A hybrid multiscale Monte Carlo algorithm (HyMSMC) to cope with disparity in time scales and species populations in intracellular networks

<p>Abstract</p> <p>Background</p> <p>The fundamental role that intrinsic stochasticity plays in cellular functions has been shown via numerous computational and experimental studies. In the face of such evidence, it is important that intracellular networks are simulated with stochastic algorithms that can capture molecular fluctuations. However, separation of time scales and disparity in species population, two common features of intracellular networks, make stochastic simulation of such networks computationally prohibitive. While recent work has addressed each of these challenges separately, a generic algorithm that can <it>simultaneously </it>tackle disparity in time scales <it>and </it>population scales in stochastic systems is currently lacking. In this paper, we propose the hybrid, multiscale Monte Carlo (HyMSMC) method that fills in this void.</p> <p>Results</p> <p>The proposed HyMSMC method blends stochastic singular perturbation concepts, to deal with potential stiffness, with a hybrid of exact and coarse-grained stochastic algorithms, to cope with separation in population sizes. In addition, we introduce the computational singular perturbation (CSP) method as a means of systematically partitioning fast and slow networks and computing relaxation times for convergence. We also propose a new criteria of convergence of fast networks to stochastic low-dimensional manifolds, which further accelerates the algorithm.</p> <p>Conclusion</p> <p>We use several prototype and biological examples, including a gene expression model displaying bistability, to demonstrate the efficiency, accuracy and applicability of the HyMSMC method. Bistable models serve as stringent tests for the success of multiscale MC methods and illustrate limitations of some literature methods.</p

Caesarean scar defect: a histopathological comparative study

Background: We have evaluated the validity of this syndrome in Indian patients and analysed the gynaecological indications for hysterectomy in women with history of caesarean sections. We have studied pathological changes in the scar area and compared the findings with matched cases without previous caesarean scar.Methods: A prospective observational case control study was done at tertiary care hospital (Seth GS Medical College and King Edward Memorial Hospital) over two years (December 2018 to December 2020) with universal sampling and enrolled all consenting eligible patients. After hysterectomy histopathological study of the specimens was done. Total cases: 16 hysterectomy samples with history of previous caesarean section. Total controls: 40 hysterectomy samples with history of no previous caesarean section. The difference between the two proportions was analysed using Chi square or Fisher exact test. All analysis was 2 tailed and the significance level was set at 0.05.Results: Women with history of previous caesarean scar had gynaecological symptoms related to the caesarean scar defect such as abnormal uterine bleeding, dysmenorrhea and chronic pelvic pain, post-menopausal bleeding and the most frequent clinical symptom related to the scar defect was abnormal uterine bleeding. The clinical symptoms were found to be associated with histopathological changes at scar site.Conclusions: This study compared caesarean cases and no caesarean controls and sheds light on the role of histopathology in detection of caesarean scar site changes. It helped in comparison of various factors affected due to the presence of caesarean scar and its long-term complications, leading to hysterectomy

The Bacillus anthracis protein MprF is required for synthesis of lysylphosphatidylglycerols and for resistance to cationic antimicrobial peptides

During inhalational anthrax, Bacillus anthracis survives and replicates in alveolar macrophages, followed by rapid invasion into the host's bloodstream, where it multiplies to cause heavy bacteremia. B. anthracis must therefore defend itself from host immune functions encountered during both the intracellular and the extracellular stages of anthrax infection. In both of these niches, cationic antimicrobial peptides are an essential component of the host's innate immune response that targets B. anthracis. However, the genetic determinants of B. anthracis contributing to resistance to these peptides are largely unknown. Here we generated Tn917 transposon mutants in the ΔANR strain (pXO1(−) pXO2(−)) of B. anthracis and screened them for altered protamine susceptibility. A protamine-sensitive mutant identified carried the transposon inserted in the BA1486 gene encoding a putative membrane protein homologous to MprF known in several gram-positive pathogens. A mutant strain with the BAS1375 gene (the orthologue of BA1486) deleted in the Sterne 34F2 strain (pXO1(+) pXO2(−)) of B. anthracis exhibited hypersusceptibility not only to protamine but also to α-helical cathelicidin LL-37 and β-sheet defensin human neutrophil peptide 1 compared to the wild-type Sterne strain. Analysis of membrane lipids using isotopic labeling demonstrated that the BAS1375 deletion mutant is unable to synthesize lysinylated phosphatidylglycerols, and this defect is rescued by genetic complementation. Further, we determined the structures of these lysylphosphatidylglycerols by using various mass spectrometric analyses. These results demonstrate that in B. anthracis a functional MprF is required for the biosynthesis of lysylphosphatidylglycerols, which is critical for resistance to cationic antimicrobial peptides

Evaluation of the tear strength, compressive resistance, and surface hardness of three commercially available bite registration materials: an in vitro study

Background: For making a successful prosthesis, it is essential to achieve harmony between the maxillomandibular relationship. The precision and occlusal quality of the prosthesis partly depends on interocclusal bite registration material. Interocclusal bite registration material plays an important role in recording and transferring of existing patient’s occlusal records. The procedure used to record and transfer interocclusal relation should be performed with the utmost care and understanding to prevent clinical error. Aim: This study aimed to evaluate the tear strength, compressive resistance and surface hardness of three commercially available bite registration materials. Material and Methods: Three types of commercially available bite registration materials, Bis-acrylate (BA), Polyvinylsiloxane (PVS), and Polyether (PE), were made in Dumbbell and cylindrical shaped samples to evaluate the tear strength and compressive resistance, respectively and were analysed using the universal testing machine. The surface hardness was assessed using a microhardness tester. The obtained data were subjected to statistical analysis using SPSS 16.0 version (Chicago, Inc., USA). ANOVA/Kruskal-Wallis test was used to compare study parameters among the groups. Tukey’s posthoc test was used for inter-group comparisons. Results: Bis-Acrylate exhibited the greatest tear strength, followed by Polyvinylsiloxane and Polyether showed the least tear strength. More compressive resistance was observed in Polyether followed by Bis-Acrylate and lowest in Polyvinylsiloxane. A similar pattern was seen in the surface hardness among the three materials. Conclusion: Bis-acrylate showed greater tear strength and surface hardness, and it can be considered a better bite registration material

The t Complex Distorter 2 Candidate Gene, Dnahc8, Encodes at Least Two Testis-Specific Axonemal Dynein Heavy Chains That Differ Extensively at Their Amino and Carboxyl Termini

AbstractHomozygosity for the t haplotype allele of the testis-specifically expressed axonemal dynein heavy chain (axDHC) gene, Dnahc8, has been linked to male sterility resulting from aberrant sperm motility. However, the near absence of Dnahc8 expression has been associated with male sterility resulting from an early breakdown in sperm flagellar development. Although axDHCs are integral participants in flagellar motility, a role in flagellar morphogenesis has never been attributed to a member of this highly conserved gene family. To gain a better understanding of this presumed novel role for Dnahc8, we have studied the organization and expression of full-length Dnahc8+ and Dnahc8t transcripts. Our results demonstrate the existence of at least two alternatively spliced, testis-specific Dnahc8 mRNAs transcribed from both the + and t alleles. A highly expressed isoform encodes a protein with significant homology nearly throughout to the γ heavy chain of the Chlamydomonas axonemal outer arm dynein, while a more poorly expressed isoform codes for a protein whose sequence diverges significantly from that of other axDHCs at both its N and C termini. While in situ hybridization studies demonstrate that both mRNA species accumulate exclusively in mid to late spermatocytes, each isoform shows spatial independence. Additional experiments demonstrate the existence of a testis-expressed mRNA with no significant open reading frame, a portion of which is antisense to the 5′-untranslated region of the highly divergent Dnahc8 isoform. The cumulative data imply that Dnahc8 may have acquired functional plasticity in the testis through the tightly controlled expression of both typical and unusual isoforms

An Ecchordosis Physaliphora, a Rare Entity, Involving the Central Nervous System: A Systematic Review of the Literature

Ecchordosis physaliphora (EP) is a benign notochordal remnant, which is often an incidental finding; however, it can rarely present with neurological symptoms. We performed a systematic review of the literature for cases of symptomatic EP published in PubMed, Web of Science and Embase from January 1982 to May 2023. This is the largest review to date and revealed 60 cases including ours. Headache (55%) and CSF rhinorrhea (32%) were the most frequent clinical manifestations. The majority of symptomatic EP lesions were located in the prepontine region (77%) and required surgical resection (75%). EP should be considered in patients with neurologic symptoms in the setting of prepontine or posterior sphenoid sinus lesions. While symptomatic patients often require surgical intervention, rare cases may respond to oral corticosteroids

An Ecchordosis Physaliphora, a Rare Entity, Involving the Central Nervous System: A Systematic Review of the Literature

Ecchordosis physaliphora (EP) is a benign notochordal remnant, which is often an incidental finding; however, it can rarely present with neurological symptoms. We performed a systematic review of the literature for cases of symptomatic EP published in PubMed, Web of Science and Embase from January 1982 to May 2023. This is the largest review to date and revealed 60 cases including ours. Headache (55%) and CSF rhinorrhea (32%) were the most frequent clinical manifestations. The majority of symptomatic EP lesions were located in the prepontine region (77%) and required surgical resection (75%). EP should be considered in patients with neurologic symptoms in the setting of prepontine or posterior sphenoid sinus lesions. While symptomatic patients often require surgical intervention, rare cases may respond to oral corticosteroids