Housing and labor market distortions in Poland : linkages and policy implications

Poland's housing and macroeconomic policies have restricted investments in housing and urban infrastructure to a level well below that of other European countries. This has resulted in a shortage of housing typified by 15 to 20 year waits for government sponsored housing. Shortages of this magnitude are likely to cause distortions with impacts on patterns of savings and consumption, the price level, and on the functioning of labor markets. This paper focuses particularly on how housing market distortions are transmitted to labor markets, with impacts on rates of migration, relative wage levels among different regions, and, by implication, on the productivity of the Polish work force. The basic thesis of the paper is that if housing markets are prevented from reaching their competitive equilibrium that labor markets will similarly be prevented. Evidence is examined on the extent of housing and labor market disequilibria, and estimates econometric models that relate internal migration and relative wages to alternative measures of housing market disequilibria. From these analyses it is concluded that labor markets are in fact distorted by housing market distortions, with potentially major macroeconomic costs.Banks&Banking Reform,Municipal Financial Management,Housing&Human Habitats,Public Sector Economics&Finance,Urban Housing

Iterative approach to computational enzyme design

A general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes

A General Tool for Engineering the NAD/NADP Cofactor Preference of Oxidoreductases

The ability to control enzymatic nicotinamide cofactor utilization is critical for engineering efficient metabolic pathways. However, the complex interactions that determine cofactor-binding preference render this engineering particularly challenging. Physics-based models have been insufficiently accurate and blind directed evolution methods too inefficient to be widely adopted. Building on a comprehensive survey of previous studies and our own prior engineering successes, we present a structure-guided, semirational strategy for reversing enzymatic nicotinamide cofactor specificity. This heuristic-based approach leverages the diversity and sensitivity of catalytically productive cofactor binding geometries to limit the problem to an experimentally tractable scale. We demonstrate the efficacy of this strategy by inverting the cofactor specificity of four structurally diverse NADP-dependent enzymes: glyoxylate reductase, cinnamyl alcohol dehydrogenase, xylose reductase, and iron-containing alcohol dehydrogenase. The analytical components of this approach have been fully automated and are available in the form of an easy-to-use web tool: Cofactor Specificity Reversal–Structural Analysis and Library Design (CSR-SALAD)

Aerobic exercise alone results in clinically significant weight loss for men and women: Midwest Exercise Trial-2

This is the peer reviewed version of the following article: Donnelly, J. E., Honas, J. J., Smith, B. K., Mayo, M. S., Gibson, C. A., Sullivan, D. K., Lee, J., Herrmann, S. D., Lambourne, K. and Washburn, R. A. (2013), Aerobic exercise alone results in clinically significant weight loss for men and women: Midwest exercise trial 2. Obesity, 21: E219–E228. doi:10.1002/oby.20145, which has been published in final form at http://doi.org/10.1002/oby.20145. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Exercise is recommended by public health agencies for weight management; however, the role of exercise is generally considered secondary to energy restriction. Few studies exist that have verified completion of exercise, measured the energy expenditure of exercise, and prescribed exercise with equivalent energy expenditure across individuals and genders. OBJECTIVE The objective of this study was to evaluate aerobic exercise, without energy restriction, on weight loss in sedentary overweight and obese men and women. DESIGN AND METHODS This investigation was a randomized, controlled, efficacy trial in 141 overweight and obese participants (body mass index, 31.0 ± 4.6 kg/m2; age 22.6 ± 3.9 years). Participants were randomized (2:2:1 ratio) to exercise at either 400 kcal/session or 600 kcal/session or to a non-exercise control. Exercise was supervised, 5 days/week, for 10 months. All participants were instructed to maintain usual ad libitum diets. Due to the efficacy design, completion of ≥ 90% of exercise sessions was an a priori definition of per protocol, and these participants were included in the analysis. RESULTS Weight loss from baseline to 10 months for the 400 and 600 kcal/session groups was 3.9 ± 4.9kg (4.3%) and 5.2 ± 5.6kg (5.7%), respectively compared to weight gain for controls of 0.5 ± 3.5kg (0.5%) (p<0.05). Differences for weight loss from baseline to 10 months between the exercise groups and differences between men and women within groups were not statistically significant. CONCLUSIONS Supervised exercise, with equivalent energy expenditure, results in clinically significant weight loss with no significant difference between men and women

Monomerization of Far-Red Fluorescent Proteins

Anthozoa-class red fluorescent proteins (RFPs) are frequently used as biological markers, with far-red (λ_(em) ∼ 600–700 nm) emitting variants sought for whole-animal imaging because biological tissues are more permeable to light in this range. A barrier to the use of naturally occurring RFP variants as molecular markers is that all are tetrameric, which is not ideal for cell biological applications. Efforts to engineer monomeric RFPs have typically produced dimmer and blue-shifted variants because the chromophore is sensitive to small structural perturbations. In fact, despite much effort, only four native RFPs have been successfully monomerized, leaving the majority of RFP biodiversity untapped in biomarker development. Here we report the generation of monomeric variants of HcRed and mCardinal, both far-red dimers, and describe a comprehensive methodology for the monomerization of red-shifted oligomeric RFPs. Among the resultant variants is mKelly1 (emission maximum, λ_(em) = 656 nm), which, along with the recently reported mGarnet2 [Matela G, et al. (2017) Chem Commun (Camb) 53:979–982], forms a class of bright, monomeric, far-red FPs

Potential Role of Platelet-Derived Growth Factor Receptor Inhibition Using Imatinib in Combination with Docetaxel in the Treatment of Recurrent Non-small Cell Lung Cancer

Introduction:Platelet-derived growth factor receptor (PDGFR) is expressed in lung cancer and is involved in angiogenesis. Preclinical models demonstrated that imatinib (Im) regulates angiogenesis through PDGFR inhibition and enhances efficacy of chemotherapy. Hypothesis: We hypothesized that Im plus docetaxel (D) would have a synergistic effect detectable by an increase in response rate in patients with recurrent non-small cell lung cancer (NSCLC).Methods:A phase II trial to evaluate Im in combination with D in patients with recurrent NSCLC was conducted. The primary end point was response rate, using a Simon two-stage design. Eligible patients had measurable disease and no more than two chemotherapy regimens. D was given at 30 mg/m2/wk intravenously ×3 every 4 weeks and oral Im at 600 mg daily for four cycles. Patients required two cycles to be evaluable for response. Nonprogressors after four cycles continued with Im maintenance until progression or for a total of 12 months.Results:Twenty-three patients were enrolled in the first stage. Toxicity was mainly nonhematologic. We observed one partial response (5.5%), four stable disease (22.2%), and 13 progressed (72.2%). Median time to progression was 1.9 months, and median overall survival was 6.1 months. Two patients who went on Im maintenance had time to progression of 7.78 months and 15.8 months.Conclusion:Im in combination with D did not achieve its primary objective of improving response rate in patients with recurrent NSCLC. An increased understanding of the complex PDGFR pathway in lung cancer and alternative strategies to inhibit it are needed

Recovery of Red Fluorescent Protein Chromophore Maturation Deficiency through Rational Design

Red fluorescent proteins (RFPs) derived from organisms in the class Anthozoa have found widespread application as imaging tools in biological research. For most imaging experiments, RFPs that mature quickly to the red chromophore and produce little or no green chromophore are most useful. In this study, we used rational design to convert a yellow fluorescent mPlum mutant to a red-emitting RFP without reverting any of the mutations causing the maturation deficiency and without altering the red chromophore’s covalent structure. We also created an optimized mPlum mutant (mPlum-E16P) that matures almost exclusively to the red chromophore. Analysis of the structure/function relationships in these proteins revealed two structural characteristics that are important for efficient red chromophore maturation in DsRed-derived RFPs. The first is the presence of a lysine residue at position 70 that is able to interact directly with the chromophore. The second is an absence of non-bonding interactions limiting the conformational flexibility at the peptide backbone that is oxidized during red chromophore formation. Satisfying or improving these structural features in other maturation-deficient RFPs may result in RFPs with faster and more complete maturation to the red chromophore

Microbiome for Mars: surveying microbiome connections to healthcare with implications for long-duration human spaceflight, virtual workshop, July 13, 2020

The inaugural “Microbiome for Mars” virtual workshop took place on July 13, 2020. This event assembled leaders in microbiome research and development to discuss their work and how it may relate to long-duration human space travel. The conference focused on surveying current microbiome research, future endeavors, and how this growing field could broadly impact human health and space exploration. This report summarizes each speaker’s presentation in the order presented at the workshop

Physical activity and academic achievement across the curriculum (A + PAAC): rationale and design of a 3-year, cluster-randomized trial

Abstract Background Improving academic achievement and reducing the rates of obesity in elementary school students are both of considerable interest. Increased physical activity during academic instruction time during school offers a potential intervention to address both issues. A program titled &#8220;Physical Activity Across the Curriculum&#8221; (PAAC) was developed in which classroom teachers in 22 elementary schools were trained to deliver academic instruction using physical activity with a primary aim of preventing increased BMI. A secondary analysis of data assessed the impact of PAAC on academic achievement using the Weschler Individual Achievement Test-II and significant improvements were shown for reading, math and spelling in students who participated in PAAC. Based on the results from PAAC, an adequately powered trial will be conducted to assess differences in academic achievement between intervention and control schools called, &#8220;Academic Achievement and Physical Activity Across the Curriculum (A&#8201;+&#8201;PAAC).&#8221; Methods/design Seventeen elementary schools were cluster randomized to A&#8201;+&#8201;PAAC or control for a 3-year trial. Classroom teachers were trained to deliver academic instruction through moderate-to-vigorous physical activity with a target of 100+ minutes of A&#8201;+&#8201;PAAC activities per week. The primary outcome measure is academic achievement measured by the Weschler Individual Achievement Test-III, which was administered at baseline (Fall 2011) and will be repeated in the spring of each year by assessors blinded to condition. Potential mediators of any association between A&#8201;+&#8201;PAAC and academic achievement will be examined on the same schedule and include changes in cognitive function, cardiovascular fitness, daily physical activity, BMI, and attention-to-task. An extensive process analysis will be conducted to document the fidelity of the intervention. School and student recruitment/randomization, teacher training, and baseline testing for A&#8201;+&#8201;PAAC have been completed. Nine schools were randomized to the intervention and 8 to control. A random sample of students in each school, stratified by gender and grade (A&#8201;+&#8201;PAAC&#8201;=&#8201;370, Control&#8201;=&#8201;317), was selected for outcome assessments from those who provided parental consent/child assent. Baseline data by intervention group are presented. Discussion If successful, the A&#8201;+&#8201;PAAC approach could be easily and inexpensively scaled and disseminated across elementary schools to improve both educational quality and health. Funding source: R01- DK85317. Trial registration: US NIH Clinical Trials, http://NCT01699295.Peer Reviewe