Programming and training rate-independent chemical reaction networks.

Embedding computation in biochemical environments incompatible with traditional electronics is expected to have a wide-ranging impact in synthetic biology, medicine, nanofabrication, and other fields. Natural biochemical systems are typically modeled by chemical reaction networks (CRNs) which can also be used as a specification language for synthetic chemical computation. In this paper, we identify a syntactically checkable class of CRNs called noncompetitive (NC) whose equilibria are absolutely robust to reaction rates and kinetic rate law, because their behavior is captured solely by their stoichiometric structure. In spite of the inherently parallel nature of chemistry, the robustness property allows for programming as if each reaction applies sequentially. We also present a technique to program NC-CRNs using well-founded deep learning methods, showing a translation procedure from rectified linear unit (ReLU) neural networks to NC-CRNs. In the case of binary weight ReLU networks, our translation procedure is surprisingly tight in the sense that a single bimolecular reaction corresponds to a single ReLU node and vice versa. This compactness argues that neural networks may be a fitting paradigm for programming rate-independent chemical computation. As proof of principle, we demonstrate our scheme with numerical simulations of CRNs translated from neural networks trained on traditional machine learning datasets, as well as tasks better aligned with potential biological applications including virus detection and spatial pattern formation.

MoËT: Mixture of Expert Trees and its application to verifiable reinforcement learning.

Rapid advancements in deep learning have led to many recent breakthroughs. While deep learning models achieve superior performance, often statistically better than humans, their adoption into safety-critical settings, such as healthcare or self-driving cars is hindered by their inability to provide safety guarantees or to expose the inner workings of the model in a human understandable form. We present MoËT, a novel model based on Mixture of Experts, consisting of decision tree experts and a generalized linear model gating function. Thanks to such gating function the model is more expressive than the standard decision tree. To support non-differentiable decision trees as experts, we formulate a novel training procedure. In addition, we introduce a hard thresholding version, MoËTh, in which predictions are made solely by a single expert chosen via the gating function. Thanks to that property, MoËTh allows each prediction to be easily decomposed into a set of logical rules in a form which can be easily verified. While MoËT is a general use model, we illustrate its power in the reinforcement learning setting. By training MoËT models using an imitation learning procedure on deep RL agents we outperform the previous state-of-the-art technique based on decision trees while preserving the verifiability of the models. Moreover, we show that MoËT can also be used in real-world supervised problems on which it outperforms other verifiable machine learning models.

Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival.

Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats' body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (ß1-AR), beta2-adrenergic receptor (ß2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while ß1-AR and ß2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.

Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats.

Cardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program.

The influence of subchronic co-application of vitamins B6 and folic acid on cardiac oxidative stress and biochemical markers in monocrotaline-induced heart failure in male Wistar albino rats.

The aim of this study was to test the hypothesis that subchronic co-application of vitamins B6 and folic acid (FA) could affect heart failure (HF) induced by monocrotaline (MCT), with the modulation of oxidative stress parameters and cardiometabolic biomarkers. Biochemical and histomorphometric analyses were assessed in blank solution-exposed controls (C1 physiological saline 1 mL/kg, 1 day, n = 8; C2 physiological saline 1 mL/kg, 28 days, n = 8), MCT-induced HF (MCT 50 mg/kg, n = 8), B6+FA (vitamin B6 7 mg·kg-1·day-1, FA 5 mg·kg-1·day-1; n = 8), and MCT+B6+FA (MCT 50 mg/kg, vitamin B6 7 mg·kg-1·day-1, FA 5 mg·kg-1·day-1; n = 8) in male Wistar albino rats (body mass 160 g at the start). Superoxide dismutase and glutathione peroxidase activities, thiol-, carbonyl groups, and nitrotyrosine were determined in cardiac tissue. Echocardiography was performed to confirm MCT-induced HF. The right ventricular wall hypertrophy, accompanied with significant increase of troponin T and preserved renal and liver function, has been shown in MCT-induced HF. However, these effects were not related to antioxidant effects of vitamin B6 and FA, since several parameters of oxidative stress were more pronounced after treatment. In this study, co-application of vitamins B6 and FA did not attenuate hypertrophy of the right ventricle wall but aggravated oxidative stress, which is involved in HF pathogenesis.

Cardiovascular variability and ß-ARs gene expression at two stages of doxorubicin - Induced cardiomyopathy.

Using comprehensive analysis of heart rate (HRV) and blood pressure (BPV) short-term variability we estimated the time course of changes of autonomic nervous system remodeling in two stages of doxorubicin-induced cardiomyopathy (DCM). We also investigated the level of gene expression of cardiac ß-1 (ß-1AR) and ß-2 (ß-2AR) adrenoceptors. Experiments were performed in adult male Wistar rats equipped with indwelling catheters for BP recording and blood withdrawal. A 15 mg/kg total cumulative dose of doxorubicin was injected i.p. to rats to induce DCM or saline for control (n=18). Rats were assessed for general toxicity, cardiovascular hemodynamic and echocardiography before treatment (n=6), 35 days (DOX35; n=6) and 70 days (DOX70; n=6) post-treatment. HRV was evaluated by spectral analysis, Poincaré plots, sample and approximate entropy. Expression of ß-1AR and ß-2AR mRNA was evaluated by RT-qPCR. Doxorubicin-treated rats exhibited poor general condition and lower survival than saline-treated rats. In DOX35 rats, there were no echocardiography signs of decompensation, no increase in serum cardiac troponins, but there was an increase of HRV and decrease of HR complexity. In these rats typical microscopic signs of cardiotoxicity were seen along with over-expression of ß-1AR mRNA. 70 days post-treatment echocardiography revealed signs of decompensation and serum cardiac troponin T was increased. At this stage BPV decreased. In conclusion, HRV increase matches transient over-expression of cardiac ß-1AR mRNA in compensate stage of DCM while decompensate stage of DCM is characterized by a decrease of BPV and no changes in ß-1AR and ß-2AR gene expression.

Measuring Patients' Knowledge About Adverse Effects of Angiotensin-Converting Enzyme Inhibitors.

BACKGROUND: Knowledge about adverse effects of medications is an important part of proper medication use and prerequisite for good treatment adherence. OBJECTIVE: The aim of our study was to construct, develop, and test a new questionnaire for the measurement of patients' knowledge about adverse drug reactions of angiotensin-converting enzyme (ACE) inhibitors. METHODS: The 8-item questionnaire was constructed to measure adverse reactions to ACE inhibitors. The questions were closed, with 7 offered answers, in the form of a Likert scale. It was tested for psychometric properties on patients who visited their general practitioners at state-owned health facilities in 5 Serbian cities: Belgrade, Kragujevac, Banja Luka, Gracanica, and Despotovac. RESULTS: The questionnaire was tested on 259 patients from general practice, taking an ACE inhibitor for more than 3 months. Experience with at least 1 adverse effect of ACE inhibitor was reported in 64 patients (24.7%), only 94 patients (36.3%) previously received any form of information about at least 1 adverse effect of ACE inhibitors from health workers, and only 42% expressed knowledge of any adverse events. The patients who were informed knew about the following adverse events as phrased in the official patient information leaflets: severe dizziness or light-headedness (44%); cough (37%); swelling of the hands, face, lips, or tongue (32%); indigestion (22%); headache (51%); and difficulty in breathing (15%). The questionnaire showed satisfactory internal consistency, with Cronbach α of 0.767, and individual scores correlated with general education of the patients. Factorial analysis revealed 2 domains (subscales): the first one with 5 questions is directed to adverse effects the patients may physically experience directly, whereas the second with 3 questions measures knowledge about adverse effects that could be experienced only indirectly, through conditions caused by the adverse effects. CONCLUSIONS: The questionnaire about knowledge of ACE inhibitors' adverse effects is a reliable and probably valid instrument for measuring patients' knowledge about adverse effects of ACE inhibitors.

Sudden death: Neurogenic causes, prediction and prevention.

Sudden death is a major health problem all over the world. The most common causes of sudden death are cardiac but there are also other causes such as neurological conditions (stroke, epileptic attacks and brain trauma), drugs, catecholamine toxicity, etc. A common feature of all these diverse pathologies underlying sudden death is the imbalance of the autonomic nervous system control of the cardiovascular system. This paper reviews different pathologies underlying sudden death with emphasis on the autonomic nervous system contribution, possibilities of early diagnosis and prognosis of sudden death using various clinical markers including autonomic markers (heart rate variability and baroreflex sensitivity), present possibilities of management and promising prevention by electrical neuromodulation.

Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats.

Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5 mg/kg), HPMA-DOX (5 mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs.

The psychometric properties of the Comprehensive Headache-related Quality of life Questionnaire (CHQQ) translated to Serbian.

BACKGROUND: The Comprehensive Headache-related Quality of life Questionnaire (CHQQ), is a recently developed and validated instrument, intended for measuring quality of life of patients with all headache types. Currently no validated headache-specific quality of life questionnaires are available in Serbian. The aim of this study was to translate the CHQQ from Hungarian to Serbian, to make necessary cultural adaptations and to test its psychometric properties in a sample of outpatients with headache. METHODS: The CHQQ was translated and adapted according to internationally accepted guidelines, and then tested on a sample of 216 Serbian headache patients (171 females and 45 males, mean age 42.3 years/SD 13.35; range 18-75). The majority of patients suffered from episodic tension-type headache (TTH); 27 (12.5 %) had episodic migraine. We calculated the internal consistency (Cronbach's alpha), criterion validity (correlations of individual items, dimensions and whole questionnaire with the clinical characteristics of headache), convergent validity (correlations of the abovementioned scores with results of other instruments measuring headache severity and impact), and discriminative validity (comparison of the scores in the two diagnostic groups) of the CHQQ. We used factor analysis to explore the underlying construct. RESULTS: The Serbian translation of CHQQ showed excellent internal consistency, both for the whole instrument (Cronbach's alpha 0.937) and its dimensions. The validity of the instrument in all aspects (criterion, convergent and discriminative validity) was also excellent when the whole sample and the subgroup of patients with TTH were analyzed, while the results for patients with migraine were less favorable. Factor analysis suggested the existence of a single dimension in this sample. CONCLUSIONS: The Serbian translation of CHQQ is as reliable and valid specific instrument for measuring headache-related quality of life in patients with TTH and probably in patients with migraine.