Cyprocide selectively kills nematodes via cytochrome P450 bioactivation.

Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.

SIGNIFICANCE deep learning based platform to fight illicit trafficking of Cultural Heritage goods.

The illicit traffic of cultural goods remains a persistent global challenge, despite the proliferation of comprehensive legislative frameworks developed to address and prevent cultural property crimes. Online platforms, especially social media and e-commerce, have facilitated illegal trade and pose significant challenges for law enforcement agencies. To address this issue, the European project SIGNIFICANCE was born, with the aim of combating illicit traffic of Cultural Heritage (CH) goods. This paper presents the outcomes of the project, introducing a user-friendly platform that employs Artificial Intelligence (AI) and Deep learning (DL) to prevent and combat illicit activities. The platform enables authorities to identify, track, and block illegal activities in the online domain, thereby aiding successful prosecutions of criminal networks. Moreover, it incorporates an ontology-based approach, providing comprehensive information on the cultural significance, provenance, and legal status of identified artefacts. This enables users to access valuable contextual information during the scraping and classification phases, facilitating informed decision-making and targeted actions. To accomplish these objectives, computationally intensive tasks are executed on the HPC CyClone infrastructure, optimizing computing resources, time, and cost efficiency. Notably, the infrastructure supports algorithm modelling and training, as well as web, dark web and social media scraping and data classification. Preliminary results indicate a 10-15% increase in the identification of illicit artifacts, demonstrating the platform's effectiveness in enhancing law enforcement capabilities.

Influence of knot strength on the mechanical performance of a biodegradable gillnet.

Ghost fishing is a global issue that can be addressed using fishing gear materials that do not persist in the marine environment. However, for these alternatives to be widely adopted, they must meet the same mechanical specifications as current commercial materials while degrading without any negative impact. The objective of this study was to compare a conventional gillnet made of polyamide 6 (PA6) with an alternative made of poly(butylene succinate-co-adipate-co-terephthalate) (PBSAT) at three different scales: monofilament, knot, and net. While the PBSAT monofilament's strength was half that of the conventional PA6 net, knot and net losses were even more significant. This indicates a greater sensitivity of the material to the knot. Since the results between the knot and net scales were coherent, testing whole net panels is not necessary. Studying the curvature and the behaviour of the knot revealed its complex geometry and mechanical behaviour. Testing the weaver's knot is a good indicator for studying the relevance of an alternative to conventional fishing gear materials. This should be considered when developing biodegradable nets in order to reduce ghost fishing at sea.

Evaluation of the Implementation of Integrated Primary Care for Patients with Type 2 Diabetes and Hypertension in Belgium, Cambodia, and Slovenia.

Introduction: Integrated care of chronic patients improves quality of their management, but there is scarce evidence of its implementation in different healthcare settings. With this article, we wanted to determine the level of integrated care implementation in the management of T2D (diabetes) and HT (hypertension) in three different settings: Belgium, Slovenia, and Cambodia. Methods: This was an observational study with integrated approach. It was conducted in primary health care organisations in three countries. In each primary health care organisation, we aimed to include primary care workers that worked with Type 2 Diabetes (T2D) and hypertension (HT) patients. Data was collected with the Integrated Care Package (ICP) grid (consisting of six elements: identification, treatment, health education, self-management, caregiver collaboration, and care organisation). Results: ICP is almost completely implemented without major differences within Slovenia. There is a considerable variability across practice types in Belgium. Implementation is constrained by health system resources in Cambodia. Some elements, especially identification, are better implemented then others, across health systems. Conclusion: Countries can enhance integrated care for chronic diseases by implementing central policies, standardized protocols, and local adaptation, addressing resource constraints, promoting systematic screening and health education, and providing training for healthcare workers, tailored to community needs, to improve patient outcomes and healthcare delivery.

Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Hyperammonemia as a Possible Cause of Dementia Not Classified as Alzheimer's Disease or Frontotemporal Dementia.

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C>T; and rs121908641, p.Gly390Arg, G>A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects.

[SIC Position paper: Treat to prevent the first event - intensive LDL cholesterol lowering in patients at very high cardiovascular risk without a previous cardiovascular event. From ESC guidelines to clinical practice]. / Position paper SIC: Trattare per prevenire ­ la riduzione intensiva del colesterolo LDL nel paziente a rischio cardiovascolare molto alto senza pregresso evento. Dalle linee guida ESC alla pratica clinica.

Cardiovascular (CV) diseases account for over 4 million deaths every year in Europe and over 220 000 deaths in Italy, representing the leading cause of morbidity and mortality worldwide. The European Society of Cardiology (ESC) guidelines have visionary included in the at very high CV risk group patients without previous acute ischemic events, such as those with subclinical atherosclerosis, chronic coronary syndrome or peripheral arterial disease, familial hypercholesterolemia, diabetes mellitus with target organ damage or multiple associated risk factors, and those with high calculated CV risk score, recommending to consider them and to achieve the same LDL-cholesterol targets as for secondary prevention patients. The aim of this position paper is to provide an updated overview of ESC guidelines that focuses on these patient categories to raise awareness within the clinical community regarding CV risk reduction in this specific epidemiological context.

Christian Worldview and Caring in Nursing: The Legacy of Sister Simone Roach.

ABSTRACT: Sister Simone Roach, a noted philosopher of caring in nursing, left behind a significant body of theoretical and practical work highlighting the areas of nursing ethics, care/caring, and compassion. This article explores the integration of the moral foundation of agape love in Pauline theology and Roach's human caring in nursing (1992) as the action of agape love. A narrative literature review explores the relationship between the scriptural ethics of St. Paul (Pauline ethics) and Roach's caring in nursing.

Maternal-fetal dyad beyond the phenomenology of pregnancy: from primordial cardiovascular prevention on out, do not miss this boat!

Pregnancy represents a stress test for every woman's cardiovascular (CV) system, and a pre-existing maternal unfavorable cardio-metabolic phenotype can uncover both adverse pregnancy outcomes and the subsequent development of cardiovascular disease (CVD) risk factors during and after pregnancy. Moreover, the maternal cardiac and extracardiac environment can affect offspring's cardiovascular health through a complex mechanism called developmental programming, in which fetal growth can be influenced by maternal conditions. This interaction continues later in life, as adverse developmental programming, along with lifestyle risk factors and genetic predisposition, can exacerbate and accelerate the development of CV risk factors and CVD in childhood and adolescence. The aim of this narrative review is to summarize the latest evidences regarding maternal-fetal dyad and its role on primordial, primary and secondary CV prevention.

Examining interpersonal metacognitive monitoring in artificial grammar learning.

This study investigates the observers' ability to monitor the ongoing cognitive processes of a partner who is implicitly learning an artificial grammar. Our hypothesis posits that learners experience metacognitive feelings as they attempt to apply their implicit knowledge, and that observers are capable of detecting and interpreting these feelings as cues of the learner's cognitive state. For instance, learners might encounter affective signals linked to cognitive conflicts and errors at different processing stages, which observers can construe as manifestations of the learner's cognitive dissonance. The research involved 126 participants organized into dyads, with one participant acting as a learner, and the other as an observer. The observer's task was to judge whether the learner agrees with the information presented (consonance judgment) and was limited to reading the learner's nonverbal signals to avoid explicit mindreading. The findings suggest that observers possess mindreading abilities, enabling them to detect both learners' confidence and accuracy in stimuli classification. This extends our understanding of non-verbal mindreading capabilities and indicates that observers can effectively interpret early implicit metacognitive information, even in the absence of explicit self-evaluation from the learners. This research offers significant insights into how individuals interpret others' mental states during implicit learning tasks, particularly in the context of utilizing early affective cues within the Artificial Grammar Learning paradigm.

Deceived by the Fick principle: blood flow distribution in heart failure.

AIMS: The Fick principle states that oxygen uptake (V̇O2) is cardiac output (Qc)*arterial-venous O2 content difference [ΔC(a-v)O2]. Blood flow distribution is hidden in Fick principle and its relevance during exercise in heart failure (HF) is undefined.To highlight the role of blood flow distribution, we evaluated peak-exercise V̇O2, Qc and ΔC(a-v)O2, before and after HF therapeutic interventions. METHODS: Symptoms-limited cardiopulmonary exercise tests with Qc measurement (inert-gas-rebreathing) was performed in 234 HF patients before and 6 months after successful exercise training, cardiac-resynchronization therapy or percutaneous-edge-to-edge mitral valve repair. RESULTS: Considering all tests (n=468) a direct correlation between peakV̇O2 and peakQc (R2=0.47) and workload (R2=0.70) were observed. Patients were grouped according to treatment efficacy in group 1 (peakV̇O2 increase >10%, n=93), group 2 (peakV̇O2 change between 0 and 10%, n=60) and group 3 (reduction in peakV̇O2, n=81). Post-treatment peakV̇O2 changes poorly correlated with peakQc and peakΔC(a-v)O2 changes. Differently, post-procedures peakQc vs. peakΔC(a-v)O2 changes showed a close negative correlation (R2=0.46), becoming stronger grouping patients according to peakV̇O2 improvement (R2=0.64, 0.79 and 0.58 in group 1, 2 and 3, respectively). In 76% of patients peakQc and ΔC(a-v)O2 changes diverged regardless of treatment. CONCLUSION: The bulk of these data suggests that blood flow distribution plays a pivotal role on peakV̇O2 determination regardless of HF treatment strategies. Accordingly, for assessing HF treatment efficacy on exercise performance the sole peakV̇O2 may be deceptive and the combination of V̇O2, Qc and ΔC(a-v)O2, must be considered.

This study aimed to understand how oxygen uptake during exercise is affected by heart failure therapeutic intervention. We evaluated 234 heart failure patients before and after treatments such as exercise training, cardiac resynchronization therapy, or mitral valve repair, finding that changes in oxygen uptake were poorly correlated with changes in cardiac output and oxygen content difference between arteries and veins. However, we observed a strong negative correlation between changes in cardiac output and oxygen content difference, especially in patients with significant improvement in oxygen uptake. This suggests that blood flow distribution is crucial for oxygen uptake during exercise, regardless of treatment. Therefore, relying solely on oxygen uptake may not accurately assess treatment effectiveness, and considering a combination of oxygen uptake, cardiac output, and oxygen content difference is important. Oxygen uptake during exercise was strongly related to cardiac output and workload.Changes in cardiac output and oxygen content difference were closely related after treatments, especially in patients with significant improvement in oxygen uptake.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Pediatric Diffuse Midline Glioma H3K27-Altered: From Developmental Origins to Therapeutic Challenges.

Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old. Despite the research and clinical trials conducted to identify a possible treatment for DIPG, no effective drug is currently available. These tumors often affect deep midline brain structures in young children, suggesting a connection to early brain development's epigenetic regulation targets, possibly affecting neural progenitor functions and differentiation. The H3K27M mutation is a known DIPG trigger, but the exact mechanisms beyond epigenetic regulation remain unclear. After thoroughly examining the available literature, we found that over 85% of DIPG tumors contain a somatic missense mutation, K27M, in genes encoding histone H3.3 and H3.1, leading to abnormal gene expression that drives tumor growth and spread. This mutation impacts crucial brain development processes, including the epithelial-mesenchymal transition (EMT) pathway, and may explain differences between H3K27M and non-K27M pediatric gliomas. Effects on stem cells show increased proliferation and disrupted differentiation. The genomic organization of H3 gene family members in the developing brain has revealed variations in their expression patterns. All these observations suggest a need for global efforts to understand developmental origins and potential treatments.

SIRT1 Serum Concentrations in Lipodystrophic Syndromes.

Lipodystrophies (LDs) are rare, complex disorders of the adipose tissue characterized by selective fat loss, altered adipokine profile and metabolic impairment. Sirtuins (SIRTs) are class III NAD+-dependent histone deacetylases linked to fat metabolism. SIRT1 plays a critical role in metabolic health by deacetylating target proteins in tissue types including liver, muscle, and adipose. Circulating SIRT1 levels have been found to be reduced in obesity and increased in anorexia nervosa and patients experiencing weight loss. We evaluated circulating SIRT1 levels in relation to fat levels in 32 lipodystrophic patients affected by congenital or acquired LDs compared to non-LD subjects (24 with anorexia nervosa, 22 normal weight, and 24 with obesity). SIRT1 serum levels were higher in LDs than normal weight subjects (mean ± SEM 4.18 ± 0.48 vs. 2.59 ± 0.20 ng/mL) and subjects with obesity (1.7 ± 0.39 ng/mL), whereas they were close to those measured in anorexia nervosa (3.44 ± 0.46 ng/mL). Our findings show that within the LD group, there was no relationship between SIRT1 levels and the amount of body fat. The mechanisms responsible for secretion and regulation of SIRT1 in LD deserve further investigation.

Response of laying hens fed diet supplemented with a mixture of olive, laurel, and rosemary leaf powders: Metabolic profile, oxidative status, intestinal histomorphology, and egg quality.

This study aimed to evaluate the effects of a mixture of olive, laurel, and rosemary leaf powders, on the oxidative state, biochemical, immune, intestinal morphophysiological parameters, and egg quality of laying hens. One hundred Lohmann Brown hens (28 weeks old) were equally assigned to two groups (n. 50) corresponding to a basal control diet (CON) or the diet supplemented with 6 g/kg feed of leaf powder mixture (LPM) containing olive, laurel, and rosemary leaves (1:1:1), for 60 days. Oxidative status, biochemical indices, immune response, cecal short chain fatty acids (SCFAs), intestinal morphological characteristics, and some egg traits were evaluated at the end of the experiment. The results indicated that LPM improved (P < 0.05) the oxidative status (TOS, ROMs), the immune system (IL-6, IL-1ß, and TNF-α), the total protein and HDL cholesterol content, whereas it decreased (P < 0.05) total cholesterol and LDL cholesterol. Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine aminotransferase were significantly (P < 0.05) lower in the LPM than in the CON group. A significant increase (P < 0.05) in SCFA content in the caecum, as well as in villi height and crypt depth in both duodenum and ileum of LPM-treated hens, was observed. Egg quality parameters were not influenced (P > 0.05) by LPM. These findings indicate that LPM can be considered a candidate as an antioxidant ingredient for functional food in laying hens.

JAK Inhibition as a Potential Treatment Target in Systemic Lupus Erythematosus.

Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules responsible for signal transduction of multiple cytokines and growth factors in different cell types, involved in the maintenance of immune tolerance. Thus, the dysregulation of this pathway plays a crucial role in the pathogenesis of multiple autoimmune, inflammatory, and allergic diseases and is an attractive treatment target. JAK inhibitors (JAKinibs) have been approved in the treatment of multiple autoimmune diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (SPA). In SLE, there is a plethora of ongoing trials evaluating their efficacy, with tofacitinib, baricitinib and deucravacitinib showing promising results, without major safety concerns. In this review, we will discuss the rationale of targeting JAKinibs in SLE and summarize the clinical data of efficacy and safety of JAKinibs in SLE patients.

Combinatorial Therapy: Targeting CD133+ Glioma Stem-like Cells with a Polysaccharide-Prodrug Complex Functionalised Gold Nanocages.

Cancer treatments are advancing to harness the body's immune system against tumours, aiming for lasting effects. This progress involves combining potent chemotherapy drugs with immunogens to kill cancer cells and trigger lasting immunity. Developing new prodrugs that integrate both chemotherapy and immune-boosting elements could significantly improve anticancer outcomes by activating multiple mechanisms to kill cancer cells. While bacterial polysaccharides are typically not used in therapy due to their immune-stimulating properties, we propose a safe application of an extremophilic bacterial polysaccharide, Mauran (MR), modified with the anticancer drug 5-fluorouracil (5FU) to create a novel prodrug. This obtained prodrug, chloracetyl-MR-5FU, is specifically targeted using gold nanocages to CD133+ glioma cells. Test results have shown a high encapsulation efficiency of the drug during the polysaccharide modification process; its anticancer activity was demonstrated in vitro and the release of the prodrug was demonstrated in ex vivo studies.

Right ventricular dysfunction in chronic heart failure: clinical laboratory and echocardiographic characteristics. (the RIVED-CHF registry).

BACKGROUND: Right ventricular dysfunction (RVD) and pulmonary hypertension have been recognized as two important prognostic features in patients with left side heart failure. Current literature does not distinguish between right heart failure (RHF) and RVD, and the two terms are used indiscriminately to describe pulmonary hypertension and RVD as well as clinical sign of RHF. Therefore, the right ventricle (RV) adaptation across the whole spectrum of left ventricular ejection fraction (LVEF) values has been poorly investigated. METHODS: This is a multicenter observational prospective study endorsed by the Italian Society of Cardiology aiming to analyze the concordance between the signs and symptoms of RHF and echocardiographic features of RVD. The protocol will assess patients affected by chronic heart failure in stable condition regardless of the LVEF threshold by clinical, laboratory, and detailed echocardiographic study. During the follow-up period, patients will be observed by direct check-up visit and/or virtual visits every 6 months for a mean period of 3 years. All clinical laboratory and echocardiographic data will be recorded in a web platform system accessible for all centers included in the study. RESULTS: The main study goals are: to investigate the concordance and discordance between clinical signs of RHF and RVD measured by ultrasonographic examination; to evaluate prognostic impact (in terms of cardiovascular mortality and heart failure hospitalization) of RVD and RHF during a mean follow-up period of 3 years; to investigate the prevalence of different right ventricular maladaptation (isolated right ventricular dilatation, isolated pulmonary hypertension, combined pattern) and the related prognostic impact. CONCLUSIONS: With this protocol, we would investigate the three main RVD patterns according to heart failure types and stages; we would clarify different RVD and pulmonary hypertension severity according to the heart failure types. Additionally, by a serial multiparametric analysis of RV, we would provide a better definition of RVD stage and how much is it related with clinical signs of RHF (ClinicalTrials.gov Identifier: NCT06002321).

Non-Invasive Assessment of Micro- and Macrovascular Function after Initiation of JAK Inhibitors in Patients with Rheumatoid Arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors constitute a novel class of oral biologic disease-modifying antirheumatic drugs for patients with rheumatoid arthritis (RA). However, their use has been associated with increased risk of major cardiovascular events. We investigated whether treatment with JAK inhibitors exerts significant alterations in the micro- and microvasculature in RA patients. METHODS: Thirteen patients with RA initiating treatment with JAK inhibitors were prospectively studied. Eventually, data from 11 patients who completed the study were analyzed. Procedures were performed at baseline and 3 months after treatment. Nailfold videocapillaroscopy was applied to detect alterations of the dermal capillary network. Participants underwent 24 h ambulatory blood pressure monitoring (Mobil-O-Graph device) for the assessment of blood pressure (both brachial and aortic) and markers of large artery stiffening [pulse wave velocity (PWV), augmentation index] throughout the whole 24 h and the respective day- and nighttime periods. Carotid intima-media thickness was assessed with ultrasound. RESULTS: Three-month treatment with JAK inhibitors was not associated with any differences in brachial and aortic blood pressure, arterial stiffness, and carotid atherosclerosis, with the only exception of nighttime PWV, which was significantly elevated at follow-up. However, three-month treatment with JAK inhibitors induced significant microvascular alterations and increased the total number of capillaroscopic abnormalities. CONCLUSIONS: Three-month treatment with JAK inhibitors may exert significant effects on microcirculation as assessed with nailfold videocapillaroscopy, whereas macrovascular structure and function appears largely unaffected. Further research toward this direction may add substantial information to the available literature regarding cardiovascular aspects of JAK inhibitors in RA.