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Rationale: Aging in the heart is a gradual process, involving continuous changes in cardiovascular cells, including cardiomyocytes (CMs), namely cellular senescence. These changes finally lead to adverse organ remodeling and resulting in heart failure. This study exploits CMs from human induced pluripotent stem cells (iCMs) as a tool to model and characterize mechanisms involved in aging. Methods and Results: Human somatic cells were reprogrammed into human induced pluripotent stem cells and subsequently differentiated in iCMs. A senescent-like phenotype (SenCMs) was induced by short exposure (3 hours) to doxorubicin (Dox) at the sub-lethal concentration of 0.2 µM. Dox treatment induced expression of cyclin-dependent kinase inhibitors p21 and p16, and increased positivity to senescence-associated beta-galactosidase when compared to untreated iCMs. SenCMs showed increased oxidative stress, alteration in mitochondrial morphology and depolarized mitochondrial membrane potential, which resulted in decreased ATP production. Functionally, when compared to iCMs, SenCMs showed, prolonged multicellular QTc and single cell APD, with increased APD variability and delayed afterdepolarizations (DADs) incidence, two well-known arrhythmogenic indexes. These effects were largely ascribable to augmented late sodium current (I NaL ) and reduced delayed rectifier potassium current (Ikr). Moreover sarcoplasmic reticulum (SR) Ca 2+ content was reduced because of downregulated SERCA2 and increased RyR2-mediated Ca 2+ leak. Electrical and intracellular Ca 2+ alterations were mostly justified by increased CaMKII activity in SenCMs. Finally, SenCMs phenotype was furtherly confirmed by analyzing physiological aging in CMs isolated from old mice in comparison to young ones. Conclusions: Overall, we showed that SenCMs recapitulate the phenotype of aged primary CMs in terms of senescence markers, electrical and Ca 2+ handling properties and metabolic features. Thus, Dox-induced SenCMs can be considered a novel in vitro platform to study aging mechanisms and to envision cardiac specific anti-aging approach in humans., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aims: Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the dual properties to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). This project aims to characterize istaroxime effects at a concentration (100 nmol/L) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in an animal model of mild diabetes., Methods and Results: Streptozotocin (STZ) treated diabetic rats were studied at 9  weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed (i) marked DD not associated to cardiac fibrosis, (ii) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, (iii) reduced LV SERCA2 protein level and activity and (iv) slower SR Ca2+ uptake rate, (v) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, (vi) increased diastolic Ca2+, and (vii) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nmol/L) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent., Conclusions: SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The present review aims toward a better understanding of the nutrition of newborn puppies and kittens. The post-natal period is very sensitive in dogs and cats, as in other animal species. During the first two weeks of life, puppies and kittens are at high risk of dehydration, hypothermia, and hypoglycemia, as well as infectious diseases as they start to acquire the physiological functions of the adult. Neonatal hepatic glycogen storage is low, and newborns depend on colostrum intake to survive. Colostrum provides immunoglobulins and other important substances such as lipids and carbohydrates. Immunoglobulins are central to the immunological link that occurs when the mother transfers passive immunity. The mechanism of transfer varies among mammalian species, but in this review, we focused our attention on dogs and cats. Furthermore, there are components of colostrum which, although their presence is not absolutely necessary, play an important role in nutrition. These components have received considerable interest because of their presumed safety and potential nutritional and therapeutic effects both in humans and animals; however, unfortunately, there are few recent studies in companion animals. Here, we have gathered the published articles that describe studies involving different species of animals, emphasizing companion animals. In particular, the purpose of this narrative of the nutritional and functional proprieties of queens' and bitches' colostrum.

Background: N6-methyladenosine (m6A) modification of messenger RNA (mRNA) is crucial for liquid-liquid phase separation in mammals. Increasing evidence indicates that liquid-liquid phase separation in proteins and RNAs affects diabetic cardiomyopathy. However, the molecular mechanism by which m6A-mediated phase separation regulates diabetic cardiac fibrosis remains elusive. Methods: Leptin receptor-deficient mice (db/db), cardiac fibroblast-specific Notch1 conditional knockout (POSTN-Cre × Notch1flox/flox) mice, and Cre mice were used to induce diabetic cardiac fibrosis. Adeno-associated virus 9 carrying cardiac fibroblast-specific periostin (Postn) promoter-driven small hairpin RNA targeting Alkbh5, Ythdf2, or Notch1, and the phase separation inhibitor 1,6-hexanediol were administered to investigate their roles in diabetic cardiac fibrosis. Histological and biochemical analyses were performed to determine how Alkbh5 and Ythdf2 regulate Notch1 expression in diabetic cardiac fibrosis. NOTCH1 was reconstituted in ALKBH5- and YTHDF2-deficient cardiac fibroblasts and mouse hearts to study its effects on mitochondrial fission and diabetic cardiac fibrosis. Heart tissue samples from patients with diabetic cardiomyopathy were used to validate our findings. Results: In mice with diabetic cardiac fibrosis, decreased Notch1 expression was accompanied by high m6A mRNA levels and mitochondrial fission. Fibroblast-specific deletion of Notch1 enhanced mitochondrial fission and cardiac fibroblast proliferation and induced diabetic cardiac fibrosis in mice. Notch1 downregulation was associated with Alkbh5-mediated m6A demethylation in the 3'UTR of Notch1 mRNA and elevated m6A mRNA levels. These elevated m6A levels in Notch1 mRNA markedly enhanced YTHDF2 phase separation, increased the recognition of m6A residues in Notch1 mRNA by YTHDF2, and induced Notch1 degradation. Conversely, epitranscriptomic downregulation rescues Notch1 expression, resulting in the opposite effects. Human heart tissues from patients with diabetic cardiomyopathy were used to validate the findings in mice with diabetic cardiac fibrosis. Conclusions: We identified a novel epitranscriptomic mechanism by which m6A-mediated phase separation suppresses Notch1 expression, thereby promoting mitochondrial fission in diabetic cardiac fibrosis. Our findings provide new insights for the development of novel treatment approaches for patients with diabetic cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) represents one of the typical complications associated with diabetes. It has been described as anomalies in heart function and structure, with consequent high morbidity and mortality. DCM development can be described by two stages; the first is characterized by left ventricular hypertrophy and diastolic dysfunction, and the second by heart failure (HF) with systolic dysfunction. The proposed mechanisms involve cardiac inflammation, advanced glycation end products (AGEs) and angiotensin II. Furthermore, different studies have focused their attention on cardiomyocyte death through the different mechanisms of programmed cell death, such as apoptosis, autophagy, necrosis, pyroptosis and ferroptosis. Exosome release, adipose epicardial tissue and aquaporins affect DCM development. This review will focus on the description of the mechanisms involved in DCM progression and development. [ABSTRACT FROM AUTHOR]

Simple Summary: The nutritional needs of kittens are normally met by the queen, but sometimes unfavorable events such as maternal behavior, blood incompatibility and maternal agalactia occur that make it necessary for breeders to use milk replacer for feeding. As the breeding of domestic cats grows, so does the demand for specialized kitten formula. The aim of this study was to investigate the effects of an experimental milk replacer (EMR) on growth, gut microbiology, immune antioxidant capacity and nutrient metabolism in kittens. The results revealed that this EMR not only increases the growth rate of kittens in the late lactation period but also modified the composition of the gut microbiome, improved antioxidant capacity and activated lipid metabolic pathways. These insights are pivotal for optimizing milk replacers for kittens, thereby addressing challenges in feline neonatal nutrition. With the rising popularity of pet cats as companion animals, the survival of newborn kittens is often threatened by factors such as inadequate nursing, maternal behavior and blood incompatibility. These challenges require the use of milk replacers for nurturing. To investigate the effects that feeding kittens with an experimental milk replacer (EMR) have on growth and development, intestinal microbiota, immune response and nutrient metabolism, 12 British shorthair kittens were randomly divided into two groups after nursing for the first week of life. Kittens were fed queen's milk or EMR, whereby kittens fed queen's milk served as the control (CON) group. The findings revealed that the CON group exhibited superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC) (p < 0.01) on day 7. However, the EMR group had better growth performance during the later stage of the experiment (p < 0.05); the immunocompetence and antioxidant capacity of the EMR group were not significantly different from those of the CON group in the middle and late stages of the experiment, and the mean values of all the indexes were slightly better than those of the control group. Sequencing of the 16S rRNA gene in microbiota demonstrated that EMR increased the colonization of bacterial genera, including Lachnospiraceae, Enterococcus, Rothia and Ligilactobacillus. Compared to the CON group, acetate acid (p < 0.05), propionate acid (p < 0.01) and total SCFAs (p < 0.01) in the EMR group were significantly increased. Moreover, the intake of the EMR resulted in the production of distinct metabolites implicated in the metabolism of lipids and amino acids, among other nutrients, thus invigorating the associated metabolic pathways. These results elucidate the impact of administering a milk replacer on gastrointestinal health and nutrient assimilation in kittens. The study provides insights into the use of milk powder alternatives and sets the stage for future research on the formulation and effectiveness of kitten milk replacers. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical perturbations in the heart. Interstitial inflammation, oxidative stress, myocardial apoptosis, mitochondria dysfunction, defective cardiac metabolism, cardiac remodeling, hypertrophy and fibrosis with consequent impaired contractility are the most common mechanisms implicated. Epigenetic changes also have an emerging role in the regulation of these crucial pathways. The aim of this review was to highlight the increasing knowledge on the molecular mechanisms of DbCM and the new therapies targeting specific pathways. [ABSTRACT FROM AUTHOR]

The use of transgenic plants as delivery system for antigenic proteins is attractive for its simplicity and increases likelihood for local immune response at sites of infection. The aim of this study was to evaluate the protective effect of oral administration of tobacco seeds, expressing the FedA, the major protein of the F18 adhesive fimbriae, and B subunit of verocytotoxin, against verocytotoxin-producing E. coli (VTEC) strain in piglets. Forty-three early weaned piglets, were randomly divided into 4 experimental groups: 3 test groups and a control. Treatment groups orally received a bolus, with different dose of tobacco seeds on 0, 1, 2, 14 days post primary administration. After challenge, with 1*10(10) CFU of O138 Escherichia coli strain, piglets showed clinical scores significantly higher in the control group compared to orally immunized groups (P < 0.05) and the latter showed a faster recovery than in CG. In conclusion, oral administration of recombinant tobacco seeds expressing antigenic proteins against VTEC strains can induce a protective effect against challenger strain in piglets.

In the feline species, the mortality of live-born kittens over the first 2 months of life is around 10%. Although some losses are inevitable, progress in veterinary medicine and improved knowledge of feline neonatalogy should make it possible to reduce them to a lower level. The objectives of this study were: (i) to describe early growth in kittens, and (ii) to assess whether low birth weight kittens develop compensatory growth during the first week of life and if so, whether compensatory growth is associated with increased chances of survival. Using data collected from 5,504 kittens born in 193 different French catteries, five growth rates were calculated to reflect the growth of kittens during the first week after birth. Low birth weight kittens had higher growth rates than normal birth weight kittens. In addition, low birth weight kittens whose early growth was in the lowest 25% had a significantly higher 0-2 months mortality rate than all the other groups. Weight loss (or lack of weight gain) between birth and Day 2 was identified as a risk factor for 0-2 months mortality whatever the birth weight category. Finally, critical early growth thresholds were determined separately for low and normal birth weight kittens. These figures could help caregivers to validate the adequacy or inadequacy of kitten early growth. They will be able to quickly identify and provide appropriate care for the kittens whose growth is deemed insufficient in order to improve their chances of survival. [ABSTRACT FROM AUTHOR]

In this work, an artificial neural network (ANN)-based model is proposed to describe the input–output relationships in a Limaçon-To-Circular (L2C) gas expander with an inlet valve. The L2C gas expander is a type of energy converter that has great potential to be used in organic Rankine cycle (ORC)-based small-scale power plants. The proposed model predicts the different performance indices of a limaçon gas expander for different input pressures, rotor velocities, and valve cutoff angles. A network model is constructed and optimized for different model parameters to achieve the best prediction performance compared to the classic mathematical model of the system. An overall normalized mean square error of 0.0014, coefficient of determination ( R 2 ) of 0.98, and mean average error of 0.0114 are reported. This implies that the surrogate model can effectively mimic the actual model with high precision. The model performance is also compared to a linear interpolation (LI) method. It is found that the proposed ANN model predictions are about 96.53% accurate for a given error threshold, compared to about 91.46% accuracy of the LI method. Thus the proposed model can effectively predict different output parameters of a limaçon gas expander such as energy, filling factor, isentropic efficiency, and mass flow for different operating conditions. Of note, the model is only trained by a set of input and target values; thus, the performance of the model is not affected by the internal complex mathematical models of the overall valved-expander system. This neural network-based approach is highly suitable for optimization, as the alternative iterative analysis of the complex analytical model is time-consuming and requires higher computational resources. A similar modeling approach with some modifications could also be utilized to design controllers for these types of systems that are difficult to model mathematically. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) often leads to heart failure (HF) through acute or chronic maladaptive remodeling processes. This establishes coronary artery disease (CAD) and HF as significant contributors to cardiovascular illness and death. Therefore, treatment strategies for patients with CAD primarily focus on preventing MI and lessening the impact of HF after an MI event. Myocardial fibrosis, characterized by abnormal extracellular matrix (ECM) deposition, is central to cardiac remodeling. Understanding these processes is key to identifying new treatment targets. Recent studies highlight SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RAs) as favorable options in managing type 2 diabetes due to their low hypoglycemic risk and cardiovascular benefits. This review explores inflammation's role in cardiac fibrosis and evaluates emerging anti-diabetic medications' effectiveness, such as SGLT2i, GLP1-RAs, and dipeptidyl peptidase-4 inhibitors (DPP4i), in preventing fibrosis in patients with diabetes post-acute MI. Recent studies were analyzed to identify effective medications in reducing fibrosis risk in these patients. By addressing these areas, we can advance our understanding of the potential benefits of anti-diabetic medications in reducing cardiac fibrosis post-MI and improve patient outcomes in individuals with diabetes at risk of HF. [ABSTRACT FROM AUTHOR]

Hypoglycemia is the most common metabolic alteration in the clinical routine of newborn dogs, acting as a predictor of mortality in these patients. The neonatal dog shows hepatic insufficiency and homeostatic mechanisms not yet fully developed, with limited glycogen reserves and limited capacity to perform glycogenolysis and gluconeogenesis. These physiological particularities make newborn dogs particularly susceptible to hypoglycemia when of fasting, even for short periods. Several maternal and neonatal factors may be related to a higher risk of developing hypoglycemia in neonates. This paper reviews glycemic homeostasis, the pathophysiology of neonatal hypoglycemia, the main causes involved and the diagnostic and therapeutic approaches to this condition. [ABSTRACT FROM AUTHOR]

The emergence of resistance to prostate cancer (PCa) treatment, particularly to androgen deprivation therapy (ADT), has posed a significant challenge in the field of PCa management. Among the therapeutic options for PCa, radiotherapy, chemotherapy, and hormone therapy are commonly used modalities. However, these therapeutic approaches, while inducing apoptosis in tumor cells, may also trigger stress-induced premature senescence (SIPS). Cellular senescence, an entropy-driven transition from an ordered to a disordered state, ultimately leading to cell growth arrest, exhibits a dual role in PCa treatment. On one hand, senescent tumor cells may withdraw from the cell cycle, thereby reducing tumor growth rate and exerting a positive effect on treatment. On the other hand, senescent tumor cells may secrete a plethora of cytokines, growth factors and proteases that can affect neighboring tumor cells, thereby exerting a negative impact on treatment. This review explores how radiotherapy, chemotherapy, and hormone therapy trigger SIPS and the nuanced impact of senescent tumor cells on PCa treatment. Additionally, we aim to identify novel therapeutic strategies to overcome resistance in PCa treatment, thereby enhancing patient outcomes. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle—a well-balanced diet and physical activity. There is also a group of compounds—including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others—that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM. [ABSTRACT FROM AUTHOR]

Background: A mother's milk is considered the gold standard of nutrition in neonates and is a source of cytokines, immunoglobulins, growth factors, and other important components, yet little is known about the components of canine milk, specifically colostrum, and the knowledge related to its microbial and metabolic profiles is particularly underwhelming. In this study, we characterized canine colostrum and milk microbiota and metabolome for several breeds of dogs and examined profile shifts as milk matures in the first 8 days post-whelping. Results: Through untargeted metabolomics, we identified 63 named metabolites that were significantly differentially abundant between days 1 and 8 of lactation. Surprisingly, the microbial compositions of the colostrum and milk, characterized using 16S rRNA gene sequencing, were largely similar, with only two differentiating genera. The shifts observed, mainly increases in several sugars and amino sugars over time and shifts in amino acid metabolites, align with shifts observed in human milk samples and track with puppy development. Conclusion: Like human milk, canine milk composition is dynamic, and shifts are well correlated with developing puppies' needs. Such a study of the metabolic profile of canine milk, and its relation to the microbial community, provides insights into the changing needs of the neonate, as well as the ideal nutrition profile for optimal functionality. This information will add to the existing knowledge base of canine milk composition with the prospect of creating a quality, tailored milk substitute or supplement for puppies. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a critical complication that poses a significant threat to the health of patients with diabetes. The intricate pathological mechanisms of DCM cause diastolic dysfunction, followed by impaired systolic function in the late stages. Accumulating researches have revealed the association between DCM and various epigenetic regulatory mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and other epigenetic molecules. Recently, a profound understanding of epigenetics in the pathophysiology of DCM has been broadened owing to advanced high-throughput technologies, which assist in developing potential therapeutic strategies. In this review, we briefly introduce the epigenetics regulation and update the relevant progress in DCM. We propose the role of epigenetic factors and non-coding RNAs (ncRNAs) as potential biomarkers and drugs in DCM diagnosis and treatment, providing a new perspective and understanding of epigenomics in DCM. [ABSTRACT FROM AUTHOR]

Wayfinding in large indoor spaces is challenging for the limited views the wayfinder has. Verbal indoor wayfinding assistance converts the weakness into an advantage: This experimental study investigates whether such a conversation-based approach based on what is in view can lead to successful wayfinding in complex indoor environments. The findings of this experimental study indicate that by using verbal guidance people can arrive at their destination successfully without experiencing ambiguity of decisions and hesitation of decision-making time, nuanced by a set of environmental and personal attributes. These attributes are captured by variables including the route instruction grammar, familiarity with the environment, and configurational information. [ABSTRACT FROM AUTHOR]

Aging is a known co-morbidity of ischemic stroke with its risk and severity increasing every year past 55+. While many of the current stroke therapies have shown success in reducing mortality, post-stroke morbidity has not seen the same substantial reduction. Recently, the involvement of cellular senescence and SASP in brain injury and neurological degeneration has been recognized. Ischemic injury causes oxidative stress and mitochondrial damage that induces senescence through the activation of p21 and p16 pathways, ultimately leading to synthesis and release of senescence-associated secretory phenotype (SASP). This ischemic event causes stress-induced premature senescence (SIPS), aging the brain decades beyond the standard biological age due to an increase in senescent cells in the ischemic core and ipsilateral hemisphere. Therefore, therapies that target the senescent cells and SASP, including senolytics, senomorphic drugs, stem cell therapies, and other cell-specific interventions, may be a new path for stroke treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the passive immune transfer process and its effects in Turkish Kangal shepherd dogs. The material of the study consisted of 15 dams and their 138 offspring in the region of Central Anatolia, Türkiye. Blood samples were collected from the surviving puppies at 48±4 h postpartum and IgG levels were measured using the ELISA method. Before the blood samples were collected, 34 of the puppies (26.64%) died, 56 of the 104 puppies (40.58%) whose blood samples were collected and IgG analyses were done died prior to weaning, and 48 (34.78%) survived until weaning. All of the analyzed blood samples had IgG levels above 230 mg/dL and there was no passive transfer failure. The average blood IgG level of the puppies was 664.86 mg/dL. The effects of litter size and birth season on passive transfer success were statistically significant (P<0.05), while maternal age and the sex of the puppy were not significant (P>0.05). There was no correlation between the average blood IgG levels of the puppies and group mortality rates (r = -0.44). In conclusion, while the rate of passive transfer success for Turkish Kangal shepherd dogs was found to be high compared to other breeds, the high rate of mortality among the puppies suggested that dams and their litters should be cared for more carefully in the neonatal period. [ABSTRACT FROM AUTHOR]

Cancer is a disease that occurs as a result of abnormal or uncontrolled growth of cells due to DNA damage, among many other causes. Certain cancer treatments aim to increase the excess of DNA breaks to such an extent that they cannot escape from the general mechanism of cell checkpoints, leading to the apoptosis of mutant cells. In this study, one of the Sarco-endoplasmic reticulum Ca2+ATPase (SERCA2a) inhibitors, Istaroxime, was investigated. There has been very limited number of articles so far reporting Istaroxime's anticancer activity; thus, we aimed to evaluate the anticancer effects of Istaroxime by cell proliferation assay and revealed the cytotoxic activity of the compound. We further determined the interaction of Istaroxime with topoisomerase enzymes through enzyme activity tests and detailed molecular modeling analysis. Istaroxime exhibited an antiproliferative effect on A549, MCF7, and PC3 cell lines and inhibited Topoisomerase I, suggesting that Istaroxime can act as a Topoisomerase I inhibitor under in vitro conditions. Molecular docking analysis supported the experimental observations. A chemical reactivity analysis of the Istaroxime molecule was made in the light of Density Functional Theory computations. For this aim, important chemical reactivity descriptors such as hardness, electronegativity, and electrophilicity were computed and discussed as detailed. [ABSTRACT FROM AUTHOR]

Aging is the main risk factor for cardiovascular disease (CVD). As the world's population ages rapidly and CVD rates rise, there is a growing need for physiologically relevant models of aging hearts to better understand cardiac aging. Translational research relies heavily on young animal models; however, these models correspond to early ages in human life, therefore cannot fully capture the pathophysiology of age‐related CVD. Here, we first investigated the transcriptomic and proteomic changes that occur with human cardiac aging. We then chronologically aged human induced pluripotent stem cell‐derived cardiomyocytes (iCMs) and showed that 14‐month‐old iCMs exhibited a similar aging profile to the human CMs and recapitulated age‐related disease hallmarks. Using aged iCMs, we studied the effect of cell age on the young extracellular matrix (ECM) therapy, an emerging approach for myocardial infarction (MI) treatment and prevention. Young ECM decreased oxidative stress, improved survival, and post‐MI beating in aged iCMs. In the absence of stress, young ECM improved beating and reversed aging‐associated expressions in 3‐month‐old iCMs while causing the opposite effect on 14‐month‐old iCMs. The same young ECM treatment surprisingly increased SASP and impaired beating in advanced aged iCMs. Overall, we showed that young ECM therapy had a positive effect on post‐MI recovery; however, cell age was determinant in the treatment outcomes without any stress conditions. Therefore, "one‐size‐fits‐all" approaches to ECM treatments fail, and cardiac tissue engineered models with age‐matched human iCMs are valuable in translational basic research for determining the appropriate treatment, particularly for the elderly. [ABSTRACT FROM AUTHOR]

Parametric cycle analysis, an on-design engine study, specifies the required design characteristics that optimize engine performance. This study aimed to conduct a parametric analysis of a low-bypass turbofan engine with an afterburner, F100-PW229, and develop a technique for estimating its performance based on data using machine learning and deep learning. Commercially available gas turbine simulation software, GasTurb 14, was used to create a dataset of engine performance response variables and input design parameters. The effects of the Mach number, fan pressure ratio, altitude, turbine entry temperature, and bypass ratio on the specific thrust, propulsive efficiency, specific fuel consumption, and total fuel flow were investigated. Regression learning models and deep neural networks were then programmed on this dataset to predict responses for new input data. In MATLAB, a total of 24 regression models were trained with cross-validation, and the model with the least root mean square error was selected as the final model. The machine learning regression models produced reliable output parameter predictions, with the least root mean square error of 9.076 × 10−5. Among the numerous regression models tested, Gaussian process regression, the quadratic support vector machine, and the wide neural network emerged to be the most successful in predicting turbofan engine performance metrics. A multilayer perceptron model was coded in Python with two hidden layers that accurately predicted the performance parameters. The mean square error value on test data was found to be as low as 0.0046. In comparison to intensive computational simulations, machine learning and deep learning models offer an efficient method for conducting parametric analysis of turbofan engines. [ABSTRACT FROM AUTHOR]

Simple Summary: The pre-weaning period in calves is a critical phase in cattle farming, where neonatal calf diarrhea can affect animal welfare, leading to death in the most severe cases. Improving animal health is necessary to reduce antibiotic use, thereby reducing antibiotic resistance. Functional ingredients such as brown seaweeds could be integrated into the calf's nutritional plan for preventive purposes to increase gut health and metabolism. These seaweeds have a high content of bioactive compounds, such as polysaccharides, polyunsaturated fatty acids, antioxidants, peptides, vitamins, and minerals. This study evaluated the effects of using a macroalgae, Ascophyllum nodosum, as a supplement in pre-weaning calf nutrition on zootechnical performance, blood metabolism, and fecal bacteria. It was found to be particularly effective in cases of moderate diarrhea. Nutrition and health during pre-weaning affect the calves' future fertility, calving age, production, and carrier length. Calves are highly susceptible to neonatal calf diarrhea (NCD), which can be fatal. NCD is due to hypovolemia and acidosis, which may involve anorexia and ataxia. The One Health principle calls for a drastic reduction in antimicrobial use. One approach is to improve animal health and reduce the use of antibiotics and functional ingredients that have beneficial effects due to bioactive compounds. Several functional ingredients and additives can be considered, and, in particular for this study, Ascophyllum nodosum was considered. The present study aimed to evaluate the role of A. nodosum as a functional ingredient implemented into the milk replacer in neonatal calves. Twelve pre-weaned Holstein Frisian calves, housed in twelve individual pens in the same environmental conditions, were divided into two groups of six animals: a control group (CTRL, n = 6) fed with a milk replacer, and a treatment group receiving milk enriched with 10 g of A. nodosum in their diet (TRT, n = 6) for 42 days. The fecal score was evaluated daily (3–0 scale) to monitor the incidence of diarrhea in the two groups. The body weight was evaluated weekly, and every two weeks feces were collected for microbiological evaluation using a selective medium for plate counting of total, lactic acid, and coliform bacteria. To verify the presence of Lactobacillus, Bifidobacterium, and Escherichia coli, real-time qPCR was used. At the beginning and at the end of the trial, blood samples were obtained for serum metabolite analysis. The growth performance did not differ in either of the two groups, but significant differences were observed in the incidence of moderate diarrhea (p-value < 0.0113), where the TRT group showed a lower incidence of cases during the 42-day period. Serum analysis highlighted higher contents of albumin, calcium, phosphorus, and total cholesterol in the TRT group compared to CTRL (p-value < 0.05). In conclusion, implementation of A. nodosum in the diet of calves can lead to better animal welfare and may reduce the use of antibiotics. [ABSTRACT FROM AUTHOR]

Salmonella enterica serovar Choleraesuis (S. Choleraesuis) C500 strain is a live, attenuated vaccine strain that has been used in China for over 40 years to prevent piglet paratyphoid. However, this vaccine is limited by its toxicity and does not offer protection against diseases caused by F18+ Shiga toxinproducing Escherichia coli (STEC), which accounts for substantial economic losses in the swine industry. We recently generated a less toxic derivative of C500 strain with both asd and crp deletion (S. Choleraesuis C520) and assessed its efficacy in mice. In addition, we demonstrate that C520 is also less toxic in pigs and is effective in protecting pigs against S. Choleraesuis when administered orally. To develop a vaccine with a broader range of protection, we prepared a variant of C520 (S. Choleraesuis C522), which expresses rSF, a fusion protein comprised of the fimbriae adhesin domain FedF and the Shiga toxin-producing IIe B domain antigen. For comparison, we also prepared a control vector strain (S. Choleraesuis C521). After oral vaccination of pigs, these strains contributed to persistent colonization of the intestinal mucosa and lymphoid tissues and elicited both cytokine expression and humoral immune responses. Furthermore, oral immunization with C522 elicited both S. Choleraesuis and rSF-specific immunoglobulin G (IgG) and IgA antibodies in the sera and gut mucosa, respectively. To further evaluate the feasibility and efficacy of these strains as mucosal delivery vectors via oral vaccination, we evaluated their protective efficacy against fatal infection with S. Choleraesuis C78-1, as well as the F18+ Shiga toxinproducing Escherichia coli field strain Ee, which elicits acute edema disease. C521 conferred complete protection against fatal infection with C78-1; and C522 conferred complete protection against fatal infection with both C78-1 and Ee. Our results suggest that C520, C521, and C522 are competent to provide complete mucosal immune protection against fatal infectionwith S. Choleraesuis in swine and that C522 equally qualifies as an oral vaccine vector for protection against F18+ Shiga toxin-producing Escherichia coli. [ABSTRACT FROM AUTHOR]

Cytosolic Ca2+ signals are organized in complex spatial and temporal patterns that underlie their unique ability to regulate multiple cellular functions. Changes in intracellular Ca2+ concentration ([Ca2+]i) are finely tuned by the concerted interaction of membrane receptors and ion channels that introduce Ca2+ into the cytosol, Ca2+-dependent sensors and effectors that translate the elevation in [Ca2+]i into a biological output, and Ca2+-clearingmechanisms that return the [Ca2+]i to prestimulation levels and prevent cytotoxic Ca2+ overload. The assortment of the Ca2+ handling machinery varies among different cell types to generate intracellular Ca2+ signals that are selectively tailored to subserve specific functions. The advent of novel high-speed, 2D and 3D time-lapse imaging techniques, single-wavelength and genetic Ca2+ indicators, as well as the development of novel genetic engineering tools to manipulate single cells and whole animals, has shed novel light on the regulation of cellular activity by the Ca2+ handlingmachinery. A symposium organized within the framework of the 72nd Annual Meeting of the Italian Society of Physiology, held in Bari on 14-16th September 2022, has recently addressed many of the unexpected mechanisms whereby intracellular Ca2+ signalling regulates cellular fate in healthy and disease states. Herein, we present a report of this symposium, in which the following emerging topics were discussed: 1) Regulation of water reabsorption in the kidney by lysosomal Ca2+ release through Transient Receptor Potential Mucolipin 1 (TRPML1); 2) Endoplasmic reticulum-to-mitochondria Ca2+ transfer in Alzheimer's disease-related astroglial dysfunction; 3) The non-canonical role of TRPMelastatin 8 (TRPM8) as a Rap1A inhibitor in the definition of some cancer hallmarks; and 4) Non-genetic optical stimulation of Ca2+ signals in the cardiovascular system. [ABSTRACT FROM AUTHOR]

Simple Summary: Brown adipose tissue (BAT) is a thermogenic tissue that greatly contributes to preventing neonatal hypothermia by activating biochemical and endocrine processes because of cold stress. The presence of uncoupling proteins and adrenergic receptors in the brown adipocyte initiates the metabolic pathway for heat production. However, the presence and absence of BAT, as well as its activation, location, and the degree of thermogenic response, are traits that depend on intrinsic and extrinsic factors of mammals. The present review aims to discuss the neuromodulation mechanisms of thermoregulation and the importance of BAT, emphasizing the analysis of the biochemical, physiological, and genetic factors that determine the distribution, amount, and efficiency of this energy resource in newborns of different species. Hypothermia is one of the most common causes of mortality in neonates, and it could be developed after birth because the uterus temperature is more elevated than the extrauterine temperature. Neonates use diverse mechanisms to thermoregulate, such as shivering and non-shivering thermogenesis. These strategies can be more efficient in some species, but not in others, i.e., altricials, which have the greatest difficulty with achieving thermoneutrality. In addition, there are anatomical and neurological differences in mammals, which may present different distributions and amounts of brown fat. This article aims to discuss the neuromodulation mechanisms of thermoregulation and the importance of brown fat in the thermogenesis of newborn mammals, emphasizing the analysis of the biochemical, physiological, and genetic factors that determine the distribution, amount, and efficiency of this energy resource in newborns of different species. It has been concluded that is vital to understand and minimize hypothermia causes in newborns, which is one of the main causes of mortality in neonates. This would be beneficial for both animals and producers. [ABSTRACT FROM AUTHOR]

Post-weaning diarrhoea and enterotoxaemia caused by Escherichia coli are serious threats in the pig (Sus scrofa domesticus) livestock industry and are responsible for economic losses related to mortality, morbidity and stunted growth. The aim of this study was to evaluate the effect of an engineered tobacco seeds-based edible vaccine in O138 Escherichia coli-challenged piglets throughout a multidisciplinary approach. Thirty-six weaned piglets were enrolled and randomly divided into two experimental groups, a control (C; n = 18) group and a tobacco edible vaccination group (T, n = 18), for 29 days of trial. At days 0, 1, 2, 5 and 14, piglets of the T group were fed with 10 g of the engineered tobacco seeds line expressing F18 and VT2eB antigens, while the C group received wild-type tobacco seeds. After 20 days, 6 piglets/group were orally challenged with the Escherichia coli O138 strain (creating four subgroups: UC = unchallenged control, CC = challenged control, UT = unchallenged tobacco, CT = challenged tobacco) and fed with a high protein diet for 3 consecutive days. Zootechnical, clinical, microbiological, histological and immunological parameters were assayed and registered during the 9 days of post-challenge follow up. At 29 days post-challenge, the CT group displayed a lower average of the sum of clinical scores compared to the CC group (p < 0.05), while the CC group showed a higher average sum of the faecal score (diarrhoea) (p < 0.05) than the CT group. A decreased number of days of shedding of the pathogenic strain was observed in the CT compared to the CC group (p < 0.05). Specific anti-F18 IgA molecules were significantly higher in the CT group compared to the CC group's faecal samples during the post-challenge period (p < 0.01). In conclusion, edible vaccination with engineered tobacco seeds showed a protective effect on clinical symptoms and diarrhoea incidence during the post-challenge period, characterized by a limited time of pathogenic strain shedding in faeces. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide, the incidence of which is increasing annually. Interest has recently grown in the anti-cancer effect of functional foods rich in selenium (Se). Although clinical studies are inconclusive and anti-cancer mechanisms of Se are not fully understood, daily doses of 100–200 µg of Se may inhibit genetic damage and the development of cancer in humans. The anti-cancer effects of this trace element are associated with high doses of Se supplements. The beneficial anti-cancer properties of Se and the difficulty in meeting the daily requirements for this micronutrient in some populations make it worth considering the use of functional foods enriched in Se. This review evaluated studies on the anti-cancer activity of the most used functional products rich in Se on the European market. [ABSTRACT FROM AUTHOR]

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Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials. [ABSTRACT FROM AUTHOR]

The application of identification techniques using artificial intelligence to the gas turbine (GT), whose nonlinear dynamic behavior is difficult to describe through differential equations and the laws of physics, has begun to gain importance for a little more than a decade. NARX (Nonlinear autoregressive network with exogenous inputs) is one of the models used to identify GT because it provides good results. However, existing studies need to show a systematic method to generate robust NARX models that can identify a GT with satisfactory accuracy. In this sense, a systematic method is proposed to design NARX models for identifying a GT, which consists of nine precise steps that go from identifying GT variables to obtaining the optimized NARX model. To validate the method, it was applied to a case study of a 215 MW SIEMENS TG, model SGT6-5000F, using a set of 2305 real-time series data records, obtaining a NARX model with an MSE of 1.945 × 10−5, RMSE of 0.4411% and a MAPE of 0.0643. [ABSTRACT FROM AUTHOR]

Acute heart failure (AHF) is the most frequent cause of unplanned hospital admission in patients of >65 years of age and it is associated with significantly increased morbidity, mortality, and healthcare costs. Different AHF classification criteria have been proposed, mainly reflecting the clinical heterogeneity of the syndrome. Regardless of the underlying mechanism, peripheral and/or pulmonary congestion is present in the vast majority of cases. Furthermore, a marked reduction in cardiac output with peripheral hypoperfusion may occur in most severe cases. Diagnosis is made on the basis of signs and symptoms, laboratory, and non-invasive tests. After exclusion of reversible causes, AHF therapeutic interventions mainly consist of intravenous (IV) diuretics and/or vasodilators, tailored according to the initial hemodynamic status with the addition of inotropes/vasopressors and mechanical circulatory support if needed. The aim of this review is to discuss current concepts on the diagnosis and management of AHF in order to guide daily clinical practice and to underline the unmet needs. Preventive strategies are also discussed. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a growing public health problem in nearly 50% of patients with heart failure. Therefore, research on new strategies for its diagnosis and management has become imperative in recent years. Few drugs have successfully improved clinical outcomes in this population. Therefore, numerous attempts are being made to find new pharmacological interventions that target the main mechanisms responsible for this disease. In recent years, pathological mechanisms such as cardiac fibrosis and inflammation, alterations in calcium handling, NO pathway disturbance, and neurohumoral or mechanic impairment have been evaluated as new pharmacological targets showing promising results in preliminary studies. This review aims to analyze the new strategies and mechanical devices, along with their initial results in pre-clinical and different phases of ongoing clinical trials for HFpEF patients. Understanding new mechanisms to generate interventions will allow us to create methods to prevent the adverse outcomes of this silent pandemic. [ABSTRACT FROM AUTHOR]

Post Weaning Diarrhea (PWD) is the most important multifactorial gastroenteric disease of the weaning in pig livestock. Phytogenic (PHY) natural extracts are largely studied as alternatives to antibiotic treatments in combating the global concern of the antimicrobial resistance. The aim of this study was to evaluate the protective effect of innovative phytogenic premix with or without short and medium chain fatty acids (SCFA and MCFA) in O138 Escherichia coli challenged piglets. Twenty-seven weaned piglets were allotted into four groups fed different diets according to the following dietary treatments: CTRL (n = 13) group fed basal diet, PHY1 (n = 7) fed the basal diet supplemented with 0.2% of phytogenic premix, PHY2 (n = 7) fed the basal diet supplemented with 0.2% of phytogenic premix added with 2000 ppm of SCFA and MCFA. After 6 days of experimental diet feeding, animals were challenged (day 0) with 2 × 109 CFU of E. coli and CTRL group was divided at day 0 into positive (challenged CTRL + ; n = 6) and negative control group (unchallenged CTRL-; n = 7). Body weights were recorded at -14, -6, 0, 4 and 7 days and the feed intake was recorded daily. E. coli shedding was monitored for 4 days post-challenge by plate counting. Fecal consistency was registered daily by a four-point scale (0–3; diarrhea > 1) during the post-challenge period. Tissue samples were obtained for gene expression and histological evaluations at day 7 from four animals per group. Lower average feed intake was observed in CTRL + compared to PHY2 and CTRL during the post-challenge period. Infected groups showed higher E. coli shedding compared to CTRL- during the 4 days post-challenge (p < 0.01). PHY2 showed lower frequency of diarrhea compared to PHY1 and CTRL + from 5 to 7 days post-challenge. No significant alterations among groups were observed in histopathological evaluation. Duodenum expression of occludin tended to be lower in challenged groups compared to CTRL- at 7 days post-challenge (p = 0.066). In conclusion, dietary supplementation of PHY plus SCFA and MCFA revealed encouraging results for diarrhea prevention and growth performance in weaned piglets. [ABSTRACT FROM AUTHOR]

Current therapeutic strategies for acute heart failure (AHF) are based on traditional inotropic agents that are often associated with untoward effects; therefore, finding new effective approaches with a safer profile is dramatically needed. Istaroxime is a novel compound, chemically unrelated to cardiac glycosides, that is currently being studied for the treatment of AHF. Its effects are essentially related to its inotropic and lusitropic positive properties exerted through a dual mechanism of action: activation of the sarcoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a) and inhibition of the Na+/K+-ATPase (NKA) activity. The advantages of istaroxime over the available inotropic agents include its lower arrhythmogenic action combined with its capability of increasing systolic blood pressure without augmenting heart rate. However, it has a limited half-life (1 hour) and is associated with adverse effects including pain at the injection site and gastrointestinal issues. Herein, we describe the main mechanism of action of istaroxime and we present a systematic overview of both clinical and preclinical trials testing this drug, underlining the latest insights regarding its adoption in clinical practice for AHF. [ABSTRACT FROM AUTHOR]

Simple Summary: Breeders still see high rates of neonatal mortality in their kennels and catteries globally, which makes the perinatal period a challenge for veterinarians and breeders. This review describes a wide variety of factors that can potentially affect the health of a litter during pregnancy, birth, and the first few weeks of life, which requires both the veterinarian and the breeder to have knowledge of maternal and neonatal care. Knowledge in neonatology is essential for correct management and preventive measures in breeding, impacting well-being and greater neonatal survival. The productivity of kennels and catteries is directly linked to maternal prolificacy and neonatal survival. During the neonatal period, mortality is high, not only due to environmental factors after birth but also with regard to gestational fetal life, complications during delivery, and management errors. Neonatology is an area of veterinary medicine where having a strong knowledge base of applied physiology and common clinical presentations for newborns can often favor better outcomes and greater neonatal survival. The teaching of animal theriogenology topics, particularly neonatal medicine, in the veterinary curriculum has evolved significantly in recent years. It is essential that the veterinarian understands the maternal and neonatal particularities and the main aspects involved in the handling of puppies and kittens for the instruction of the correct handling to the breeders and better medical conduct. The breeder of dogs and cats, experienced or not, must count on the help of a veterinarian in their breeding. Proper management, constant monitoring of the litter, and prompt assistance are the keys to successful breeding. [ABSTRACT FROM AUTHOR]

This study focuses on an investigation of the operating performance and pollutant emission characteristics of a micro gas turbine combined cycle using biomass gas, replacing natural gas. The models of both recuperative cycle micro gas turbines with a waste heat utilization system and a micro gas-steam turbine combined cycle system are established. When the gas turbine works at 100 kW and the same types of fuel are burnt, the recuperative cycle system consumes less fuel than the gas-steam combined cycle system. The electric efficiency of the recuperative cycle system can reach more than 29%, which is higher than 24% of the gas-steam combined system. The combined cycle thermal efficiency of the recuperative system is as high as 66%, with 36% waste heat utilization efficiency. The electrical efficiency of the recuperative cycle system in the biomass gas case decreases, while that of the gas-steam combined cycle system undergoes little change. When the gas turbine power output increases from 50 kW to 100 kW, the electrical efficiency and combined cycle thermal efficiency increases, but the thermal efficiency of waste heat utilization of recuperative cycle decreases, the NOX and SO2 emissions gradually rise. Under the same working conditions, the NOX emissions of the recuperative cycle system are greater than that of the steam-gas combined cycle system. [ABSTRACT FROM AUTHOR]

Bad choices in municipal waste (MW) management cause negative effects on sustainability. Evolving regulation has identified prevention and recycling as the best strategies; nevertheless, disposal in landfilling sites plays an essential role since a complete zero-waste scenario is not realistic, currently. Nowadays, policies require a preliminary waste stabilization to decrease the putrescible content. Therefore, mechanical biological treatment (MBT) has replaced the previous crushing, aimed at simple volume reduction. Literature has proved the effectiveness of MBT when MW collection system is ineffective. The present paper considered a facility in an area with a high-performance MW collection system. A long-term (1999–2019) on-site sampling allowed the comparison between two sites of the facility: the old site (before the MBT activation) and the new area, where the stabilized waste is disposed of. Monitoring of biogas, leachate (analyzed parameters: pH, BOD5, COD, ammonia-nitrogen) and odorous emissions was performed to verify the effect of the stabilization process. The considered long period and the on-site sampling support the relevance of the results, compared to the available literature, often referred to as laboratory scale. The results proved the relatively low benefit of stabilization at the considered facility, which cannot justify the energy consumption of MBT. [ABSTRACT FROM AUTHOR]