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Abstract Objective Obesity represents a significant global health challenge characterized by chronic low-grade inflammation and metabolic dysregulation. The hypothalamus, a key regulator of energy homeostasis, is particularly susceptible to obesity’s deleterious effects. This study investigated the role of the immunoproteasome, a specialized proteasomal complex implicated in inflammation and cellular homeostasis, during metabolic diseases. Methods The levels of the immunoproteasome β5i subunit were analyzed by immunostaining, western blotting, and proteasome activity assay in mice fed with either a high-fat diet (HFD) or a regular diet (CHOW). We also characterized the impact of autophagy inhibition on the levels of the immunoproteasome β5i subunit and the activation of the AKT pathway. Finally, through confocal microscopy, we analyzed the contribution of β5i subunit inhibition on mitochondrial function by flow cytometry and mitophagy assay. Results Using an HFD-fed obese mouse model, we found increased immunoproteasome levels in hypothalamic POMC neurons. Furthermore, we observed that palmitic acid (PA), a major component of saturated fats found in HFD, increased the levels of the β5i subunit of the immunoproteasome in hypothalamic neuronal cells. Notably, the increase in immunoproteasome expression was associated with decreased autophagy, a critical cellular process in maintaining homeostasis and suppressing inflammation. Functionally, PA disrupted the insulin-glucose axis, leading to reduced AKT phosphorylation and increased intracellular glucose levels in response to insulin due to the upregulation of the immunoproteasome. Mechanistically, we identified that the protein PTEN, a key regulator of insulin signaling, was reduced in an immunoproteasome-dependent manner. To further investigate the potential therapeutic implications of these findings, we used ONX-0914, a specific immunoproteasome inhibitor. We demonstrated that this inhibitor prevents PA-induced insulin-glucose axis imbalance. Given the interplay between mitochondrial dysfunction and metabolic disturbances, we explored the impact of ONX-0914 on mitochondrial function. Notably, ONX-0914 preserved mitochondrial membrane potential and attenuated mitochondrial ROS production in the presence of PA. Moreover, we found that ONX-0914 reduced mitophagy in the presence of PA. Conclusions Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions.

Abstract Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases, yet its association with progressive periodontitis remains unexplored. To investigate the involvement and significance of ferroptosis in periodontitis progression, we assessed sixteen periodontitis-diagnosed patients. Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid (GCF) collection was performed for further analyses. Clinical metrics, proteomic data, in silico methods, and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis. Subsequent western blot analyses validated key findings. Finally, a single-cell RNA sequencing (scRNA-seq) dataset (GSE164241) for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression. Periodontitis progression was identified as occurring at a faster rate than traditionally thought. GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles. In addition, specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins, including SNCA, CA1, HBB, SLC4A1, and ANK1 was strongly associated with the clinical progression status of periodontitis. Moreover, we found specific proteins - drivers or suppressors - associated with ferroptosis (SNCA, FTH1, HSPB1, CD44, and GCLC), revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis. Additionally, the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis. Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients, which offer new insights into the molecular mechanisms of progressive periodontal disease. These findings may lead to novel diagnostic and therapeutic strategies.

Purpose: Hand postural physiological tremor increases during arithmetic computation. The present work aims at investigating whether this could be attributed to a raise in stress for having to provide a correct answer within a constrained period of time, or to voice vibration for having to speak to report the answer. Methods: In 16 participants tremor was recorded by using a 3-axial accelerometer during 5 min of a hand postural task performed simultaneously while: 1) subtracting 13 from a 3-digit number within 4 s and with mistakes correction (intervention: math stress task), 2) same as for the “intervention task” but without time limit and mistakes correction (intervention: math nonstress task), 3) adding 1 to a 3-digit number (intervention: voice vibration task), and 4) only postural task while keeping quiet (control task). Electromyographic (EMG) activity from the extensor carpi radialis was measured during the hand postural task. Results: Compared to control, tremor increased during both math interventions (+30.9 % p = 0.002, math stress; +15.0 % p = 0.01, math nonstress), but not during the voice vibration task (+12.2 % p = 0.239). During the math stress trial tremor was greater compared to both the voice vibration trial (+21.0 % p = 0.021), and the math nonstress trial (+13.5 % p = 0.01). EMG activity was not affected. Conclusion: The results suggest that during arithmetic computation the “stress component” contributes only partially to the observed increase in hand postural tremor, and that this increase cannot be attributed to voice vibrations.

Background: Skin tags or acrochordons are benign fibroepithelioma skin tumors with soft consistency, usually pedunculated, primarily originating from the dermis. High levels of blood sugar and a high lipid profile are risk factors for inflammation and hormonal imbalance, which can contribute to the development of skin tags. Purpose: The objective of this study is to identify the association between blood sugar and lipid profile with skin tags. Methods: This study is a cross-sectional study conducted from April to August 2019 at the Dermatovenereology and Endocrine Policlinic, Dr. Zainoel Abidin General Hospital, Banda Aceh. The sampling method of this study was consecutive sampling with 60 samples that met the inclusion and exclusion criteria. A blood glucose, lipid profile, and skin tag examination was conducted on all subjects. Result: The majority of the subjects are women (61.5%), have an average age of 41-50 years old (43.3%), are obese (41.7%), and have one to five lessions of 1-5 (53.3%). There was a significant correlation between blood glucose, 2 hours post-prandial, total cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels with skin tags with Spearman’s correlation values of 0.645, 0.645, 0.794, 0.704, 0.606, and 0.606 consecutively. Conclusion: A high level of blood sugar and lipid profile, whether it is total cholesterol, triglycerides, HDL, or LDL level, can contribute to the development of skin tags.

Background:. This study presents a case of thumb replantation performed despite several risk factors: age, comorbidities, and trauma mechanism are major adverse prognostic factors directly impacting thumb replantation. Most of the literature backs up this claim that a thumb that works, even partially, is a better outcome for the patient than amputation. Methods:. We performed thumb replantation on a 94-year-old patient with type 2 diabetes mellitus who arrived at the emergency department with a thumb avulsion due to a dog bite. The intraoperative indocyanine green fluorescence angiography method aided us in carrying out the operation. Results:. We successfully used indocyanine green angiography intraoperatively to guide surgical debridement and evaluate the efficacy of anastomosis and reperfusion of the replanted segment during surgery. Two months after the operation, the patient had regained satisfactory hand function. Conclusions:. Although indocyanine green angiography is not a technology created for revascularization procedures, it is instrumental in assessing vascular function and predicting a successful outcome. Given its undeniable potential, more research is needed on the possibility of widespread use in hand surgery and its indications.

Within Florence's District 4, there are two Isolotti: the first is a well-designed suburb born in the 1950s thanks to the INA-Casa plan, inspired by English garden-neighbourhood models with lots of public greenery, low houses and wide pedestrian spaces. The second, which arose in the 1970s-1980s thanks to funding from Gescal and the Ministry of the Treasury, is characterised by a concentration of large apartment blocks separated by green spaces, but also by a fragmented urban fabric and a rarefaction of daily activities. The pandemic has led to new thinking on the importance of neighbourhoods as places from which to rebuild new networks of active citizenship; to rethink more flexible uses of publicly owned spaces. In the wake of the Children's Geographies studies, we want to give voice to the every-day geographies of adolescent girls and boys in order to get their vision of the neighbourhood as social actors; observe their practices of appropriation of neighbourhood spaces and listen to some of their proposals for urban regeneration. Places are not only areas where visions, narratives and symbolic meanings meet, but also instruments through which something is publicly affirmed, where a political act is realized. The material and physical characteristics of places play an important role. The conditions that determine the freedom or constraint of actions for the boys and girls are contained within the materiality of the street, the square, the gardens or the condominium areas.

In this work, we implemented an off-axis digital holographic microscopy (DHM) setup to study the behavior of liquid drops on nanostructured porous silicon (PS) membranes. When a liquid comes into contact with the PS structure, capillary action and surface tension give rise to imbibition of the liquid into the intricate volume of the pores. At the same time, the vapor field developed around the drop enhances liquid condensation and evaporation into and from the pores. The complex interplay between these phenomena (capillary driven internal flows, condensation, and evaporation) is not yet fully understood but the methods we propose can provide new insights. We demonstrate how DHM allows determining the filling fraction of the porous membrane around drying drops of water and isobutyl alcohol. The phase information obtained from registered holograms provides quantitative information that permits to reconstruct the filling fraction along the porous membrane and its evolution during the drying process. Additionally, relevant parameters such as speed and contact angle during retraction of the drops can be measured. These methods can be further extended to other porous materials, such as porous alumina, micro- and macro-PS, to develop better fluid-dynamic models for describing fluid behavior in highly confined structures. [ABSTRACT FROM AUTHOR]

Abstract Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.

ABSTRACT. In Alzheimer's disease (AD) patients, low levels of physical fitness (PF) and cognitive status are associated with high rates of depression. However, this condition can be improved through physical training. Objective: The aim of the present study was to investigate the effect of multimodal exercise training (MET) on aerobic endurance, muscular strength, agility, dynamic balance, cognitive status, and depressive symptoms in men with mild-to-moderate AD. Methods: A total of 25 elderly men with a diagnosis of mild-to-moderate AD were randomly categorized into an MET or a control group. The subjects in the MET group participated in a 12-week, three sessions per week MET program that included resistance, balance, and aerobic exercises. While the participants in the control group did not perform any regular exercise training during this period. Patients’ cognitive status and depressive symptoms were assessed by Mini-Mental State Examination and the Geriatric Depression Scale-15 (GDS-15) questionnaires. PF indicators such as aerobic endurance, muscular strength, agility, and dynamic balance, as well as cognitive status and depressive symptoms, were taken from all the subjects before and after MET. Results: The participants in the MET group improved handgrip, upper and lower body strength, agility, dynamic balance, and depressive symptoms (p0.05). Conclusions: MET is an effective strategy to improve muscular strength, agility, dynamic balance, and depressive symptoms in men with mild-to-moderate AD. It is recommended for AD patients to engage in this type of exercise to reduce AD complications.

Backgrounds: Morbus Hansen or leprosy is a chronic granulomatous infectious disease caused by the obligate intracellular Mycobacterium leprae bacillus. Leprosy can cause loss of sensation in the skin with or without lesions and body dysfunction during the course of the disease. In Aceh, there were 337 new cases of leprosy in 2019 and this was the highest case in Sumatra. Purpose: To analyze the profile of leprosy patients in the Department of Dermatology and Venereology of RSUDZA Banda Aceh. Methods: Observational descriptive study with retrospective design, using medical record of leprosy patients who visited Dermatology and Venereology Outpatient Clinic RSUDZA Banda Aceh for the period of January 2017 – December 2021. Result: A total of 183 leprosy patients were obtained from the study. Most cases occured in male patients (68.3%), the majority was in the 18-40 year age group (60.1%), most patients live outside of Banda Aceh (71%). The most frequently reported type of leprosy was the multibacillary type (71.6%). Leprosy patients without disability were 35.5%, the majority did not experience a leprosy reaction (71%), the most common morphology of the lesion was erythematous (29.5%), and the highest proportion of the bacteriological and morphological index was negative (46.4% and 50.8% respectively). Conclusion: The diagnosis of leprosy was based on clinical, bacteriological, and histopathological features. Early diagnosis, patient access to treatment, early initiation of treatment and adherence to therapy would reduce the disease transmission thus would decrease the prevalence of leprosy in Aceh.

Abstract Background Recurrence and resistance of Candida spp. infections is associated with the ability of these microorganisms to present several virulence patterns such as morphogenesis, adhesion, and biofilm formation. In the search for agents with antivirulence activity, essential oils could represent a strategy to act against biofilms and to potentiate antifungal drugs. Objective To evaluate the antivirulence effect of Origanum vulgare L. essential oil (O-EO) against Candida spp. and to potentiate the effect of fluconazole and nystatin. Methods The effect of O-EO was evaluated on ATCC reference strains of C. albicans and non-albicans Candida species. Minimum inhibitory concentration (MIC) was determined through broth microdilution assay. Adhesion to microplates was determined by crystal violet (CV) assay. An adapted scratch assay in 24-well was used to determine the effect of essential oil on biofilms proliferation. Viability of biofilms was evaluated by MTT reduction assay and through a checkerboard assay we determined if O-EO could act synergistically with fluconazole and nystatin. Results MIC for C. albicans ATCC-90029 and ATCC-10231 was 0.01 mg/L and 0.97 mg/L, respectively. For non-albicans Candida strains MIC values were 2.6 mg/L for C. dubliniensis ATCC-CD36 and 5.3 mg/L for C. krusei ATCC-6258. By using these concentrations, O-EO inhibited morphogenesis, adhesion, and proliferation at least by 50% for the strains assayed. In formed biofilms O-EO decreased viability in ATCC 90029 and ATCC 10231 strains (IC50 7.4 and 2.8 mg/L respectively). Finally, we show that O-EO interacted synergistically with fluconazole and nystatin. Conclusions This study demonstrate that O-EO could be considered to improve the antifungal treatment against Candida spp.

Corticospinal excitability is known to be affected by afferent inflow arising from the proprioceptors during active or passive muscle movements. Also during static stretching (SS) afferent activity is enhanced, but its effect on corticospinal excitability received limited attention and has only been investigated as a single average value spread over the entire stretching period. Using transcranial magnetic stimulation (TMS) the present study was conducted to explore the time course of corticospinal excitability during 30 seconds SS. Motor evoked potentials (MEPs) after TMS were recorded from soleus (SOL) and tibialis anterior (TA) muscles in 14 participants during: a passive dynamic ankle dorsiflexion (DF), at six different time points during maximal individual SS (3, 6, 9, 18, 21 and 25 seconds into stretching), during a passive dynamic ankle plantar flexion (PF) and following SS. To explore the time course of corticospinal excitability during the static lengthened phase of a muscle stretch, the stretching protocol was repeated several times so that it was possible to collect a sufficient number of stimulations at each specific time point into SS, as well as during DF and PF. During passive DF, MEPs amplitude was greater than baseline in both TA and SOL (p = .001 and p = .005 respectively). During SS, MEPs amplitude was greater than baseline in TA (p = .006), but not in SOL. No differences between the investigated time points were found and no trend was detected throughout the stretching time. No effect in either muscle was observed during passive PF and after SS. These results could suggest that an increased activity of secondary afferents from SOL muscle spindles exert a corticomotor facilitation on TA. The muscle-nonspecific response observed during passive DF could instead be attributed to an increased activation within the sensorimotor cortical areas as a result of the awareness of the foot passive displacements.