Scientific discovery as a combinatorial optimisation problem: How best to navigate the landscape of possible experiments?

A considerable number of areas of bioscience, including gene and drug discovery, metabolic engineering for the biotechnological improvement of organisms, and the processes of natural and directed evolution, are best viewed in terms of a ‘landscape’ representing a large search space of possible solutions or experiments populated by a considerably smaller number of actual solutions that then emerge. This is what makes these problems ‘hard’, but as such these are to be seen as combinatorial optimisation problems that are best attacked by heuristic methods known from that field. Such landscapes, which may also represent or include multiple objectives, are effectively modelled in silico, with modern active learning algorithms such as those based on Darwinian evolution providing guidance, using existing knowledge, as to what is the ‘best’ experiment to do next. An awareness, and the application, of these methods can thereby enhance the scientific discovery process considerably. This analysis fits comfortably with an emerging epistemology that sees scientific reasoning, the search for solutions, and scientific discovery as Bayesian processes

Curative and organ-preserving treatment with intra-arterial carboplatin induction followed by surgery and/or radiotherapy for advanced head and neck cancer: single-center five-year results

BACKGROUND: This study evaluated the feasibility, toxicity, response rate and survival of neoadjuvant superselective intra-arterial infusion of high dose carboplatin in advanced head and neck cancer. METHODS: Forty-six patients with primary head and neck squamous cell carcinoma received 3 cycles of intra-arterial carboplatin (300 to 350 mg/m(2 )per cycle every 2 weeks), followed by radiotherapy or surgery plus radiotherapy. RESULTS: No complications or severe toxicity occurred. Sixteen patients (35%) were complete responders, 20 (43%) partial responders while 10 (22%) did not respond to treatment. After completion of the multimodality treatment, 38/46 patients (83%) were complete responders. After a 5-year follow-up period, 18/46 patients (39%) are alive and disease-free, 3 (6,5%) have died of a second primary tumor and 25 (54,5%) have died of the disease. CONCLUSION: Intra-arterial carboplatin induction chemotherapy is a safe, well-tolerated technique that discriminates between responders and non-responders and so may have prognostic significance in planning further integrated treatments aimed to organ preservation for advanced head and neck carcinomas

Clutch Frequency Affects the Offspring Size-Number Trade-Off in Lizards

Background: Studies of lizards have shown that offspring size cannot be altered by manipulating clutch size in species with a high clutch frequency. This raises a question of whether clutch frequency has a key role in influencing the offspring sizenumber trade-off in lizards. Methodology/Principal Findings: To test the hypothesis that females reproducing more frequently are less likely to tradeoff offspring size against offspring number, we applied the follicle ablation technique to female Eremias argus (Lacertidae) from Handan (HD) and Gonghe (GH), the two populations that differ in clutch frequency. Follicle ablation resulted in enlargement of egg size in GH females, but not in HD females. GH females switched from producing a larger number of smaller eggs in the first clutch to a smaller number of larger eggs in the second clutch; HD females showed a similar pattern of seasonal shifts in egg size, but kept clutch size constant between the first two clutches. Thus, the egg sizenumber trade-off was evident in GH females, but not in HD females. Conclusions/Significance: As HD females (mean = 3.1 clutches per year) reproduce more frequently than do GH females (mean = 1.6 clutches per year), our data therefore validate the hypothesis tested. Our data also provide an inference that maximization of maternal fitness could be achieved in females by diverting a large enough, rather than a higher-than-usual

Recurring alcohol-related care between 1998 and 2007 among people treated for an alcohol-related disorder in 1997: A register study in Stockholm County

<p>Abstract</p> <p>Background</p> <p>Inpatient care for alcohol intoxication is increasing in Sweden, especially among young women. Since it is well known that alcohol disorder is a chronic relapsing illness, this study examines the extent to which people return for more care.</p> <p>Method</p> <p>All inpatients with alcohol-related diagnoses in Stockholm County during 1997 were followed prospectively to 2007 through registers. The proportion reappearing for the same diagnosis, other alcohol-related inpatient, or outpatient care each year after baseline, as well as the number of years the inpatients reappeared were calculated (n = 2735). Three diagnoses were examined separately; alcohol dependence, harmful use of alcohol, and alcohol intoxication.</p> <p>Results</p> <p>Three out of five inpatients with an alcohol diagnoses reappeared for more alcohol-related inpatient care during the following decade. The proportion returning was largest the year after baseline and then decreased curvilinearly over time. The inclusion of outpatient care increased proportions, but did not change patterns. Of those with an alcohol dependence diagnosis at baseline 42 percent returned for more alcohol-related inpatient care the first, 28 percent the fifth, and 25 percent the tenth year. Corresponding proportions for harmful use and intoxication were smaller. One in five among those with an alcohol dependence returned for more than five of the ten years. Ordered logistic regressions confirmed that besides diagnosis, age and gender were independently related to the number of years returning to care.</p> <p>Conclusions</p> <p>While middle-aged males with alcohol dependence were in a revolving door, young female inpatients with intoxication diagnosis returned to a comparably lower degree.</p

Population structure and genetic diversity in a commercial maize breeding program assessed with SSR and SNP markers

Information about the genetic diversity and population structure in elite breeding material is of fundamental importance for the improvement of crops. The objectives of our study were to (a) examine the population structure and the genetic diversity in elite maize germplasm based on simple sequence repeat (SSR) markers, (b) compare these results with those obtained from single nucleotide polymorphism (SNP) markers, and (c) compare the coancestry coefficient calculated from pedigree records with genetic distance estimates calculated from SSR and SNP markers. Our study was based on 1,537 elite maize inbred lines genotyped with 359 SSR and 8,244 SNP markers. The average number of alleles per locus, of group specific alleles, and the gene diversity (D) were higher for SSRs than for SNPs. Modified Roger’s distance (MRD) estimates and membership probabilities of the STRUCTURE matrices were higher for SSR than for SNP markers but the germplasm organization in four heterotic pools was consistent with STRUCTURE results based on SSRs and SNPs. MRD estimates calculated for the two marker systems were highly correlated (0.87). Our results suggested that the same conclusions regarding the structure and the diversity of heterotic pools could be drawn from both markers types. Furthermore, although our results suggested that the ratio of the number of SSRs and SNPs required to obtain MRD or D estimates with similar precision is not constant across the various precision levels, we propose that between 7 and 11 times more SNPs than SSRs should be used for analyzing population structure and genetic diversity

The regularized visible fold revisited

The planar visible fold is a simple singularity in piecewise smooth systems. In this paper, we consider singularly perturbed systems that limit to this piecewise smooth bifurcation as the singular perturbation parameter $\epsilon\rightarrow 0$. Alternatively, these singularly perturbed systems can be thought of as regularizations of their piecewise counterparts. The main contribution of the paper is to demonstrate the use of consecutive blowup transformations in this setting, allowing us to obtain detailed information about a transition map near the fold under very general assumptions. We apply this information to prove, for the first time, the existence of a locally unique saddle-node bifurcation in the case where a limit cycle, in the singular limit $\epsilon\rightarrow 0$, grazes the discontinuity set. We apply this result to a mass-spring system on a moving belt described by a Stribeck-type friction law

Portuguese recommendations for the use of biological and targeted synthetic diseasemodifying antirheumatic drugs in patients with rheumatoid arthritis – 2020 update

Objective: To update the recommendations for the treatment of rheumatoid arthritis (RA) with biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs), endorsed by the Portuguese Society of Rheumatology (SPR). Methods: These treatment recommendations were formulated by Portuguese rheumatologists taking into account previous recommendations, new literature evidence and consensus opinion. At a national meeting, in a virtual format, three of the ten previous recommendations were re-addressed and discussed after a more focused literature review. A first draft of the updated recommendations was elaborated by a team of SPR rheumatologists from the SPR rheumatoid arthritis study group, GEAR. The resulting document circulated among all SPR rheumatologists for discussion and input. The level of agreement with each of all the recommendations was anonymously voted online by all SPR rheumatologists. Results: These recommendations cover general aspects such as shared decision, treatment objectives, systematic assessment of disease activity and burden and its registry in Reuma.pt. Consensus was also achieved regarding specific aspects such as initiation of bDMARDs and tsDMARDs, assessment of treatment response, switching and definition of persistent remission. Conclusion: These recommendations may be used for guidance of treatment with bDMARDs and tsDMARDs in patients with RA. As more evidence becomes available and more therapies are licensed, these recommendations will be updated.info:eu-repo/semantics/publishedVersio

Conceptions of learning factors in postgraduate health sciences master students: a comparative study with nonhealth science students and between genders

Background: The students’ conceptions of learning in postgraduate health science master studies are poorly understood. The aim of this study was to compare the factors influencing conceptions of learning in health sciences and non-health sciences students enrolled in postgraduate master programs in order to obtain information that may be useful for students and for future postgraduate programs. Methods: A modified version of the Learning Inventory Conception Questionnaire (COLI) was used to compare students’ conception learning factors in 131 students at the beginning of their postgraduate studies in health sciences, experimental sciences, arts and humanities and social sciences. Results: The present study demonstrates that a set of factors may influence conception of learning of health sciences postgraduate students, with learning as gaining information, remembering, using, and understanding information, awareness of duty and social commitment being the most relevant. For these students, learning as a personal change, a process not bound by time or place or even as acquisition of professional competences, are less relevant. According to our results, this profile is not affected by gender differences. Conclusions: Our results show that the overall conceptions of learning differ among students of health sciences and non-health sciences (experimental sciences, arts and humanities and social sciences) master postgraduate programs. These finding are potentially useful to foster the learning process of HS students, because if they are metacognitively aware of their own conception or learning, they will be much better equipped to self-regulate their learning behavior in a postgraduate master program in health sciences.Supported by CTS-115 (Tissue Engineering Group of the University of Granada). The funding body did not took part in the design of the study and collection, analysis and interpretation of data and in writing the manuscript

Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition

Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF∶Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF∶CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU/ml versus 1.9 IU/ml; p<0.005). This increased VWF∶CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF∶Ag and VWF∶CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (∼55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor