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Daily behavioral and physiological rhythms are controlled by the brain's circadian timekeeping system, a synchronized network of neurons that maintains endogenous molecular oscillations. These oscillations are based on transcriptional feedback loops of clock genes, which in Drosophila include the transcriptional activators Clock (Clk) and cycle (cyc). While the mechanisms underlying this molecular clock are very well characterized, the roles that the core clock genes play in neuronal physiology and development are much less understood. The Drosophila timekeeping center is composed of ~150 clock neurons, among which the four small ventral lateral neurons (sLNvs) are the most dominant pacemakers under constant conditions. Here, we show that downregulating the clock gene cyc specifically in the Pdf-expressing neurons leads to decreased fasciculation both in larval and adult brains. This effect is due to a developmental role of cyc, as both knocking down cyc or expressing a dominant negative form of cyc exclusively during development lead to defasciculation phenotypes in adult clock neurons. Clk downregulation also leads to developmental effects on sLNv morphology. Our results reveal a non-circadian role for cyc, shedding light on the additional functions of circadian clock genes in the development of the nervous system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Biondi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The circadian system regulates the timing of multiple molecular, physiological, metabolic, and behavioral phenomena. In Drosophila as in other species, most of the research on how the timekeeping system in the brain controls timing of behavioral outputs has been conducted in males, or sex was not included as a biological variable. The main circadian pacemaker neurons in Drosophila release the neuropeptide Pigment Dispersing Factor (PDF), which functions as a key synchronizing factor in the network with complex effects on other clock neurons. Lack of Pdf or its receptor, PdfR, results in most flies displaying arrhythmicity in activity-rest cycles under constant conditions. However, our results show that female circadian rhythms are less affected by mutations in both Pdf and PdfR. Crispr-Cas9 mutagenesis of Pdf specifically in the ventral lateral neurons (LNvs) also has a greater effect on male rhythms. We tested the influence of the M-cells over the circadian network and show that speeding up the molecular clock specifically in the M-cells leads to sexually dimorphic phenotypes, with a more pronounced effect on male rhythmic behavior. Our results suggest that the female circadian system is more resilient to manipulations of the PDF pathway and that circadian timekeeping is more distributed across the clock neuron network in females.

Cell-based therapy using insulin-producing cells (IPCs) is anticipated as an alternative treatment option to insulin injection or pancreatic islet transplantation for the treatment of diabetes mellitus in both human and veterinary medicine. Several protocols were reported for the differentiation of mesenchymal stem cells (MSCs) into IPCs; to date, glucose-responsive IPCs have only been obtained from canine adipose tissue-derived MSCs (c AD -MSCs), but not from canine bone marrow-derived MSCs (cBM-MSCs). Therefore, this study aims to generate in vitro glucose-responsive IPCs from cBM-MSCs using two differentiation protocols: a two-step protocol using trichostatin (TSA) and a three-step protocol using mercaptoethanol to induce pancreatic and duodenal homeobox gene 1 (PDX-1) expression. A single experiment was carried out for each protocol. BM-MSCs from one dog were successfully cultured and expanded. Cells exposed to the two-step protocol appeared rarely grouped to form small clusters; gene expression analysis showed a slight increase in PDX-1 and insulin expression, but no insulin protein production nor secretion in the culture medium was detected either under basal conditions or following glucose stimulation. Conversely, cells exposed to the three-step protocol under a 3D culture system formed colony-like structures; insulin gene expression was upregulated compared to undifferentiated control and IPCs colonies secreted insulin in the culture medium, although insulin secretion was not enhanced by high-glucose culture conditions. The single experiment results suggest that the three-step differentiation protocol could generate IPCs from cBM-MSCs; however, further experiments are needed to confirm these data. The ability of IPCs from cBM- MSCs to produce insulin, described here for the first time, is a preliminary interesting result. Nevertheless, the IPCs' unresponsiveness to glucose, if confirmed, would affect its clinical application. Further studies are necessary to establish a differentiation protocol in this perspective.

Background : Psoriatic disease, a chronic immune-mediated systemic inflammatory condition, significantly impairs patients' quality of life. The advent of highly targeted biological therapies has transformed treatment strategies, emphasizing the importance of selecting the most effective and cost-efficient option. Secukinumab, an IL-17A inhibitor, has demonstrated efficacy and safety in treating moderate-to-severe plaque psoriasis (PsO). However, long-term real-world data on its effectiveness and persistence rate are limited. Methods : This retrospective study, conducted across eight Italian dermatology centers, aimed to evaluate the 6-year persistence rate and effectiveness of secukinumab in patients with PsO. Additionally, the study investigated the onset of psoriatic arthritis during treatment. Results : Overall, 166 adult patients were analyzed. Their median age was 53.9 years. The mean BMI was 26.5. Of the 166 patients, 64 were bio-experienced while 102 were bio-naïve. A progressive reduction in PsO severity measured by PASI scores over 6 years of treatment was revealed: the PASI score decreased from a baseline value of 18.1 (±9.1) to 0.7 (±1.6) after 6 years of follow-up. Adverse events, including mucocutaneous fungal infections and cardiovascular disturbances, were reported in 19.9% of patients. The persistence rate was 86.8% at 24 months, decreasing to 66.4% at 72 months. Psoriatic arthritis onset during treatment was observed in 15 (9.0%) of patients. Conclusions : This study highlights the sustained effectiveness and favorable safety profile of secukinumab over 6 years, providing valuable real-world evidence. Understanding the long-term persistence rate and predictors of discontinuation could help clinicians optimize treatment decisions and improve patient outcomes in PsO management. We found that the absence of scalp PsO, no involvement of the genital area and normal weight were the best factors of persistence in secukinumab treatment in the long term.

An efficient treatment plan using a temporary anchorage device should be built following the principle of reducing the number of tads to obtain a multiple biomechanical advantage. The following case report concerns the Biga system, a strategy that supports orthodontists during class II corrections and vertical control through treatment. A 12-year-old girl with a high angle of skeletal class II was selected. A novel biomechanical strategy was effectively applied using two tads on the upper arch to obtain sequential distalization of the upper teeth and to correct the lower arch spee curve using third-class elastics. Eventually, on the same tads, a double cantilever was applied to control the overbite and intrusion during incisors' retraction. The Biga system is an easy biomechanical strategy that ensures the three-dimensional control of treatment mechanics in class II patients.

Hyperglucagonemia is one of the 'ominous' eight factors underlying the pathogenesis of type 2 diabetes (T2D). Glucagon is a peptide hormone involved in maintaining glucose homoeostasis by increasing hepatic glucose output to counterbalance insulin action. Long neglected, the introduction of dual and triple agonists exploiting glucagon signalling pathways has rekindled the interest in this hormone beyond its classic effect on glycaemia. Glucagon can promote weight loss by regulating food intake, energy expenditure, and brown and white adipose tissue functions through mechanisms still to be fully elucidated, thus its role in T2D pathogenesis should be further investigated. Moreover, the role of glucagon in the development of T2D micro- and macro-vascular complications is elusive. Mounting evidence suggests its beneficial effect in non-alcoholic fatty liver disease, while few studies postulated its favourable role in peripheral neuropathy and retinopathy. Contrarily, glucagon receptor agonism might induce renal changes resembling diabetic nephropathy, and data concerning glucagon actions on the cardiovascular system are conflicting. This review aims to summarise the available findings on the role of glucagon in the pathogenesis of T2D and its complications. Further experimental and clinical data are warranted to better understand the implications of glucagon signalling modulation with new antidiabetic drugs., (© 2023 John Wiley & Sons Ltd.)

Diabetes mellitus is a chronic metabolic disease, the prevalence of which is constantly increasing worldwide. It is often burdened by disabling comorbidities that reduce the quality and expectancy of life of the affected individuals. The traditional complications of diabetes are generally described as macrovascular complications (e.g., coronary heart disease, peripheral arterial disease, and stroke), and microvascular complications (e.g., diabetic kidney disease, retinopathy, and neuropathy). Recently, due to advances in diabetes management and the increased life expectancy of diabetic patients, a strong correlation between diabetes and other pathological conditions (such as liver diseases, cancer, neurodegenerative diseases, cognitive impairments, and sleep disorders) has emerged. Therefore, these comorbidities have been proposed as emerging complications of diabetes. P66 Shc is a redox protein that plays a role in oxidative stress, apoptosis, glucose metabolism, and cellular aging. It can be regulated by various stressful stimuli typical of the diabetic milieu and is involved in various types of organ and tissue damage under diabetic conditions. Although its role in the pathogenesis of diabetes remains controversial, there is strong evidence regarding the involvement of p66 Shc in the traditional complications of diabetes. In this review, we will summarize the evidence supporting the role of p66 Shc in the pathogenesis of diabetes and its complications, focusing for the first time on the emerging complications of diabetes.

Derived inflammatory indexes from routine hematological parameters might be useful for predicting early-response vs. late/non-response to dupilumab, the first biological agent approved for moderate-to-severe atopic dermatitis (AD). We tested this hypothesis by retrospectively investigating the association between pre-specified baseline inflammatory indexes and dupilumab response (≥50% reduction in the Eczema Area and Severity Index, EASI 50) at 4 and 16 weeks in a consecutive series of 66 AD patients (38 males and 28 females). Forty-six patients (69.7%) were early-responders at 4 weeks, whereas the remaining twenty (30.3%) were late/non-responders at 16 weeks. In logistic regression, the platelet-to-lymphocyte ratio (PLR) was independently associated with early-response (OR = 1.0159, 95% CI 1.0005 to 1.0315, p = 0.0426). The predictive performance of PLR and other derived indexes towards early-response was further improved by their combination with serum IgE concentrations, with a maximum AUC value for the combined systemic immune inflammation index (SII)-IgE of 0.797 (95% CI = 0.677 to 0.884, p < 0.0001). Derived inflammatory indexes, particularly SII-IgE, might be useful to identify early-responders to dupilumab and develop alternative treatment protocols for late/non-responders.

Health care spending in Italy is high and continues to increase; assessing the long-term health and economic outcomes of new therapies is essential. Atopic dermatitis (AD) is a chronic, pruritic, immune-mediated inflammatory dermatosis, a clinical condition that significantly affects patients' quality of life at a high cost and requires continuous care. This retrospective study aimed to assess the direct cost and adverse drug reactions (ADRs) of Dupilumab and patients' clinical outcomes. All AD patients treated with Dupilumab at the Sassari University Hospital, Italy, between January 2019 and December 2021 were included. Eczema Area Severity Index, Dermatology Life Quality Index, and Itch Numeric Rating Scale scores were measured. ADRs and drug expenses were analyzed. A statistically significant posttreatment improvement was observed for all the indices measured: EASI ( P < 0.0001), DLQI ( P < 0.0001), NRS ( P < 0.0001). The total expenditure for Dupilumab, in the observed period, amounted to € 589.748,66 for 1358 doses, and a positive correlation was shown between annual expenditure and delta percentage of variation pre- and posttreatment for the clinical parameters evaluated., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Marco Ferrari et al.)

Type 2 diabetes (T2D) and Alzheimer's diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4-2-fold increase in the risk of developing AD among T2D patients, the involvement of possible common triggers in the pathogenesis of these two diseases remains largely unknown. Of note, recent mechanistic insights suggest that lipotoxicity could represent the missing ring in the pathogenetic mechanisms linking T2D to AD. Indeed, obesity, which represents the main cause of lipotoxicity, has been recognized as a major risk factor for both pathological conditions. Lipotoxicity can lead to inflammation, insulin resistance, oxidative stress, ceramide and amyloid accumulation, endoplasmic reticulum stress, ferroptosis, and autophagy, which are shared biological events in the pathogenesis of T2D and AD. In the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in T2D and AD, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives.