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Prebiotic synthesis of the major classes of iron-sulfur clusters
No full textConditions that led to the synthesis of iron-sulfur clusters coordinated to tripeptides with a single thiolate ligand were investigated by UV-vis, NMR, EPR, and M & ouml;ssbauer spectroscopies and by electrochemistry. Increasing concentrations of hydrosulfide correlated with the formation of higher nuclearity iron-sulfur clusters from mononuclear to [2Fe-2S] to [4Fe-4S] and finally to a putative, nitrogenase-like [6Fe-9S] complex. Increased nuclearity was also associated with decreased dynamics and increased stability. The synthesis of higher nuclearity iron-sulfur clusters is compatible with shallow, alkaline bodies of water on the surface of the early Earth, although other niche environments are possible. Because of the plasticity of such complexes, the type of iron-sulfur cluster formed on the prebiotic Earth would have been greatly influenced by the chemical environment and the thiolate containing scaffold. The discovery that all the major classes of iron-sulfur clusters easily form under prebiotically reasonable conditions broadens the chemistry accessible to protometabolic systems
Magnetic hyperthermia drastically enhances killing of Mycobacterium tuberculosis by bacteriocin AS-48 grafted on biomimetic nanoparticles
No full text: Mycobacterium tuberculosis, the etiological agent of human tuberculosis, is an intracellular pathogen responsible for one of the infectious diseases with highest mortality rates. Its ability to replicate inside alveolar macrophages and trigger the formation of granulomas, alongside the appearance of multidrug-resistant strains, impose the employment of drugs that exacerbate their toxic effects after the long therapies necessary to deal with the infection. As an alternative to conventional drugs, this work proposes the use of bacteriocin AS-48 immobilized on biomimetic magnetic nanoparticles (BMNPs) as a nanoformulation capable of killing M. tuberculosis in infected THP-1 macrophages, which allows combination with magnetic hyperthermia to increase its effectiveness. This work is a proof of concept of a nanosystem that could potentially be magnetically directed to infected areas, where it could be applied locally. Our results show that AS-48_BMNP nanoassemblies used against M. tuberculosis in vitro display a synergistic effect with magnetic hyperthermia that can completely eradicate the bacteria from infected macrophages in four days. This combined treatment represents a promising opportunity for the future development of a local therapy for the treatment of M. tuberculosis
Corti costituzionali e potere politico: brevi riflessioni a partire dal sistema francese
No full textil contributo riflette sul rapporto fra corte costituzione e organi politici in Franci
Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
Get PDFBackground and objectives: The objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS). Methods: This five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume. Results: During the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, p = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2-4] for PIRA vs 1.5 [range 1-2] for no PIRA group, p < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61-39.10], p = 0.001), sTNFR2 (HR 5.05 [1.63-15.64], p = 0.005), and LIGHT (HR 1.79 [1.11-2.88], p = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97-0.99], p = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01-0.72], p = 0.028), and CLn (HR 1.15 [1.05-1.25], p = 0.003) were MRI predictors of PIRA. Discussion: A specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS
An International Delphi Consensus About Tumor Rupture During Robotic Partial Nephrectomy (Researching UnPredictable TUmor RupturE during Robotic Partial Nephrectomy—The RUPTURE Project)
No full textBackground and objective: Tumor rupture during robot-assisted partial nephrectomy (RAPN) poses oncological risks, including potential malignant cell spread and recurrence. Despite these risks, standardized guidelines for defining, managing, and assessing risk factors of tumor rupture in RAPN are lacking. This Delphi consensus study aimed to frame the definition, risk factors, and oncological implications of tumor rupture in RAPN, as well as to propose management strategies. Methods: Using a modified Delphi method, a steering committee from multiple urological societies (the RUPTURE project) led a consensus-building study that followed the ACcurate COnsensus Reporting Document (ACCORD) checklist. A panel of international experts participated in a two-phase Delphi survey, rating their agreement with statements on tumor rupture, risk factors, and management in RAPN. Consensus was defined as ≥70% agreement, with unresolved statements discussed in an online meeting and subjected to a second voting round. Key findings and limitations: Thirty-three experts evaluated 58 statements. Consensus was reached on 33% of statements in the first round and 37.5% in the second round. Tumor rupture was defined, with risk factors including larger tumor size, complexity, and endophytic growth patterns. Recommended management strategies focused on minimizing tumor spillage by suctioning—rather than grasping—the cancerous tissue, and promptly securing the specimen in an endobag. Routine conversion to radical nephrectomy was not advised unless unresectable tumor remnants were found. Tumor rupture was not linked to distant metastasis, although its oncological impact varied by the rupture extent (ie, gross rupture vs focal; tumor spilled out macroscopically completely removed vs not). Conclusions and clinical implications: This consensus forms a basis for future research on tumor rupture in RAPN, emphasizing standardized definitions and uniform management strategies. Empirical validation through future clinical research is warranted. Patient summary: This research looks at tumor rupture during robotic kidney surgery, which can happen but is rare. The study involved a panel of experts who discussed finding a consensus on when it is more likely to occur and how to manage it effectively to reduce risks. It was also emphasized that while a rupture may not always lead to cancer spreading, the impact on a patient's health can vary and is yet to be determined
Regional Heterogeneity in Vastus Lateralis Architecture Influences Fascicle Behavior During In Vivo Contractions
Get PDFSkeletal muscle is heterogeneous in its architecture, with regional differences in fiber length and pennation angle that make up anatomically distinct regions. This study aimed to understand how these regional differences influence vastus lateralis (VL) behavior during isokinetic contractions in vivo. Knee extensor torque was measured in twelve healthy young adults using an isokinetic dynamometer during maximal contractions at different angular velocities (30 degrees s-1, 75 degrees s-1, 150 degrees s-1, 210 degrees s-1, 270 degrees s-1). The fascicle length of VL was recorded by two ultrasound devices in its distal and middle regions, and muscle-belly length was calculated as the longitudinal length change in the muscle belly. Fascicle (Vf) and muscle-belly (Vm) velocities were calculated as the first derivative of the length-time curve in the phase at constant angular velocity. Muscle-belly gearing (Gb) was calculated as Vm/Vf. At rest, greater thickness and pennation angles and lower fascicle lengths were observed in the middle vs. distal regions. During contraction, Vf and Vm increased as a function of angular velocity in both the investigated regions. The distal regions showed higher Vf and Vm values at all the investigated angular velocities. Significant differences in Gb were observed between regions but not as a function of knee angular velocity. Our data indicate that the architectural differences within a muscle affect the behavior of the active components during contraction. These results could help develop new musculoskeletal models to predict the muscle's mechanical output better
Un gravoso equilibrio di carte. «Il castello» di Franz Kafka secondo i burattini di Otello Sarzi
No full textl castello è uno degli ultimi romanzi, rimasto incompiuto, dello scrittore boemo Franz Kafka, si tratta di un testo enigmatico che, riprendendo le parole di Roberto Leydi, si pone a metà «fra realismo quotidiano e trasposizione fantastica». Diviene pertanto scontato che un eccentrico artista come Otello Sarzi, a cui si deve molto del rinnovamento del teatro di figura, si avvicinasse all’opera dello scrittore praghese. Non si tratta di un’operazione di semplice riscrittura teatrale da testo letterario, in questo caso è stato utile e fondamentale mettere in luce, già dal testo e dalla sua composizione tutti gli espedienti necessari per l’animazione delle figure. Il volume, a fianco del copione concepito con Gabriele Marchesini per i burattini di Sarzi e le musiche di Giorgio Gaslini, presenta la storia e l’evoluzione sia della rielaborazione drammaturgica sia della prima messinscena dello spettacolo, realizzata nel 1980 presso il Teatro Nazionale di Milano, attraverso gli interventi dei protagonisti e dei testimoni del tempo
Chronic kidney disease in a population-based cohort: an analytical study of prevalence, dietary patterns, and gene-diet interactions affecting kidney function
No full textLa malattia renale cronica (CKD) rappresenta una significativa sfida per la salute pubblica, in cui dieta e predisposizione genetica svolgono un ruolo cruciale nello sviluppo e nella progressione. Tuttavia, le relazioni tra questi fattori e la funzionalità renale sono solo parzialmente comprese, specialmente nel contesto della prevenzione. Questa tesi si propone di affrontare tre obiettivi: (Obiettivo 1) valutare la prevalenza e la consapevolezza della CKD nel distretto della Val Venosta/Vinschgau (Alto Adige, Italia); (Obiettivo 2) identificare i dietary patterns (DPs) associati alla funzionalità renale e al rischio di CKD; e (Obiettivo 3) esplorare l'interazione tra i DPs e la predisposizione genetica in relazione alla disfunzione renale.
Obiettivo 1: Abbiamo valutato la prevalenza e la consapevolezza della CKD nel distretto della Val Venosta/Vinschgau utilizzando i dati dello studio Cooperative Health Research in South Tyrol (CHRIS). Sono stati combinati biomarcatori standard, come il tasso di filtrazione glomerulare stimato (eGFR) e il rapporto albumina-creatinina urinaria (UACR), con le risposte ad un questionario specifico sulla salute renale. I risultati hanno evidenziato un divario tra la prevalenza auto-riportata di CKD e quella definita secondo gli standard clinici utilizzando i marcatori misurati, suggerendo una scarsa consapevolezza o sottodiagnosi della malattia.
Obiettivo 2: L’indagine è stata condotta da tre prospettive distinte, ciascuna trattata in un progetto dedicato. In tutti i progetti, è stata utilizzata la Reduced Rank Regression (RRR) per derivare i dietary patterns (DPs) legati alla CKD.
In primo luogo, abbiamo derivato tre DPs basati sulla RRR utilizzando quattro nutrienti (proteine, fosforo, potassio e sodio) come mediatori. I DPs hanno mostrato effetti eterogenei sugli esiti renali, riflettendo probabilmente una specificità legata alla funzionalità o al danno renale. In particolare, un DP (DP1), caratterizzato da alti livelli di tutti e quattro i nutrienti, è stato associato a livelli inferiori di eGFR negli uomini, indicando una funzionalità renale ridotta.
In secondo luogo, la RRR è stata utilizzata per derivare DPs specifici per sesso utilizzando nove marcatori cardio-renali-metabolici come mediatori. Inoltre, è stato derivato un indice dietetico orientato all’ipertensione, il DASH score. Negli uomini, i risultati hanno generalmente confermato le evidenze precedenti sugli effetti della dieta DASH. Nelle donne, l’associazione tra i DPs e l’eGFR risultava influenzata dallo stato mestruale.
Infine, sfruttando i dati prospettici della Swedish National March Cohort (SNMC), abbiamo replicato i DPs basati sui nutrienti ottenuti nello studio trasversale CHRIS utilizzando la RRR e derivato il DASH score e il Nordic Nutrition Recommendation (NNR) score. Successivamente, abbiamo studiato gli effetti di tutti i DPs sul rischio di incidenza di CKD in un follow-up di 19 anni. Sono stati identificati tre DPs basati sulla RRR, le cui associazioni con l’incidenza di CKD sono risultate eterogenee tra i sessi. Lo score NNR ha mostrato un effetto protettivo sul rischio di CKD, stabilizzandosi però a livelli di aderenza elevati. Il DASH score risultava protettivo, ma solo nelle femmine.
Obiettivo 3: È stato calcolato uno score poligenico (PGS) basato su varianti genetiche associate all’eGFR in individui di ascendenza europea per investigare l’interazione tra predisposizione genetica e DPs nella determinazione della funzionalità renale. Sono state rilevate interazioni non lineari tra il PGS e l’assunzione di proteine e fosforo. Questi risultati suggeriscono che l’impatto dell’assunzione di proteine e fosforo sull’eGFR potrebbe essere modificato dalla predisposizione genetica.
In sintesi, questa ricerca ha fornito nuove conoscenze sull’epidemiologia delle malattie renali nella popolazione generale, sulla prevalenza e consapevolezza della CKD, sugli effetti della dieta sulla funzionalità renale e sul ruolo della predisposizione genetica nelle associazioni tra dieta e salute renale. Sebbene gli effetti benefici della dieta DASH siano stati confermati, i risultati suggeriscono che l’approccio dietetico ottimale può variare tra diversi sottogruppi di popolazione e in base al sesso. Pertanto, l’uso di un approccio flessibile come la RRR per derivare i DPs può essere particolarmente efficace. Infine, i risultati indicano che la predisposizione genetica può influenzare la relazione tra dieta e funzionalità renale.Chronic kidney disease (CKD) is a significant public health challenge, with diet and genetic predisposition playing crucial roles in its development and progression. However, the relationships between these factors and kidney function are only partially understood, especially in the context of prevention. This thesis aimed to address three objectives: (Objective 1) assess CKD prevalence and public awareness in the Val Venosta/Vinschgau district (South Tyrol, Italy); (Objective 2) identify dietary patterns (DPs) associated with kidney function and CKD risk, and (Objective 3) explore the interplay between DPs and genetic predisposition in relation to kidney dysfunction.
Objective 1: We assessed CKD prevalence and awareness in the Val Venosta/Vinschgau district using data from the Cooperative Health Research in South Tyrol (CHRIS) study. We combined standard biomarkers, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), with data from a custom-developed kidney health questionnaire. Findings revealed a gap between self-reported CKD prevalence and the prevalence of CKD defined according to clinical standards using measured markers, indicating a major lack of awareness or diagnosis in participants.
Objective 2: The investigation was conducted from three distinct perspectives, each one covered by a dedicated project. In all projects, Reduced Rank Regression (RRR) was employed to derive CKD-related dietary patterns (DPs).
First, we derived three RRR-based DPs using four nutrients (protein, phosphorus, potassium, and sodium) as mediators. DPs showed heterogeneous effects across kidney out-comes, possibly reflecting specificity to kidney function or damage. Notably, one DP (DP1), characterized by high levels of all four nutrients, was associated with lower eGFR levels in males, indicating poorer kidney function.
Second, RRR was used to derive sex-specific DPs using nine cardio-renal-metabolic markers as mediators. In addition, an hypertension-oriented dietary index, the DASH score, was derived. In males, results generally corroborated previous evidence on the effects of the DASH-style diet. In females, the association between DPs and eGFR was influenced by menstrual status.
Third, by leveraging prospective data from the Swedish National March Cohort (SNMC), we used RRR to replicate the nutrient-based DPs obtained in the cross-sectional CHRIS study and derived the DASH score and the Nordic Nutrition Recommendation (NNR) score. We then investigated the effects of all DPs on CKD incidence risk over a 19-year follow-up. Three RRR-DPs were identified and associations with CKD incidence were heterogenous across sexes. The NNR-score showed a protective effect on CKD risk, but the benefit plateaued at higher levels of adherence. The DASH-score was protective for CKD, but only in females.
Objective 3: A polygenic score (PGS) was calculated based on genetic variants associated with eGFR in European ancestry individuals to investigate the interplay between genetic predisposition and the DPs in determining kidney function. Non-linear interactions be-tween PGS and dietary protein and phosphorus were detected. These results suggested that the impact of protein and phosphorus intake on eGFR may be modified by genetic predisposition.
To summarise, this research provided new insights into the epidemiology of kidney diseases in the general population, CKD prevalence and awareness, as well as the effects of diet on kidney function, and the role of genetic predisposition in diet-renal health associations. While the beneficial effects of the DASH diet were confirmed, results also suggested that the optimal dietary approach may vary across different population subgroups and by sex. Therefore, using a flexible approach like the RRR to derive DPs can be particularly effective. Finally, findings indicated that genetic predisposition may influence the relationship be-tween diet and kidney function
Correction: Nocini et al. Improving Nasal Protection for Preventing SARS-CoV-2 Infection. Biomedicines 2022, 10, 2966
No full textIn the original publication [1], a correction is needed in the first paragraph in Section 3.2.2 as published. Part of the text related to reference 52 of Balmforth et al. (https://pubmed.ncbi.nlm.nih.gov/40374451/) needs to be removed, since the article has been retracted after the publication of the present article. A correction has been made to Section 3.2.2. With this correction, the order of some references has been adjusted accordingly
The QSMA algorithm for quantifiers in SMT
Get PDFDeciding the satisfiability of formulas involving both quantifiers and theory defined symbols is a challenge in automated reasoning.
This article presents an algorithm, called QSMA (Quantified Satisfiability Modulo Assignment), for the satisfiability of an arbitrary quantified formula modulo a complete theory and an initial assignment. The algorithm is proved partially correct and terminating, so that its total correctness is established. An optimized variant called OptiQSMA is also described and shown to preserve both partial correctness and termination. OptiQSMA is implemented in the YicesQS solver. OptiQSMA enabled YicesQS to achieve top of the line results, especially in linear rational arithmetic, in the 2022, 2023, and 2024 editions of the International Satisfiability Modulo Theories Competition (SMT-COMP). A report on these results in four fragments of arithmetic (LRA - Linear Rational Arithmetic, LIA - Linear Integer Arithmetic, NRA - Nonlinear Real Arithmetic, and NIA - Nonlinear Integer Arithmetic) and in the theory of bitvectors (BV) is included