Modeling stochasticity and robustness in gene regulatory networks

Motivation: Understanding gene regulation in biological processes and modeling the robustness of underlying regulatory networks is an important problem that is currently being addressed by computational systems biologists. Lately, there has been a renewed interest in Boolean modeling techniques for gene regulatory networks (GRNs). However, due to their deterministic nature, it is often difficult to identify whether these modeling approaches are robust to the addition of stochastic noise that is widespread in gene regulatory processes. Stochasticity in Boolean models of GRNs has been addressed relatively sparingly in the past, mainly by flipping the expression of genes between different expression levels with a predefined probability. This stochasticity in nodes (SIN) model leads to over representation of noise in GRNs and hence non-correspondence with biological observations. Results: In this article, we introduce the stochasticity in functions (SIF) model for simulating stochasticity in Boolean models of GRNs. By providing biological motivation behind the use of the SIF model and applying it to the T-helper and T-cell activation networks, we show that the SIF model provides more biologically robust results than the existing SIN model of stochasticity in GRNs. Availability: Algorithms are made available under our Boolean modeling toolbox, GenYsis. The software binaries can be downloaded from http://si2.epfl.ch/∼garg/genysis.html. Contact: [email protected]

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Implications of Reduced Health Care Services for Cancer Patients in India and Similar Resource-Limited Health Care Systems During COVID-19 Pandemic

Ophthalmic researc

Osteochondral Lesions of the Distal Tibial Plafond: A Systematic Review of Lesion Locations and Treatment Outcomes.

BackgroundOsteochondral lesions of the tibial plafond (OLTPs) remain less common than osteochondral lesions of the talus (OLTs), but recognition of the condition has increased.PurposeTo systematically evaluate the literature on lesion locations and treatment outcomes of OLTPs, whether in isolation or in combination with OLTs.Study designSystematic review; Level of evidence, 4.MethodsA search was performed using the PubMed, Embase, and CINAHL databases for studies on lesion locations or with imaging or treatment outcomes of OLTPs. Case reports and reports based on expert opinion were excluded. Lesion locations as well as outcome measure results were aggregated. The Methodological Index for Non-randomized Studies score was used to assess methodological quality when applicable.ResultsIncluded in this review were 10 articles, all published in 2000 or later. Most studies were evidence level 4, and the mean Methodological Index for Non-randomized Studies score was 8.6 (range, 8-10). Overall, 174 confirmed OLTP cases were identified, and the mean patient age was 38.8 years. Of the 157 lesions with confirmed locations, the most common was central-medial (32/157; 20.4%). Of 6 studies on treatment outcomes, all but 1 evaluated bone marrow stimulation techniques. Microfracture of small lesions (<150 mm2) was the most common treatment utilized. Imaging and functional outcomes appeared favorable after treatment. The data did not support differences in outcomes between isolated OLTPs and OLTPs with coexisting OLTs.ConclusionOsteochondral lesions of the distal tibia most commonly occurred at the central-medial tibial plafond. Microfracture of small lesions was the most common treatment utilized, and clinical and magnetic resonance imaging results were favorable, although data were heterogeneous. Areas for future research include the following: the effect of patient factors and additional pathologies on outcomes; larger or deeper lesion treatment; more direct comparisons of outcomes between kissing or coexisting lesions and isolated lesions; and head-to-head comparison of treatments, such as microfracture, bone marrow-derived cell transplantation, and osteochondral autografts/allografts

Application of C-Terminal Clostridium Perfringens Enterotoxin in Treatment of Brain Metastasis from Breast Cancer

Claudin-4 is part of the Claudin family of transmembrane tight junction (TJ) proteins found in almost all tissues and, together with adherens junctions and desmosomes, forms epithelial and endothelial junctional complexes. Although the distribution of Claudin-4 occurs in many cell types, the level of expression is cell-specific. Claudin proteins regulate cell proliferation and differentiation by binding cell-signaling ligands, and its expression is upregulated in several cancers. As a result, alterations in Claudin expression patterns or distribution are vital in the pathology of cancer. Profiling the genetic expression of Claudin-4 showed that Claudin-4 is also a receptor for the clostridium perfringens enterotoxin (CPE) and that Claudin-4 has a high sequence similarity with CPE’s high-affinity receptor. CPE is cytolytic due to its ability to form pores in cellular membranes, and CPE treatment in breast cancer cells have shown promising results due to the high expression of Claudin-4. The C-terminal fragment of CPE (c-CPE) provides a less toxic alternative for drug delivery into breast cancer cells, particularly metastatic tumors in the brain, especially as Claudin-4 expression in the central nervous system (CNS) is low. Therefore, c-CPE provides a unique avenue for the treatment of breast–brain metastatic tumors

Peripapillary sparing in <i>RDH12</i>-associated Leber congenital amaurosis

<p><i>Background</i>: Peripapillary sparing is a characteristic that is traditionally described as pathognomonic for Stargardt disease.</p> <p><i>Materials and methods</i>: We present a multimodal assessment of four Leber congenital amaurosis (LCA) cases with congenital macular atrophy and severely attenuated electroretinogram findings caused by bilallelic mutations in <i>RDH12</i>.</p> <p><i>Results</i>: Fundus autofluorescence imaging revealed a general loss of retinal pigment epithelium across the macula except for the peripapillary region in both eyes of all patients. Spectral domain-optical coherence tomography confirmed relative preservation in this area along with retinal thinning and excavation throughout the rest of the macula. LCA was diagnosed based on clinical exam and retinal imaging, and subsequently confirmed with genetic testing.</p> <p><i>Conclusions</i>: Peripapillary sparing is a novel phenotypic feature of <i>RDH12</i>-associated LCA.</p