The cardiorespiratory system of miniature frogs.

Anurans of the genus Brachycephalus are among the smallest vertebrates in the world, due to an extreme process of miniaturization. As an example of this process, Brachycephalus species show loss of fingers, loss of the eardrum and middle ear, bone fusions, and the presence of paravertebral plates and parotic plaque. However, no studies addressing the consequences of miniaturization on internal organs, such as the lungs and heart, are currently available. Thus, this study aimed to investigate if overall small body size has affected the cardiorespiratory system. We investigated, via dissections, individuals of four Brachycephaloidea species: Brachycephalus rotenbergae, B. pitanga, Eleutherodactylus johnstonei, and Ischnocnema parva. We observed that B. rotenbergae and B. pitanga present a reduction of the atrial septum and absence of the carotid body. On the other hand, despite being a member of the sister genus to Brachycephalus (both genera belong to the Brachycephalidae), individuals of Ischnocnema present a heart with a complete septum and carotid body; this is also observed in E. johnstonei (Eleutherodactylidae). We observed that B. rotenbergae and B. pitanga have thin skin with a one to two cell thick germ layer, and their lungs likely exhibit lower blood supply when compared to individuals of the E. johnstonei and I. parva species. Based on the observed structures, we suggest that in species of Brachycephalus, respiration is performed mainly through the skin, and their lungs may have a reduced respiratory function.

Delayed sleep phase disorder during the COVID-19 pandemic and its health implications.

Circadian rhythm sleep disorders are alterations that are characterized by a shift in the sleep-wake cycle relative to day and night, such as the delayed sleep phase disorder (DSPD), which is a retard of at least 2 hours in the sleep start. Typically, the patient falls asleep after 2 a.m. and wakes up after 10 a.m. and with symptom of sleep onset insomnia. The prevalence of DSPD in young adults is 0.48%, increasing to 3.3% in adolescents. Interestingly, patients with COVID-19 infection report anxiety due to the intensive care unit lockdown and constant exposure to bright light. In addition, post-COVID patients have an increased risk of developing DSPD. For example, in adolescent post-COVID patients, the prevalence of DSPD increases to 63.3%. Patients with DSPD also have alterations in metabolic health, poor school performance, cognitive impairment, and a higher risk of developing other diseases. The objective of the present review is therefore to describe the characteristics of DSPD during the COVID-19 pandemic and to outline its possible implications for physical health (eg, metabolism) and mental health (eg, anxiety or depression).

LSTM-GARCH Hybrid Model for the Prediction of Volatility in Cryptocurrency Portfolios.

In the present work, the volatility of the leading cryptocurrencies is predicted through generalised autoregressive conditional heteroskedasticity (GARCH) models, multilayer perceptron (MLP), long short-term memory (LSTM), and hybrid models of the type LSTM and GARCH, where parameters of the GARCH family are included as features of LSTM models. The study period covered the scenario of the World Health Organization pandemic declaration around March 2020 at hourly frequency. We have found that the different variants of deep neural network models outperform those of the GARCH family in the sense of the hetorerocedastic error, and absolute and squared error (HSE). Under the sharpe ratio, the volatility forecasting of a uniform portfolio at long horizons systematically outperforms the stablecoin Tether, which is considered here as the risk-free asset. Also, including transaction volume helps reduce the value at risk or loss probability for the uniform portfolio. Moreover, in a minimum variance portfolio, it is observed that before the pandemic declaration, a large proportion of the capital was allocated to bitcoin (BTC). In contrast, after March 2020, the portfolio is more diversified with short positions for BTC. Moreover, the MLP models give the best predictive results, although not statistically different in accuracy compared to the LSTM and LSTM-GARCH versions under the Diebold-Mariano test. In sum, MLP models outperform most stylised financial models and are less computationally expensive than more complex neural networks. Therefore, simple learning models are suggested in highly non-linear time series volatility forecasts as it is the cryptocurrency market.

Parasomnias in patients with addictions-a systematic review.

Parasomnias are involuntary behaviors or subjective experiences during sleep. Our objective was to review existing information on the presence of parasomnias in patients with addictions or during treatment for addictions. Information about parasomnias related to rapid-eye-movement (REM) and non-REM sleep in patients with addictions, while using substances or in abstinence, was reviewed. A systematic search of published articles reporting parasomnias as a consequence of drug use or abuse was conducted in the PubMed and SciELO databases. The search for the studies was performed in three phases: (1) by title, (2) by abstract, and (3) by complete text. The search was performed independently by two researchers, who then compared their results from each screening phase. Seventeen articles were found. The consumption of alcohol was reported in association with arousal disorders, such as sexsomnia and sleep-related eating disorder; and REM sleep behavior disorder was reported during alcohol withdrawal. Cocaine abuse was associated with REM sleep behavior disorder with drug consumption dream content. Overall, we found that several types of parasomnias were very frequent in patients with addictions. To avoid accidents in bedroom, legal problems, and improve evolution and prognosis; must be mandatory to include security measures related to sleep period; avoid pharmacological therapy described as potential trigger factor; improve sleep hygiene; and give pharmacological and behavioral treatments for patients with these comorbid sleep disorders.

What Drives Bitcoin? An Approach from Continuous Local Transfer Entropy and Deep Learning Classification Models.

Bitcoin has attracted attention from different market participants due to unpredictable price patterns. Sometimes, the price has exhibited big jumps. Bitcoin prices have also had extreme, unexpected crashes. We test the predictive power of a wide range of determinants on bitcoins' price direction under the continuous transfer entropy approach as a feature selection criterion. Accordingly, the statistically significant assets in the sense of permutation test on the nearest neighbour estimation of local transfer entropy are used as features or explanatory variables in a deep learning classification model to predict the price direction of bitcoin. The proposed variable selection do not find significative the explanatory power of NASDAQ and Tesla. Under different scenarios and metrics, the best results are obtained using the significant drivers during the pandemic as validation. In the test, the accuracy increased in the post-pandemic scenario of July 2020 to January 2021 without drivers. In other words, our results indicate that in times of high volatility, Bitcoin seems to self-regulate and does not need additional drivers to improve the accuracy of the price direction.

Cardiac up-regulation of NBCe1 emerges as a beneficial consequence of voluntary wheel running in mice.

Physical training stimulates the development of physiologic cardiac hypertrophy (CH), being a key event in this process the inhibition of the Na+/H+ exchanger. However, the role of the sodium bicarbonate cotransporter (NBC) has not been explored yet under this circumstance. C57/Bl6 mice were allowed to voluntary exercise (wheel running) for five weeks. Cardiac mass was evaluated by echocardiography and histomorphometry detecting that training promoted the development of physiological CH (heart weight/tibia length ratio, mg/mm: 6.54 ± 0.20 vs 8.81 ± 0.24; interstitial collagen content, %: 3.14 ± 0.63 vs. 1.57 ± 0.27; and cross-sectional area of cardiomyocytes, µm2: 200.6 ± 8.92 vs. 281.9 ± 24.05; sedentary (Sed) and exercised (Ex) mice, respectively). The activity of the electrogenic isoform of the cardiac NBC (NBCe1) was estimated by recording intracellular pH under high potassium concentration and by measuring action potential duration (APD). NBCe1 activity was significantly increased in isolated cardiomyocytes of trained mice. Additionally, the APD was shorter and the alkalization due to high extracellular potassium-induced depolarization was greater in this group, indicating that the NBCe1 was hyperactive. These results are online with the observed myocardial up-regulation of the NBCe1 (Western Blot, %: 100 ± 13.86 vs. 202 ± 29.98; Sed vs. Ex, n = 6 each group). In addition, we detected a reduction in H2O2 production in the myocardium of trained mice. These results support that voluntary training induces the development of physiologic CH with up-regulation of the cardiac NBCe1 in mice. Furthermore, the improvement in the antioxidant capacity contributes to the beneficial cardiovascular consequences of physical training.

Network Analysis of Multivariate Transfer Entropy of Cryptocurrencies in Times of Turbulence.

We investigate the effects of the recent financial turbulence of 2020 on the market of cryptocurrencies taking into account the hourly price and volume of transactions from December 2019 to April 2020. The data were subdivided into time frames and analyzed the directed network generated by the estimation of the multivariate transfer entropy. The approach followed here is based on a greedy algorithm and multiple hypothesis testing. Then, we explored the clustering coefficient and the degree distributions of nodes for each subperiod. It is found the clustering coefficient increases dramatically in March and coincides with the most severe fall of the recent worldwide stock markets crash. Further, the log-likelihood in all cases bent over a power law distribution, with a higher estimated power during the period of major financial contraction. Our results suggest the financial turbulence induce a higher flow of information on the cryptocurrency market in the sense of a higher clustering coefficient and complexity of the network. Hence, the complex properties of the multivariate transfer entropy network may provide early warning signals of increasing systematic risk in turbulence times of the cryptocurrency markets.

Mechanisms of plant protection against two oxalate-producing fungal pathogens by oxalotrophic strains of Stenotrophomonas spp.

KEY MESSAGE: Oxalotrophic Stenotrophomonas isolated from tomato rhizosphere are able to protect plants against oxalate-producing pathogens by a combination of actions including induction of plant defence signalling callose deposition and the strengthening of plant cell walls and probably the degradation of oxalic acid. Oxalic acid plays a pivotal role in the virulence of the necrotrophic fungi Botrytis cinerea and Sclerotinia sclerotiorum. In this work, we isolated two oxalotrophic strains (OxA and OxB) belonging to the bacterial genus Stenotrophomonas from the rhizosphere of tomato plants. Both strains were capable to colonise endophytically Arabidopsis plants and protect them from the damage caused by high doses of oxalic acid. Furthermore, OxA and OxB protected Arabidopsis from S. sclerotiorum and B. cinerea infections. Bacterial inoculation induced the production of phenolic compounds and the expression of PR-1. Besides, both isolates exerted a protective effect against fungal pathogens in Arabidopsis mutants affected in the synthesis pathway of salicylic acid (sid2-2) and jasmonate perception (coi1). Callose deposition induced by OxA and OxB was required for protection against phytopathogens. Moreover, B. cinerea and S. sclerotiorum mycelial growth was reduced in culture media containing cell wall polysaccharides from leaves inoculated with each bacterial strain. These findings suggest that cell walls from Arabidopsis leaves colonised by these bacteria would be less susceptible to pathogen attack. Our results indicate that these oxalotrophic bacteria can protect plants against oxalate-producing pathogens by a combination of actions and show their potential for use as biological control agents against fungal diseases.

p38-MAP Kinase Negatively Regulates the Slow Force Response to Stretch in Rat Myocardium through the Up-Regulation of Dual Specificity Phosphatase 6 (DUSP6).

BACKGROUND/AIMS: Myocardial stretch increases cardiac force in two consecutive phases: The first one due to Frank-Starling mechanism, followed by the gradually developed slow force response (SFR). The latter is the mechanical counterpart of an autocrine/paracrine mechanism involving the release of angiotensin II (Ang II) and endothelin (ET) leading to Na⁺/H⁺ exchanger 1 (NHE-1) phosphorylation and activation. Since previous evidence indicates that p38-MAP kinase (p38-MAPK) negatively regulates the Ang II-induced NHE1 activation in vascular smooth muscle and the positive inotropic effect of ET in the heart, we hypothesized that this kinase might modulate the magnitude of the SFR to stretch. METHODS: Experiments were performed in isolated rat papillary muscles subjected to sudden stretch from 92 to 98% of its maximal length, in the absence or presence of the p38-MAPK inhibitor SB202190, or its inactive analogous SB202474. Western blot technique was used to determine phosphorylation level of p38-MAPK, ERK1/2, p90RSK and NHE-1 (previously immunoprecipitated with NHE-1 polyclonal antibody). Dual specificity phosphatase 6 (DUSP6) expression was evaluated by RT-PCR and western blot. Additionally, the Na⁺-dependent intracellular pH recovery from an ammonium prepulse-induced acid load was used to asses NHE-1 activity. RESULTS: The SFR was larger under p38-MAPK inhibition (SB202190), effect that was not observed in the presence of an inactive analogous (SB202474). Myocardial stretch activated p38-MAPK, while pre-treatment with SB202190 precluded this effect. Inhibition of p38-MAPK increased stretched-induced NHE-1 phosphorylation and activity, key event in the SFR development. Consistently, p38-MAPK inhibition promoted a greater increase in ERK1/2-p90RSK phosphorylation/activation after myocardial stretch, effect that may certainly be responsible for the observed increase in NHE-1 phosphorylation under this condition. Myocardial stretch induced up-regulation of the DUSP6, which specifically dephosphorylates ERK1/2, effect that was blunted by SB202190. CONCLUSION: Taken together, our data support the notion that p38-MAPK activation after myocardial stretch restricts the SFR by limiting ERK1/2-p90RSK phosphorylation, and consequently NHE-1 phosphorylation/activity, through a mechanism that involves DUSP6 up-regulation.

Silencing of the Na+/H+ exchanger 1(NHE-1) prevents cardiac structural and functional remodeling induced by angiotensin II.

Chronic activation of the renin angiotensin system (RAS) favors several cardiac diseases, among which myocardial hypertrophy occupies an outstanding place. In this context, the hyperactivity of the cardiac Na+/H+ (NHE-1) exchanger plays a key role. The pathologic remodeling of the myocardium constitutes an independent risk factor for morbidity and mortality with continuously increasing healthcare cost. Therefore, the development of better therapeutic strategies emerges as highly mandatory. Our goal was to prevent angiotensin II (ANGII)-induced cardiac hypertrophy by NHE-1 gene silencing in Wistar rats. The intramyocardial injection of a lentivirus coding a specific small interference RNA (l-shNHE1) significantly reduced NHE-1 expression exclusively in the heart (~ 50%) and prevented cardiac remodeling in rats exposed to chronic infusion of ANG II (heart weigh/tibia length: 24,03 ±â€¯0,7915 mg/mm vs 28,45 ±â€¯0,9779 mg/mm and collagen volume fraction 2526 ±â€¯0,5003 vs 5982 ±â€¯1043 in l-shNHE1 + ANGII and ANGII, respectively). Interestingly, this was accompanied by an improvement in cardiac function determined by echocardiography even though blood pressure remained elevated (Fractional shortening 0,5960 ±â€¯0,4228 vs -0,9567 ±â€¯0,06888 and blood pressure at the end of ANGII treatment 141,2 ±â€¯6117 mmHg vs 134,1 ±â€¯6723 mmHg; in l-shNHE1 + ANGII and ANGII, respectively). ANGII infusion increased myocardial NADPH oxidase activity but the l-shNHE1 injection prevented oxidative stress as revealed by the normalization of lipid peroxidation (T-BARS 12,40 ±â€¯2887.vs 23,05 ±â€¯1537 in l-shNHE1 + ANGII and ANGII, respectively). These results allow as to propose the partial silencing of the cardiac NHE-1 through lentiviral injection as a promising tool in the prevention of ANGII-induced cardiac hypertrophy.

Physiological cardiac hypertrophy: critical role of AKT in the prevention of NHE-1 hyperactivity.

BACKGROUND: The involvement of NHE-1 hyperactivity, critical for pathological cardiac hypertrophy (CH), in physiological CH has not been elucidated yet. Stimulation of NHE-1 increases intracellular Na(+) and Ca(2+) favouring calcineurin activation. Since myocardial stretch, an activator of NHE-1, is common to both types of CH, we speculate that NHE-1 hyperactivity may also happen in physiological CH. However, calcineurin activation is characteristic only for pathological hypertrophy. We hypothesize that an inhibitory AKT-dependent mechanism prevents NHE-1 hyperactivity in the setup of physiological CH. METHODS: Physiological CH was induced in rats by swimming (90 min/day, 12 weeks) or in cultured isolated cardiomyocytes with IGF-1 (10 nmol/L). RESULTS: Training induced eccentric CH development (left ventricular weight/tibial length: 22.0±0.3 vs. 24.3±0.7 mg/mm; myocyte cross sectional area: 100±3.2 vs. 117±4.1 %; sedentary (Sed) and swim-trained (Swim) respectively; p<0.05] with decreased myocardial stiffness and collagen deposition [1.7±0.05 % (Sed) vs. 1.4±0.09 % (Swim); p<0.05]. Increased phosphorylation of AKT, ERK1/2, p90(RSK) and NHE-1 at the consensus site for ERK1/2-p90(RSK) were detected in the hypertrophied hearts (P-AKT: 134±10 vs. 100±5; P-ERK1/2: 164±17 vs. 100±18; P-p90(RSK): 160±18 vs. 100±9; P-NHE-1 134±10 vs. 100±10; % in Swim vs. Sed respectively; p<0.05). No significant changes were detected neither in calcineurin activation [calcineurin Aß 100±10 (Sed) vs. 96±12 (Swim)], nor NFAT nuclear translocation [100±3.11 (Sed) vs. 95±9.81 % (Swim)] nor NHE-1 expression [100±8.5 (Sed) vs. 95±6.7 % (Swim)]. Interestingly, the inhibitory phosphorylation of the NHE-1 consensus site for AKT was increased in the hypertrophied myocardium (151.6±19.4 (Swim) vs. 100±9.5 % (Sed); p<0.05). In isolated cardiomyocytes 24 hours IGF-1 increased cell area (114±1.3 %; p<0.05) and protein/DNA content (115±3.9 %, p<0.05), effects not abolished by NHE-1 inhibition with cariporide (114±3 and 117±4.4 %, respectively). IGF-1 significantly decreased NHE-1 activity during pHi recovery from sustained intracellular acidosis (JH+ at pHi 6.8: 4.08±0.74 and 9.09±1.21 mmol/L/min, IGF-1 vs. control; p<0.05), and abolished myocardial slow force response, the mechanical counterpart of stretch-induced NHE-1 activation. CONCLUSIONS: NHE-1 hyperactivity seems not to be involved in physiological CH development, contrary to what characterizes pathological CH. We propose that AKT, through an inhibitory phosphorylation of the NHE-1, prevents its stretch-induced activation. This posttranslational modification emerges as an adaptive mechanism that avoids NHE-1 hyperactivity preserving its housekeeping functioning.

Las Bolitas Syndrome in Penaeus vannamei Hatcheries in Latin America.

In September 2023, several hatcheries in Latin America experienced significant mortality rates, up to 90%, in zoea stage 2 of Penaeus vannamei. Observations of fresh mounts revealed structures resembling lipid droplets, similar to those seen in a condition known as "las bolitas syndrome". Routine histopathological examinations identified detached cells and tissues in the digestive tracts of affected zoea, contrasting with the typical algal cell contents seen in healthy zoea. Polymerase chain reaction (PCR) testing for over 20 known shrimp pathogens indicated minimal differences between diseased and healthy batches. Both groups tested negative for acute hepatopancreatic necrosis disease (AHPND) but positive for Vibrio species and Rickettsia-like bacteria in the diseased samples. Histological analyses of the affected zoea revealed characteristic tissue degeneration in the hepatopancreas, forming spheres that eventually migrated into the upper gut, midgut, and midgut caeca, a pathology identified as bolitas syndrome (BS). Microbiological assessments revealed Vibrio species at concentrations of 106 CFU zoea/g in affected zoea, approximately two orders of magnitude higher than in healthy zoea. Bacterial isolation from both healthy and BS-affected zoea on thiosulphate-citrate-bile salts-sucrose (TCBS) agar and CHROMagar™ (Paris, France), followed by identification using API 20E, identified six strains of Vibrio alginolyticus. Despite similarities to "las bolitas syndrome" in fresh mounts, distinct histopathological differences were noted, particularly the presence of sloughed cells in the intestines and variations in hepatopancreatic lobes. This study highlights the critical need for further research to fully understand the etiology and pathology of bolitas syndrome in zoea stage 2 of P. vannamei to develop effective mitigation strategies for hatchery operations.

Implementing youth participatory action research at a continuation high school.

OBJECTIVE: To describe the process of implementing a Youth Participatory Action Research (YPAR) project at a continuation high school (CHS) and share the results of a youth-designed research project that explores barriers to high school completion. DATA SOURCES AND STUDY SETTING: YPAR was implemented across three cohorts at a CHS in the central coast of California from 2019 to 2022. Student survey respondents were enrolled CHS students between March and April 2021. STUDY DESIGN: A modified YPAR curriculum integrating research methodology and social justice topics was used to guide student-led research that resulted in a cross-sectional survey. DATA COLLECTION: Field notes maintained by the first author documented the process of implementing YPAR including the curriculum, conversations, and research decisions and procedures. A student-designed survey disseminated to all enrolled students resulted in 76 (66%) participant responses. The survey included 18 close-ended questions and three narrative responses. PRINCIPAL FINDINGS: This study details how YPAR methodologies can be translated to a high school credit recovery program. For example, student cohorts were needed to maintain continuity over time. A student-designed survey revealed that 72% of student respondents reported taking care of family members and illuminated high rates of depression symptoms. CONCLUSIONS: This study offers a detailed description of how we implemented YPAR at a credit recovery program and provides student-driven perspectives on educational reform and evaluation. This project addresses the implementation and challenges of using YPAR to engage youth in transformational resistance to rapidly study and improve CHS' policy and practice.

Two-step estimators of high-dimensional correlation matrices.

We investigate block diagonal and hierarchical nested stochastic multivariate Gaussian models by studying their sample cross-correlation matrix on high dimensions. By performing numerical simulations, we compare a filtered sample cross-correlation with the population cross-correlation matrices by using several rotationally invariant estimators (RIEs) and hierarchical clustering estimators (HCEs) under several loss functions. We show that at large but finite sample size, sample cross-correlations filtered by RIE estimators are often outperformed by HCE estimators for several of the loss functions. We also show that for block models and for hierarchically nested block models, the best determination of the filtered sample cross-correlation is achieved by introducing two-step estimators combining state-of-the-art nonlinear shrinkage models with hierarchical clustering estimators.

The economic costs of insomnia comorbid with depression and anxiety disorders: an observational study at a sleep clinic in Mexico.

Significant advances documenting the costs associated with insomnia have been achieved. However, those related to insomnia associated with mood disorders remain understudied, even though insomnia is more severe in the presence of comorbid conditions such as depression and anxiety. The aim of this study was to determine the direct and indirect costs of insomnia associated with depression and anxiety disorders (DAD) from the perspective of the patient in a private healthcare system. This was an observational study of chronic insomnia associated with DAD at a private Sleep Disorders Clinic in Mexico City between 2019 and 2020. Patients were followed for up to one year. Healthcare resource utilization data were collected through clinical records. Direct and indirect costs associated with insomnia treatment were estimated through micro-costing. The estimated economic burden was projected to 5 years adjusting for inflation and discounting future costs. A deterministic sensitivity analysis was performed. The median cost of the first year of insomnia treatment associated with DAD was US$3537.57 per patient. The work productivity loss represented the highest economic burden (63.84%) followed by direct medical costs (28.32%), and the direct non-medical costs (7.85%). The estimated annual economic burden for patients treated in the private healthcare system in Mexico was US$293 million. The costs of insomnia associated with DAD at a private clinic in México were found to be high. The burden of the costs faced by these patients is substantial relative to the median income of the population. The economic costs at an individual and societal levels are substantial. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00412-6.

Sixteen Years since the Convention on the Rights of Persons with Disabilities: What Have We Learned since Then?

Persons with disabilities have historically been subjected to discrimination and exclusion, placing them in dangerous situations of social vulnerability. The Convention on the Rights of Persons with Disabilities, passed on the 13th of December 2006, was an important legislative landmark for valuing the rights of this population group. This study involved a bibliometric analysis of 1024 research articles published in Scopus on the social, workplace, educational, and financial inclusion of persons with disabilities since the Convention. The results show an increase in scientific production, and there is also a great deal of multi-disciplinarity, which has led to important breakthroughs for the all-encompassing inclusion of this section of the population. The most productive journals, authors, institutions, and countries, as well as the international cooperation networks, are presented here. The review concludes by setting out the main themes and trends in the research.

A Method for Rapid and Reliable Molecular Detection of Drought-Response Genes in Sorghum bicolor (L.) Moench Roots.

Drought is a major environmental stress that limits growth and productivity in agricultural ecosystems limiting crop yield worldwide. Breeding crops for enhanced drought tolerance is a priority to preserve food security on the increasing world population. Recent work in Arabidopsis has shown that vascular brassinosteroid receptor BRL3 (Brassinosteroid insensitive like-3) transcriptionally controls the production of osmoprotectant metabolites that confer drought resistance without penalizing growth, offering new and exciting possibilities for biotechnological improvement of drought-resistant crops. In cereals, understanding transcriptional responses to drought is an essential step for the production of gene-edited drought-resistant cereals. In this chapter, we present a method to analyze the transcriptional responses to drought in Sorghum bicolor (L.) Moench, our cereal of choice. Among the genes we tested, we found that drought marker gene SbDHN1 has a 1000-fold increase only after 1 day of drought, bringing possibilities for the development of molecular sensors for testing drought. Overall, this analysis is useful to set up conditions of high-throughput transcriptomic analysis of drought stressed plants before drought phenotype is observed.

Alteration in tyrosine phosphorylation of cardiac proteome and EGFR pathway contribute to hypertrophic cardiomyopathy.

Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and α myosin heavy chain R403Q (R403Q-αMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-αMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirm the above-described pathways and the effectiveness of AG-825 Treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models.

Evolutionary advantage of a dissociative search mechanism in DNA mismatch repair.

Protein complexes involved in DNA mismatch repair diffuse along dsDNA as sliding clamps in order to locate a hemimethylated incision site. They have been observed to use a dissociative mechanism, in which two proteins, while continuously remaining attached to the DNA, sometimes associate into a single complex sliding on the DNA and sometimes dissociate into two independently sliding proteins. Here, we study the probability that these complexes locate a given target site via a semi-analytic, Monte Carlo calculation that tracks the association and dissociation of the sliding complexes. We compare such probabilities to those obtained using a nondissociative diffusive scan in the space of physically realistic diffusion constants, hemimethylated site distances, and total search times to determine the regions in which dissociative searching is more or less efficient than nondissociative searching. We conclude that the dissociative search mechanism is advantageous in the majority of the physically realistic parameter space, suggesting that the dissociative search mechanism confers an evolutionary advantage.