Optimal topological simplification of discrete functions on surfaces

We solve the problem of minimizing the number of critical points among all functions on a surface within a prescribed distance {\delta} from a given input function. The result is achieved by establishing a connection between discrete Morse theory and persistent homology. Our method completely removes homological noise with persistence less than 2{\delta}, constructively proving the tightness of a lower bound on the number of critical points given by the stability theorem of persistent homology in dimension two for any input function. We also show that an optimal solution can be computed in linear time after persistence pairs have been computed.Comment: 27 pages, 8 figure

THERMAL DENATURATION OF MONOMERIC AND TRIMERIC PHYCOCYANINS STUDIED BY STATIC AND SPECTROSCOPY POLARIZED TIME-RESOLVED FLUORESCENCE

C-Phycocyanin (PC) and allophycocyanin (APC). as well as the a-subunit of PC. have been isolated from the blue-green alga (cyanobacterium). Spirulina platensis. The effects of partial thermal denaturation of PC and of its state of aggregation have been studied by ps time-resolved, polarized fluorescence spectroscopy. All measurements have been performed under low photon fluxes (< 10’ ’ photonsipulse x cm’) to minimize singlet-singlet annihilation processes. A complex decay is obtained under most conditions, which can be fitted satisfactorily with a bi-exponential (7’ = 70400 ps. T? = 1000-3000 ps) for both the isotropic and the polarized part, but with different intensities and time constants for the two decay curves. The data are interpreted in the frameworkof the model first developed by Teak and Dale (Biochern. J. 116, 161 (1970)], which divides the spectroscopically different chromophores in (predominantly) sensitizing (s) and fluorescing U, ones. If one assumes temperature dependent losses in the energy transfer from the s to the f and between f chromophores. both the biexponential nature of the isotropic fluorescence decay and the polarization data can be rationalized. In the isotropic emission (corresponding to the population of excited states) the short lifetime is related to the s-,f transfer. the longer one to the “free“ decay of the final acceptor(s) (= f). The polarized part is dominated by an extremely short decay time. which is related to s+f transfer, as well as to resonance transfer between the f-chromophores

FÖRSTER TRANSFER CALCULATIONS BASED ON CRYSTAL STRUCTURE DATA FROM Agmenellum quadruplicatum C-PHYCOCYANIN

Excitation energy transfer in C-phycocyanin is modeled using the Forster inductive resonance mechanism. Detailed calculations are carried out using coordinates and orientations of the chromophores derived from X-ray crystallographic studies of C-phycocyanin from two different species (Schirmer et al, J. Mol. Biol. 184, 257–277 (1985) and ibid., 188, 651-677 (1986)). Spectral overlap integrals are estimated from absorption and fluorescence spectra of C-phycocyanin of Mastigocladus laminosus and its separated subunits. Calculations are carried out for the β-subunit, αβ-monomer, (αβ)3-trimer and (αβ)0-hexamer species with the following chromophore assignments: β155 = 's’(sensitizer), β84 =‘f (fluorescer) and α84 =‘m’(intermediate):]:. The calculations show that excitation transfer relaxation occurs to 3=98% within 200 ps in nearly every case; however, the rates increase as much as 10-fold for the higher aggregates. Comparison with experimental data on fluorescence decay and depolarization kinetics from the literature shows qualitative agreement with these calculations. We conclude that Forster transfer is sufficient to account for all of the observed fluorescence properties of C-phycocyanin in aggregation states up to the hexamer and in the absence of linker polypeptides

Who knows best? A Q methodology study to explore perspectives of professional stakeholders and community participants on health in low-income communities

Abstract Background Health inequalities in the UK have proved to be stubborn, and health gaps between best and worst-off are widening. While there is growing understanding of how the main causes of poor health are perceived among different stakeholders, similar insight is lacking regarding what solutions should be prioritised. Furthermore, we do not know the relationship between perceived causes and solutions to health inequalities, whether there is agreement between professional stakeholders and people living in low-income communities or agreement within these groups. Methods Q methodology was used to identify and describe the shared perspectives (‘subjectivities’) that exist on i) why health is worse in low-income communities (‘Causes’) and ii) the ways that health could be improved in these same communities (‘Solutions’). Purposively selected individuals (n = 53) from low-income communities (n = 25) and professional stakeholder groups (n = 28) ranked ordered sets of statements – 34 ‘Causes’ and 39 ‘Solutions’ – onto quasi-normal shaped grids according to their point of view. Factor analysis was used to identify shared points of view. ‘Causes’ and ‘Solutions’ were analysed independently, before examining correlations between perspectives on causes and perspectives on solutions. Results Analysis produced three factor solutions for both the ‘Causes’ and ‘Solutions’. Broadly summarised these accounts for ‘Causes’ are: i) ‘Unfair Society’, ii) ‘Dependent, workless and lazy’, iii) ‘Intergenerational hardships’ and for ‘Solutions’: i) ‘Empower communities’, ii) ‘Paternalism’, iii) ‘Redistribution’. No professionals defined (i.e. had a significant association with one factor only) the ‘Causes’ factor ‘Dependent, workless and lazy’ and the ‘Solutions’ factor ‘Paternalism’. No community participants defined the ‘Solutions’ factor ‘Redistribution’. The direction of correlations between the two sets of factor solutions – ‘Causes’ and ‘Solutions’ – appear to be intuitive, given the accounts identified. Conclusions Despite the plurality of views there was broad agreement across accounts about issues relating to money. This is important as it points a way forward for tackling health inequalities, highlighting areas for policy and future research to focus on

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65–0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67–1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45–1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69–1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality

Computational detection of allergenic proteins attains a new level of accuracy with in silico variable-length peptide extraction and machine learning

The placing of novel or new-in-the-context proteins on the market, appearing in genetically modified foods, certain bio-pharmaceuticals and some household products leads to human exposure to proteins that may elicit allergic responses. Accurate methods to detect allergens are therefore necessary to ensure consumer/patient safety. We demonstrate that it is possible to reach a new level of accuracy in computational detection of allergenic proteins by presenting a novel detector, Detection based on Filtered Length-adjusted Allergen Peptides (DFLAP). The DFLAP algorithm extracts variable length allergen sequence fragments and employs modern machine learning techniques in the form of a support vector machine. In particular, this new detector shows hitherto unmatched specificity when challenged to the Swiss-Prot repository without appreciable loss of sensitivity. DFLAP is also the first reported detector that successfully discriminates between allergens and non-allergens occurring in protein families known to hold both categories. Allergenicity assessment for specific protein sequences of interest using DFLAP is possible via [email protected]

Transient activation of dopaminergic neurons during development modulates visual responsiveness, locomotion and brain activity in a dopamine ontogeny model of schizophrenia

It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the "dopamine ontogeny hypothesis of schizophrenia". To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain model, Drosophila melanogaster. By applying genetic tools allowing transient activation or silencing of dopaminergic neurons in the fly brain, we investigated whether a critical window exists during development when altered dopamine (DA) activity levels could lead to impairments in arousal states in adult animals. We found that increased activity in dopaminergic neurons in later stages of development significantly increased visual responsiveness and locomotion, especially in adult males. This misallocation of visual salience and hyperactivity mimicked the effect of acute methamphetamine feeding to adult flies, suggesting up-regulated DA signaling could result from developmental manipulations. Finally, brain recordings revealed significantly reduced gamma-band activity in adult animals exposed to the transient developmental insult. Together, these data support the idea that transient alterations in DA signaling during development can permanently alter behavior in adults, and that a reductionist model such as Drosophila can be used to investigate potential mechanisms underlying complex cognitive disorders such as schizophrenia

Relevant issues in tumor regression grading of histopathological response to neoadjuvant treatment in adenocarcinomas of the esophagus and gastroesophageal junction

 Multimodality treatment combining surgery and oncologic treatment has become widely applied in curative treatment of esophageal and gastroesophageal junction adenocarcinoma. There is a need for a standardized tumor regression grade scoring system for clinically relevant effects of neoadjuvant treatment effects. There are numerous tumor regression grading systems in use and there is no international standardization. This review has found nine different international systems currently in use. These systems all differ in detail, which inhibits valid comparisons of results between studies. Tumor regression grading in esophageal and gastroesophageal junction adenocarcinoma needs to be improved and standardized. To achieve this goal, we have invited a significant group of international esophageal and gastroesophageal junction adenocarcinoma pathology experts to perform a structured review in the form of a Delphi process. The aims of the Delphi include specifying the details for the disposal of the surgical specimen and defining the details of, and the reporting from, the agreed histological tumor regression grade system including resected lymph nodes. The second step will be to perform a validation study of the agreed tumor regression grading system to ensure a scientifically robust inter- and intra-observer variability and to incorporate the consented tumor regression grading system in clinical studies to assess its predictive and prognostic role in treatment of esophageal and gastroesophageal junction adenocarcinomas. The ultimate aim of the project is to improve survival in esophageal and gastroesophageal adenocarcinoma by increasing the quality of tumor regression grading, which is a key component in treatment evaluation and future studies of individualized treatment of esophageal cancer.</p

Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling

The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems

Intestinal carriage of Staphylococcus aureus: How does its frequency compare with that of nasal carriage and what is its clinical impact?

The bacterial species Staphylococcus aureus, including its methicillin-resistant variant (MRSA), finds its primary ecological niche in the human nose, but is also able to colonize the intestines and the perineal region. Intestinal carriage has not been widely investigated despite its potential clinical impact. This review summarizes literature on the topic and sketches the current state of affairs from a microbiological and infectious diseases' perspective. Major findings are that the average reported detection rate of intestinal carriage in healthy individuals and patients is 20% for S. aureus and 9% for MRSA, which is approximately half of that for nasal carriage. Nasal carriage seems to predispose to intestinal carriage, but sole intestinal carriage occurs relatively frequently and is observed in 1 out of 3 intestinal carriers, which provides a rationale to include intestinal screening for surveillance or in outbreak settings. Colonization of the intestinal tract with S. aureus at a young age occurs at a high frequency and may affect the host's immune system. The frequency of intestinal carriage is generally underestimated and may significantly contribute to bacterial dissemination and subsequent risk of infections. Whether intestinal rather than nasal S. aureus carriage is a primary predictor for infections is still ill-defined