Traveling waves in a coarse-grained model of volume-filling cell invasion: Simulations and comparisons

Many reaction-diffusion models produce traveling wave solutions that can be interpreted as waves of invasion in biological scenarios such as wound healing or tumor growth. These partial differential equation models have since been adapted to describe the interactions between cells and extracellular matrix (ECM), using a variety of different underlying assumptions. In this work, we derive a system of reaction-diffusion equations, with cross-species density-dependent diffusion, by coarse-graining an agent-based, volume-filling model of cell invasion into ECM. We study the resulting traveling wave solutions both numerically and analytically across various parameter regimes. Subsequently, we perform a systematic comparison between the behaviors observed in this model and those predicted by simpler models in the literature that do not take into account volume-filling effects in the same way. Our study justifies the use of some of these simpler, more analytically tractable models in reproducing the qualitative properties of the solutions in some parameter regimes, but it also reveals some interesting properties arising from the introduction of cell and ECM volume-filling effects, where standard model simplifications might not be appropriate

Neural crest migration is driven by a few trailblazer cells with a unique molecular signature narrowly confined to the invasive front

Neural crest (NC) cell migration is crucial to the formation of peripheral tissues during vertebrate development. However, how NC cells respond to different microenvironments to maintain persistence of direction and cohesion in multicellular streams remains unclear. To address this, we profiled eight subregions of a typical cranial NC cell migratory stream. Hierarchical clustering showed significant differences in the expression profiles of the lead three subregions compared with newly emerged cells. Multiplexed imaging of mRNA expression using fluorescent hybridization chain reaction (HCR) quantitatively confirmed the expression profiles of lead cells. Computational modeling predicted that a small fraction of lead cells that detect directional information is optimal for successful stream migration. Single-cell profiling then revealed a unique molecular signature that is consistent and stable over time in a subset of lead cells within the most advanced portion of the migratory front, which we term trailblazers. Model simulations that forced a lead cell behavior in the trailing subpopulation predicted cell bunching near the migratory domain entrance. Misexpression of the trailblazer molecular signature by perturbation of two upstream transcription factors agreed with the in silico prediction and showed alterations to NC cell migration distance and stream shape. These data are the first to characterize the molecular diversity within an NC cell migratory stream and offer insights into how molecular patterns are transduced into cell behaviors

COPD patients hospitalized with exacerbations have greater cognitive impairment than patients hospitalized with decompensated heart failure

Purpose: People with COPD have cognitive dysfunction, which is greater in those hospitalized for exacerbations than in stable outpatients. We tested the hypothesis that cognitive dysfunction at exacerbation is a disease-specific feature of COPD, rather than a nonspecific feature of hospitalization for acute illness, by comparing cognition between patients hospitalized for acute COPD exacerbations and those with worsening heart failure (HF). Patients and methods: A total of 40 hospital inpatients were recruited, 20 patients with COPD exacerbations and 20 patients with congestive or left-sided HF. Exclusion criteria included previous stroke, known neurological disease, and marked alcohol excess. Participants completed the Montreal cognitive assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) and underwent spirometry and review of clinical records. Results: Age (mean±SD, COPD 73±10; HF 76±11 years), acute illness severity (Acute Physiology and Chronic Health Evaluation [APACHE]-II, COPD 15.4±3.5; HF 15.9±3.0), comorbidities (Charlson index, COPD 1.3±1.9; HF 1.6±1.5), and educational background were similar between COPD and HF groups. MoCA total was significantly lower in COPD than in HF (COPD 20.6±5.6; HF 24.8±3.5, P=0.007); however, significance was lost after correction for age, sex, and pack year smoking history. When compared with HF patients, the COPD cohort performed worse on the following domains of the MoCA: visuospatial function (median [IQR], COPD 0 [1]; HF 2 [1], P=0.003), executive function (COPD 2 [1]; HF 3 [1], P=0.035), and attention (COPD 4 [3]; HF 6 [2], P=0.020). Age (P=0.012) and random glucose concentration (P=0.041) were associated with cognitive function in whole group analysis, with pack year smoking history reaching borderline significance (P=0.050). Conclusion: Total MoCA score for COPD and HF indicated that both groups had mild cognitive impairment, although this was greater in people with COPD. Mechanisms underlying the observed cognitive dysfunction in COPD remain unclear but appear related to blood glucose concentrations and greater lifetime smoking load

Contributions of cardiovascular risk and smoking to chronic obstructive pulmonary disease (COPD)-related changes in brain structure and function

Background: Brain damage and cardiovascular disease are extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD). Cardiovascular risk factors and smoking are contributors to neurodegeneration. This study investigates whether there is a specific, COPD-related deterioration in brain structure and function independent of cardiovascular risk factors and smoking. Materials and methods: Neuroimaging and clinical markers of brain structure (micro- and macro-) and function (cognitive function and mood) were compared between 27 stable COPD patients (age: 63.0±9.1 years, 59.3% male, forced expiratory volume in 1 second [FEV1]: 58.1±18.0% pred.) and 23 non-COPD controls with >10 pack years smoking (age: 66.6±7.5 years, 52.2% male, FEV1: 100.6±19.1% pred.). Clinical relationships and group interactions with brain structure were also tested. All statistical analyses included correction for cardiovascular risk factors, smoking, and aortic stiffness. Results: COPD patients had significantly worse cognitive function (p=0.011), lower mood (p=0.046), and greater gray matter atrophy (p=0.020). In COPD patients, lower mood was associated with markers of white matter (WM) microstructural damage (p<0.001), and lower lung function (FEV1/forced vital capacity and FEV1) with markers of both WM macro (p=0.047) and microstructural damage (p=0.028). Conclusion: COPD is associated with both structural (gray matter atrophy) and functional (worse cognitive function and mood) brain changes that cannot be explained by measures of cardiovascular risk, aortic stiffness, or smoking history alone. These results have important implications to guide the development of new interventions to prevent or delay progression of neuropsychiatric comorbidities in COPD. Relationships found between mood and microstructural abnormalities suggest that in COPD, anxiety, and depression may occur secondary to WM damage. This could be used to better understand disabling symptoms such as breathlessness, improve health status, and reduce hospital admissions

The timing of death in patients with tuberculosis who die during anti-tuberculosis treatment in Andhra Pradesh, South India

Background: India has 2.0 million estimated tuberculosis (TB) cases per annum with an estimated 280,000 TBrelated deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India:- i) treatment outcomes including the number who died while on treatment, ii) the month of death and iii) characteristics associated with “early” death, occurring in the initial 8 weeks of treatment. Methods: This was a retrospective study in 16 selected Designated Microscopy Centres (DMCs) in Hyderabad, Krishna and Adilabad districts of Andhra Pradesh, South India. A review was performed of treatment cards and medical records of all TB patients (adults and children) registered and placed on standardized anti-tuberculosis treatment from January 2005 to September 2009. Results: There were 8,240 TB patients (5183 males) of whom 492 (6%) were known to have died during treatment. Case-fatality was higher in those previously treated (12%) and lower in those with extra-pulmonary TB (2%). There was an even distribution of deaths during anti-tuberculosis treatment, with 28% of all patients dying in the first 8 weeks of treatment. Increasing age and new as compared to recurrent TB disease were significantly associated with “early death”. Conclusion: In this large cohort of TB patients, deaths occurred with an even frequency throughout anti-TB treatment. Reasons may relate to i) the treatment of the disease itself, raising concerns about drug adherence, quality of anti-tuberculosis drugs or the presence of undetected drug resistance and ii) co-morbidities, such as HIV/ AIDS and diabetes mellitus, which are known to influence mortality. More research in this area from prospective and retrospective studies is needed

Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma

Rationale: Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA. Objectives: We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n = 10) and subjects with severe (n = 8) and nonsevere asthma (N-SA; n = 8) were cultured from endobronchial biopsies. Measurements and Main Results: GR expression in ASMC from SA and N-SA was reduced compared with that from healthy subjects by 49% (P < 0.01). Although baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10−7 M) in SA was 60% of that measured in either healthy subjects or subjects with N-SA. Tumor necrosis factor (TNF)-α induced greater nuclear factor (NF)-κB (p65) mRNA expression in ASMC from subjects with SA (5.6- vs. 2.0-fold; P < 0.01), whereas baseline and TNF-α–induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, although not modulating TNF-α–induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA groups, but this suppressive effect was impaired in subjects with SA. Conclusions: Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NF-κB–dependent gene promoters, may underlie CS insensitivity of severe asthma

Factors affecting brain structure in smoking-related diseases: Chronic Obstructive Pulmonary Disease (COPD) and coronary artery disease.

BACKGROUND: Changes in brain structure and cognitive decline occur in Chronic Obstructive Pulmonary Disease (COPD). They also occur with smoking and coronary artery disease (CAD), but it is unclear whether a common mechanism is responsible. METHODS: Brain MRI markers of brain structure were tested for association with disease markers in other organs. Where possible, principal component analysis (PCA) was used to group markers within organ systems into composite markers. Univariate relationships between brain structure and the disease markers were explored using hierarchical regression and then entered into multivariable regression models. RESULTS: 100 participants were studied (53 COPD, 47 CAD). PCA identified two brain components: brain tissue volumes and white matter microstructure, and six components from other organ systems: respiratory function, plasma lipids, blood pressure, glucose dysregulation, retinal vessel calibre and retinal vessel tortuosity. Several markers could not be grouped into components and were analysed as single variables, these included brain white matter hyperintense lesion (WMH) volume. Multivariable regression models showed that less well organised white matter microstructure was associated with lower respiratory function (p = 0.028); WMH volume was associated with higher blood pressure (p = 0.036) and higher C-Reactive Protein (p = 0.011) and lower brain tissue volume was associated with lower cerebral blood flow (p<0.001) and higher blood pressure (p = 0.001). Smoking history was not an independent correlate of any brain marker. CONCLUSIONS: Measures of brain structure were associated with a range of markers of disease, some of which appeared to be common to both COPD and CAD. No single common pathway was identified, but the findings suggest that brain changes associated with smoking-related diseases may be due to vascular, respiratory, and inflammatory changes

Options for sampling and stratification for national forest inventories to implement REDD+ under the UNFCCC

<p>Abstract</p> <p>Background</p> <p>Developing countries that are willing to participate in the recently adopted (16^thSession of the Conference of Parties (COP) in Cancun) mitigation mechanism of Reducing emissions from Deforestation and Forest Degradation - and the role of conservation, sustainable management of forests and enhancement of forest carbon stocks (REDD+) - will have to establish a national forest monitoring system in order to assess anthropogenic forest-related greenhouse gas emissions by sources and removals by sinks. Such a system should support the Measurement, Reporting and Verification (MRV) requirement of the United Nations Framework Convention on Climate Change (UNFCCC) as the REDD+ mechanism is results-based. A national forest inventory (NFI) is one potential key component of such an MRV system. Following the Decision adopted during the 15^thSession of the COP in Copenhagen, the most recent Intergovernmental Panel on Climate Change (IPCC) Guidance and Guidelines should be used as a basis for estimating anthropogenic forest-related greenhouse gas emissions by sources and removals by sinks and changes in forest carbon stocks and area.</p> <p>Results</p> <p>First, we present the key indispensable elements of the IPCC Guidance and Guidelines that have been developed to fulfil the UNFCCC reporting requirements. This is done in order to set the framework to develop the MRV requirement in which a NFI for REDD+ implementation could be developed. Second, within this framework, we develop and propose a novel scheme for the stratification of forest land for REDD+. Finally, we present some non-exhaustive optional elements within this framework that a country could consider to successfully operationalise and implement its REDD+ NFI.</p> <p>Conclusion</p> <p>Evidently, both the methodological guidance and political decisions on REDD+ under the UNFCCC will continue to evolve. Even so, and considering that there exists decades of experience in setting up traditional NFIs, developing a NFI that a country may use to directly support REDD+ activities under the UNFCCC represents the development of a new challenge in this field. It is therefore important that both the scientific community and national implementing agencies acquaint themselves with both the context and content of this challenge so that REDD+ mitigation actions may be implemented successfully and with environmental integrity. This paper provides important contributions to the subject through our proposal of the stratification of forest land for REDD+.</p

Cell cycle-dependent association of polo kinase Cdc5 with CENP-A contributes to faithful chromosome segregation in budding yeast.

Evolutionarily conserved polo-like kinase, Cdc5 (Plk1 in humans), associates with kinetochores during mitosis; however, the role of cell cycle-dependent centromeric ( CEN) association of Cdc5 and its substrates that exclusively localize to the kinetochore have not been characterized. Here we report that evolutionarily conserved CEN histone H3 variant, Cse4 (CENP-A in humans), is a substrate of Cdc5, and that the cell cycle-regulated association of Cse4 with Cdc5 is required for cell growth. Cdc5 contributes to Cse4 phosphorylation in vivo and interacts with Cse4 in mitotic cells. Mass spectrometry analysis of in vitro kinase assays showed that Cdc5 phosphorylates nine serine residues clustered within the N-terminus of Cse4. Strains with cse4-9SA exhibit increased errors in chromosome segregation, reduced levels of CEN-associated Mif2 and Mcd1/Scc1 when combined with a deletion of MCM21. Moreover, the loss of Cdc5 from the CEN chromatin contributes to defects in kinetochore integrity and reduction in CEN-associated Cse4. The cell cycle-regulated association of Cdc5 with Cse4 is essential for cell viability as constitutive association of Cdc5 with Cse4 at the kinetochore leads to growth defects. In summary, our results have defined a role for Cdc5-mediated Cse4 phosphorylation in faithful chromosome segregation