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51.
Modern methods of high-throughput molecular biology render it possible to generate time series of metabolite concentrations and the expression of genes and proteins in vivo. These time profiles contain valuable information about the structure and dynamics of the underlying biological system. This information is implicit and its extraction is a challenging but ultimately very rewarding task for the mathematical modeler. Using a well-suited modeling framework, such as Biochemical Systems Theory (BST), it is possible to formulate the extraction of information as an inverse problem that in principle may be solved with a genetic algorithm or nonlinear regression. However, two types of issues associated with this inverse problem make the extraction task difficult. One type pertains to the algorithmic difficulties encountered in nonlinear regressions with moderate and large systems. The other type is of an entirely different nature. It is a consequence of assumptions that are often taken for granted in the design and analysis of mathematical models of biological systems and that need to be revisited in the context of inverse analyses. The article describes the extraction process and some of its challenges and proposes partial solutions. 相似文献
52.
Gallois M Gidenne T Fortun-Lamothe L Le Huerou-Luron I Lallès JP 《Reproduction, nutrition, development》2005,45(1):109-122
The impact of dietary factors on the gut morphological maturation is poorly documented in rabbits. The weights of the digestive segments as well as the morphology of villi and crypts along the small intestine were analysed weekly from day 14 till day 49, in two rabbit groups weaned at either 21 (W21 group, n = 12 litters) or 35 days (W35 group, n = 12 litters) of age. From 21 till 35 days, the W21 group ate 57% more solid feed than the W35 group (P < 0.01), and presented slighter body weights from day 28 till day 49 (-9%, P < 0.05). Tissue weights of the empty digestive segments, as expressed relative to the body weights, were higher in the W21 than in the W35 group from day 28 till day 49 (P < 0.001), whereas absolute tissue weights appeared similar (except for the proximal colon). From day 28 to day 49, small intestinal villi grew in height and surface area (P < 0.05) whereas the crypts deepened. Villous height followed a proximo-distal decreasing gradient from the duodenum to the ileum (P < 0.05) from day 28 onward. The villous height to width ratio changed with the beginning of significant solid feed intake: from a thin shape until day 21, villi became wider from day 28 on. The effect of weaning age on mucosal morphology was insignificant, except for the jejunal crypts whose surface area and depth were higher in the W21 group. The present results showed that morphological changes in the digestive tract of young rabbits were weakly influenced by an early stimulation of solid feed intake. 相似文献
53.
Patel NH Hayward DC Lall S Pirkl NR DiPietro D Ball EE 《Development (Cambridge, England)》2001,128(18):3459-3472
While the expression patterns of segment polarity genes such as engrailed have been shown to be similar in Drosophila melanogaster and Schistocerca americana (grasshopper), the expression patterns of pair-rule genes such as even-skipped are not conserved between these species. This might suggest that the factors upstream of pair-rule gene expression are not conserved across insect species. We find that, despite this, many aspects of the expression of the Drosophila gap gene hunchback are shared with its orthologs in the grasshoppers S. americana and L. migratoria. We have analyzed both mRNA and protein expression during development, and find that the grasshopper hunchback orthologs appear to have a conserved role in early axial patterning of the germ anlagen and in the specification of gnathal and thoracic primordia. In addition, distinct stepped expression levels of hunchback in the gnathal/thoracic domains suggest that grasshopper hunchback may act in a concentration-dependent fashion (as in Drosophila), although morphogenetic activity is not set up by diffusion to form a smooth gradient. Axial patterning functions appear to be performed entirely by zygotic hunchback, a fundamental difference from Drosophila in which maternal and zygotic hunchback play redundant roles. In grasshoppers, maternal hunchback activity is provided uniformly to the embryo as protein and, we suggest, serves a distinct role in distinguishing embryonic from extra-embryonic cells along the anteroposterior axis from the outset of development - a distinction made in Drosophila along the dorsoventral axis later in development. Later hunchback expression in the abdominal segments is conserved, as are patterns in the nervous system, and in both Drosophila and grasshopper, hunchback is expressed in a subset of extra-embryonic cells. Thus, while the expected domains of hunchback expression are conserved in Schistocerca, we have found surprising and fundamental differences in axial patterning, and have identified a previously unreported domain of expression in Drosophila that suggests conservation of a function in extra-embryonic patterning. 相似文献
54.
J Peter Figueroa Peter J. Hotez Carolina Batista Yanis Ben Amor Onder Ergonul Sarah Gilbert Mayda Gursel Mazen Hassanain Gagandeep Kang David C. Kaslow Jerome H. Kim Bhavna Lall Heidi Larson Denise Naniche Timothy Sheahan Shmuel Shoham Annelies Wilder-Smith Samba O. Sow Nathalie Strub-Wourgaft Prashant Yadav Maria Elena Bottazzi 《PLoS medicine》2021,18(9)
Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.Many may not be aware of the full extent of global inequity in the rollout of Coronavirus Disease 2019 (COVID-19) vaccines in response to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. As of June 20, 2021, only 0.9% of those living in low-income countries and less than 10% of those in low- and middle-income countries (LMICs) had received at least 1 dose of a COVID-19 vaccine compared with 43% of the population living in high-income countries (HICs) [1] (Fig 1). Only 2.4% of the population of Africa had been vaccinated compared with 41% of North America and 38% of Europe [1,2] (S1 Fig). Primarily due to the inability to access COVID-19 vaccines, less than 10% of the population in as many as 85 LMICs had been vaccinated compared with over 60% of the population in 26 HICs [1]. Only 10 countries account for more than 75% of all COVID-19 vaccines administered [3]. This striking and ongoing inequity has occurred despite the explicit ethical principles affirming equity of access to COVID-19 vaccines articulated in WHO SAGE values framework [4,5] prepared in mid-2020, well prior to the availability of COVID-19 vaccines.Open in a separate windowFig 1Proportion of people vaccinated with at least 1 dose of COVID-19 vaccine by income (April 14 to June 23, 2021).Note: Data on China appeared on the database on June 9, hence the jump in upper middle-income countries. COVID-19, Coronavirus Disease 2019. Source: https://ourworldindata.org/covid-vaccinations.The COVID-19 pandemic highlights the grave inequity and inadequacy of the global preparedness and response to serious emerging infections. The establishment of the Coalition for Epidemic Preparedness Innovations (CEPI) in 2018, the Access to COVID-19 Tools Accelerator (ACT-A), and the COVID-19 Vaccines Global Access (COVAX) Facility in April 2020 and the rapid development of COVID-19 vaccines were all positive and extraordinary developments [6]. The COVAX Facility, as of June 2021, has delivered approximately 83 million vaccine doses to 75 countries, representing approximately 4% of the global supply, and one-fifth of this was for HICs [7]. The COVAX Facility has been challenged to meet its supply commitments to LMICs due to insufficient access to doses of COVID-19 vaccines with the prerequisite WHO emergency use listing (EUL) or, under exceptional circumstances, product approval by a stringent regulatory authority (SRA) [8,9]. Because of the anticipated insufficient COVID-19 vaccine supply through the COVAX Facility, the majority of nonvaccine-producing LMIC countries made the decision, early in the COVID-19 pandemic, to secure and use vaccines produced in China or Russia prior to receipt of WHO EUL or SRA approval. Most of the vaccines used in LMICs as of June 20, 2021 (nearly 1.5 billion doses of the 2.6 billion doses administered) were neither WHO EUL or SRA approved at the time they were given [10]. This may raise possible concerns with respect to the effectiveness, safety, and acceptability of individual vaccines used by many countries [8,9]. 相似文献
55.
Werner Louwrens Vos Sebastian Vaughan Patrick Y. Lall John G. McCaffrey Monika Wysocka-Kapcinska John B. C. Findlay 《European biophysics journal : EBJ》2010,39(4):679-688
Peripherin/RDS is a member of the tetraspanin family of integral membrane proteins and plays a major role in the morphology
of photoreceptor outer segments. Peripherin/RDS has a long extracellular loop (hereafter referred to as the LEL domain), which
is vital for its function. Point mutations in the LEL domain often lead to impaired photoreceptor formation and function,
making peripherin/RDS an important drug target. Being a eukaryotic membrane protein, acquiring sufficient peripherin/RDS for
biophysical characterisation represents a significant challenge. Here, we describe the expression and characterisation of
peripherin/RDS in Drosophila melangolaster Schneider (S2) insect cells and in the methylotrophic yeast Pichia pastoris. The wild-type peripherin/RDS and the retinitis pigmentosa causing P216L mutant from S2 cells are characterised using circular dichroism (CD) spectroscopy. The structure of peripherin/RDS
and of a pathogenic mutant is assessed spectroscopically for the first time. These findings are evaluated in relation to a
three-dimensional model of the functionally important LEL domain obtained by protein threading. 相似文献
56.
Abner B. Lall Thomas W. Cronin Alexandre A. Carvalho John M. de Souza Marcelo P. Barros Cassius V. Stevani Etelvino J. H. Bechara Dora F. Ventura Vadim R. Viviani Avionne A. Hill 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2010,196(9):629-638
Among lampyrids, intraspecific sexual communication is facilitated by spectral correspondence between visual sensitivity and bioluminescence emission from the single lantern in the tail. Could a similar strategy be utilized by the elaterids (click beetles), which have one ventral abdominal and two dorsal prothoracic lanterns? Spectral sensitivity [S(λ)] and bioluminescence were investigated in four Brazilian click beetle species Fulgeochlizus bruchii, Pyrearinus termitilluminans, Pyrophorus punctatissimus and P. divergens, representing three genera. In addition, in situ microspectrophotometric absorption spectra were obtained for visual and screening pigments in P. punctatissimus and P. divergens species. In all species, the electroretinographic S(λ) functions showed broad peaks in the green with a shoulder in the near-ultraviolet, suggesting the presence of short- and long-wavelength receptors in the compound eyes. The long-wavelength receptor in Pyrophorus species is mediated by a P540 rhodopsin in conjunction with a species-specific screening pigment. A correspondence was found between green to yellow bioluminescence emissions and its broad S(λ) maximum in each of the four species. It is hypothesized that in elaterids, bioluminescence of the abdominal lantern is an optical signal for intraspecifc sexual communication, while the signals from the prothoracic lanterns serve to warn predators and may also provide illumination in flight. 相似文献
57.
Yusuke Sato Diego M Marzese Katsuya Ohta Sharon K Huang Myung Shin Sim Kelly Chong Dave SB Hoon 《Epigenetics》2013,8(10):1043-1052
Regenerating gene 1A (REG1A) plays an important role in tissue regeneration and in cell proliferation in epithelium origin tumors; however, its role in melanoma has not been explored in details. The objective of this study was to identify whether REG1A is expressed in cutaneous melanoma and if REG1A expression status can predict prognosis in cutaneous melanoma patients with metastasis. We also determined whether epigenetic regulation of the promoter region regulates REG1A expression. AJCC stage III cutaneous melanoma specimens with clinically well annotated stage III lymph node melanoma metastasis tissue microarray were assessed by IHC. MALDI-TOF-mass spectrometry and HM450K array were used to identify REG1A promoter region CpG site methylation. Chemotherapeutic agent response by melanoma cells as related to REG1A protein expression was assessed. Post-surgery melanoma patients followed by adjuvant chemotherapy with high REG1A expression had a significantly better prognosis (disease-specific survival) compared with patients with low REG1A expression (log rank test; p = 0.0013). The demethylating reagent 5-Aza-2′-deoxycytidine activated REG1A promoter region resulting in enhanced REG1A mRNA and protein expression in melanoma cell lines. Promoter region CpG methylation was shown to regulate REG1A expression in melanoma cells. Moreover, melanoma lines with high REG1A mRNA expression were more susceptible to Dacarbazine and Cisplatin, as compared with those with low REG1A mRNA expression. In conclusion, REG1A expression status may be useful as a biomarker in melanoma patients for sensitivity to these chemotherapeutic agents. The epigenetic regulation of the REG1A promoter region may offer a potential therapeutic approach to improve chemotherapy for metastatic melanoma patients. 相似文献
58.
Robert A Terkeltaub H Ralph Schumacher John D Carter Herbert SB Baraf Robert R Evans Jian Wang Shirletta King-Davis Steven P Weinstein 《Arthritis research & therapy》2013,15(1):R25
Introduction
In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares.Methods
Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0 = none; 4 = extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments.Results
Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean ± SD age of 50.3 ± 10.6 years. All treatment groups reported within-group pain reductions from baseline (P < 0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55 ± 0.92) relative to indomethacin alone (-1.40 ± 0.96), the difference was not statistically significant (P = 0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69 ± 0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness.Conclusions
Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare.Trial registration
ClinicalTrials.gov registration number . NCT00855920相似文献59.
60.
Brenda M. Auffinger Rishi R. Lall Nader S. Dahdaleh Albert P. Wong Sandi K. Lam Tyler Koski Richard G. Fessler Zachary A. Smith 《PloS one》2013,8(6)