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Alterations of insulin sensitivity, clearance, and secretion, either alone or in combination, in women with PCOS: impact on metabolic profile and androgenemia
No full textSTUDY QUESTION What is the role of insulin resistance (IR), increased insulin secretion, and impaired insulin clearance, either alone or in combination, on metabolic features and androgen levels in women with PCOS?SUMMARY ANSWER IR, reduced insulin clearance and increased insulin secretion independently contribute to predicting hyperandrogenemia, whereas metabolic abnormalities may differ according to the mechanisms underlying hyperinsulinemia.WHAT IS KNOWN ALREADY Hyperinsulinemia is a common finding in women with PCOS, and it is closely associated with the metabolic and endocrine alterations of these women. It is considered a compensatory mechanism to IR, and results from two separate mechanisms: increased secretion and/or reduced insulin clearance. The contribution of these two distinct adaptive processes may differ, and the implications of these differences are poorly understood.STUDY DESIGN, SIZE, DURATION Cross-sectional study of 355 women with PCOS recruited in the Verona 3P study from 2010 to 2021.PARTICIPANTS/MATERIALS, SETTING, METHODS Women with PCOS, diagnosed by the Rotterdam criteria, underwent a hyperinsulinemic euglycemic clamp, to measure insulin sensitivity (M-clamp) and to calculate insulin clearance (MCRI). Insulin secretion was estimated by the HOMA beta-index. Serum androgens were measured by LC/MS-MS and equilibrium dialysis.MAIN RESULTS AND THE ROLE OF CHANCE Hyperinsulinemia was found in 65.4% women with PCOS. Insulin sensitivity was impaired in 69.6% subjects, MCRI was reduced in 57.2%, and HOMA beta-index was increased in 60.0% women. Overall, 311 subjects (87.6%) had at least one of these insulin metabolism alterations. The combination of the three alterations was found in 127 (35.8%) women, whereas 98 (27.6%) had two alterations: 30 had IR and reduced MCRI, 47 had IR and increased HOMA beta-index, 21 had reduced MCRI and increased HOMA beta-index. Eighty-six (24.2%) women had only one alteration: 43 had IR, 25 had reduced MCRI, 18 had increased HOMA beta-index; finally, 44 (12.4%) subjects showed no alterations. Anthropometric parameters, and fasting glucose and insulin, were progressively lower in women with 3, 2, 1, or 0 insulin metabolism alterations. Similar trends were observed for serum triglycerides, blood pressure, and androgens, whereas progressively increasing values were observed for high-density lipoprotein-cholesterol and sex hormone-binding globulin. In logistic regression analysis, after adjusting for age and fat mass, IR and increased insulin secretion were independent predictors of altered glucose tolerance, whereas IR and low MCRI were independent predictors of metabolic syndrome; in multivariable analysis, M-clamp, MCRI, and HOMA beta-index were all independent predictors of serum free testosterone.MAIN RESULTS AND THE ROLE OF CHANCE Hyperinsulinemia was found in 65.4% women with PCOS. Insulin sensitivity was impaired in 69.6% subjects, MCRI was reduced in 57.2%, and HOMA beta-index was increased in 60.0% women. Overall, 311 subjects (87.6%) had at least one of these insulin metabolism alterations. The combination of the three alterations was found in 127 (35.8%) women, whereas 98 (27.6%) had two alterations: 30 had IR and reduced MCRI, 47 had IR and increased HOMA beta-index, 21 had reduced MCRI and increased HOMA beta-index. Eighty-six (24.2%) women had only one alteration: 43 had IR, 25 had reduced MCRI, 18 had increased HOMA beta-index; finally, 44 (12.4%) subjects showed no alterations.Anthropometric parameters, and fasting glucose and insulin, were progressively lower in women with 3, 2, 1, or 0 insulin metabolism alterations. Similar trends were observed for serum triglycerides, blood pressure, and androgens, whereas progressively increasing values were observed for high-density lipoprotein-cholesterol and sex hormone-binding globulin. In logistic regression analysis, after adjusting for age and fat mass, IR and increased insulin secretion were independent predictors of altered glucose tolerance, whereas IR and low MCRI were independent predictors of metabolic syndrome; in multivariable analysis, M-clamp, MCRI, and HOMA beta-index were all independent predictors of serum free testosterone.LIMITATIONS, REASONS FOR CAUTION Insulin secretion was estimated by a validated surrogate index, whose performance may be suboptimal. This study was carried out in Caucasian women. Therefore, our findings may not be generalizable to other ethnic groups. Finally, the cross-sectional design of the study limits the causal inference of the results.WIDER IMPLICATIONS OF THE FINDINGS The presence of IR, reduced MCRI, and increased insulin secretion, especially when combined, worsens metabolic outcomes and androgen levels in women with PCOS. However, these factors may play a different role in determining altered glucose metabolism or metabolic syndrome, whereas all of them independently contribute to hyperandrogenemia.STUDY FUNDING/COMPETING INTEREST(S) Academic grants to P. Moghetti from the University of Verona (FUR 2010-2022). All authors declare no conflict of interest.TRIAL REGISTRATION NUMBER N/A
The impact of muscle-tendon degeneration on functional ability in healthy and pathological populations
No full textLocomotion is an important function of our lives. It is fundamental for the physical and psychological well-being of humans. The bioenergetics and biomechanics of walking could be altered by the onset of a pathological condition, thus negatively affecting the quality of life of this population. Muscles and tendons are involved in each human movement, such as walking, since the force generated by muscle contraction is transmitted to the bone through tendons, generating joint movement. Muscles consume oxygen to generate energy to restore the ATP necessary for muscle contraction. Since tendons are collagenous structures, they don’t directly affect oxygen consumption. Still, during walking, the Achilles tendon conserves some of the energy during heel strike. Then, it returns it at the toe-off, reducing activity for the triceps surae muscles.
Thus, muscle-tendon properties and mechanics should be assessed to understand their influence on pathological gait. However, different pathologies lead to different peripheral alterations, and identifying them could help find specific strategies to counteract muscle-tendon alteration and improve walking energetics and biomechanics. In this thesis, muscle-tendon behaviour was investigated for the following aims: 1) to investigate a possible effect of an altered glucose environment on tendon structure and walking ability, 2) to investigate muscle and tendon mechanical alterations in diabetic patients and how they affect the biomechanics and energetics of walking; 3) to determine a possible effect of a minute oscillation stretching training on muscle-tendon function and walking capability in diabetic people; 4) to investigate the role of muscle architecture on maximal torque production in PD patients; 5) to investigate the alterations of muscle behaviour in PD patients and their effect on the ability to produce torque rapidly. Altered (yet not pathological) levels of HbA1c are associated with alterations in Achilles tendon characteristics and walking mechanics (Study 1). Similar results are observed in Study 2: diabetic patients (well-controlled and physically active) are characterized by alterations in Achilles tendon characteristics (e.g. an increase in stiffness), which limit the ankle ROM during locomotion; these alterations, however, do not impact the energetics of walking, compared to healthy controls. The MOS training protocol (Study 3) allows for reversing these differences by reducing tendon stiffness at the ankle level (without affecting muscle stiffness); in turn, this allows for an increase in ankle ROM during walking, improving walking mechanics (increasing stride length) and energetics (reducing the energy cost). An impaired mechanical output is observed in the more affected limb of PD patients, along with an altered muscle behaviour during contraction (Study 4). The reduced ability to produce torque rapidly in these patients is related to lower muscle activation, altered muscle behaviour and muscle mechanical properties (i.e. stiffness) (Study 5)
A Lightweight CNN for Real-Time Pre-Impact Fall Detection
No full textFalls can have significant and far-reaching effects on various groups, particularly the elderly, workers, and the general population. These effects can impact both physical and psychological well-being, leading to long-term health problems, reduced productivity, and a decreased quality of life. Numerous fall detection systems have been developed to prompt first aid in the event of a fall and reduce its impact on people's lives. However, detecting a fall after it has occurred is insufficient to mitigate its consequences, such as trauma. These effects can be further minimized by activating safety systems (e.g., wearable airbags) during the fall itself—specifically in the pre-impact phase—to reduce the severity of the impact when hitting the ground. Achieving this, however, requires recognizing the fall early enough to provide the necessary time for the safety system to become fully operational before impact. To address this challenge, this paper introduces a novel lightweight convolutional neural network (CNN) designed to detect pre-impact falls. The proposed model overcomes the limitations of current solutions regarding deployability on resource-constrained embedded devices, specifically for controlling the inflation of an airbag jacket. We extensively tested and compared our model, deployed on an STM32F722 microcontroller, against state-of-the-art approaches using two different datasets
Biochemical investigation of pathogenic missense mutations of human 4-amino butyrate aminotransferase towards the understanding of the molecular pathogenesis of GABA transaminase deficiency
Get PDFGamma-amino butyrate aminotransferase (GABA-AT or ABAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of GABA and α-ketoglutarate into succinic semialdehyde and L-glutamate. In humans, the primary physiological role of GABA-AT is to control the level of GABA in neuronal tissues. Mutations on ABAT gene are associated to GABA-AT deficiency, an ultra-rare autosomal recessive disorder characterized by accelerated linear growth, severe psychomotor retardation, seizures, hypotonia, and hyperreflexia. So far, several missense pathogenic mutations of GABA-AT have been identified; however, their molecular effects at protein level have been poorly investigated. In this work a biochemical characterization of 10 pathogenic variants of human GABA-AT was carried out by expressing the protein in HEK-293 cells. Moreover, in-silico analyses of the variants were performed to corroborate the experimental findings. Altogether, the data obtained on protein expression level, GABA transaminase activity, and the predicted structural impact allowed us to classify the variants into three distinct groups, such as: (i) variants with strong structural and catalytic defects (p.P152S, p.L211F, and p.L478P); (ii) variants characterized mainly by a strong catalytic defect (p.R220K, p.Q296H, and p.R377W); (iii) variants exhibiting moderate structural and catalytic defects maintaining substantial transaminase activity (p.R92Q, p.F213C, p.G465D, and p.G465R). Based on these results, we provide a picture of the molecular defects of different GABA-AT pathogenic variants with the aim of gaining insights into the enzymatic phenotypes in GABA-AT deficiency
The State in Pantaleoni: A Theoretical Analysis in Evolution
No full textMaffeo Pantaleoni (1857-1924) maintained that the liberal State should be based on general, universal norms, therefore rejecting those aimed at taking care of special interests. This view was not incompatible with the expansion of the scope of the government. However, the actual government intervention that took place in Italy made him aware of the necessity of restoring a classical, liberal state, which he saw as possible with the advent of Fascism
α-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via “Catalytically Correct” Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery?
No full textWe present evidence that supports a 'correct hydrazone tautomer/Dunathan alignment model' for how α-hydrazino analogues of α-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis of l- and d-α-hydrazino acid l-lysine analogues and their inhibition of Hafnia alvei lysine decarboxylase (LdcI) via kinetic analysis, stopped-flow spectrophotometry, and cryo-EM. We describe a similar investigation of the important anti-Parkinsonism drug, carbidopa, with its human DOPA decarboxylase (hDdc) target. Evidence is consistent with these three hydrazino analogues forming the catalytically relevant ketoenamine PLP-hydrazone tautomer in their target active sites, with the α-carboxylate groups, though insulated, aligning with the PLP-π-system in a Dunathan-model-like orientation. High-resolution cryo-EM structures of the H. alvei LdcI holoenzyme (pdb 9E0M-2.1Å) and LdcI-bound l- and d-hydrazones (pdb 9E0O-2.0 Å; pdb 9E0Q-2.3Å) and the first X-ray crystal structure of hDdc-bound carbidopa (pdb 9GNS-1.93Å) support this 'correct tautomer' model. These insights are expected to guide future PLP enzyme inhibitor development.
© 2025 The Authors. Published by American Chemical Society
Stimulator of interferon genes (STING) immunohistochemical expression in fumarate hydratase-deficient renal cell carcinoma: biological and potential predictive implications
No full textFumarate hydratase (FH)-deficient renal cell carcinoma is an aggressive neoplasm driven by inactivating mutations of the FH gene, which cause metabolites like S-(2-succinyl)cysteine (2SC) to accumulate and trigger cascades supporting malignant transformation. Although in preclinical models the c-GAS-STING pathway is activated by fumarate metabolites, its role in humans has not been explored yet. Eleven FH-deficient renal cell carcinomas, including primary neoplasms and metastases, were retrieved and evaluated for clinical-pathological features and immunohistochemical expression of FH, 2SC (commercially available), and STING. The in-house collection accounted for 0.2% of the 2011-2023 renal cell carcinomas cohort (5/2210). Eight-on-ten cases with available follow-up behaved aggressively (local recurrence/distant metastases). All tumors revealed FH staining loss and strong and diffuse 2SC immunolabeling. At least focal STING expression was detected in most primary tumors (9/11, 82%), often (78%) in a wide percentage of cells (>= 30%). Notably, significant STING expression was observed in all but two aggressive renal neoplasms, with one of the remaining showing increased staining in its hepatic localization, and in 86% (6/7) of neoplasms significantly expressing PD-L1. In our series, (i) FH-deficient renal cell carcinoma represents 0.2% of in-house cases; (ii) combining FH loss and positive 2SC staining now commercially available is useful in primary and secondary tumors, supporting this latter marker's safe routine adoption; and (iii) a significant STING labeling (>= 30%) in most of the samples, especially in those behaving aggressively and expressing PD-L1, provides novel insights regarding the molecular basis of FH-deficient renal cell carcinomas, proposing STING as a potential predictive marker
Oxidized-LDL aggravates renal injury via tubular cuproptosis
No full textObjective: The imbalance of copper homeostasis is closely related to development of kidney injury. We aimed to clarify the mechanism of oxidation of low-density lipoprotein (ox-LDL) aggravated renal injury via tubular copper overload and cuproptosis in lipid-related renal injury. Methods: 313 patients with kidney disease (KD) confirmed by renal biopsy and 19 healthy participants were enrolled in this study. The copper levels in serum, urine and kidney tissue were assessed and the association between copper and renal function analyzed. We used ox-LDL and a high fat diet (HFD) to develop a pre-clinical renal injury model in HFD fed mice, and measured the levels of copper and cuproptosis biomarkers both in vivo and in vitro, respectively. Results: Compared to the healthy control group, KD patients showed higher serum and urinary copper levels. Estimated glomerular filtration rate was inversely correlated to serum copper, while 24-hour proteinuria was directly correlated to urinary copper levels. Abnormal deposition of copper salts were observed in kidney tissue of both ORN patients and HFD mice. In vivo and in vitro data showed that lipid may induce mitochondrial dysfunction and promote cuproptosis in tubular epithelial cells, which was related to changes in copper transporter protein ATP7B. Conclusion: ox-LDL can promote copper overload in renal tubular cells by suppressing ATP7B, thereby inducing cuproptosis and promoting lipid-related kidney injury
Modelli di business, performance e sostenibilità nella catena del valore del settore agroalimentare
No full textIl volume, una monografia scientifica in ambito economico-aziendale, offre una trattazione organica e aggiornata sul tema della sostenibilità nel settore agroalimentare. Attraverso un approccio teorico-pratico, analizza modelli di business sostenibili e sistemi di misurazione della performance di sostenibilità. Vengono esplorate le specificità della filiera agroalimentare, evidenziando le sfide e le opportunità strategiche nella transizione verso modelli sostenibili e circolari. Il testo presenta tre casi studio rappresentativi della filiera (agricoltura, trasformazione, distribuzione), che illustrano criticità, soluzioni operative e potenzialità di valore condiviso. I risultati evidenziano approcci differenziati all’integrazione della sostenibilità, con effetti positivi su relazioni con gli stakeholder, governance e innovazione nei processi. Inoltre, i sistemi di misurazione delle performance mostrano diversi gradi di maturità, con una forte consapevolezza che la loro evoluzione sia un fattore critico per il successo delle strategie di sostenibilità nel settore agroalimentare. Infatti, particolare attenzione è dedicata alla multidimensionalità della performance (ambientale, sociale, economica e di governance) e alla creazione di impatti positivi lungo la catena del valore. L’opera si rivolge a studenti, docenti, professionisti e policy maker interessati a comprendere e promuovere modelli imprenditoriali sostenibili