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961.
Cellular decision making is the process whereby cells assume different, functionally important and heritable fates without an associated genetic or environmental difference. Such stochastic cell fate decisions generate nongenetic cellular diversity, which may be critical for metazoan development as well as optimized microbial resource utilization and survival in a fluctuating, frequently stressful environment. Here, we review several examples of cellular decision making from viruses, bacteria, yeast, lower metazoans, and mammals, highlighting the role of regulatory network structure and molecular noise. We propose that cellular decision making is one of at least three key processes underlying development at various scales of biological organization. 相似文献
962.
The mechanisms that govern receptor coalescence into functional clusters--often a critical step in their stimulation by ligand--are poorly understood. We used single-molecule tracking to investigate the dynamics of CD36, a clustering-responsive receptor that mediates oxidized LDL uptake by macrophages. We found that CD36 motion in the membrane was spatially structured by the cortical cytoskeleton. A subpopulation of receptors diffused within linear confinement regions whose unique geometry simultaneously facilitated freedom of movement along one axis while increasing the effective receptor density. Co-confinement within troughs enhanced the probability of collisions between unligated receptors and promoted their clustering. Cytoskeleton perturbations that inhibited diffusion in linear confinement regions reduced receptor clustering in the absence of ligand and, following ligand addition, suppressed CD36-mediated signaling and internalization. These observations demonstrate a role for the cytoskeleton in controlling signal transduction by structuring receptor diffusion within membrane regions that increase their collision frequency. 相似文献
963.
Complete and accurate knowledge of the genes and allelic variants of the human immunoglobulin gene loci is critical for studies
of B cell repertoire development and somatic point mutation, but evidence from studies of VDJ rearrangements suggests that
our knowledge of the available immunoglobulin gene repertoire is far from complete. The reported repertoire has changed little
over the last 15 years. This is, in part, a consequence of the inefficiencies involved in searching for new members of large,
multigenic gene families by cloning and sequencing. The advent of high-throughput sequencing provides a new avenue by which
the germline repertoire can be explored. In this report, we describe pyrosequencing studies of the heavy chain IGHV1, IGHV3
and IGHV4 gene subgroups in ten Papua New Guineans. Thousands of 454 reads aligned with complete identity to 51 previously
reported functional IGHV genes and allelic variants. A new gene, IGHV3-NL1*01, was identified, which differs from the nearest
previously reported gene by 15 nucleotides. Sixteen new IGHV alleles were also identified, 15 of which varied from previously
reported functional IGHV genes by between one and four nucleotides, while one sequence appears to be a functional variant
of the pseudogene IGHV3-25. BLAST searches suggest that at least six of these new genes are carried within the relatively
well-studied populations of North America, Europe or Asia. This study substantially expands the known immunoglobulin gene
repertoire and demonstrates that genetic variation of immunoglobulin genes can now be efficiently explored in different human
populations using high-throughput pyrosequencing. 相似文献
964.
Alpizar YA Chain B Collins MK Greenwood J Katz D Stauss HJ Mitchison NA 《Cancer immunology, immunotherapy : CII》2011,60(8):1127-1135
Although cancer immunology has made vigorous progress over the last decade, its future remains uncertain. Tumors have clearly
proved subject to immune surveillance, leading to antigenic editing, and means of activating both T and B arms of the immune
system have been devised. Therapeutic vaccination and monoclonal antibody therapy have so far proved disappointing, because
tumors prove adept at evasion from immune control. Dual targeting could well counteract evasion, provided that the two targets
are independent and are attacked simultaneously. This stage has nearly but not quite been reached in several forms of immunotherapy,
particularly of B-cell cancers, although such treatment also carries hazards. 相似文献
965.
Bergquist AJ Clair JM Collins DF 《Journal of applied physiology (Bethesda, Md. : 1985)》2011,110(3):627-637
Neuromuscular electrical stimulation (NMES) can be delivered over a nerve trunk or muscle belly and can generate contractions by activating motor (peripheral pathway) and sensory (central pathway) axons. In the present experiments, we compared the peripheral and central contributions to plantar flexion contractions evoked by stimulation over the tibial nerve vs. the triceps surae muscles. Generating contractions through central pathways follows Henneman's size principle, whereby low-threshold motor units are activated first, and this may have advantages for rehabilitation. Statistical analyses were performed on data from trials in which NMES was delivered to evoke 10-30% maximum voluntary torque 2-3 s into the stimulation (Time(1)). Two patterns of stimulation were delivered: 1) 20 Hz for 8 s; and 2) 20-100-20 Hz for 3-2-3 s. Torque and soleus electromyography were quantified at the beginning (Time(1)) and end (Time(2); 6-7 s into the stimulation) of each stimulation train. H reflexes (central pathway) and M waves (peripheral pathway) were quantified. Motor unit activity that was not time-locked to each stimulation pulse as an M wave or H reflex ("asynchronous" activity) was also quantified as a second measure of central recruitment. Torque was not different for stimulation over the nerve or the muscle. In contrast, M waves were approximately five to six times smaller, and H reflexes were approximately two to three times larger during NMES over the nerve vs. the muscle. Asynchronous activity increased by 50% over time, regardless of the stimulation location or pattern, and was largest during NMES over the muscle belly. Compared with NMES over the triceps surae muscles, NMES over the tibial nerve produced contractions with a relatively greater central contribution, and this may help reduce muscle atrophy and fatigue when NMES is used for rehabilitation. 相似文献
966.
Kominsky DJ Keely S MacManus CF Glover LE Scully M Collins CB Bowers BE Campbell EL Colgan SP 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(11):6505-6514
Tissues of the mucosa are lined by an epithelium that provides barrier and transport functions. It is now appreciated that inflammatory responses in inflammatory bowel diseases are accompanied by striking shifts in tissue metabolism. In this paper, we examined global metabolic consequences of mucosal inflammation using both in vitro and in vivo models of disease. Initial analysis of the metabolic signature elicited by inflammation in epithelial models and in colonic tissue isolated from murine colitis demonstrated that levels of specific metabolites associated with cellular methylation reactions are significantly altered by model inflammatory systems. Furthermore, expression of enzymes central to all cellular methylation, S-adenosylmethionine synthetase and S-adenosylhomocysteine hydrolase, are increased in response to inflammation. Subsequent studies showed that DNA methylation is substantially increased during inflammation and that epithelial NF-κB activity is significantly inhibited following treatment with a reversible S-adenosylhomocysteine hydrolase inhibitor, DZ2002. Finally, these studies demonstrated that inhibition of cellular methylation in a murine model of colitis results in disease exacerbation while folate supplementation to promote methylation partially ameliorates the severity of murine colitis. Taken together, these results identify a global change in methylation, which during inflammation, translates to an overall protective role in mucosal epithelia. 相似文献
967.
968.
Krakauer DC Collins JP Erwin D Flack JC Fontana W Laubichler MD Prohaska SJ West GB Stadler PF 《Journal of theoretical biology》2011,276(1):269-476
Scientific theories seek to provide simple explanations for significant empirical regularities based on fundamental physical and mechanistic constraints. Biological theories have rarely reached a level of generality and predictive power comparable to physical theories. This discrepancy is explained through a combination of frozen accidents, environmental heterogeneity, and widespread non-linearities observed in adaptive processes. At the same time, model building has proven to be very successful when it comes to explaining and predicting the behavior of particular biological systems. In this respect biology resembles alternative model-rich frameworks, such as economics and engineering. In this paper we explore the prospects for general theories in biology, and suggest that these take inspiration not only from physics, but also from the information sciences. Future theoretical biology is likely to represent a hybrid of parsimonious reasoning and algorithmic or rule-based explanation. An open question is whether these new frameworks will remain transparent to human reason. In this context, we discuss the role of machine learning in the early stages of scientific discovery. We argue that evolutionary history is not only a source of uncertainty, but also provides the basis, through conserved traits, for very general explanations for biological regularities, and the prospect of unified theories of life. 相似文献
969.
Boonyaratanakornkit J Bartlett E Schomacker H Surman S Akira S Bae YS Collins P Murphy B Schmidt A 《Journal of virology》2011,85(4):1495-1506
Human parainfluenza virus type 1 (HPIV1) is an important respiratory pathogen in young children, the immunocompromised, and the elderly. We found that infection with wild-type (WT) HPIV1 suppressed the innate immune response in human airway epithelial cells by preventing not only phosphorylation of interferon regulatory factor 3 (IRF3) but also degradation of IκBβ, thereby inhibiting IRF3 and NF-κB activation, respectively. Both of these effects were ablated by a F170S substitution in the HPIV1 C proteins (F170S) or by silencing the C open reading frame [P(C-)], resulting in a potent beta interferon (IFN-β) response. Using murine knockout cells, we found that IFN-β induction following infection with either mutant relied mainly on melanoma-associated differentiation gene 5 (MDA5) rather than retinoic acid-inducible gene I (RIG-I). Infection with either mutant, but not WT HPIV1, induced a significant accumulation of intracellular double-stranded RNA (dsRNA). These mutant viruses directed a marked increase in the accumulation of viral genome, antigenome, and mRNA that was coincident with the accumulation of dsRNA. In addition, the amount of viral proteins was reduced compared to that of WT HPIV1. Thus, the accumulation of dsRNA might be a result of an imbalance in the N protein/genomic RNA ratio leading to incomplete encapsidation. Protein kinase R (PKR) activation and IFN-β induction followed the kinetics of dsRNA accumulation. Interestingly, the C proteins did not appear to directly inhibit intracellular signaling involved in IFN-β induction; instead, their role in preventing IFN-β induction appeared to be in suppressing the formation of dsRNA. PKR activation contributed to IFN-β induction and also was associated with the reduction in the amount of viral proteins. Thus, the HPIV1 C proteins normally limit the accumulation of dsRNA and thereby limit activation of IRF3, NF-κB, and PKR. If C protein function is compromised, as in the case of F170S HPIV1, the resulting PKR activation and reduction in viral protein levels enable the host to further reduce C protein levels and to mount a potent antiviral type I IFN response. 相似文献
970.
During studies on the microflora of human feces we have isolated a strictly anaerobic, non-spore-forming, Gram-negative staining organism which exhibits a somewhat variable coccus-shaped morphology. Comparative 16S ribosomal RNA gene sequencing studies show the unidentified organism is phylogenetically a member of the Clostridium leptum supra-generic rRNA cluster and displays a close affinity to some rDNA clones derived from human and pig feces. The nearest named relatives of the unidentified isolate corresponded to Faecalibacterium prausnitzii (formerly Fusobacterium prausnitzii) displaying a 16S rRNA sequence divergence of approximately 9%, with Anaerofilum agile and A. pentosovorans the next closest relatives of the unidentified bacterium (sequence divergence approximately 10%). Based on phenotypic and phylogenetic considerations, it is proposed that the unusual coccoid-shaped organism be classified as a new genus and species, Subdoligranulum variabile. The type strain of S. variabile is BI 114(T) (=CCUG 47106(T)=DSM 15176(T)). 相似文献