaccines and
maintaining a level of protection in the population to deal with old and new infectious diseases. 相似文献
2.
Farooqui AA Farooqui T Panza F Frisardi V 《Cellular and molecular life sciences : CMLS》2012,69(5):741-762
The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin
resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation
in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone
released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the
hypothalamic ‘bodyweight/appetite/satiety set point,’ resulting in the initiation and development of metabolic syndrome. Metabolic
syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer’s disease. The molecular mechanism
underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However,
it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment
of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with
abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders
such as stroke, Alzheimer’s disease and depression. The purpose of this review is not only to describe the involvement of
brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical
changes in stroke, Alzheimer’s disease and depression to a wider audience of neuroscientists with the hope that this discussion
will initiate more studies on the relationship between metabolic syndrome and neurological disorders. 相似文献
3.
Adnan S. Syed Alfredo Sansone Thomas Hassenklöver Ivan Manzini Sigrun I. Korsching 《Cellular and molecular life sciences : CMLS》2017,74(9):1711-1719
All olfactory receptors identified in teleost fish are expressed in a single sensory surface, whereas mammalian olfactory receptor gene families segregate into different olfactory organs, chief among them the main olfactory epithelium expressing ORs and TAARs, and the vomeronasal organ expressing V1Rs and V2Rs. A transitional stage is embodied by amphibians, with their vomeronasal organ expressing more ‘modern’, later diverging V2Rs, whereas more ‘ancient’, earlier diverging V2Rs are expressed in the main olfactory epithelium. During metamorphosis, the main olfactory epithelium of Xenopus tadpoles transforms into an air-filled cavity (principal cavity, air nose), whereas a newly formed cavity (middle cavity) takes over the function of a water nose. We report here that larval expression of ancient V2Rs is gradually lost from the main olfactory epithelium as it transforms into the air nose. Concomitantly, ancient v2r gene expression begins to appear in the basal layers of the newly forming water nose. We observe the same transition for responses to amino acid odorants, consistent with the hypothesis that amino acid responses may be mediated by V2R receptors. 相似文献
4.
Pocker Y 《Cellular and molecular life sciences : CMLS》2000,57(7):1008-1017
Water has been recognized as one of the major structuring factors in biological macromolecules. Indeed, water clusters influence
many aspects of biological function, and the water-protein interaction has long been recognized as a major determinant of
chain folding, conformational stability, internal dynamics, binding specificity and catalysis. I discuss here several themes
arising from recent progress in understanding structural aspects of ‘direct’ and ‘indirect’ ligands in terms of enzyme-substrate
interactions, and the role of water bridges in enzyme catalysis. The review also attempts to illuminate issues relating to
efficiency, through solvent interactions associated with enzymic specificity, and versatility. Over the years, carbonic anhydrase
(CA; carbonate hydro-lyase, EC 4.2.1.1) has played a significant role in the continuing delineation of principles underlying
the role of water in enzyme reactions. As a result of its pronounced catalytic power and robust constitution CA was transformed
into a veritable ‘laboratory’ in which active site mechanisms were rigorously tested and explored. 相似文献
5.
In 1905, Albert Einstein proposed that the forces that cause the random Brownian motion of a particle also underlie the resistance
to macroscopic motion when a force is applied. This insight, of a coupling between fluctuation (stochastic behavior) and responsiveness
(non-stochastic behavior), founded an important branch of physics. Here we argue that his insight may also be relevant for
understanding evolved biological systems, and we present a ‘fluctuation–response relationship’ for biology. The relationship
is consistent with the idea that biological systems are similarly canalized to stochastic, environmental, and genetic perturbations.
It is also supported by in silico evolution experiments, and by the observation that ‘noisy’ gene expression is often both
more responsive and more ‘evolvable’. More generally, we argue that in biology there is (and always has been) an important
role for macroscopic theory that considers the general behavior of systems without concern for their intimate molecular details. 相似文献
6.
Dennis Duke 《Archive for History of Exact Sciences》2009,63(6):635-654
In the Planetary Hypotheses, Ptolemy summarizes the planetary models that he discusses in great detail in the Almagest, but he changes the mean motions to account for more prolonged comparison of observations. He gives the mean motions in two
different forms: first, in terms of ‘simple, unmixed’ periods and next, in terms of ‘particular, complex’ periods, which are
approximations to linear combinations of the simple periods. As a consequence, all of the epoch values for the Moon and the
planets are different at era Philip. This is in part a consequence of the changes in the mean motions and in part due to changes
in Ptolemy’s time in the anomaly, but not the longitude or latitude, of the Moon, the mean longitude of Saturn and Jupiter,
but not Mars, and the anomaly of Venus and Mercury, the former a large change, the latter a small one. The pattern of parameter
changes we see suggests that the analyses that yielded the Planetary Hypotheses parameters were not the elegant trio analyses of the Almagest but some sort of serial determinations of the parameters based on sequences of independent observations. 相似文献
7.
Although its operations are not limited to the spatial domain, there is a near consensus that the hippocampus plays a critical
role in memory for place. This review aims to explore this role, with a particular emphasis on the functions performed by
distinct hippocampal subregions. The use of innovative lesioning techniques, localized pharmacological treatments, and molecular
genetic interventions is offering increasingly precise brain-regional specificity and temporal control. Together with the
electrophysiological recording of neuronal activity, these techniques are beginning to shed light on the functioning of specific
components of the hippocampal circuitry in the different phases of memory – encoding, storage, consolidation, and retrieval.
In view of these developments, we examine the involvement of the hippocampus in the encoding versus retrieval of spatial memory,
before turning to the issue of long-term information storage and the role of ‘cellular’ and ‘systems’ consolidation processes
in the formation of lasting memories.
Received 17 July 2006; received after revision 24 October 2006; accepted 16 November 2006 相似文献
8.
Human skin is permanently exposed to microorganisms, but rarely infected. One reason for this natural resistance might be
the existence of a ‘chemical barrier’ consisting in constitutively and inducibly produced antimicrobial peptides and proteins
(AMPs). Many of these AMPs can be induced in vitro by proinflammatory cytokines or bacteria. Apart from being expressed in vivo in inflammatory lesions, some AMPs are also focally expressed in skin in the absence of inflammation. This suggests that
non-inflammatory stimuli of endogenous and/or exogenous origin can also stimulate AMP synthesis without inflammation. Such
mediators might be ideal ‘immune stimulants’ to induce only the innate antimicrobial skin effector molecules without causing
inflammation.
Received 9 August 2005; received after revision 21 October 2005; accepted 16 November 2005 相似文献
9.
Insulin secretion is finely tuned to the requirements of tissues by tight coupling to prevailing blood glucose levels. The
normal regulation of insulin secretion is coupled to glucose metabolism in the pancreatic B cell, a major but not exclusive
signal for secretion being closure of K+ATP (adenosine triphosphate)-dependent channels in the cell membrane through an increase in cytosolic ATP/adenosine diphosphate.
Insulin secretion in type 2 diabetes is abnormal in several respects due to genetic causes but also due to the metabolic environment
of the pancreatic B cells. This environment may be particularly important for the deterioration of insulin secretion which
occurs with increasing duration of diabetes. Factors in the environment with potential importance include overstimulation,
a negative effect of hyperglycemia per se (‘glucotoxicity’) as well as adverse effects of elevated fatty acids (‘lipotoxicity’).
Elucidating the mechanisms behind these factors as well as their clinical importance will pave the way for treatment which
could preserve B-cell function in type 2 diabetic patients.
Received 4 October 1999; received after revision 1 November 1999; accepted 3 December 1999 相似文献
10.
The application of fractal dimension-based constructs to probe the protein interior dates back to the development of the concept
of fractal dimension itself. Numerous approaches have been tried and tested over a course of (almost) 30 years with the aim
of elucidating the various facets of symmetry of self-similarity prevalent in the protein interior. In the last 5 years especially,
there has been a startling upsurge of research that innovatively stretches the limits of fractal-based studies to present
an array of unexpected results on the biophysical properties of protein interior. In this article, we introduce readers to
the fundamentals of fractals, reviewing the commonality (and the lack of it) between these approaches before exploring the
patterns in the results that they produced. Clustering the approaches in major schools of protein self-similarity studies,
we describe the evolution of fractal dimension-based methodologies. The genealogy of approaches (and results) presented here
portrays a clear picture of the contemporary state of fractal-based studies in the context of the protein interior. To underline
the utility of fractal dimension-based measures further, we have performed a correlation dimension analysis on all of the
available non-redundant protein structures, both at the level of an individual protein and at the level of structural domains.
In this investigation, we were able to separately quantify the self-similar symmetries in spatial correlation patterns amongst
peptide–dipole units, charged amino acids, residues with the π-electron cloud and hydrophobic amino acids. The results revealed
that electrostatic environments in the interiors of proteins belonging to ‘α/α toroid’ (all-α class) and ‘PLP-dependent transferase-like’
domains (α/β class) are highly conducive. In contrast, the interiors of ‘zinc finger design’ (‘designed proteins’) and ‘knottins’
(‘small proteins’) were identified as folds with the least conducive electrostatic environments. The fold ‘conotoxins’ (peptides)
could be unambiguously identified as one type with the least stability. The same analyses revealed that peptide–dipoles in
the α/β class of proteins, in general, are more correlated to each other than are the peptide–dipoles in proteins belonging
to the all-α class. Highly favorable electrostatic milieu in the interiors of TIM-barrel, α/β-hydrolase structures could explain
their remarkably conserved (evolutionary) stability from a new light. Finally, we point out certain inherent limitations of
fractal constructs before attempting to identify the areas and problems where the implementation of fractal dimension-based
constructs can be of paramount help to unearth latent information on protein structural properties. 相似文献
11.
Polyphenolic phytochemicals are ubiquitous in plants, in which they function in various protective roles. A ‘recommended’
human diet contains significant quantities of polyphenolics, as they have long been assumed to be ‘antioxidants’ that scavenge
excessive, damaging, free radicals arising from normal metabolic processes. There is recent evidence that polyphenolics also
have ‘indirect’ antioxidant effects through induction of endogenous protective enzymes. There is also increasing evidence
for many potential benefits through polyphenolic-mediated regulation of cellular processes such as inflammation. Inductive
or signalling effects may occur at concentrations much lower than required for effective radical scavenging. Over the last
2 – 3 years, there have been many exciting new developments in the elucidation of the in vivo mechanisms of the health benefits of polyphenolics. We summarise the current knowledge of the intake, bio-availability and
metabolism of polyphenolics, their antioxidant effects, regulatory effects on signalling pathways, neuro-protective effects
and regulatory effects on energy metabolism and gut health.
Received 14 May 2007; received after revision 27 June 2007; accepted 24 July 2007 相似文献
12.
Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: convergent evolution of the SPFH domain 总被引:1,自引:0,他引:1
Rivera-Milla E Stuermer CA Málaga-Trillo E 《Cellular and molecular life sciences : CMLS》2006,63(3):343-357
Reggies (flotillins) are detergent-resistant microdomains involved in the scaffolding of large heteromeric complexes that
signal across the plasma membrane. Based on the presence of an evolutionarily widespread motif, reggies/flotillins have been
included within the SPFH (stomatin-prohibitin-flotillin-HflC/K) protein superfamily. To better understand the origin and evolution
of reggie/flotillin structure and function, we searched databases for reggie/flotillin and SPFH-like proteins in organisms
at the base and beyond the animal kingdom, and used the resulting dataset to compare their structural and functional domains.
Our analysis shows that the SPFH grouping has little phylogenetic support, probably due to convergent evolution of its members.
We also find that reggie/flotillin homologues are highly conserved among metazoans but are absent in plants, fungi and bacteria,
where only proteins with ‘reggie-like’ domains can be found. However, despite their low sequence similarities, reggie/flotillin
and ‘reggie-like’ domains appear to subserve related functions, suggesting that their basic biological role was acquired independently
during evolution.
Received 21 September 2005; received after revision 14 November 2005; accepted 21 November 2005 相似文献
13.
Anneliese A. Pontius 《Cellular and molecular life sciences : CMLS》1982,38(5):577-581
Summary Among colonial North-American artisans, subgroups of South-Americans, Indonesians and New Guineans, a close correspondence
exists between illiteracy rates and specifically spatially inaccurate representations of the upper face configuration, a characteristic
also seen in the pre-literate period of ‘neolithic’ art, in early individual development, and in certain pathological regressions.
Common to the configuration both of lexical signs and of the face is a specific spatial-relational ratio and orientation.
Accurate representation of both configurations appears to be neuro-developmentally linked, within a cultural context, and
consistent with a novel position that the ‘ontogeny’ of such cognitive functions recapitulates their prevailingly culturally
determined ‘phylogeny’.
I thank Katherine F. Ruttiger for being an independent rater, and Bernard H. Fox for statistical help. 相似文献
14.
SNAREs and SNARE regulators in membrane fusion and exocytosis 总被引:21,自引:0,他引:21
J. E. Gerst 《Cellular and molecular life sciences : CMLS》1999,55(5):707-734
Eukaryotes have a remarkably well-conserved apparatus for the trafficking of proteins between intracellular compartments
and delivery to their target organelles. This apparatus comprises the secretory (or ‘protein export’) pathway, which is responsible
for the proper processing and delivery of proteins and lipids, and is essential for the derivation and maintenance of those
organelles. Protein transport between intracellular compartments is mediated by carrier vesicles that bud from one organelle
and fuse selectively with another. Therefore, organelle-specific trafficking of vesicles requires specialized proteins that
regulate vesicle transport, docking and fusion. These proteins are generically termed SNAREs and comprise evolutionarily conserved
families of membrane-associated proteins (i.e. the synaptobrevin/VAMP, syntaxin and SNAP-25 families) which mediate membrane
fusion. SNAREs act at all levels of the secretory pathway, but individual family members tend to be compartment-specific and,
thus, are thought to contribute to the specificity of docking and fusion events. In this review, we describe the different
SNARE families which function in exocytosis, as well as discuss the role of possible negative regulators (e.g. ‘SNARE-masters’)
in mediating events leading to membrane fusion. A model to illustrate the dynamic cycling of SNAREs between fusion-incompetent
and fusion-competent states, called the SNARE cycle, is presented.
Received 8 October 1998; received after revision 26 November 1998; accepted 26 November 1998 相似文献
15.
Synaptic target recognition is a complex molecular event. In a differentiating presynaptic terminal, relatively ‘rare’ molecules
first detect the cell identity of the synaptic target. Subsequently, many ‘common’ molecules continue the process of synaptogenesis.
We present a theoretical framework for understanding synaptic target recognition and discuss the features of its molecular
components and their integration, drawing on the rapid progress made in recent studies. 相似文献
16.
Hurtaud C Gelly C Chen Z Lévi-Meyrueis C Bouillaud F 《Cellular and molecular life sciences : CMLS》2007,64(14):1853-1860
Uncoupling protein 2 (UCP2) belongs to a family of transporters/exchangers of the mitochondrial inner membrane. Using cell
lines representing natural sites of UCP2 expression (macrophages, colonocytes, pancreatic beta cells), we show that UCP2 expression
is stimulated by glutamine at physiological concentrations. This control is exerted at the translational level. We demonstrate
that the upstream open reading frame (ORF1) in the 5’ untranslated region (5’UTR) of the UCP2 mRNA is required for this stimulation
to take place. Cloning of the 5’ UTR of the UCP2 mRNA in front of a GFP cDNA resulted in a reporter gene with which GFP expression
could be induced by glutamine. An effect of glutamine on translation of a given mRNA has not been identified before, and this
is the first evidence for a link between UCP2 and glutamine, an amino acid oxidized by immune cells or intestinal epithelium
and playing a role in the control of insulin secretion.
Received 26 January 2007; received after revision 16 April 2007; accepted 8 May 2007
C. Hurtaud, C. Gelly: These authors contributed equally to this work. 相似文献
17.
Immunophilins: for the love of proteins 总被引:1,自引:0,他引:1
Barik S 《Cellular and molecular life sciences : CMLS》2006,63(24):2889-2900
Immunophilins are chaperones that may also exhibit peptidylprolyl isomerase (PPIase) activity. This review summarizes our
knowledge of the two largest families of immunophilins, namely cyclophilin and FK506-binding protein, and a novel chimeric
dual-family immunophilin, named FK506- and cyclosporin-binding protein (FCBP). The larger members of each family are modular
in nature, consisting of multiple PPIase and/or protein-protein interaction domains. Despite the apparent difference in their
sequence and three-dimensional structure, the three families encode similar enzymatic and biological functions. Recent studies
have revealed that many immunophilins possess a chaperone function independent of PPIase activity. Knockout animal studies
have confirmed multiple essential roles of immunophilins in physiology and development. An immunophilin is indeed a natural
‘protein-philin’ (Greek ‘philin’ = friend) that interacts with proteins to guide their proper folding and assembly.
Received: 7 May 2006; received after revision 3 July 2006; accepted 24 August 2006 相似文献
18.
Natascha Cremers Marie-Ange Deugnier Jonathan Sleeman 《Cellular and molecular life sciences : CMLS》2010,67(13):2311-2322
CD24 is expressed on mammary stem cells and is used as a marker for their isolation, yet its function in the mammary gland
still needs to be examined. Here we show that CD24 is expressed throughout the luminal epithelial cell layer, but only weakly
in myoepithelial cells. During lactation, CD24 expression was suppressed within alveoli, but upregulated post-lactation, returning
to a pre-pregnant spatial distribution. CD24-deficient mice exhibited an accelerated mammary gland ductal extension during
puberty and an enhanced branching morphogenesis, resulting in increased furcation in the ductal structure. CD24−/− mammary
epithelial cells were able to completely repopulate cleared mammary fat pads and to give rise to fully functional mammary
glands. Together, these data suggest that while CD24 is expressed in mammary epithelium compartments thought to contain stem
cells, CD24 is not a major regulator of mammary stem/progenitor cell function, but rather plays a role in governing branching
morphogenesis. 相似文献
19.
Sebastian Gliem Adnan S. Syed Alfredo Sansone Eugen Kludt Evangelia Tantalaki Thomas Hassenklöver Sigrun I. Korsching Ivan Manzini 《Cellular and molecular life sciences : CMLS》2013,70(11):1965-1984
In contrast to the single sensory surface present in teleost fishes, several spatially segregated subsystems with distinct molecular and functional characteristics define the mammalian olfactory system. However, the evolutionary steps of that transition remain unknown. Here we analyzed the olfactory system of an early diverging tetrapod, the amphibian Xenopus laevis, and report for the first time the existence of two odor-processing streams, sharply segregated in the main olfactory bulb and partially segregated in the olfactory epithelium of pre-metamorphic larvae. A lateral odor-processing stream is formed by microvillous receptor neurons and is characterized by amino acid responses and Gαo/Gαi as probable signal transducers, whereas a medial stream formed by ciliated receptor neurons is characterized by responses to alcohols, aldehydes, and ketones, and Gαolf/cAMP as probable signal transducers. To reveal candidates for the olfactory receptors underlying these two streams, the spatial distribution of 12 genes from four olfactory receptor gene families was determined. Several class II and some class I odorant receptors (ORs) mimic the spatial distribution observed for the medial stream, whereas a trace amine-associated receptor closely parallels the spatial pattern of the lateral odor-processing stream. Other olfactory receptors (some class I odorant receptors and vomeronasal type 1 receptors) and odor responses (to bile acids, amines) were not lateralized, the latter not even in the olfactory bulb, suggesting an incomplete segregation. Thus, the olfactory system of X. laevis exhibits an intermediate stage of segregation and as such appears well suited to investigate the molecular driving forces behind olfactory regionalization. 相似文献