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

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

Translational Control of FOG-2 Expression in Cardiomyocytes by MicroRNA-130a

MicroRNAs are increasingly being recognized as regulators of embryonic development; however, relatively few microRNAs have been identified to regulate cardiac development. FOG-2 (also known as zfpm2) is a transcriptional co-factor that we have previously shown is critical for cardiac development. In this report, we demonstrate that FOG-2 expression is controlled at the translational level by microRNA-130a. We identified a conserved region in the FOG-2 3′ untranslated region predicted to be a target for miR-130a. To test the functional significance of this site, we generated an expression construct containing the luciferase coding region fused with the 3′ untranslated region of FOG-2 or a mutant version lacking this microRNA binding site. When these constructs were transfected into NIH 3T3 fibroblasts (which are known to express miR-130a), we observed a 3.3-fold increase in translational efficiency when the microRNA target site was disrupted. Moreover, knockdown of miR-130a in fibroblasts resulted in a 3.6-fold increase in translational efficiency. We also demonstrate that cardiomyocytes express miR-130a and can attenuate translation of mRNAs with a FOG-2 3′ untranslated region. Finally, we generated transgenic mice with cardiomyocyte over-expression of miR-130a. In the hearts of these mice, FOG-2 protein levels were reduced by as much as 80%. Histological analysis of transgenic embryos revealed ventricular wall hypoplasia and ventricular septal defects, similar to that seen in FOG-2 deficient hearts. These results demonstrate the importance of miR-130a for the regulation of FOG-2 protein expression and suggest that miR-130a may also play a role in the regulation of cardiac development

Secure Biomedical Document Protection Framework to Ensure Privacy Through Blockchain

In the recent health care era, biomedical documents play a crucial role, and they contain much evidence-based documentation associated with many stakeholders data. Protecting those confidential research documents is more difficult and effective, and a significant process in the medical-based research domain. Those bio-documentation related to health care and other relevant community-valued data are suggested by medical professionals and processed. Many traditional security mechanisms such as akteonline and Health Insurance Portability and Accountability Act (HIPAA) are used to protect the biomedical documents as they consider the problem of non-repudiation and data integrity related to the retrieval and storage of documents. Thus, there is a need for a comprehensive framework that improves protection in terms of cost and response time related to biomedical documents. In this research work, blockchain-based biomedical document protection framework (BBDPF) is proposed, which includes blockchain-based biomedical data protection (BBDP) and blockchain-based biomedical data retrieval (BBDR) algorithms. BBDP and BBDR algorithms provide consistency on the data to prevent data modification and interception of confidential data with proper data validation. Both the algorithms have strong cryptographic mechanisms to withstand post-quantum security risks, ensuring the integrity of biomedical document retrieval and non-deny of data retrieval transactions. In the performance analysis, Ethereum blockchain infrastructure is deployed BBDPF and smart contracts using Solidity language. In the performance analysis, request time and searching time are determined based on the number of request to ensure data integrity, non-repudiation, and smart contracts for the proposed hybrid model as it gets increased gradually. A modified prototype is built with a web-based interface to prove the concept and evaluate the proposed framework. The experimental results revealed that the proposed framework renders data integrity, non-repudiation, and support for smart contracts with Query Notary Service, MedRec, MedShare, and Medlock