共查询到20条相似文献,搜索用时 31 毫秒
1.
We summarize the clinical presentation and molecular basis of a unique group of congenital immunodeficiency disorders in which
defects in immune tolerance mechanisms result in severe autoimmunity. Patients with severe, familial forms of multi-organ
autoimmunity have been recognized and clinically described for more than 40 years (Clin Exp Immunol 1: 119–128, 1966; Clin Exp Immunol 2: 19–30, 1967). Some are characterized primarily by autoimmunity and others by autoimmunity combined with susceptibility to specific infectious
organisms. The first mechanistic understanding of these disorders began to emerge approximately 10 years ago with the initial
identification of causative genes. As a result, our understanding of how immune tolerance is established and maintained in
humans has expanded dramatically. Data generated over the last 3–4 years including identification of additional gene defects
and functional characterization of each identified gene product in human and animal models have added clarity. This, in turn,
has improved our ability to diagnose and effectively treat these severe, life-threatening disorders. Inherited disorders characterized
by immune dysregulation have dramatically expanded our understanding of immune tolerance mechanisms in humans. Recognition
and diagnosis of these disorders in the clinic allows timely initiation of life-saving therapies that may prevent death or
irreversible damage to vital organs. 相似文献
2.
Ruth Seelige Stephen Searles Jack D. Bui 《Cellular and molecular life sciences : CMLS》2018,75(2):225-240
The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57–70, 67; Cell 144:646–674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823–837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response. 相似文献
3.
Bruce Pourciau 《Archive for History of Exact Sciences》2003,57(4):267-311
The first proposition of the Principia records two fundamental properties of an orbital motion: the Fixed Plane Property (that the orbit lies in a fixed plane)
and the Area Property (that the radius sweeps out equal areas in equal times). Taking at the start the traditional view, that
by an orbital motion Newton means a centripetal motion – this is a motion ``continually deflected from the tangent toward
a fixed center' – we describe two serious flaws in the Principia's argument for Proposition 1, an argument based on a polygonal impulse approximation. First, the persuasiveness of the argument
depends crucially on the validity of the Impulse Assumption: that every centripetal motion can be represented as a limit of polygonal impulse motions. Yet Newton tacitly takes the Impulse Assumption for granted. The resulting gap in the argument for Proposition 1 is serious,
for only a nontrivial analysis, involving the careful estimation of accumulating local errors, verifies the Impulse Assumption.
Second, Newton's polygonal approximation scheme has an inherent and ultimately fatal disability: it does not establish nor
can it be adapted to establish the Fixed Plane Property. Taking then a different view of what Newton means by an orbital motion
– namely that an orbital motion is by definition a limit of polygonal impulse motions – we show in this case that polygonal approximation can be used to establish both the fixed plane and area properties without too much trouble, but that Newton's own argument still
has flaws. Moreover, a crucial question, haunted by error accumulation and planarity problems, now arises: How plentiful are
these differently defined orbital motions? Returning to the traditional view, that Newton's orbital motions are by definition
centripetal motions, we go on to give three proofs of the Area Property which Newton ``could have given' – two using polygonal
approximation and a third using curvature – as well as a proof of the Fixed Plane Property which he ``almost could have given.'
(Received August 14, 2002)
Published online March 26, 2003
Communicated by G. Smith 相似文献
4.
A. Gerson-Gurwitz N. Movshovich R. Avunie V. Fridman K. Moyal B. Katz M. A. Hoyt L. Gheber 《Cellular and molecular life sciences : CMLS》2009,66(2):301-313
S. cerevisiae anaphase spindle elongation is accomplished by the overlapping function of dynein and the kinesin-5 motor proteins, Cin8
and Kip1. Cin8 and dynein are synthetically lethal, yet the arrest phenotypes of cells eliminated for their function had not
been identified. We found that at a non-permissive temperature, dyn1Δ cells that carry a temperature-sensitive cin8 – 3 mutation arrest at mid-anaphase with a unique phenotype, which we named TAN (two microtubule asters in one nucleus). These
cells enter anaphase, but fail to proceed through the slow phase of anaphase B. At a permissive temperature, dyn1Δ, cin8 – 3 or dyn1Δcin8 – 3 cells exhibit perturbed spindle midzone morphologies, with dyn1Δcin8 – 3 anaphase spindles also being profoundly bent and nonrigid. Sorbitol, which has been suggested to stabilize microtubules,
corrects these defects and suppresses the TAN phenotype. We conclude that dynein and Cin8 cooperate in anaphase midzone organization
and influence microtubule dynamics, thus enabling progression through the slow phase of anaphase B.
Received 10 August 2008; received after revision 22 October 2008; accepted 27 October 2008 相似文献
5.
W. C. Wimsatt 《Archive for History of Exact Sciences》2012,66(4):359-396
A square tabular array was introduced by R. C. Punnett in (1907) to visualize systematically and economically the combination of gametes to make genotypes according to Mendel’s theory. This mode of representation evolved and rapidly became standardized as the canonical way of representing like problems in genetics. Its advantages over other contemporary methods are discussed, as are ways in which it evolved to increase its power and efficiency, and responded to changing theoretical perspectives. It provided a natural visual decomposition of a complex problem into a number of inter-related stages. This explains its computational and conceptual power, for one could simply “read off” answers to a wide variety of questions simply from the “right” visual representation of the problem, and represent multiple problems, and multiple layers of problems in the same diagram. I relate it to prior work on the evolution of Weismann diagrams by Griesemer and Wimsatt (What Philosophy of Biology Is, Martinus-Nijhoff, the Hague, 1989), and discuss a crucial change in how it was interpreted that midwifed its success. 相似文献
6.
Glycoconjugates of the intestinal goblet cells of four cyprinids 总被引:3,自引:0,他引:3
The aim of this work was to show differences in the terminal and subterminal sugar composition of carbohydrate chains of
glycoconjugates produced by the goblet cells of the intestines of four cyprinids. We analysed intestines of two herbivorous
species – sneep and grass carp – and two omnivorous ones – chub and common carp. We compared four intestinal regions of every
studied species. In every region, the presence of neutral and acidic glycoconjugates was confirmed. The smallest amount of
acidic glycoconjugates was present in the second region of sneep intestine. Sulphated glycoconjugates were absent in the third
and fourth region of chub intestine. Lectin histochemistry provided evidence for the presence of β-D-galactose, α-N-acetylgalactosamine, β-N-acetylglucosamine and sialic acids. Additionally, the occurrence of α-L-fucose in the goblet cells of chub, grass carp and sneep was confirmed. We tried to correlate the patern of glycoconjugate
glycosylation with feeding habits of the studied fishes.
Received 1 July 2002; received after revision 8 August 2002; accepted 19 August 2002
RID="*"
ID="*"Corresponding author. 相似文献
7.
8.
Proinsulin C-peptide and its analogues induce intracellular Ca2+ increases in human renal tubular cells 总被引:3,自引:0,他引:3
Shafqat J Juntti-Berggren L Zhong Z Ekberg K Köhler M Berggren PO Johansson J Wahren J Jörnvall H 《Cellular and molecular life sciences : CMLS》2002,59(7):1185-1189
Based on the findings that proinsulin C-peptide binds specifically to cell membranes, we investigated the effects of C-peptide
and related molecules on the intracellular Ca2+ concentration ([Ca2+]i) in human renal tubular cells using the indicator fura-2/AM. The results show that human C-peptide and its C-terminal pentapeptide
(positions 27–31, EGSLQ), but not the des (27–31) C-peptide or randomly scrambled C-peptide, elicit a transient increase in
[Ca2+]i. Rat C-peptide and rat C-terminal pentapeptide also induce a [Ca2+]i response in human tubular cells, while a human pentapeptide analogue with Ala at position 1 gives no [Ca2+]i response, and those with Ala at positions 2–5 induce responses with different amplitudes. These results define a species
cross-reactivity for C-peptide and demonstrate the importance of Glu at position 1 of the pentapeptide. Preincubation of cells
with pertussis toxin abolishes the effect on [Ca2+]i by both C-peptide and the pentapeptide. These results are compatible with previous data on C-peptide binding to cells and
activation of Na+,K+ATPase. Combined, all data show that C-peptide is a bioactive peptide and suggest that it elicits changes in [Ca2+]i via G-protein-coupled pathways, giving downstream enzyme effects.
Received 13 May 2002; accepted 16 May 2002 相似文献
9.
Studies have shown prostaglandin F2α
to be an endogenous tumor promoter in mouse models of skin carcinogenesis; however, the mechanisms by which PGF2α affects cell cycle events remain unknown. Here we performed cell cycle analyses on HEK cells stably expressing the human
FP receptor and found that treatment with PGF2α delays mitosis and is associated with an increased expression of cyclin B1 and Cdc2 kinase activity. In addition, multipolar
spindles and misaligned chromosomes were observed in a significant proportion of cells treated with PGF2α. Defective cytokinesis was also observed which resulted in gross aneuploidy and polyploidy. Expression of dominant negative
Rho attenuated the cell cycle delay and prevented the generation of micronuclei following treatment with PGF2α. This suggests that FP receptor activation of Rho signaling by PGF2α can interfere with nuclear division. Aneuploidy is associated with genomic instability and may underlie the tumor-promoting
properties of PGF2α.
Received 7 July 2005; received after revision 22 October 2005; accepted 11 November 2005 相似文献
10.
A. E. L. Davis 《Archive for History of Exact Sciences》2003,57(5):355-393
Epitome V (1621), and consisted of matching an element of area to an element of time, where each was mathematically determined. His
treatment of the area depended solely on the geometry of Euclid's Elements, involving only straight-line and circle propositions – so we have to account for his deliberate avoidance of the sophisticated
conic-geometry associated with Apollonius. We show also how his proof could have been made watertight according to modern
standards, using methods that lay entirely within his power.
The greatest innovation, however, occurred in Kepler's fresh formulation of the measure of time. We trace this concept in
relation to early astronomy and conclude that Kepler's treatment unexpectedly entailed the assumption that time varied nonuniformly;
meanwhile, a geometrical measure provided the independent variable. Even more surprisingly, this approach turns out to be
entirely sound when assessed in present-day terms.
Kepler himself attributed the cause of the motion of a single planet around the Sun to a set of `physical' suppositions which
represented his religious as well as his Copernican convictions; and we have pared to a minimum – down to four – the number
he actually required to achieve this.
In the Appendix we use modern mathematics to emphasize the simplicity, both geometrical and kinematical, that objectively
characterizes the Sun-focused ellipse as an orbit. Meanwhile we highlight the subjective simplicity of Kepler's own techniques
(most of them extremely traditional, some newly created). These two approaches complement each other to account for his success.
(Received April 19, 2002)
Published online April 2, 2003
Communicated by N. M. Swerdlow 相似文献
11.
Jean Delcourt 《Archive for History of Exact Sciences》2011,65(3):229-293
Cet article est consacré à l’histoire de la théorie locale des courbes “à double courbure”. Initiée par Clairaut en 1731, cette théorie se développe en parallèle à la théorie des surfaces et trouve son achèvement avec les formules de Serret et
Frenet et leur interprétation par Darboux, en 1887. Au delà de l’analyse des contributions de nombreux mathématiciens, parmi lesquels Monge bien s?r mais aussi Fourier, Lagrange
et Cauchy, notre étude donne un regard particulier sur l’évolution conjointe de l’Analyse et de la Géométrie, dans une longue
période riche de nombreuses remises en cause théoriques. 相似文献
12.
Bignold LP 《Cellular and molecular life sciences : CMLS》2003,60(5):883-891
The mutator phenotype theory of carcinogenesis suggests that genetic instability is an early and essential part of tumour development. This instability provides for substantially random cell-to-cell genomic variation (genomic heterogeneity) to arise among cells of individual tumours. Genetically unstable cells then produce 'successful' clones of cells with the necessary mutations for malignant behaviour. In a previous paper (Bignold L. P., Cell. Mol. Life Sci. 2002; 59: 950-958), it was pointed out that a population of cells which is heterogeneous for behaviour-related genes may well also be heterogeneous for morphology-related genes. This would result in cellular pleomorphism among cells of individual tumours, and so explain this almost universal characteristic of solid malignancies. paragraph sign If the concept of random genomic variability applies fully to the histopathology of tumours, then most tumours should show a mixture of neoplastic features, especially nuclear atypia, loss of specialised function (such as loss of production of mucus by glandular cells) and invasiveness. However, occasional lesions might be expected to occur which show these characteristics independently. That is, lesions should exist which exhibit one or two of the three characteristics of neoplasms without the other(s). paragraph sign This paper identifies, among human tumours, lesions which show independence of these characteristics. Two of the examples discussed are a Bowenoid solar keratosis that shows severe nuclear atypia, but no apparent loss of specialisation and no invasiveness. On the other hand, anaplastic small cell carcinoma of the lung often exhibits marked loss of differentiation, very aggressive invasion and metastasis, but little nuclear pleomorphism. paragraph sign These examples are considered to provide further support for the importance of the mutator phenotype to the pathogenesis of neoplasia. 相似文献
13.
4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease 总被引:3,自引:0,他引:3
Shringarpure R Grune T Sitte N Davies KJ 《Cellular and molecular life sciences : CMLS》2000,57(12):1802-1809
The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s
disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data
do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins
in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated
that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins.
Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by
the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized
that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ
1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Aβ
1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ
1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized
protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s
disease
Received 26 September 2000; accepted 26 September 2000 相似文献
14.
Breast and ovarian cancer are among the most common malignancies diagnosed in women worldwide. Together, they account for
the majority of cancer-related deaths in women. These cancer types share a number of features, including their association
with hereditary cancer syndromes caused by heterozygous germline mutations in BRCA1 or BRCA2. BRCA-associated breast and ovarian cancers are hallmarked by genomic instability and high sensitivity to DNA double-strand
break (DSB) inducing agents due to loss of error-free DSB repair via homologous recombination (HR). Recently, poly(ADP-ribose)
polymerase inhibitors, a new class of drugs that selectively target HR-deficient tumor cells, have been shown to be highly
active in BRCA-associated breast and ovarian cancers. This finding has renewed interest in hallmarks of HR deficiency and
the use of other DSB-inducing agents, such as platinum salts or bifunctional alkylators, in breast and ovarian cancer patients.
In this review we discuss the similarities between breast and ovarian cancer, the hallmarks of genomic instability in BRCA-mutated and BRCA-like breast and ovarian cancers, and the efforts to search for predictive markers of HR deficiency in order
to individualize therapy in breast and ovarian cancer. 相似文献
15.
16.
The public perception of selenium has changed significantly over the last decades. Originally mainly known for its high toxicity,
it was later recognized as an essential trace element and is now (despite its narrow therapeutic window) almost being marketed
as a lifestyle drug. Indeed, some clinical and preclinical studies suggest that selenium supplementation may be beneficial
in a large number of clinical conditions. However, its mode of action is unresolved in most of these cases. Selenocysteine
– identified as the 21st amino acid used in ribosome-mediated protein synthesis – is incorporated in at least 25 specific, genetically determined
human selenoproteins, many of which have only recently been discovered. Restoration of normal selenoprotein levels may be
– apart from direct supranutritional effects – one possible explanation for the effects of selenium supplements. In this review
we provide a brief but up-to-date overview of what is currently known about these 25 acknowledged human selenoproteins and
their synthesis.
Received 30 March 2005; received after revision 4 July 2005; accepted 13 July 2005 相似文献
17.
Johansson S Gullbo J Lindholm P Ek B Thunberg E Samuelsson G Larsson R Bohlin L Claeson P 《Cellular and molecular life sciences : CMLS》2003,60(1):165-175
Four novel proteins (phoratoxins C–F) have been isolated from the North American mistletoe Phoradendron tomentosum. The amino acid sequences of these phoratoxins were determined unambiguously using a combination of Edman degradation and
trypsin enzymatic digestion, and by electrospray ionization tandem mass spectrometry sequencing. Phoratoxins C, E and F consist
of 46 amino acid residues; and phoratoxin D of 41. All proteins had six cysteines, similar to the earlier described phoratoxins
A and B, which are thionins. The cytotoxicity of each protein was evaluated in a human cell line panel that represented several
cytotoxic drug-resistance mechanisms. For the half-maximal inhibitory concentrations (IC50 values) of the different cell lines in the panel, correlation with those of standard drugs was low. The most potent cytotoxic
phoratoxin C was further tested on primary cultures of human tumor cells from patients. The solid tumor samples from breast
cancer cells were 18 times more sensitive to phoratoxin C than the tested hematological tumor samples.
Received 30 September 2002; received after revision 28 October 2002; accepted 7 November 2002
RID="*"
ID="*"Corresponding author. 相似文献
18.
The human hair follicle is composed of different concentric compartments, which reflect different programmes of differentiation.
Using monoclonal antibodies against α2β1 and α3β1 integrins we demonstrated a shift in their expression, from a basolateral distribution in the basal cells of the lower outer
root sheath, to an apicolateral expression in the upper outer root sheath, as in epidermis. This shift takes place in a transition
zone, localized to the midpart of the follicle. The distinct basolateral distribution of α2β1 and α3β1 integrins in the lower portion of the outer root sheath coincides with the presence of basal cell protrusions and is probably
linked to the presence of the vitreous membrane which surrounds the bottom part of the anagen human hair follicle. Moreover,
we showed that the expression of α6β4 integrin is discontinuous along the hair follicle and coincides with that of laminin 5. Together these results establish
that within a given compartment – namely the outer root sheath – several domains can be clearly identified, which probably
reflect the onset of successive differentiation pathways along the hair follicle.
Received 17 January 1997; received after revision 18 February 1997; accepted 24 February 1997 相似文献
19.
From Problems to Structures: the Cousin Problems and the Emergence of the Sheaf Concept 总被引:1,自引:1,他引:0
Renaud Chorlay 《Archive for History of Exact Sciences》2010,64(1):1-73
Historical work on the emergence of sheaf theory has mainly concentrated on the topological origins of sheaf cohomology in the period from 1945 to 1950 and on subsequent developments. However, a shift of emphasis both in time-scale and disciplinary
context can help gain new insight into the emergence of the sheaf concept. This paper concentrates on Henri Cartan’s work in the theory of analytic functions of several complex variables and the
strikingly different roles it played at two stages of the emergence of sheaf theory: the definition of a new structure and
formulation of a new research programme in 1940–1944; the unexpected integration into sheaf cohomology in 1951–1952. In order
to bring this two-stage structural transition into perspective, we will concentrate more specifically on a family of problems,
the so-called Cousin problems, from Poincaré (1883) to Cartan. This medium-term narrative provides insight into two more general
issues in the history of contemporary mathematics. First, we will focus on the use of problems in theory-making. Second, the
history of the design of structures in geometrically flavoured contexts—such as for the sheaf and fibre-bundle structures—which
will help provide a more comprehensive view of the structuralist moment, a moment whose algebraic component has so far been the main focus for historical work. 相似文献
20.
ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts 总被引:3,自引:0,他引:3
Fortino V Torricelli C Gardi C Valacchi G Rossi Paccani S Maioli E 《Cellular and molecular life sciences : CMLS》2002,59(12):2165-2171
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through
at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of
phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative
role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction,
we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously
activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two
counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein
kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate
d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time,
their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002
RID="*"
ID="*"Corresponding author. 相似文献