Deterministic and stochastic descriptions of gene expression dynamics

A key goal of systems biology is the predictive mathematical description of gene regulatory circuits. Different approaches are used such as deterministic and stochastic models, models that describe cell growth and division explicitly or implicitly etc. Here we consider simple systems of unregulated (constitutive) gene expression and compare different mathematical descriptions systematically to obtain insight into the errors that are introduced by various common approximations such as describing cell growth and division by an effective protein degradation term. In particular, we show that the population average of protein content of a cell exhibits a subtle dependence on the dynamics of growth and division, the specific model for volume growth and the age structure of the population. Nevertheless, the error made by models with implicit cell growth and division is quite small. Furthermore, we compare various models that are partially stochastic to investigate the impact of different sources of (intrinsic) noise. This comparison indicates that different sources of noise (protein synthesis, partitioning in cell division) contribute comparable amounts of noise if protein synthesis is not or only weakly bursty. If protein synthesis is very bursty, the burstiness is the dominant noise source, independent of other details of the model. Finally, we discuss two sources of extrinsic noise: cell-to-cell variations in protein content due to cells being at different stages in the division cycles, which we show to be small (for the protein concentration and, surprisingly, also for the protein copy number per cell) and fluctuations in the growth rate, which can have a significant impact.Comment: 23 pages, 5 figures; Journal of Statistical physics (2012

Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis

IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS.DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members.RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p. Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.Genetics of disease, diagnosis and treatmen

Diagnosis and management of urothelial carcinoma in situ of the lower urinary tract: a systematic review.

CONTEXT: Urothelial carcinoma in situ (CIS) has a high propensity for progression. It is usually reported within the heterogeneous context of non-muscle-invasive bladder cancer (NMIBC) but warrants special consideration. OBJECTIVE: To review the contemporary literature on the diagnosis and management of CIS. EVIDENCE ACQUISITION: A systematic search using broad terms to capture the diagnosis and treatment of CIS was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria. Full-text original articles, reviews, and editorials from 1966 to 2014 in English were included. References from selected articles, relevant guidelines, and conference abstracts were searched. Abstracts were excluded. EVIDENCE SYNTHESIS: A total of 1887 articles were identified, of which 120 were used in this review. Most reports were retrospective and heterogeneous in caseload. There is a lack of standardised classification of CIS. Many studies consider CIS in the context of NMIBC without a clear separation of the subset with CIS. Recent prospective phase 2 and 3 studies have improved the evidence base. CONCLUSIONS: We are beginning to understand that CIS has a spectrum of biologic potential. Bacillus Calmette-Guérin immunotherapy appears superior to other intravesical agents and may alter the natural history of CIS. New imaging modalities, agents, and treatment strategies have emerged in recent years with the aim of better identification of CIS, more bladder-preserving treatments, and prevention of surgical overtreatment. PATIENT SUMMARY: Improvements in imaging techniques combined with new bladder-preserving treatments will continue to have an impact on the outcomes of bladder carcinoma in situ

Fluorogenic dansyl-ligated gold nanoparticles for the detection of sulfur mustard by displacement assay

The dansyl fluorophore ligated to gold nanoparticles via imidazole and amine groups affords conjugates capable of detecting micromolar concentrations of the chemical warfare agent sulfur mustard by a fluorescence switching 'ON' displacement assay. This journal is © The Royal Society of Chemistry

Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD-SIU joint consultation on bladder cancer

Item does not contain fulltex

Intermediate-risk Non-muscle-invasive Bladder Cancer: Updated Consensus Definition and Management Recommendations from the International Bladder Cancer Group

CONTEXT: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease. OBJECTIVE: To update the International Bladder Cancer Group (IBCG) guidance and provide practical recommendations on IR NMIBC management. EVIDENCE ACQUISITION: A collaborative review of published randomized clinical trials, meta-analyses, systematic reviews, and clinical practice guidance on IR NMIBC published before January 2022 was undertaken using PubMed/Medline. EVIDENCE SYNTHESIS: Variation exists between guidelines in defining IR NMIBC. The IBCG recommends defining IR NMIBC as any TaLG tumor that is either recurrent or multifocal or has size ≥3 cm, OR any T1LG tumor. If the 3 tier grading system is used, than any TaG2 tumor would also be considered IR diease regardless of whether new diagnosis or recurrent. Accurate grading and staging of tumor, particularly in ruling out HG/G3 disease and/or carcinoma in situ, are crucial. The IBCG recommends that management of IR NMIBC should be further based on the following risk factors: multifocal tumor (more than one), early recurrence (1/yr), tumor size (≥3 cm), and failure of prior intravesical treatment. Patients with no risk factors are best managed by one dose of postoperative intravesical chemotherapy. Patients with one to two risk factors should be offered additional adjuvant induction intravesical chemotherapy (or bacillus Calmette-Guérin (BCG) if prior chemotherapy has been used). Patients with three or more risk factors should be offered induction plus 1-yr maintenance BCG. Where BCG is not available or recurrent disease following BCG is present, alternative intravesical treatments such as chemotherapy (single agent, combination, or chemohyperthermia) or a clinical trial are recommended. CONCLUSIONS: Standardizing the definition of IR NMIBC is critical for appropriate management of patients and for allowing a comparison of outcomes across clinical trials. The IBCG recommends defining IR NMIBC as any TaLG tumor that is either recurrent or multifocal or  ≥3 cm, OR any T1LG tumor. If the 3 tier grading system is used, than any TaG2 tumor would also be considered IR disease regardless of whether new diagnosis or recurrent.  Adjunctive management should then be based on established risk factors. PATIENT SUMMARY: Standardizing the definition of intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC), which is a heterogeneous disease, is critical for appropriate management of patients. The International Bladder Cancer Group recommends classification of IR NMIBC tumors and personalized management based on the following risk factors: multifocal tumor (more than one), early recurrence (1/yr), tumor size (≥3 cm), and previous intravesical treatment