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Post‐translational regulation of human D‐3‐phosphoglycerate dehydrogenase in Alzheimer's disease
No full textEmerging evidence suggests that sex-specific differences in L-serine (L-Ser) metabolism play a key role in Alzheimer's disease (AD). While disruptions in amino acid balance are well known, recent findings point to a dimorphic regulation of the serine biosynthetic pathway. To explore this, we examined post-translational modifications (PTMs) of D-3-phosphoglycerate dehydrogenase (PHGDH)-the rate-limiting enzyme for de novo L-Ser synthesis-as a potentialmechanism underlying this difference. PHGDH was immunoprecipitated from hippocampal tissue of healthy and AD-affected males and females and analyzed by mass spectrometry. Five phosphorylation sites (S55, T60, T78, S383, and S473) were shared across all groups, but a unique deacetylation at K289 appeared exclusively in AD males. Functional assays using recombinant PHGDH variants revealed that changes at solvent-exposed sites (K289, S383, and S473) reduced solubility, while phosphomimetic substitutions at S55 and T78 within the catalytic cleft strongly impaired activity. Notably, mimicking acetylation at K289 improved protein stability. Overall, these PTMs act both as subtle modulators and as on/off switches, fine-tuning PHGDH function and potentially contributing to sex-dependent metabolic vulnerability in AD
Diagnostic Performance of the α-Synuclein Seed Amplification Assay for Dementia With Lewy Bodies: A Comparison Across 4 Laboratories
No full textBackground and objectives: The α-synuclein (α-syn) seed amplification assay (SAA) has shown promising results for diagnosing dementia with Lewy bodies (DLB) using CSF samples. A barrier to implementing α-syn SAA clinically is the use of different protocols for the assay. It is unknown how different protocols perform in comparison with each other. We compared the performance of α-syn SAA across 4 laboratories using CSF samples of patients with DLB. Methods: This was a retrospective cross-sectional study that included data from 4 different European laboratories. We included probable patients with DLB with a positive dopamine transporter (DaT)-SCAN and known amyloid-β status who had mild-to-moderate dementia, along with age-matched and sex-matched controls. The α-syn SAA was run across 4 laboratories using different protocols varying α-syn concentration and plate reader settings. CSF samples were provided by a fifth independent laboratory, which also performed statistical and result analyses. Results: We included 20 patients with DLB (mean age 67 ± 6 years, 60% male) and 10 controls (mean age 67 ± 2 years, 70% male). Neuropathologic confirmation was available for 2 patients with DLB. On average, the 4 laboratories achieved 78.8% sensitivity (minimum 55%, maximum 100%), 77.5% specificity (minimum 60%, maximum 100%), and 78.5% accuracy (minimum 57%, maximum 100%) for discriminating DLB from controls, but our findings show that diagnostic performance of SAA varied across laboratories: Lab A achieved 100% sensitivity (CI 84%-100%) and 100% specificity (CI 72%-100%); Lab B achieved 85% sensitivity (CI 64%-95%) and 90% specificity (CI 59%-99%); Lab C achieved 55% sensitivity (CI 34%-74%) and 60% specificity (CI 31%-83%); and Lab D achieved 75% sensitivity (CI 53%-89%) and 60% specificity (CI 31%-83%). In general, SAA results showed numerically lower sensitivity in β-amyloid (Aβ)-positive patients with DLB (70%) compared with Aβ-negative patients with DLB (87.5%) (nonstatistically significant). A fair agreement of SAA results was obtained across the 4 laboratories (average κ = 0.246). Discussion: This study highlights challenges for the reproducibility of α-syn SAA results across different protocols applied by different laboratories. This finding, together with the methodological variability reported across laboratories, may challenge the clinical implementation of the α-syn SAA. This study provides relevant support for initiating harmonization and standardization of SAA protocols to move the field toward the clinical implementation of SAAs for the biomarker-based diagnosis of DLB. Classification of evidence: This study provides Class III evidence of variations in the accuracy of CSF α-syn SAA across 4 separate laboratories in distinguishing patients with DLB from healthy controls
STEERING THE GREEN TRANSITION: BUSINESS MODELS AND INNOVATION DYNAMICS IN THE AGRI-TECH SECTOR
No full textThe agri-food sector stands at a defining crossroads, tasked with the dual challenge of feeding a growing global population while urgently reducing its environmental footprint. This dissertation investigates the mechanisms of the "Green Transition", arguing that technological invention alone is insufficient to drive systemic change. Instead, it posits that a durable transformation requires a strategic reconfiguration of business models and a synergistic approach to innovation. The research unfolds as a cumulative journey from theory to practice, and from global trends to economic impact. It begins by mapping the intellectual landscape of sustainable business strategies, identifying a shift from theoretical frameworks to applied, interdisciplinary solutions. Moving to the empirical level, the study tests the viability of circular economy principles through the application of a novel strategic framework, the Circular Triple-Layered Business Model Canvas, to a real-world case of urban waste valorization. Broadening the scope to the global arena, the dissertation analyses the worldwide patent landscape to understand the supply of green technologies. This analysis reveals a critical disconnect between the sheer volume of inventions and their effective market adoption, highlighting distinct regional approaches to innovation strategy. Finally, the research rigorously evaluates the economic returns of these strategies for European agricultural firms.
The ultimate conclusion challenges the efficacy of siloed approaches: the findings demonstrate that pursuing green or digital innovations in isolation yields limited competitive benefits. Conversely, the "Twin Transition", he synergistic integration of digital capabilities with sustainability goals, emerges as the superior paradigm for generating lasting economic value. This work thus provides a strategic playbook for scholars, managers, and policymakers, demonstrating that the future of agriculture depends not just on new technologies but on the integrated business architectures built to deploy them
The hidden strength of weak forces: the role of non-covalent interactions in electrocatalytic CO2 reduction
No full textDespite their weak nature, non-covalent interactions are fundamental to chemical systems, shaping a wide spectrum of physicochemical processes. Defined by their tunable strength, reversibility, and environmental sensitivity, they are central to molecular recognition, the assembly and stabilization of molecular architectures, and the modulation of reaction pathways at both the molecular and supramolecular levels. In recent years, the intentional incorporation of non-covalent donor or acceptor sites into homogeneous and heterogeneous catalysts has emerged as a powerful strategy to enhance control over catalytic selectivity and efficiency. By mimicking nature’s reliance on weak yet cooperative interactions, chemists have unlocked new routes for designing catalysts that can fine-tune reaction environments. In this Review, we provide an overview of recent advances that underscore the auxiliary and often crucial role of non-covalent interactions in the electrochemical reduction reaction of CO2 (CO2RR). Following a brief discussion of their fundamental nature and influence on electrocatalytic processes, we examine representative cases in which non-covalent interactions emerge as pivotal, sometimes in unexpected ways, in shaping reactivity and selectivity
HEPATIC ESTROGEN RECEPTOR ALPHA ACTS AS A MOLECULAR TIMER ALIGNING LIVER METABOLISM TO PREGNANCY PROGRESSION
No full textIl fegato è coinvolto nell’omeostasi dei macronutrienti, nell’eliminazione di sostanze tossiche e nel metabolismo dei farmaci, e gli ormoni sessuali, in particolare gli estrogeni, regolano il metabolismo epatico agendo principalmente attraverso il recettore degli estrogeni α (ERα). ERα regola con precisione il metabolismo del fegato in relazione alle esigenze riproduttive e alla disponibilità di nutrienti.
Questa regolazione potrebbe raggiungere il massimo grado di complessità durante la gravidanza, quando ERα epatico è probabilmente coinvolto nell’adattamento metabolico per sostenere i fabbisogni dell’embrione in via di sviluppo. Tuttavia, il suo ruolo esatto durante la gravidanza deve ancora essere studiato.
Per questo, topi geneticamente modificati per l’assenza di ERα a livello epatico (LERKO) sono stati confrontati con femmine controllo (CTRL) in diverse fasi della gestazione, e sono state effettuate analisi di trascrittomica, metabolomica e fisiologiche durante il progredire della gravidanza.
Nelle femmine CTRL, la gravidanza ha indotto un programma trascrizionale molto preciso nel fegato, ed ERα epatico si è dimostrato fondamentale nel controllare la proliferazione degli epatociti, che ha raggiunto il picco a metà gestazione, in concomitanza con la soppressione delle vie metaboliche ad alto consumo energetico. ERα epatico ha poi permesso la sincronizzazione tra gli adattamenti nel fegato, il metabolismo sistemico del glucosio e i ritmi circadiani. L’assenza di ERα nelle femmine LERKO ha portato ad una proliferazione prematura, espressione persistente di geni coinvolti in vie cataboliche, intolleranza al glucosio e alterazione dei ritmi circadiani, rivelando che ERα epatico agisce come un timer molecolare che allinea la proliferazione degli epatociti alle transizioni metaboliche durante il progredire della gravidanza.
Nel complesso, questi risultati evidenziano il ruolo fondamentale della via di segnale degli estrogeni nell’orchestrazione degli adattamenti metabolici materni durante la gestazione. Questi risultati gettano le basi per ulteriori studi volti a identificare la rilevanza delle alterazioni nella via di segnale degli estrogeni nella suscettibilità a disturbi epatici e metabolici associati alla gravidanza.The liver is involved in macronutrient homeostasis, detoxification and drug metabolism, and sex hormones, particularly estrogens, regulate hepatic metabolism acting mainly through estrogen receptor α (ERα). ERα finely tunes liver metabolic programs in relation to the reproductive needs and nutrients availability.
This regulation might reach its maximum degree of complexity during pregnancy, when hepatic ERα is likely involved in the metabolic adaptation to sustain the needs of the developing embryo. However, its exact role during pregnancy still needs to be investigated.
To fill this gap, liver-specific ERα knockout (LERKO) mice were compared to ERα-floxed (CTRL) females at different gestational timepoints, and transcriptomic, metabolomic and physiological analyses during pregnancy progression were carried out.
In CTRL mice, pregnancy induced a very precise transcriptional program in the liver, and hepatic ERα controlled the timing of hepatocyte proliferation, that peaked mid-gestation, coinciding with the suppression of energy-intensive pathways. Moreover, hepatic ERα synchronized liver adaptations, systemic glucose handling and circadian rhythms. Hepatic ERα deficiency in LERKO led to premature proliferation, persistent expression of catabolic genes, glucose intolerance and disrupted circadian rhythms, revealing that hepatic ERα acts as a molecular timer aligning hepatocyte proliferation to metabolic transitions during pregnancy progression.
Altogether, these results highlight the fundamental role of estrogen signaling in the orchestration of maternal metabolic adaptations during gestation. These findings lay the basis for further studies aimed at identifying the relevance of alterations in estrogen signaling in the susceptibility to liver and metabolic disorders associated to pregnancy
IL RUOLO DELLA CORTE COSTITUZIONALE NELLO SPAZIO DELLA DISCREZIONALITÀ LEGISLATIVA: LA GIURISPRUDENZA A ¿RIME OBBLIGATE¿ E A ¿RIME ADEGUATE¿
No full textIl lavoro di ricerca affronta la dibattuta questione dei rapporti tra Corte costituzionale e legislatore, analizzando la dialettica tra il rispetto della discrezionalità politica e la tutela dei diritti fondamentali. Il fondamento teorico di tale tensione risiede nel principio di separazione dei poteri, che ha condotto la Corte, in alcune circostanze, ad autolimitarsi attraverso decisioni di inammissibilità o di accoglimento tout court, con conseguente vuoto normativo. Tali pronunce, pur preservando la sfera legislativa, sollevano l’interrogativo circa la capacità della Corte di garantire effettivamente la supremazia della Costituzione. Parallelamente, la giurisprudenza costituzionale ha progressivamente ampliato il proprio arsenale decisionale, introducendo tecniche manipolative e sperimentando nuove forme di intervento, non sempre coronate da successo, al fine di rafforzare la tutela dei diritti. Ne emerge un nodo problematico centrale: i limiti del potere creativo della Corte e la ricerca di un equilibrio tra self-restraint e intervento manipolativo.
La tesi si interroga sulla possibilità che le decisioni della Corte realizzino un bilanciamento autentico tra discrezionalità legislativa e primato della Costituzione, con particolare attenzione alla contrapposizione – e talvolta alla sovrapposizione – tra decisioni “a rime obbligate” e decisioni “a rime adeguate”. L’analisi, che si sofferma con particolare attenzione sulla giurisprudenza costituzionale dal 2018 al 2025, prende le mosse dalle origini storiche e normative della giustizia costituzionale, per soffermarsi dapprima sul consolidamento della dottrina crisafulliana delle rime obbligate, e successivamente sull’evoluzione giurisprudenziale che ha portato alla legittimazione delle decisioni a rime adeguate. Il periodo più recente, inaugurato con la sentenza n. 222 del 2018, viene indagato con particolare dettaglio, evidenziando come la Corte abbia privilegiato interventi manipolativi spesso in materia penale, con conseguenti implicazioni sia sul piano della legittimazione istituzionale sia sulla tenuta del rapporto con il legislatore.
Il percorso ricostruttivo consente di mettere in luce il superamento del dogma delle rime obbligate e, al tempo stesso, l’emergere di nuove prospettive: dal possibile ritorno a forme più rigorose di self-restraint, testimoniato da alcune recenti decisioni, fino alla discussione su strumenti normativi o istituzionali che possano meglio raccordare il ruolo della Corte con quello del legislatore, garantendo una tutela effettiva dei diritti senza intaccare la centralità della rappresentanza politica. In tale prospettiva, la ricerca si propone di offrire una chiave di lettura aggiornata dei rapporti tra Corte costituzionale e Parlamento, collocandosi nel solco delle trasformazioni più recenti della giustizia costituzionale italiana.The research addresses the contested issue of the relationship between the Italian Constitutional Court and the legislature, analyzing the dialectic between respect for political discretion and the protection of fundamental rights. The theoretical foundation of this tension lies in the principle of separation of powers, which has led the Court, in certain circumstances, to exercise self-restraint through decisions of inadmissibility or outright annulment, thereby creating regulatory gaps. While such rulings preserve the legislative domain, they raise the question of the Court’s actual capacity to ensure the supremacy of the Constitution. At the same time, constitutional jurisprudence has progressively expanded its decisional arsenal, introducing manipulative techniques and experimenting with novel forms of intervention—sometimes unsuccessful—in order to strengthen the protection of rights. This dynamic brings into focus a central issue: the limits of the Court’s creative power and the pursuit of a balance between self-restraint and manipulative intervention.
The dissertation investigates whether the Court’s decisions can achieve a genuine balance between legislative discretion and constitutional primacy, with particular attention to the opposition—and at times the overlap—between rime obbligate decisions (mandatory rhymes), grounded in the Crisafullian doctrine, and rime adeguate decisions (adequate rhymes). The analysis, focusing especially on constitutional jurisprudence from 2018 to 2025, begins with the historical and normative foundations of constitutional justice, first addressing the consolidation of the Crisafullian doctrine of rime obbligate, and then tracing the jurisprudential evolution that led to the legitimation of rime adeguate decisions. The most recent period, inaugurated by judgment no. 222 of 2018, is examined in detail, highlighting how the Court has favored manipulative interventions, often in the field of criminal law, with significant implications both for institutional legitimacy and for the stability of its relationship with the legislature.
This reconstruction brings to light the overcoming of the rime obbligate dogma and, at the same time, the emergence of new perspectives: from a possible return to more rigorous forms of self-restraint, as evidenced by certain recent decisions, to the debate on normative or institutional instruments better suited to align the role of the Court with that of the legislature, thereby ensuring the effective protection of rights without undermining the centrality of political representation. In this perspective, the research aims to provide an updated interpretive framework for the relationship between the Constitutional Court and Parliament, within the context of the most recent transformations of Italian constitutional justice
Disk Evolution Study Through Imaging of Nearby Young Stars (DESTINYS): V721 CrA and BN CrA have wide and structured disks in the polarised infrared
No full textContext. The environment within which stars form and evolve can play a crucial role in shaping their surrounding protoplanetary disks. This is the reason why homogeneous analyses of protoplanetary disks around young stars in the same star-forming region has become of great relevance in recent years.
Aims. We present near-infrared scattered-light observations of the disks around two stars of the Corona Australis star-forming region, V721 CrA and BN CrA, obtained with VLT/SPHERE in the H band, as part of the DESTINYS large programme. Our objective is to analyse the morphology of these disks and highlight their main properties.
Methods. We adopted an analytical axisymmetric disk model to fit the observations and performed a regression on key disk parameters, namely the dust mass, the height profile, and the inclination. We used RADMC-3D code to produce synthetic observations of the analytical models, with full polarised scattering treatment.
Results. Both stars show resolved and extended disks with substructures in the near-IR. The disk of V721 CrA is vertically thicker, radially smaller (∼120 au), and brighter than that of BN CrA (∼190 au). It also shows spiral arms in the inner regions. The disk of BN CrA shows a dark circular lane, which could be either an intrinsic dust gap or a self-cast shadow, and a brightness enhancement along the disk minor axis. Both disks are compatible with the evolutionary stage of their parent subgroup within the CrA region: V721 CrA belongs to the on-cloud part of CrA, which is dustier, denser, and younger, whereas BN CrA is found on the outskirts of the older off-cloud group
Meeting Report Session 3: Neurobiomarkers STP 44th Annual Symposium 2025 Development and Utility of Neurobiomarkers in Nonclinical Toxicology Studies
No full textThe objective of the third session (Neurobiomarkers) in the 2025 Society of Toxicologic Pathology (STP) symposium was to provide an overview of different types of existing neural biomarkers, highlight the value of novel biomarkers to detect and/or predict nervous system changes in preclinical species, and provide perspectives on their translational potential. These biomarkers can also help evaluate the efficacy of new drugs, monitor neurological diseases, and better characterize neuropathology findings. The lectures in this session featured distinguished experts in their respective scientific disciplines such as electrophysiology, molecular pathology tools to characterize pathology lesions in the visual pathways, fluid-based biomarkers, the use of MRI imaging to visualize test article delivery to the CNS of monkeys, and quantifying DRG changes using techniques like stereology, micro-CT, and nano-CT. In this session, there was also a presentation about immunohistochemical stains performed to evaluate ketamine-induced neurotoxicity in neonatal Sprague Dawley rats as a model for pediatric anesthesia. The integration of neural biomarkers in nonclinical studies in conjunction with a dedicated histopathology evaluation provides the necessary scientific data to better predict and derisk neurotoxicity in clinical studies
Radiation risk mitigation in human space exploration: a primer, a vision, and the state of the art
No full textHuman exploration beyond low Earth orbit poses unique health and operational challenges, with space radiation recognized as one of the most significant hazards. This comprehensive review examines the complex nature of the space radiation environment, its biological effects on humans and life support systems, and current strategies for risk assessment and mitigation. It details the composition and properties of galactic cosmic rays (GCRs) and solar particle events (SPEs), their interactions with spacecraft shielding, and the resulting biological impacts ranging from DNA damage to systemic effects including cancer, cardiovascular disease, and central nervous system impairments. Special emphasis is given to the combined effects of radiation and microgravity, which together alter cellular function and influence health outcomes. The paper also explores the effects of radiation on plants and microorganisms as biological components of bioregenerative life support systems (BLSS). The issue of radiation-induced degradation of food and pharmaceuticals is also considered. Existing and emerging countermeasures, encompassing passive and active shielding, pharmacological agents, nutrition, physiological adaptations like synthetic hibernation, and personalized risk assessment through targeted crew selection are critically reviewed. Additionally, the work highlights the importance of high-fidelity analog studies, space-based experiments, and advanced risk models integrating physical, biological, and operational data to inform future mission planning. Finally, the paper reviews existing infrastructures, experimental platforms, and European research programs, emphasizing the critical role of ground-based accelerators, space analog environments, and in-flight studies in advancing our understanding of radiation risks. By identifying key knowledge gaps and proposing a structured mitigation framework, this study presents a strategic roadmap for protecting human health and sustaining life during long-duration missions to the Moon, Mars, and beyond. (The review work described in the paper stems from the discussions within the working group on Radiation sponsored by the Italian Space Agency.
ATHEROSCLEROSIS AND ENDOTHELIAL DYSFUNCTION IN THALASSEMIA
No full textIn the last decades, thalassemia patients’ survival has dramatically improved thus, new disease-related and age-related comorbidities are emerging. Little is known about the impact of atherosclerotic cardiovascular disease on these patients. The 2021 European Society of Cardiology (ESC) guidelines on atherosclerotic cardiovascular disease (ASCVD) underline the importance of screening every person for ASCVD risk factors to better prevent the disease. However, only a few small studies evaluated the prevalence of ASCVD and its risk factors in thalassemia patients, and the majority are conducted in very young populations.
Aim and methods
This study aimed to determine ASCVD prevalence and risk factors in adult transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) patients, linking them to cardiovascular risk, endothelial function, and iron/heme parameters. Methods included clinical data, biochemical analysis, T2* MRI for iron overload, and carotid Doppler ultrasounds for plaque detection and intima-media thickness. Inflammatory and endothelial markers were assessed in a subgroup.
Results
We enrolled 235 patients (153 TDT, 82 NTDT). ASCVD prevalence was 15% in TDT and 20% in NTDT, increasing with age, and was more common in males. Carotid plaques were found in 7.19% of TDT and 14.4% of NTDT patients, all uncomplicated. Median ccIMT was low (0.55 mm). Patients exhibited a non-atherogenic lipid profile, hindering standard ASCVD risk score applicability. Notably, no differences in iron parameters, inflammation, or endothelial dysfunction related to ASCVD were found. Still, we discovered that sTfR, a marker of ineffective erythropoiesis, is greater in TNDT patients and in patients with atherosclerotic plaque, suggesting a possible role of ineffective erythropoiesis in atherosclerosis pathophysiology.
Conclusion
In conclusion, this is the largest group of beta thalassemia patients evaluated for atherosclerosis and its risk factors.
Atherosclerosis-related cardiovascular disease affects about 1 out of 5 subjects in our cohort, aged 49. Thus, we suggest including the evaluation of the Carotid Doppler assessment in routine follow-up to detect ACSVD. Further studies are needed better to elucidate peculiarities such as a low lipid profile