Order Preserving Clustering over Multiple Time Course Experiments

Author(s):  
Stefan Bleuler ◽  
Eckart Zitzler
Keyword(s):  
2013 ◽  
Vol 304 (8) ◽  
pp. R675-R682 ◽  
Author(s):  
Jan Mulder ◽  
Tomas Hökfelt ◽  
Mark M. Knuepfer ◽  
Ulla C. Kopp

Efferent renal sympathetic nerves reinnervate the kidney after renal denervation in animals and humans. Therefore, the long-term reduction in arterial pressure following renal denervation in drug-resistant hypertensive patients has been attributed to lack of afferent renal sensory reinnervation. However, afferent sensory reinnervation of any organ, including the kidney, is an understudied question. Therefore, we analyzed the time course of sympathetic and sensory reinnervation at multiple time points (1, 4, and 5 days and 1, 2, 3, 4, 6, 9, and 12 wk) after renal denervation in normal Sprague-Dawley rats. Sympathetic and sensory innervation in the innervated and contralateral denervated kidney was determined as optical density (ImageJ) of the sympathetic and sensory nerves identified by immunohistochemistry using antibodies against markers for sympathetic nerves [neuropeptide Y (NPY) and tyrosine hydroxylase (TH)] and sensory nerves [substance P and calcitonin gene-related peptide (CGRP)]. In denervated kidneys, the optical density of NPY-immunoreactive (ir) fibers in the renal cortex and substance P-ir fibers in the pelvic wall was 6, 39, and 100% and 8, 47, and 100%, respectively, of that in the contralateral innervated kidney at 4 days, 4 wk, and 12 wk after denervation. Linear regression analysis of the optical density of the ratio of the denervated/innervated kidney versus time yielded similar intercept and slope values for NPY-ir, TH-ir, substance P-ir, and CGRP-ir fibers (all R2 > 0.76). In conclusion, in normotensive rats, reinnervation of the renal sensory nerves occurs over the same time course as reinnervation of the renal sympathetic nerves, both being complete at 9 to 12 wk following renal denervation.


BMC Genomics ◽  
2019 ◽  
Vol 20 (S12) ◽  
Author(s):  
Wazim Mohammed Ismail ◽  
Haixu Tang

Abstract Background Bacterial cells during many replication cycles accumulate spontaneous mutations, which result in the birth of novel clones. As a result of this clonal expansion, an evolving bacterial population has different clonal composition over time, as revealed in the long-term evolution experiments (LTEEs). Accurately inferring the haplotypes of novel clones as well as the clonal frequencies and the clonal evolutionary history in a bacterial population is useful for the characterization of the evolutionary pressure on multiple correlated mutations instead of that on individual mutations. Results In this paper, we study the computational problem of reconstructing the haplotypes of bacterial clones from the variant allele frequencies observed from an evolving bacterial population at multiple time points. We formalize the problem using a maximum likelihood function, which is defined under the assumption that mutations occur spontaneously, and thus the likelihood of a mutation occurring in a specific clone is proportional to the frequency of the clone in the population when the mutation occurs. We develop a series of heuristic algorithms to address the maximum likelihood inference, and show through simulation experiments that the algorithms are fast and achieve near optimal accuracy that is practically plausible under the maximum likelihood framework. We also validate our method using experimental data obtained from a recent study on long-term evolution of Escherichia coli. Conclusion We developed efficient algorithms to reconstruct the clonal evolution history from time course genomic sequencing data. Our algorithm can also incorporate clonal sequencing data to improve the reconstruction results when they are available. Based on the evaluation on both simulated and experimental sequencing data, our algorithms can achieve satisfactory results on the genome sequencing data from long-term evolution experiments. Availability The program (ClonalTREE) is available as open-source software on GitHub at https://github.com/COL-IU/ClonalTREE.


Reproduction ◽  
2001 ◽  
pp. 905-913 ◽  
Author(s):  
SJ Tsai ◽  
K Kot ◽  
OJ Ginther ◽  
MC Wiltbank

There is growing evidence to indicate that PGF(2alpha)-induced luteolysis involves altered gene expression in the corpus luteum. Concentrations of mRNA encoding nine different gene products were quantified at three time points from corpora lutea in situ. Serial luteal biopsies (2.1-5.5 mg per biopsy) were collected using an ultrasound-guided transvaginal method and mRNA concentrations were quantified with standard curve quantitative competitive RT-PCR. In the first experiment, three luteal biopsies were collected from three heifers and analysed in multiple assays to evaluate the repeatability of the methods. Concentrations of mRNA for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PGF(2alpha) receptor (FP receptor) and LH receptor were found to be highly repeatable between assays, between multiple biopsies and between animals (coefficients of variation 1.3-17.3%). In the second experiment, heifers on days 9-11 after ovulation were assigned randomly to receive saline only (n = 6), saline with biopsies taken at t = 0, 0.5 and 4.0 h after injection (n = 6), PGF(2alpha) only (n = 6) or PGF(2alpha) with biopsies taken at t = 0, 0.5 and 4.0 h after treatment (n = 7). Biopsy alone did not change corpus luteum diameter, serum progesterone concentrations or days to next ovulation within the saline- or PGF(2alpha)-treated groups. Concentrations of mRNA for steroidogenic acute regulatory protein, FP receptor, 3beta-hydroxysteroid dehydrogenase, cytosolic phospholipase A(2) and LH receptor were decreased at 4.0 h after PGF(2alpha) injection. In contrast, PGF(2alpha) increased mRNA concentrations for prostaglandin G/H synthase-2, monocyte chemoattractant protein-1 and c-fos but the time course differed for induction of these mRNAs. Concentrations of mRNA for GAPDH did not change after PGF(2alpha) treatment. In conclusion, the techniques allowed analysis of multiple, specific mRNAs in an individual corpus luteum at multiple time points without altering subsequent luteal function. Use of these techniques confirmed that luteolysis involves both up- and downregulation of specific mRNA by PGF(2alpha).


2017 ◽  
Author(s):  
Romain Libbrecht ◽  
Peter R. Oxley ◽  
Daniel J. C. Kronauer

AbstractDivision of labor between reproductive queens and non-reproductive workers that perform brood care is the hallmark of insect societies. However, the molecular basis of this fundamental dichotomy remains poorly understood, in part because the caste of an individual cannot typically be experimentally manipulated at the adult stage. Here we take advantage of the unique biology of the clonal raider ant, Ooceraea biroi, where reproduction and brood care behavior can be experimentally manipulated in adults. To study the molecular regulation of reproduction and brood care, we induced transitions between both states, and monitored brain gene expression at multiple time points. We found that introducing larvae that inhibit reproduction and induce brood care behavior caused much faster changes in adult gene expression than removing larvae. The delayed response to the removal of the larval signal prevents untimely activation of reproduction in O. biroi colonies. This resistance to change when removing a signal also prevents premature modifications in many other biological processes. Furthermore, we found that the general patterns of gene expression differ depending on whether ants transition from reproduction to brood care or vice versa, indicating that gene expression changes between phases are cyclic rather than pendular. Our analyses also identify genes with large and early expression changes in one or both transitions. These genes likely play upstream roles in regulating reproduction and behavior, and thus constitute strong candidates for future molecular studies of the evolution and regulation of reproductive division of labor in insect societies.


2019 ◽  
Vol 4 (4) ◽  
pp. 719-732 ◽  
Author(s):  
Steven Sandoval ◽  
Rene L. Utianski ◽  
Heike Lehnert-LeHouillier

Purpose The use and study of formant frequencies for the description of vowels is commonplace in acoustic phonetics and in attempts to understand results of speech perception studies. Numerous studies have shown that listeners are better able to distinguish vowels when the acoustic parameters are based on spectral information extracted at multiple time points during the duration of the vowel, rather than at a single point in time. The purpose of this study was to validate an automated method for extracting formant trajectories, using information across the time course of production, and subsequently characterize the formant trajectories of vowels using a large, diverse corpus of speech samples. Method Using software tools, we automatically extract the 1st 2 formant frequencies (F1/F2) at 10 equally spaced points over a vowel's duration. Then, we compute the average trajectory for each vowel token. The 1,600 vowel observations in the Hillenbrand database and the more than 50,000 vowel observations in the TIMIT database are analyzed. Results First, we validate the automated method by comparing against the manually obtained values in the Hillenbrand database. Analyses reveal a strong correlation between the automated and manual formant estimates. Then, we use the automated method on the 630 speakers in the TIMIT database to compute average formant trajectories. We noted that phonemes that have close F1 and F2 values at the temporal midpoint often exhibit formant trajectories progressing in different directions, hence highlighting the importance of formant trajectory progression. Conclusions The results of this study support the importance of formant trajectories over single-point measurements for the successful discrimination of vowels. Furthermore, this study provides a baseline for the formant trajectories for men and women across a broad range of dialects of Standard American English.


2021 ◽  
pp. 1-9
Author(s):  
Emily E. Bernstein ◽  
Katharine A. Phillips ◽  
Jennifer L. Greenberg ◽  
Joshua Curtiss ◽  
Susanne S. Hoeppner ◽  
...  

Abstract Background Body dysmorphic disorder (BDD) is a severe and undertreated condition. Although cognitive-behavioral therapy (CBT) is the first-line psychosocial treatment for this common disorder, how the intervention works is insufficiently understood. Specific pathways have been hypothesized, but only one small study has examined the precise nature of treatment effects of CBT, and no prior study has examined the effects of supportive psychotherapy (SPT). Methods This study re-examined a large trial (n = 120) comparing CBT to SPT for BDD. Network intervention analyses were used to explore symptom-level data across time. We computed mixed graphical models at multiple time points to examine relative differences in direct and indirect effects of the two interventions. Results In the resulting networks, CBT and SPT appeared to differentially target certain symptoms. The largest differences included CBT increasing efforts to disengage from and restructure unhelpful thoughts and resist BDD rituals, while SPT was directly related to improvement in BDD-related insight. Additionally, the time course of differences aligned with the intended targets of CBT; cognitive effects emerged first and behavioral effects second, paralleling cognitive restructuring in earlier sessions and the emphasis on exposure and ritual prevention in later sessions. Differences in favor of CBT were most consistent for behavioral targets. Conclusions CBT and SPT primarily affected different symptoms. To improve patient care, the field needs a better understanding of how and when BDD treatments and treatment components succeed. Considering patient experiences at the symptom level and over time can aid in refining or reorganizing treatments to better fit patient needs.


2019 ◽  
Author(s):  
Zhuo Chen ◽  
Yao Lu ◽  
Kerou Zhang ◽  
Yang Xiao ◽  
Jun Lu ◽  
...  

AbstractThe effector response of immune cells dictated by an array of secreted proteins is a highly dynamic process, requiring sequential measurement of all relevant proteins from single cells. Herein we show a microchip-based, 10-plexed, sequential secretion assay on the same single cells and at the scale of ~5000 single cells measured simultaneously over 4 time points. It was applied to investigating the time course of single human macrophage response to Toll-like receptor 4 (TLR4) ligand lipopolysaccharide and revealed four distinct activation modes for different proteins in single cells. In particular, we observed that secreted factors regulated by transcription factor NFkB (e.g., TNF and CCL2) predominantly show on-off mode over off-on mode. The dynamics of all proteins combined classified the cells into two major activation states, which were found to be dependent on the basal state of each cell. Single-cell RNA-Seq was performed on the same samples at the matched time points and further demonstrated at the transcriptional level the existence of two major activation states, which are enriched for translation vs inflammatory programs, respectively. These results showed a cell-intrinsic heterogeneous response in phenotypically homogeneous cell population. This work demonstrated the longitudinal tracking of protein secretion signature in thousands of single cells at multiple time points, providing dynamic information to better understand how individual immune cells react to pathogenic challenges over time and how they together constitute a population response.


2021 ◽  
Vol 30 (3) ◽  
pp. 238-247
Author(s):  
Rhy Norton ◽  
Phillip J Finley

Objective: Silver has become a global treatment option with the US Food and Drug Administration providing marketing clearance for many silver-impregnated wound dressings and topical agents. However, the increased use of silver-based products across medical disciplines has raised questions concerning the development of acute silver resistance. In this study, the efficacy of previously identified silver-resistant clinical bacteria (Klebsiella pneumoniae and Enterobacter cloacae) against a variety of commercially available silver-based wound dressings was further investigated. Method: To further explore the clinical significance of these isolates, multiple time-course and repeat-challenge assays were conducted with nine dressings using a panel of silver-resistant and silver-sensitive microorganisms. Silver-impregnated dressings were ranked by silver species, quantity of silver and overall efficacy. Results: Both silver-resistant strains were largely unaffected and exhibited phenotypic resistance even when exposed to the high silver concentrations found in commercially available wound dressings. In stark contrast, the majority of the dressings were able to maintain a high degree of efficacy over the course of 72 hours and during repeated bacterial challenges against silver-sensitive microorganisms. Conclusion: Our findings provide additional evidence that clinically significant silver-resistance has emerged in the clinical setting. Such resistant microbes are capable of sustained silver resistance against a wide variety of silver adjuvants. These findings suggest that the further development and dissemination of these resistance mechanisms could significantly impact current practices in wound healing.


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