139 research outputs found
Genetic noise control via protein oligomerization
Gene expression in a cell entails random reaction events occurring over
disparate time scales. Thus, molecular noise that often results in phenotypic
and population-dynamic consequences sets a fundamental limit to biochemical
signaling. While there have been numerous studies correlating the architecture
of cellular reaction networks with noise tolerance, only a limited effort has
been made to understand the dynamic role of protein-protein interactions. Here
we have developed a fully stochastic model for the positive feedback control of
a single gene, as well as a pair of genes (toggle switch), integrating
quantitative results from previous in vivo and in vitro studies. We find that
the overall noise-level is reduced and the frequency content of the noise is
dramatically shifted to the physiologically irrelevant high-frequency regime in
the presence of protein dimerization. This is independent of the choice of
monomer or dimer as transcription factor and persists throughout the multiple
model topologies considered. For the toggle switch, we additionally find that
the presence of a protein dimer, either homodimer or heterodimer, may
significantly reduce its random switching rate. Hence, the dimer promotes the
robust function of bistable switches by preventing the uninduced (induced)
state from randomly being induced (uninduced). The specific binding between
regulatory proteins provides a buffer that may prevent the propagation of
fluctuations in genetic activity. The capacity of the buffer is a non-monotonic
function of association-dissociation rates. Since the protein oligomerization
per se does not require extra protein components to be expressed, it provides a
basis for the rapid control of intrinsic or extrinsic noise
Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review
Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p
Quantum dots in axillary lymph node mapping: Biodistribution study in healthy mice
<p>Abstract</p> <p>Background</p> <p>Breast cancer is the first cause of cancer death among women and its incidence doubled in the last two decades. Several approaches for the treatment of these cancers have been developed. The axillary lymph node dissection (ALND) leads to numerous morbidity complications and is now advantageously replaced by the dissection and the biopsy of the sentinel lymph node. Although this approach has strong advantages, it has its own limitations which are manipulation of radioactive products and possible anaphylactic reactions to the dye. As recently proposed, these limitations could in principle be by-passed if semiconductor nanoparticles (quantum dots or QDs) were used as fluorescent contrast agents for the <it>in vivo </it>imaging of SLN. QDs are fluorescent nanoparticles with unique optical properties like strong resistance to photobleaching, size dependent emission wavelength, large molar extinction coefficient, and good quantum yield.</p> <p>Methods</p> <p>CdSe/ZnS core/shell QDs emitting around 655 nm were used in our studies. 20 μL of 1 μM (20 pmol) QDs solution were injected subcutaneously in the anterior paw of healthy nude mice and the axillary lymph node (ALN) was identified visually after injection of a blue dye. <it>In vivo </it>fluorescence spectroscopy was performed on ALN before the mice were sacrificed at 5, 15, 30, 60 min and 24 h after QDs injection. ALN and all other organs were removed, cryosectioned and observed in fluorescence microscopy. The organs were then chemically made soluble to extract QDs. Plasmatic, urinary and fecal fluorescence levels were measured.</p> <p>Results</p> <p>QDs were detected in ALN as soon as 5 min and up to 24 h after the injection. The maximum amount of QDs in the ALN was detected 60 min after the injection and corresponds to 2.42% of the injected dose. Most of the injected QDs remained at the injection site. No QDs were detected in other tissues, plasma, urine and feces.</p> <p>Conclusion</p> <p>Effective and rapid (few minutes) detection of sentinel lymph node using fluorescent imaging of quantum dots was demonstrated. This work was done using very low doses of injected QDs and the detection was done using a minimally invasive method.</p
The Formation of the First Massive Black Holes
Supermassive black holes (SMBHs) are common in local galactic nuclei, and
SMBHs as massive as several billion solar masses already exist at redshift z=6.
These earliest SMBHs may grow by the combination of radiation-pressure-limited
accretion and mergers of stellar-mass seed BHs, left behind by the first
generation of metal-free stars, or may be formed by more rapid direct collapse
of gas in rare special environments where dense gas can accumulate without
first fragmenting into stars. This chapter offers a review of these two
competing scenarios, as well as some more exotic alternative ideas. It also
briefly discusses how the different models may be distinguished in the future
by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First
Galaxies - Theoretical Predictions and Observational Clues", Springer
Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B.
Mobasher, in pres
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On the price of morals in markets: an empirical study of the Swedish AP-Funds and the Norwegian Government Pension Fund
This study empirically analyses the exclusion of companies from investors’ investment universe due to a
company’s business model (sector-based exclusion) or due
to a company’s violations of international norms (normbased exclusion). We conduct a time-series analysis of the performance implications of the exclusion decisions of two leading Nordic investors, Norway’s Government Pension Fund-Global (GPFG) and Sweden’s AP-funds. We find that their portfolios of excluded companies do not generate an abnormal return relative to the funds’ benchmark index. While the exclusion portfolios show higher risk than the respective benchmark, this difference is only statistically
significant for the case of GPFG. These findings suggest
that the exclusion of the companies generally does not
harm funds’ performance. We interpret these findings as
indicative that with exclusionary screening, as practiced by the sample funds, asset owners can meet the ethical
objectives of their beneficiaries without compromising
financial returns
The management of patients with primary chronic anal fissure: a position paper
Anal fissure is one of the most common and painful proctologic diseases. Its treatment has long been discussed and several different therapeutic options have been proposed. In the last decades, the understanding of its pathophysiology has led to a progressive reduction of invasive and potentially invalidating treatments in favor of conservative treatment based on anal sphincter muscle relaxation. Despite some systematic reviews and an American position statement, there is ongoing debate about the best treatment for anal fissure. This review is aimed at identifying the best treatment option drawing on evidence-based medicine and on the expert advice of 6 colorectal surgeons with extensive experience in this field in order to produce an Italian position statement for anal fissures. While there is little chance of a cure with conservative behavioral therapy, medical treatment with calcium channel blockers, diltiazem and nifepidine or glyceryl trinitrate, had a considerable success rate ranging from 50 to 90%. Use of 0.4% glyceryl trinitrate in standardized fashion seems to have the best results despite a higher percentage of headache, while the use of botulinum toxin had inconsistent results. Nonresponding patients should undergo lateral internal sphincterotomy. The risk of incontinence after this procedure seems to have been overemphasized in the past. Only a carefully selected group of patients, without anal hypertonia, could benefit from anoplasty
Structural Maintenance of Chromosomes (SMC) Proteins Promote Homolog-Independent Recombination Repair in Meiosis Crucial for Germ Cell Genomic Stability
In meiosis, programmed DNA breaks repaired by homologous recombination (HR) can be processed into inter-homolog crossovers that promote the accurate segregation of chromosomes. In general, more programmed DNA double-strand breaks (DSBs) are formed than the number of inter-homolog crossovers, and the excess DSBs must be repaired to maintain genomic stability. Sister-chromatid (inter-sister) recombination is postulated to be important for the completion of meiotic DSB repair. However, this hypothesis is difficult to test because of limited experimental means to disrupt inter-sister and not inter-homolog HR in meiosis. We find that the conserved Structural Maintenance of Chromosomes (SMC) 5 and 6 proteins in Caenorhabditis elegans are required for the successful completion of meiotic homologous recombination repair, yet they appeared to be dispensable for accurate chromosome segregation in meiosis. Mutations in the smc-5 and smc-6 genes induced chromosome fragments and dismorphology. Chromosome fragments associated with HR defects have only been reported in mutants, which have disrupted inter-homolog crossover. Surprisingly, the smc-5 and smc-6 mutations did not disrupt the formation of chiasmata, the cytologically visible linkages between homologous chromosomes formed from meiotic inter-homolog crossovers. The mutant fragmentation defect appeared to be preferentially enhanced by the disruptions of inter-homolog recombination but not by the disruptions of inter-sister recombination. Based on these findings, we propose that the C. elegans SMC-5/6 proteins are required in meiosis for the processing of homolog-independent, presumably sister-chromatid-mediated, recombination repair. Together, these results demonstrate that the successful completion of homolog-independent recombination is crucial for germ cell genomic stability
The effects of living distantly from peritoneal dialysis units on peritonitis risk, microbiology, treatment and outcomes: a multi-centre registry study
Extent: 9p.Background:The aim of the study was to determine whether distance between residence and peritoneal dialysis (PD) unit influenced peritonitis occurrence, microbiology, treatment and outcomes. Methods: The study included all patients receiving PD between 1/10/2003 and 31/12/2008, using ANZDATA Registry data. Results: 365 (6%) patients lived ≥100 km from their nearest PD unit (distant group), while 6183 (94%) lived <100 km (local group). Median time to first peritonitis in distant patients (1.34 years, 95% CI 1.07-1.61) was significantly shorter than in local patients (1.68 years, 95% CI 1.59-1.77, p = 0.001), whilst overall peritonitis rates were higher in distant patients (incidence rate ratio 1.32, 95% CI 1.20-1.46). Living ≥100 km away from a PD unit was independently associated with a higher risk of S. aureus peritonitis (adjusted odds ratio [OR] 1.64, 95% CI 1.09-2.47). Distant patients with first peritonitis episodes were less likely to be hospitalised (64% vs 73%, p = 0.008) and receive antifungal prophylaxis (4% vs 10%, p = 0.01), but more likely to receive vancomycin-based antibiotic regimens (52% vs 42%, p < 0.001). Using multivariable logistic regression analysis of peritonitis outcomes, distant patients were more likely to be cured with antibiotics alone (OR 1.55, 95% CI 1.03-2.24). All other outcomes were comparable between the two groups. Conclusions: Living ≥100 km away from a PD unit was associated with increased risk of S. aureus peritonitis, modified approaches to peritonitis treatment and peritonitis outcomes that were comparable to, or better than patients living closer to a PD unit. Staphylococcal decolonisation should receive particular consideration in remote living patients.Yeoungjee Cho, Sunil V Badve, Carmel M Hawley, Stephen P McDonald, Fiona G Brown, Neil Boudville M, Kathryn J Wiggins, Kym M Bannister, Philip Clayton, and David W Johnso
Changing Domesticity of Aedes aegypti in Northern Peninsular Malaysia: Reproductive Consequences and Potential Epidemiological Implications
BACKGROUND: The domestic dengue vector Aedes aegypti mosquitoes breed in indoor containers. However, in northern peninsular Malaysia, they show equal preference for breeding in both indoor and outdoor habitats. To evaluate the epidemiological implications of this peridomestic adaptation, we examined whether Ae. aegypti exhibits decreased survival, gonotrophic activity, and fecundity due to lack of host availability and the changing breeding behavior. METHODOLOGY/PRINCIPAL FINDINGS: This yearlong field surveillance identified Ae. aegypti breeding in outdoor containers on an enormous scale. Through a sequence of experiments incorporating outdoors and indoors adapting as well as adapted populations, we observed that indoors provided better environment for the survival of Ae. aegypti and the observed death patterns could be explained on the basis of a difference in body size. The duration of gonotrophic period was much shorter in large-bodied females. Fecundity tended to be greater in indoor acclimated females. We also found increased tendency to multiple feeding in outdoors adapted females, which were smaller in size compared to their outdoors breeding counterparts. CONCLUSION/SIGNIFICANCE: The data presented here suggest that acclimatization of Ae. aegypti to the outdoor environment may not decrease its lifespan or gonotrophic activity but rather increase breeding opportunities (increased number of discarded containers outdoors), the rate of larval development, but small body sizes at emergence. Size is likely to be correlated with disease transmission. In general, small size in Aedes females will favor increased blood-feeding frequency resulting in higher population sizes and disease occurrence
A de novo transcriptome of the Asian tiger mosquito, Aedes albopictus, to identify candidate transcripts for diapause preparation
<p>Abstract</p> <p>Background</p> <p>Many temperate insects survive the harsh conditions of winter by undergoing photoperiodic diapause, a pre-programmed developmental arrest initiated by short day lengths. Despite the well-established ecological significance of photoperiodic diapause, the molecular basis of this crucial adaptation remains largely unresolved. The Asian tiger mosquito, <it>Aedes albopictus </it>(Skuse), represents an outstanding emerging model to investigate the molecular basis of photoperiodic diapause in a well-defined ecological and evolutionary context. <it>Ae. albopictus </it>is a medically significant vector and is currently considered the most invasive mosquito in the world. Traits related to diapause appear to be important factors contributing to the rapid spread of this mosquito. To generate novel sequence information for this species, as well as to discover transcripts involved in diapause preparation, we sequenced the transcriptome of <it>Ae. albopictus </it>oocytes destined to become diapausing or non-diapausing pharate larvae.</p> <p>Results</p> <p>454 GS-FLX transcriptome sequencing yielded >1.1 million quality-filtered reads, which we assembled into 69,474 contigs (N50 = 1,009 bp). Our contig filtering approach, where we took advantage of strong sequence similarity to the fully sequenced genome of <it>Aedes aegypti</it>, as well as other reference organisms, resulted in 11,561 high-quality, conservative ESTs. Differential expression estimates based on normalized read counts revealed 57 genes with higher expression, and 257 with lower expression under diapause-inducing conditions. Analysis of expression by qPCR for 47 of these genes indicated a high correlation of expression levels between 454 sequence data and qPCR, but congruence of statistically significant differential expression was low. Seven genes identified as differentially expressed based on qPCR have putative functions that are consistent with the insect diapause syndrome; three genes have unknown function and represent novel candidates for the transcriptional basis of diapause.</p> <p>Conclusions</p> <p>Our transcriptome database provides a rich resource for the comparative genomics and functional genetics of <it>Ae. albopictus</it>, an invasive and medically important mosquito. Additionally, the identification of differentially expressed transcripts related to diapause enriches the limited knowledge base for the molecular basis of insect diapause, in particular for the preparatory stage. Finally, our analysis illustrates a useful approach that draws from a closely related reference genome to generate high-confidence ESTs in a non-model organism.</p
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