Louis Pasteur (1822-1895), Ignaz Semmelweis (1818-1865), Joseph Lister (1827-1912) and the Link Between Their Works Toward the Development of Antisepsis: A Narrative Review.

Infection control remains a significant burden for healthcare systems. The irrational use of antibiotics in the fight against microbial diseases has led to the fast development of antimicrobial resistance. Considering how the latter can adversely influence the effectiveness of modern treatments and the way medicine is practiced, we should revise the events that led to the establishment of the general principles of antisepsis and pay special tribute to the people who contributed to their formation, bearing in mind that they remain unmodified to a great extent until today. Without Semmelweis' conceptualization of the idea of direct transmission of sepsis, Pasteur's emblematic figure that helped promote the idea even further, and Lister's methodology structuring, the scientific community would have significantly delayed winning the battle against germs.

A novel role for phospholamban in the thalamic reticular nucleus.

The thalamic reticular nucleus (TRN) is a brain region that influences vital neurobehavioral processes, including executive functioning and the generation of sleep rhythms. TRN dysfunction underlies hyperactivity, attention deficits, and sleep disturbances observed across various neurodevelopmental disorders. A specialized sarco-endoplasmic reticulum calcium (Ca2+) ATPase 2 (SERCA2)-dependent Ca2+ signaling network operates in the dendrites of TRN neurons to regulate their bursting activity. Phospholamban (PLN) is a prominent regulator of SERCA2 with an established role in myocardial Ca2+-cycling. Our findings suggest that the role of PLN extends beyond the cardiovascular system to impact brain function. Specifically, we found PLN to be expressed in TRN neurons of the adult mouse brain, and utilized global constitutive and innovative conditional genetic knockout mouse models in concert with electroencephalography (EEG)-based somnography and the 5-choice serial reaction time task (5-CSRTT) to investigate the role of PLN in sleep and executive functioning, two complex behaviors that map onto thalamic reticular circuits. The results of the present study indicate that perturbed PLN function in the TRN results in aberrant TRN-dependent phenotypes in mice (i.e., hyperactivity, impulsivity and sleep deficits) and support a novel role for PLN as a critical regulator of SERCA2 in the TRN neurocircuitry.

A genomics perspective of personalized prevention and management of obesity.

This review discusses the landscape of personalized prevention and management of obesity from a nutrigenetics perspective. Focusing on macronutrient tailoring, we discuss the impact of genetic variation on responses to carbohydrate, lipid, protein, and fiber consumption. Our bioinformatic analysis of genomic variants guiding macronutrient intake revealed enrichment of pathways associated with circadian rhythm, melatonin metabolism, cholesterol and lipoprotein remodeling and PPAR signaling as potential targets of macronutrients for the management of obesity in relevant genetic backgrounds. Notably, our data-based in silico predictions suggest the potential of repurposing the SYK inhibitor fostamatinib for obesity treatment in relevant genetic profiles. In addition to dietary considerations, we address genetic variations guiding lifestyle changes in weight management, including exercise and chrononutrition. Finally, we emphasize the need for a refined understanding and expanded research into the complex genetic landscape underlying obesity and its management.

A Novel Role for Phospholamban in the Thalamic Reticular Nucleus.

The thalamic reticular nucleus (TRN) is a critical brain region that greatly influences vital neurobehavioral processes, including executive functioning and the generation of sleep rhythms. Recently, TRN dysfunction was suggested to underlie hyperactivity, attention deficits, and sleep disturbances observed across various devastating neurodevelopmental disorders, including autism, schizophrenia and attention-deficit/hyperactivity disorder (ADHD). Notably, a highly specialized sarco- endoplasmic reticulum calcium (Ca 2+ ) ATPase 2 (SERCA2)-dependent Ca 2+ signaling network operates in the dendrites of TRN neurons to regulate their high-frequency bursting activity. Phospholamban (PLN) is a prominent regulator of the SERCA2 with an established role in maintaining Ca 2+ homeostasis in the heart; although the interaction of PLN with SERCA2 has been largely regarded as cardiac-specific, our findings challenge this view and suggest that the role of PLN extends beyond the cardiovascular system to impact brain function. Specifically, we found PLN to be expressed in the TRN neurons of the adult mouse brain and utilized global constitutive and innovative conditional genetic mouse models, in combination with 5-choice serial reaction time task (5-CSRTT) and electroencephalography (EEG)-based somnography to assess the role of PLN in regulating executive functioning and sleep, two complex behaviors that map onto thalamic reticular circuits. Overall, the results of the present study show that perturbed PLN function in the TRN results in aberrant thalamic reticular behavioral phenotypes in mice (i.e., hyperactivity, impulsivity and sleep deficits) and support a novel role for PLN as a critical regulator of the SERCA2 in the thalamic reticular neurocircuitry.

Therapeutic Targets and Personalized Medicine in Cardiac Disease.

Despite extensive research that has achieved notable advancements over the last decades, cardiovascular disease (CVD) remains the leading cause of death worldwide, with millions affected around the world [...].

Evolving cardiovascular genetic counseling needs in the era of precision medicine.

In the era of Precision Medicine the approach to disease diagnosis, treatment, and prevention is being transformed across medical specialties, including Cardiology, and increasingly involves genomics approaches. The American Heart Association endorses genetic counseling as an essential component in the successful delivery of cardiovascular genetics care. However, with the dramatic increase in the number of available cardiogenetic tests, the demand, and the test result complexity, there is a need not only for a greater number of genetic counselors but more importantly, for highly specialized cardiovascular genetic counselors. Consequently, there is a pressing need for advanced cardiovascular genetic counseling training, along with innovative online services, telemedicine, and patient-facing digital tools, as the most effective way forward. The speed of implementation of these reforms will be of essence in the translation of scientific advancements into measurable benefits for patients with heritable cardiovascular disease and their families.

Precision Medicine in Fatty Liver Disease/Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and is related to fatal and non-fatal liver, metabolic, and cardiovascular complications. Its non-invasive diagnosis and effective treatment remain an unmet clinical need. NAFLD is a heterogeneous disease that is most commonly present in the context of metabolic syndrome and obesity, but not uncommonly, may also be present without metabolic abnormalities and in subjects with normal body mass index. Therefore, a more specific pathophysiology-based subcategorization of fatty liver disease (FLD) is needed to better understand, diagnose, and treat patients with FLD. A precision medicine approach for FLD is expected to improve patient care, decrease long-term disease outcomes, and develop better-targeted, more effective treatments. We present herein a precision medicine approach for FLD based on our recently proposed subcategorization, which includes the metabolic-associated FLD (MAFLD) (i.e., obesity-associated FLD (OAFLD), sarcopenia-associated FLD (SAFLD, and lipodystrophy-associated FLD (LAFLD)), genetics-associated FLD (GAFLD), FLD of multiple/unknown causes (XAFLD), and combined causes of FLD (CAFLD) as well as advanced stage fibrotic FLD (FAFLD) and end-stage FLD (ESFLD) subcategories. These and other related advances, as a whole, are expected to enable not only improved patient care, quality of life, and long-term disease outcomes, but also a considerable reduction in healthcare system costs associated with FLD, along with more options for better-targeted, more effective treatments in the near future.

Phospholamban R14del disease: The past, the present and the future.

Arrhythmogenic cardiomyopathy affects significant number of patients worldwide and is characterized by life-threatening ventricular arrhythmias and sudden cardiac death. Mutations in multiple genes with diverse functions have been reported to date including phospholamban (PLN), a key regulator of sarcoplasmic reticulum (SR) Ca2+ homeostasis and cardiac contractility. The PLN-R14del variant in specific is recognized as the cause in an increasing number of patients worldwide, and extensive investigations have enabled rapid advances towards the delineation of PLN-R14del disease pathogenesis and discovery of an effective treatment. We provide a critical overview of current knowledge on PLN-R14del disease pathophysiology, including clinical, animal model, cellular and biochemical studies, as well as diverse therapeutic approaches that are being pursued. The milestones achieved in <20 years, since the discovery of the PLN R14del mutation (2006), serve as a paradigm of international scientific collaboration and patient involvement towards finding a cure.

Ageotypes revisited: The brain and central nervous system dysfunction as a major nutritional and lifestyle target for healthy aging.

Undeniably, biological age can significantly differ between individuals of similar chronological age. Longitudinal, deep multi-omic profiling has recently enabled the identification of individuals with distinct aging phenotypes, termed 'ageotypes'. This effort has provided a plethora of data and new insights into the diverse molecular mechanisms presumed to drive aging. Translational opportunities stemming from this knowledge continue to evolve, providing an opportunity for the provision of nutritional interventions aiming to decelerate the aging process. In this framework, the contemporary ageotypes classification was revisited via in silico analyses, with the brain and nervous system being identified as the primary targets of age-related biomolecules, acting through inflammatory and metabolic pathways. Nutritional and lifestyle factors affecting these pathways in the brain and central nervous system that could help guide personalized recommendations for the attainment of healthy aging are discussed.

Early metabolomic, lipid and lipoprotein changes in response to medical and surgical therapeutic approaches to obesity.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes in response to GLP-1RA (liraglutide) therapy vs. placebo and in comparison to bariatric surgery. METHODS: Three clinical studies were conducted: a bariatric surgery cohort study of participants with morbid obesity who underwent either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) studied over four and twelve weeks, and two randomized placebo-controlled, crossover double blind studies of liraglutide vs. placebo administration in participants with type 2 diabetes (T2D) and participants with obesity studied for three and five weeks, respectively. Nuclear magnetic resonance spectroscopy-derived metabolomic data were assessed in all eligible participants who completed all the scheduled in-clinic visits. The primary outcome of the study was to explore the changes of the metabolome among participants with obesity with and without T2D receiving the GLP-1RA liraglutide vs. placebo and participants with obesity undergoing bariatric surgery during the three to five-week study period. In addition, we assessed the bariatric surgery effects longitudinally over the twelve weeks of the study and the differences between the bariatric surgery subgroups on the metabolome. The trials are registered with ClinicalTrials.gov, numbers NCT03851874, NCT01562678 and NCT02944500. RESULTS: Bariatric surgery had a more pronounced effect on weight and body mass index reduction (-14.19 ± 5.27 kg and - 5.19 ± 5.27, respectively, p < 0.001 for both) and resulted in more pronounced metabolomic and lipidomic changes compared to liraglutide therapy at four weeks postoperatively. Significant changes were observed in lipoprotein parameters, inflammatory markers, ketone bodies, citrate, and branched-chain amino acids after the first three to five weeks of intervention. After adjusting for the amount of weight loss, a significant difference among the study groups remained only for acetoacetate, ß-hydroxybutyrate, and citrate (p < 0.05 after FDR correction). Glucose levels were significantly reduced in all intervention groups but mainly in the T2D group receiving GLP-1RA treatment. After adjusting for weight loss, only glucose levels remained significant (p = 0.001 after FDR correction), mainly due to the glucose change in the T2D group receiving GLP-1RA. Similar results with those observed at four weeks were observed in the surgical group when delta changes at twelve weeks were assessed. Comparing the two types of bariatric surgery, an intervention effect was more pronounced in the RYGB subgroup regarding total triglycerides, triglyceride-rich lipoprotein size, and trimethylamine-N-oxide (p for intervention: 0.031, 0.028, 0.036, respectively). However, after applying FDR correction, these changes deemed to be only suggestive; only time effects remained significant with no significant changes persisting in relation to the types of bariatric surgery. CONCLUSIONS: The results of this study suggest that the early metabolomic, lipid and lipoprotein changes observed between liraglutide treatment and bariatric surgery are similar and result largely from the changes in patients' body weight. Specific changes observed in the short-term post-surgical period between bariatric vs. nonsurgical treated participants, i.e., acetoacetate, ß-hydroxybutyrate, and citrate changes, may reflect changes in patient diets and calorie intake indicating potential calorie and diet-driven metabolomics/lipidomic effects in the short-term postoperatively. Significant differences observed between SG and RYGB need to be confirmed and extended by future studies.

Isoform changes of action potential regulators in the ventricles of arrhythmogenic phospholamban-R14del humanized mouse hearts.

Arrhythmogenic cardiomyopathy (ACM) is characterized by life-threatening ventricular arrhythmias and sudden cardiac death and affects hundreds of thousands of patients worldwide. The deletion of Arginine 14 (p.R14del) in the phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is a key regulator of sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Despite global gene and protein expression studies, the molecular mechanisms of PLN-R14del ACM pathogenesis remain unclear. Using a humanized PLN-R14del mouse model and human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), we investigated the transcriptome-wide mRNA splicing changes associated with the R14del mutation. We identified >200 significant alternative splicing (AS) events and distinct AS profiles were observed in the right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts. Enrichment analysis of the AS events showed that the most affected biological process was associated with "cardiac cell action potential", specifically in the RV. We found that splicing of 2 key genes, Trpm4 and Camk2d, which encode proteins regulating calcium homeostasis in the heart, were altered in PLN-R14del mouse hearts and human iPSC-CMs. Bioinformatical analysis pointed to the tissue-specific splicing factors Srrm4 and Nova1 as likely upstream regulators of the observed splicing changes in the PLN-R14del cardiomyocytes. Our findings suggest that aberrant splicing may affect Ca2+-homeostasis in the heart, contributing to the increased risk of arrythmogenesis in PLN-R14del ACM.

Does the Addition of Strength Training to a High-Intensity Interval Training Program Benefit More the Patients with Chronic Heart Failure.

Background: Aerobic exercise, either continuous or high intensity interval training (HIIT), induces important benefits in chronic heart failure (CHF) patients. Resistance training has been also shown to be beneficial in CHF. However, data regarding combined aerobic exercise and muscle strength training is still limited. The aim of this study was to investigate whether adding strength training to a HIIT protocol within a cardiac rehabilitation (CR) program has a cumulative beneficial effect on the functional capacity (FC) and quality of life (QoL) in patients with CHF. Methods: Forty-four consecutive patients [35 males, ejection fraction (EF) < 50%] with CHF under medication enrolled in a 36-session CR program and were randomized in two exercise groups; HIIT (HIIT group) or HIIT combined with strength training (high intensity interval training combined with strength training (COM) group). All patients underwent baseline and endpoint outcome measures of a symptom-limited maximal cardiopulmonary exercise testing (CPET), 1 repetition maximum (1RM) test, muscular endurance test, echocardiography, and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Results: Most of the CPET indices, EF, 1RM test, muscular endurance and QoL were improved after the CR program in each exercise training group (p < 0.05). However, COM group demonstrated a further improvement in chest muscle testing and workload at anaerobic threshold (AT) compared to HIIT group. Conclusions: An exercise-based CR program, consisted of either HIIT or HIIT combined with strength training, improves FC and QoL of patients with CHF. However, the addition of strength training to HIIT seems to have further beneficial effects on chest muscle strength and endurance, as well as workload at AT. Clinical Trial Registration: The study was registered in ClinicalTrials.gov with number NCT02387411.

Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability.

In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-ß, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERß-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERß. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.

Aberrant PLN-R14del Protein Interactions Intensify SERCA2a Inhibition, Driving Impaired Ca2+ Handling and Arrhythmogenesis.

Phospholamban (PLN), a key modulator of Ca2+-homeostasis, inhibits sarcoplasmic reticulum (SR) calcium-ATPase (SERCA2a) and regulates cardiac contractility. The human PLN mutation R14del has been identified in arrhythmogenic cardiomyopathy patients worldwide and is currently extensively investigated. In search of the molecular mechanisms mediating the pathological phenotype, we examined PLN-R14del associations to known PLN-interacting partners. We determined that PLN-R14del interactions to key Ca2+-handling proteins SERCA2a and HS-1-associated protein X-1 (HAX-1) were enhanced, indicating the super-inhibition of SERCA2a's Ca2+-affinity. Additionally, histidine-rich calcium binding protein (HRC) binding to SERCA2a was increased, suggesting the inhibition of SERCA2a maximal velocity. As phosphorylation relieves the inhibitory effect of PLN on SERCA2a activity, we examined the impact of phosphorylation on the PLN-R14del/SERCA2a interaction. Contrary to PLN-WT, phosphorylation did not affect PLN-R14del binding to SERCA2a, due to a lack of Ser-16 phosphorylation in PLN-R14del. No changes were observed in the subcellular distribution of PLN-R14del or its co-localization to SERCA2a. However, in silico predictions suggest structural perturbations in PLN-R14del that could impact its binding and function. Our findings reveal for the first time that by increased binding to SERCA2a and HAX-1, PLN-R14del acts as an enhanced inhibitor of SERCA2a, causing a cascade of molecular events contributing to impaired Ca2+-homeostasis and arrhythmogenesis. Relieving SERCA2a super-inhibition could offer a promising therapeutic approach for PLN-R14del patients.

Darling: A Web Application for Detecting Disease-Related Biomedical Entity Associations with Literature Mining.

Finding, exploring and filtering frequent sentence-based associations between a disease and a biomedical entity, co-mentioned in disease-related PubMed literature, is a challenge, as the volume of publications increases. Darling is a web application, which utilizes Name Entity Recognition to identify human-related biomedical terms in PubMed articles, mentioned in OMIM, DisGeNET and Human Phenotype Ontology (HPO) disease records, and generates an interactive biomedical entity association network. Nodes in this network represent genes, proteins, chemicals, functions, tissues, diseases, environments and phenotypes. Users can search by identifiers, terms/entities or free text and explore the relevant abstracts in an annotated format.

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: a Review of Shared Cardiometabolic Risk Factors.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising. NAFLD/nonalcoholic steatohepatitis (NASH) is associated not only with hepatic morbidity and mortality but also with an increased cardiovascular risk. NAFLD and cardiovascular disease (CVD) share several risk factors, such as obesity, metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. This review summarizes the evidence linking cardiometabolic risk factors and NAFLD in the context of risk for CVD. The cause of NAFLD/NASH is complex, involving a range of factors from genetics to lifestyle and energy balance. Genetically driven high liver fat content does not appear to be causally associated with increased CVD risk. In contrast, metabolic dysfunction not only predisposes to liver pathology but also leads to a significantly higher CVD risk. Given that NAFLD pathophysiology is influenced by multiple factors, each patient is unique as to their risk of developing CVD and liver pathology. At the same time, the rising burden of NAFLD/NASH is closely linked with the global increase in metabolic disorders, including obesity and type 2 diabetes. Therefore, both personalized therapeutic approaches that recognize individual pathophysiology, as well as public health policies that address the root causes of cardiometabolic risk factors for NAFLD may be needed to effectively address the NAFLD/NASH epidemic.