Insights from the classical MD simulations

Salt bridges and ionic interactions play an important role in protein stability, protein-protein interactions, and protein folding. Here, we provide the classical MD simulations of the structure and IR signatures of the arginine (Arg)–glutamate (Glu) salt bridge. The Arg-Glu model is based on the infinite polyalanine antiparallel two-stranded β-sheet structure. The 1 μs NPT simulations show that it preferably exists as a salt bridge (a contact ion pair). Bidentate (the end-on and side-on structures) and monodentate (the backside structure) configurations are localized [Donald et al., Proteins 79, 898–915 (2011)]. These structures are stabilized by the short +N–H⋯O− bonds. Their relative stability depends on a force field used in the MD simulations. The side-on structure is the most stable in terms of the OPLS-AA force field. If AMBER ff99SB-ILDN is used, the backside structure is the most stable. Compared with experimental data, simulations using the OPLS all-atom (OPLS-AA) force field describe the stability of the salt bridge structures quite realistically. It decreases in the following order: side-on > end-on > backside. The most stable side-on structure lives several nanoseconds. The less stable backside structure exists a few tenth of a nanosecond. Several short-living species (solvent shared, completely separately solvated ionic groups ion pairs, etc.) are also localized. Their lifetime is a few tens of picoseconds or less. Conformational flexibility of amino acids forming the salt bridge is investigated. The spectral signature of the Arg-Glu salt bridge is the IR-intensive band around 2200 cm−1. It is caused by the asymmetric stretching vibrations of the +N–H⋯O− fragment. Result of the present paper suggests that infrared spectroscopy in the 2000–2800 frequency region may be a rapid and quantitative method for the study of salt bridges in peptides and ionic interactions between proteins. This region is usually not considered in spectroscopic studies of peptides and proteins

A Protein Phosphorylation Threshold for Functional Stacking of Plant Photosynthetic Membranes

Phosphorylation of photosystem II (PSII) proteins affects macroscopic structure of thylakoid photosynthetic membranes in chloroplasts of the model plant Arabidopsis. In this study, light-scattering spectroscopy revealed that stacking of thylakoids isolated from wild type Arabidopsis and the mutant lacking STN7 protein kinase was highly influenced by cation (Mg++) concentrations. The stacking of thylakoids from the stn8 and stn7stn8 mutants, deficient in STN8 kinase and consequently in light-dependent phosphorylation of PSII, was increased even in the absence of Mg++. Additional PSII protein phosphorylation in wild type plants exposed to high light enhanced Mg++-dependence of thylakoid stacking. Protein phosphorylation in the plant leaves was analyzed during day, night and prolonged darkness using three independent techniques: immunoblotting with anti-phosphothreonine antibodies; Diamond ProQ phosphoprotein staining; and quantitative mass spectrometry of peptides released from the thylakoid membranes by trypsin. All assays revealed dark/night-induced increase in phosphorylation of the 43 kDa chlorophyll-binding protein CP43, which compensated for decrease in phosphorylation of the other PSII proteins in wild type and stn7, but not in the stn8 and stn7stn8 mutants. Quantitative mass spectrometry determined that every PSII in wild type and stn7 contained on average 2.5±0.1 or 1.4±0.1 phosphoryl groups during day or night, correspondingly, while less than every second PSII had a phosphoryl group in stn8 and stn7stn8. It is postulated that functional cation-dependent stacking of plant thylakoid membranes requires at least one phosphoryl group per PSII, and increased phosphorylation of PSII in plants exposed to high light enhances stacking dynamics of the photosynthetic membranes

\u3cem\u3eWomen Bound to Be Active\u3c/em\u3e (Year 3 & 4): Can a Book Club Help Women Overcome Barriers to Physical Activity and Improve Self-Worth?

Little progress has been made toward increasing physical activity (PA) in women. This study aimed to determine if an 8-month theory-based book club intervention (Women Bound to Be Active) was effective in increasing: (a) self-worth, (b) benefits relative to barriers to PA, and (c) PA in women (n=51). Findings suggested a book-club was effective for improving: self-worth, the benefits relative to barriers to PA, and possibly participation in PA. This is an innovative model to help women become more active and learn skills that may enable them to be active on their own long after a PA program has ended

First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis

Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk [RR], 4.28; 95% confidence interval [CI], 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities

Applying Interconnected Game Theory to Analyze Transboundary Waters: A Case Study of the Kura-Araks Basin

A number of environmental problems are international in nature, including many water management issues. Rivers, for example, do not recognize political boundaries. Therefore, pollution generated in one country can affect neighboring countries, while water extraction in an upstream country can affect water flow and water availability in a downstream country. The situation creates an interdependency among countries, which might lead to disputes over the management of transboundary water. Therefore, coordination among the countries is necessary for effective management of these transboundary resources. The focus of a recently published study (Khachaturyan and Schoengold, 2018) is the transboundary Kura-Araks Basin (see Figure 1 for its location), which is a major river system in the South Caucasus, with about 11 million people living in the basin. The countries in the basin are Armenia, Azerbaijan, Georgia, Iran, and Turkey, with Armenia, Azerbaijan, and Georgia having over 80 percent of the streamflow. The Kura-Araks Basin is a primary source of water for agricultural, industrial, and municipal uses in the South Caucasian countries. The study determines whether there are economic benefits to be gained from cooperation in the management of the Kura River (shared between Azerbaijan and Georgia), and under what conditions cooperation is an achievable outcome. Azerbaijan withdraws about 35 percent of the total available renewable water resources while Georgia only withdraws about 3 percent

Women Bound To Be Active: A Pilot Study to Explore the Feasibility of an Intervention to Increase Physical Activity and Self-Worth in Women

Increasing physical activity (PA) has become a national health objective due to its associated health benefits, but low participation rates. Therefore, the purpose of this study was to determine the feasibility of an 8-month (September 2006 - April 2007) PA book club (Women Bound to Be Active-WBA) in increasing PA and self-worth (SW) among women. Fifty-six adult women participated in an 8-month intervention consisting of weekly meetings designed to improve PA knowledge, awareness, confidence, and SW. Results indicated a significant increase in PA and SW. The WBA program represents a creative theory-based approach to empowering women to be more active

Modelling the progression of cervical dilatation in spontaneous labour

Introduction The first attempt to model the progression of cervical dilation during spontaneous labour of pregnant women dates back to 1955 [1]. From the graphical analysis of the time profiles of dilation observed in 500 women aged 13 to 42 years, the Author derived a mean labour sigmoid curve, consisting in a latent phase followed by an active phase ending in a deceleration phase. This cervimetric graph, or cervicogram, is still reported in current manuals of obstetrics. Zhang et al [2, 3] fitted cervical dilation profiles with mixed models based on 10th or 8th degree polynomials, and concluded that the duration of latent and active phases largely differs from woman to woman, and that there is no deceleration at the end of the active phase. For this reason, these Authors supply charts reporting the empirical 95th centile of the distribution of labour duration for different values of cervical dilation at admission to labour room, thus abandoning the idea of modelling the progression of cervical dilation. The aim of this presentation is to show the use of parsimonious nonlinear mixed models to trace cervimetric charts, reporting current cervical dilation vs time to full dilation. Data and methods Data here used derive from an observational study including 328 low-risk women (146 primiparae and 182 multiparae), who delivered at Buzzi Children\u2019s Hospital between April and June 2013 [4]. All women delivered vaginally at term, after uncomplicated single pregnancy and spontaneous labour managed by midwives, without any kind of medical intervention. We had to take into account a lot of difficulties and hindrances to construct a model for the progression of cervical dilation. The time of the beginning of labour is unknown (1); women are admitted to labour room at different degrees of dilation (2); cervical dilation measures are taken at irregular intervals as required by clinical practice (3); midwives usually assess cervical dilation with fingers, though the measure is reported in cm, from 0 (no dilation) to 10 (full dilation) (4); full cervical dilation is not indicated with a measure, but with a value of 10 cm, arbitrarily assigned to all women (5); individual dilation profiles are largely incomplete, a maximum of 5 measures per woman was recorded before full dilation, and only 60 women (18%) were assessed twice or more (6); the progression of cervical dilation is extremely erratic (7). Since dilation cannot be related to the unknown time from the onset of labour, we considered, as already suggested by Zhang et al [2], the time remaining to the attainment of full cervical dilation (t, time to full dilation), and expressed current dilation (yi(t), from 1 to 9 cm) observed in the ith woman as a function of a parsimonious nonlinear model (3 parameters only), instead of the 9 to 11 parameters of the polynomials used by Zhang et al [2, 3]: i i i i i(t) logit(y (t)/10) \u3b1= 7\u3b2+ log(t \u3b4+ ) \u3b5+ In {1}, logit(yi(t)/10) is a linear function of the log-transformation of time: parameter \u3b2i is the dilation velocity constant, the ratio \u3b1 \u3b2ii determines the time at maximum dilation velocity, and \u3b4i modulates the shape of the log-transformation of time; intra-individual random terms \u3b5i(t) were assumed to approximate a normal distribution, with variance proportional to {[E(yi(t))/10][1\u2013E(yi(t))}-1. When back-transformed to the original scale, expression {1} defines a family of strongly asymmetrical never-decreasing (since cervical dilation is an irreversible process) sigmoid curves, with a slight slowdown of dilation velocity a little before, or at full dilation, in this latter case the curve presents an exponential shape. Because cervical dilation profiles were largely incomplete, we could not resort to the usual two-stage models [5] to trace cervimetric charts, but we were forced to adopt a nonlinear mixed model [6], which can obtain estimates of the parameters of the individual cervical dilation curves also for the women with profiles made up by a number of observations lower the number of paramtes (in our case 1 or 2 assesments only): i 0 i P 0 i P 0 P i(t) logit(y (t)/10) \u3b1= \u3b1+ \u3b1+ x (\u3b2+ \u3b2+\u3b2+ x)log(t \u3b4+ \u3b4+ x) \u3b5+ {2} Parity (x=0 for primiparae, x=1 for multiparae) was included as a covariate into model {2}, since multiparae are known to progress somewhat faster in active-phase labour [7]. Parameters \u3b10 and \u3b20 refer to primiparae, \u3b1P and \u3b2P refer to the difference between multiparae and primiparae, whereas \u3b40 and \u3b4P modulate the log-transformation of time by parity. Random terms \u3b1i and \u3b2i, which model inter-individual differences, are assumed to have bivariate normal distribution with E(\u3b1i)=E(\u3b2i)=0 and unstructered covariance matrix Cov(\u3b1i,\u3b2i)=[ ] 2 2 \u3c3\u3b1 \u3c3\u3b1\u3b2 \u3c3\u3b2 , , . Models {1} and {2} were fitted using PROC NLIN and NLMIXED of SAS/STAT\uae software (SAS Institute, Cary, NC; v.9.4, 2013). Results Although based on 3 parameters only, model {1} proved to be flexible enough to describe cervical dilation profiles of rather different shape. As shown in figure 1 (left), concerning primiparous women, profiles may present an inflection point (i.e. a maximum dilation velocity) already 4 hours before the attainment of full dilation (orange curve) or at about 1 hour (dark red and green curves) or in the last half hour of the dilation process (the remaining profiles). Ten hours before the attainment of full dilation there are women with no more than 1 cm dilation and women with so much as 4 cm dilation. During the labour, dilation velocity may vary considerably from woman to woman: 10 hours before the attainment of full dilation, dilation velocity is always less than 0.5 cm/hr, but maximum velocity may be more than 3.5 cm/hr when initial dilation is 1 cm (red and blue curves) or be about 1 cm/hr when initial dilation is 4 cm (green curve). It is worth noting that women with different initial dilation (red curve: 1.7 cm, olive green curve: 2.7 cm) may present the same maximum velocity (1.7 cm/hr), since their dilation profiles differ in convexity. Figure 1 (right) shows, plotted on the cervicometric charts traced with mixed model {2}, the cervical dilation profiles (green lines) of the 95 primiparous women with 2 or more assessments and the dilation values (green dots) of the 51 women with 1 assessment only, predicted on the basis of model {2}. Green dots As expected, though individual profiles differ largely, the large majority of them lies completely within the interval 3rd \u2013 97th centile of the cervicometric charts. At 10 hours, the distribution of dilation values conditional on time to full dilation is highly right skewed, then positive skewness decreases and the distribution becomes symmetrical when median dilation is 5 cm, and left skewed subsequently. The same results were observed in the 182 multiparous women included in the study. We observe that a 4 cm dilation is the 97th centile 10 hours before the attainment of full dilation, and is the 3 rd centile at 0.5 hours. This means that, at 10 hours, 3% of women present more than 4 cm dilation, but that another 3% of women still present a 4 cm dilation half an hour before the end of dilation process. So a 4 cm dilation observed from 10 to 0.5 hours before the attainment of full dilation cannot be regarded as unusual. Analogously, at 10 hours, 10% and 25% of women present more than 3 and 2 cm dilation, respectively, but 10% and 25% of women still present a 3 or 2 cm dilation, 1 and 3 hours before the end of dilation process. Our data confirm that labour progresses faster in multiparae than in primiparae: e.g. a 5 cm dilation is achieved 45 min vs 1 hour and half before the end of dilation process in multiparae. Primiparae present a wider variability (+30% in terms of interquartile range) in the distribution of dilation values conditional on time to full dilation. Conclusions In 1955 Friedman [1] wrote: \u201cThe dynamic nature of parturitional change has, in the past, rendered exceedingly difficult the detailed and critical analysis of its vagaries\u201d. Actually, try to model the kinetics of the cervical dilation process turned out still to be a very hard task. Nonetheless some important points were established: (1) a parsimonious nonlinear parametric model is suitable to describe very different shapes of the dilation process, (2) mixed nonlinear models allow to trace plausible cervimetric charts even in the case of dilation profiles largely incomplete, (3) the above model provide quantitative estimates of the inter-individual variability and of the difference in the progression of cervical dilation between primiparae and multiparae. Unfortunately, the classical cervicograms give an unrealistic and useless picture of labour progression when referred to a single patient, the course of cervical dilation being largely erratic even in the case of spontaneous labour in uncomplicated pregnancies. In the first place, during labour the time remaining to the attainment of full cervical dilation is unknown, so the charts cannot be used in obstetric practice; in the second place a subsequent value of dilation cannot be predicted on the basis of the previous assessments. For these reasons, Ferrazzi et al [4] proposed cervimetric charts reporting the distribution of time needed to gain 1 cm in cervical dilation as a function of current dilation. Although theoretically usable, the practical value of these charts remains very low. In primiparous women, the time needed to gain 1 cm in dilation ranges from 10 (10th centile) to 110 min (90th centile) when current dilation is 1 cm, and from 5 to 70 min when current dilation is 9 cm. In multiparous women, the reference interval is somewhat narrower, the time needed ranging from 3 to 70 min when current dilation is 1 cm, and from 2 to 45 min when current dilation is 9 cm. On the basis of these results they concluded that the progression of cervical dilatation in normal human labour is unpredictable. References 1. Friedman EA. Primigravid labor. A graphicostatistical analysis. Obstetrics and Gynecology 1955; 6:567-589. 2. Zhang J, Troendle JF, Yancey MK. Reassessing the labor curve in nulliparous women. American Journal of Obstetrics and Gynecology 2002; 187:824-828. 3. Zhang J, Landy HJ, Branch DW, et al. Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstetrics and Gynecology 2010; 116:1281-1287. 4. Ferrazzi E, Milani S, Cirillo F, at al. Progression of cervical dilatation in normal human labor is unpredictable. Acta Obstet Gynecol Scand 2015; 94:1136-1144. 5. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982; 38:963-974. 6. Goldstein H. Nonlinear multilevel models, with an application to discrete response data. Biometrika 1991; 78:45-51. 7. Friedman EA. An objective approach to the diagnosis and management of abnormal labor. Bull N Y Acad Med 1972; 48:842-858

Impaired photosystem I oxidation induces STN7-dependent phosphorylation of the light-harvesting complex I protein Lhca4 in Arabidopsis thaliana

Reduction of the plastoquinone (PQ) pool is known to activate phosphorylation of thylakoid proteins. In the Arabidopsis thaliana mutants psad1-1 and psae1-3, oxidation of photosystem I (PSI) is impaired, and the PQ pool is correspondingly over-reduced. We show here that, under these conditions, the antenna protein Lhca4 of PSI becomes a target for phosphorylation. Phosphorylation of the mature Lhca4 protein at Thr16 is suppressed in stn7 psad1 and stn7 psae1 double mutants. Thus, under extreme redox conditions, hyperactivation of thylakoid protein kinases and/or reorganization of thylakoid protein complex distribution increase the susceptibility of PSI to phosphorylation

Urban Climate Action. The urban content of the NDCs: Global review 2022

This report was prepared by United Nations Human Settlement Programme (UN-Habitat) and the UNESCO Chair on Urban Resilience at the University of Southern Denmark (SDU.Resilience). It offers a global analysis of the urban content of 193 Nationally Determined Contributions (NDCs) submitted to the Secretariat of the United Nations Framework Convention on Climate Change (UNFCCC) before the 19th of June 2022. For this report, more than 200 indicators were used to analyse external data (e.g., Human Development Index and income categorisation) and data within the NDCs, including climate mitigation and adaptation challenges and responses, as well as specific sectors. This analysis is instrumental to supporting Parties’ efforts in further integrating national climate policies and urban climate actions, which is considered fundamental to raising ambition and developing adequate and timely actions as required by the current climate emergency. This review can be instrumental for advocacy and direct support to countries by partner organisations. The work was supported by a group of experts from bilateral and multilateral organisations and academia. Three expert group meetings were convened, and a peer review was organised for the final report