A Constraint Programming Approach for Non-Preemptive Evacuation Scheduling

Large-scale controlled evacuations require emergency services to select evacuation routes, decide departure times, and mobilize resources to issue orders, all under strict time constraints. Existing algorithms almost always allow for preemptive evacuation schedules, which are less desirable in practice. This paper proposes, for the first time, a constraint-based scheduling model that optimizes the evacuation flow rate (number of vehicles sent at regular time intervals) and evacuation phasing of widely populated areas, while ensuring a nonpreemptive evacuation for each residential zone. Two optimization objectives are considered: (1) to maximize the number of evacuees reaching safety and (2) to minimize the overall duration of the evacuation. Preliminary results on a set of real-world instances show that the approach can produce, within a few seconds, a non-preemptive evacuation schedule which is either optimal or at most 6% away of the optimal preemptive solution.Comment: Submitted to the 21st International Conference on Principles and Practice of Constraint Programming (CP 2015). 15 pages + 1 reference pag

Adult Cardiac Surgery During Covid-19 Pandemic

Coronavirus Disease 2019 (COVID-19), which is caused by the SARS Coronavirus 2 (SARS-CoV-2), has affected over 200 countries worldwide. First case of COVID-19 wasfound in Wuhan, China, precisely around December 2019. COVID-19, especially in thosewith underlying health conditions or comorbidities, has an increasingly rapid and severeprogression, often leading to death. This virus is a single-strand RNA coronavirus, binding the angiotensin-converting enzyme 2 (ACE2) receptor which enters human cells. Coronavirusdisease has been reported to affect cardiac and vascular organs. cardiomyocyte death andinflammation are results of a direct mechanism that involves viral infiltration into myocardialtissue. Some cardiovascular manifestations of myocardial injuries associated with COVID-19are arrhythmias, myocardial infarction, heart failure, and elevated biomarkers (cardiactroponin I and brain-type natriuretic peptide). Some of this manifestation requires immediate intervention or surgery. Criteria are needed for hospitals or institutions that mostly maintain cardiac surgery services and surgery-urgent patients depending on severity of the disease and hospital resources. These criteria also limit the risk of exposure to patients and healthcare workers and allocate resources appropriately to those in greatest need. This paper aims to share our discussion and give an overview of patients undergoing cardiac surgery, providing clinicians with recommendations to triage and plan these procedures during the COVID-19 outbreak effectively

Thoracic Surgery Preparation, Patient Election, and Its Management During Covid-19 Pandemic: Surabaya Experiences

A novel coronavirus pneumonia outbreak began in Wuhan, Hubei Province, in December 2019. It has spread rapidly from China to worldwide. The COVID-19 pandemic of 2020 posed a historic challenge to health care systems around the world, healthcare systems needed to consider providing clinical services to other patients in need. The specialty of general thoracic surgery includes the management of serious diseases such as chest wall congenital anomaly, lung cancers, esophageal cancers, mediastinal tumor, chest wall infection, and trauma. Thoracic surgery is one of high risk procedure in this pandemic, however, a high level of evidence supports the surgical management of potential patients with thoracic disease and anomaly is still lacking. Critical determinants of robust thoracic surgery service provision are pre-existing plans for epidemic response. "Flatten the curve" as an aggressive action is needed. Prioritizations of thoracic surgery cases are needed to differ between elective and emergency cases to limit any contamination. Before surgery, important pre-operative assessments were conducted aims to identify patients' high risk and adjust the procedure. example of a recommendation, if urgent / emergency surgery with symptoms clear clinical pneumonia or rapid test (+). The lessons learned can apply to the other areas during this pandemic, and the world, in preparation for the next one

iRFP is a real time marker for transformation based assays in high content screening

Anchorage independent growth is one of the hallmarks of oncogenic transformation. Here we show that infrared fluorescent protein (iRFP) based assays allow accurate and unbiased determination of colony formation and anchorage independent growth over time. This protocol is particularly compatible with high throughput systems, in contrast to traditional methods which are often labor-intensive, subjective to bias and do not allow further analysis using the same cells. Transformation in a single layer soft agar assay could be documented as early as 2 to 3 days in a 96 well format, which can be easily combined with standard transfection, infection and compound screening setups to allow for high throughput screening to identify therapeutic targets

Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method

This article has been made available through the Brunel Open Access Publishing Fund.Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past. © 2014 Scholze et al

Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1

Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. Methodology/Principal Findings: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V_L12.3, turnover of soluble mHDx-1 in living cells is blocked. Conclusions/Significance: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications

TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

Expression of Human Beta-Defensins in Children with Chronic Inflammatory Bowel Disease

Background: Human beta-defensins (hBDs) are antimicrobial peptides known to play a major role in intestinal innate host defence. Altered mucosal expression of hBDs has been suggested to be implicated in chronic inflammatory bowel disease pathogenesis. However, little is known about expression of these peptides in children. Methods: Intestinal biopsies were obtained from the duodenum (n = 88), terminal ileum (n = 90) and ascending colon (n = 105) of children with Crohn’s disease (n = 26), ulcerative colitis (n = 11) and healthy controls (n = 16). Quantitative realtime (RT) PCR was performed and absolute mRNA copy numbers analyzed for hBD1-3 as well as inflammatory cytokines IL-8 and TNF-alpha. Results: Significant induction of hBD2 and hBD3 was observed in the inflamed terminal ileum and ascending colon of IBD children. In the ascending colon induction of hBD2 was found to be significantly lower in children with Crohn’s disease compared to ulcerative colitis. A strong correlation was found between inducible defensins hBD2 and 3 and the inflammatory cytokines IL-8 and TNF-alpha, both in the terminal ileum and ascending colon. Conclusion: Our study demonstrates distinct changes in hBD expression throughout the intestinal tract of children with IBD