PyKoopman: A Python Package for Data-Driven Approximation of the Koopman Operator

PyKoopman is a Python package for the data-driven approximation of the Koopman operator associated with a dynamical system. The Koopman operator is a principled linear embedding of nonlinear dynamics and facilitates the prediction, estimation, and control of strongly nonlinear dynamics using linear systems theory. In particular, PyKoopman provides tools for data-driven system identification for unforced and actuated systems that build on the equation-free dynamic mode decomposition (DMD) and its variants. In this work, we provide a brief description of the mathematical underpinnings of the Koopman operator, an overview and demonstration of the features implemented in PyKoopman (with code examples), practical advice for users, and a list of potential extensions to PyKoopman. Software is available at http://github.com/dynamicslab/pykoopmanComment: 16 page

4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.

BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.Methodology/principal findingsBoth acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart.Conclusions/significanceThe positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life

Quality of Life of Patients with Type 1 Diabetes Mellitus Using Insulin Analog Glargine Compared with NPH Insulin: A Systematic Review and Policy Implications

INTRODUCTION: Insulin analogue glargine (GLA) has been available as one of the therapeutic options for patients with type 1 diabetes mellitus to enhance glycemic control. Studies have shown that a decrease in the frequency of hypoglycemia episodes improves the Quality of Life (QoL) of diabetic patients. However, there are appreciable acquisition cost differences between different insulins. Consequently, a need to assess their impact on QoL to provide future guidance to health authorities. METHOD: A Systematic review (SR) of multiple databases including Medline, LILACS, Cochrane and EMBASE databases with several combinations of agreed terms involving randomized controlled trials (RCTs) and cohorts, as well as manual searches and gray literature was undertaken. The primary outcome measure was a change in QoL. The quality of the studies and the risk of bias was also assessed. RESULTS: Eight studies were eventually included in the systematic review out of 634 publications. Eight different QoL instruments were used (2 generic, 2 mixed and 4 specific), in which the Diabetes Treatment Satisfaction Questionnaire (DTSQs) was the most used. The systematic review did not consistently show any significant difference overall in QoL scores whether as part of subsets or combined into a single score with the use of GLA versus NPH insulin. Only in patients’ satisfaction measured by DTSQ was a better result consistently seen with GLA versus NPH insulin but not using the WED scale. However, none of the cohort studies scored a maximum on the Newcastle-Ottawa scale for quality and they generally were of moderate quality with bias in the studies. CONCLUSION: There was no consistent difference in QoL or patient reported outcomes when the findings from the eight studies were collated. In view of this, we believe the current price differential between GLA and NPH insulin in Brazil cannot be justified by these findings

3D-Printed Ergonomic Tool Handles

Although hand tools serve as an instrument for extending one’s capabilities through the use of hands, the comfort it brings is important especially since the welfare of the user is at stake. Aside from using the hand tools repetitively and with an awkward posture, the tool handle compositions and design also contribute to accumulating some work-related musculoskeletal disorders that require further attention in the long run. To provide a long-term solution, 3D-printed new designs of six commonly used hand tools that fit the average hand measurements of Filipinos have been developed. The hand tools are printed using two filaments namely; thermoplastic polyurethane (TPU) which was found to be skin-friendly and polylactic acid (PLA) which is proven to be more functional, both are used on the outer and inner layer of the handle, respectively. The 3D-printed tool handles were evaluated through the use of a comfort questionnaire for hand tools distributed to 10 respondents per tool handle testing, results show that 3D-printed tool handles are found to be more comfortable and convenient rather than the commercial ones. Meanwhile, the researchers note that the adequate length of tool handles may also vary according to functions and not rely alone on the average hand measurements

Cluster Control in Oligouranyl Complexes of p-t-Butylcalix[8]arene

Formation of uranyl ion complexes of p-t-butylcalix[8]arene by reaction of the calixarene with [UO2(dmso)5]2+ in the presence of various bases leads to the crystallisation of solids with interestingly different stoichiometry, involving both di- and tri-uranate oligomers bound to the calixarene in anionic species. In all, the calixarene hexa-anion is present in a virtually identical conformation, suggesting that conformational preferences of the ligand must be a major factor controlling the form of the bound oxo-metal complex. Hydrogen bonding to the anions does not appear to be prominent even in the presence of protonated amines and this may explain the formation of some remarkable cation/solvent/simple anion clusters found within the lattices

Designed, highly expressing, thermostable dengue virus 2 envelope protein dimers elicit quaternary epitope antibodies

Dengue virus (DENV) is a worldwide health burden, and a safe vaccine is needed. Neutralizing antibodies bind to quaternary epitopes on DENV envelope (E) protein homodimers. However, recombinantly expressed soluble E proteins are monomers under vaccination conditions and do not present these quaternary epitopes, partly explaining their limited success as vaccine antigens. Using molecular modeling, we found DENV2 E protein mutations that induce dimerization at low concentrations (\u3c100 pM) and enhance production yield by more than 50-fold. Cross-dimer epitope antibodies bind to the stabilized dimers, and a crystal structure resembles the wild-type (WT) E protein bound to a dimer epitope antibody. Mice immunized with the stabilized dimers developed antibodies that bind to E dimers and not monomers and elicited higher levels of DENV2-neutralizing antibodies compared to mice immunized with WT E antigen. Our findings demonstrate the feasibility of using structure-based design to produce subunit vaccines for dengue and other flaviviruses

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels