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Upon separation of a crude preparation of β subunit (“β fraction”) from mitochondrial F1-ATPase containing one equivalent of Fe(III) in the nucleotide-independent site (1Fe(III)-loaded MF1), Fe(III) is almost completely recovered. CD spectra show that “β fraction” maintains the structural changes induced by Fe(III) in the whole enzyme. In accordance, EPR reveals that the Fe(III) site geometry is conserved in “β fraction.” Moreover, the EPR spectra of 1Fe(III)-loaded MF1 and its “β fraction” undergo similar changes of the line-shape upon Pi binding at the catalytic site, indicating that the Pi and Fe(III) are proximal on β. Highly purified β in nucleotide-free form binds 1 mol of Fe(III)/mol of protein. MF1 “freezed” by inhibitors with two β in closed conformation and one β in open or half-closed conformation binds 1 mol of Fe(III)/mol of enzyme. Therefore, the Fe(III) site location in the unique β subunit not adopting the closed conformation is proposed. [Copyright &y& Elsevier]

The Pauli exclusion principle (PEP), a cornerstone of quantum mechanics and whole science, states that in a system, two fermions can not simultaneously occupy the same quantum state. Several experimental tests have been performed to place increasingly stringent bounds on the validity of PEP. Among these, the series of VIP experiments, performed at the Gran Sasso Underground National Laboratory of INFN, is searching for PEP-violating atomic X-ray transitions in copper. In this paper, the upgraded VIP-3 setup is described, designed to extend these investigations to higher-Z elements such as zirconium, silver, palladium, and tin. We detail the enhanced design of this setup, including the implementation of cutting-edge, 1 mm thick, silicon drift detectors, which significantly improve the measurement sensitivity at higher energies. Additionally, we present calculations of expected PEP-violating energy shifts in the characteristic lines of these elements, performed using the multi-configurational Dirac-Fock method from first principles. The VIP-3 realization will contribute to ongoing research into PEP violation for different elements, offering new insights and directions for future studies.

Fermions are subject to the Pauli Exclusion Principle (PEP), which is grounded on the spin-statistics theorem and, hence, related to the very same structure of the underlying symmetries. The VIP-2 (VIolation of Pauli exclusion principle - 2) experiment has been performing extreme sensitivity tests of the PEP, up to its current and final configuration, exploiting several experimental setups designed to study different theoretical models of PEP violation, looking for a faint signal of physics Beyond the Standard Model.A current is introduced in the copper target to bring new electrons into the system and, hence, fulfill the requirements of the Messiah-Greenberg Super-Selection rule. The searched spin-statistics violating signal corresponds to X-rays emitted when the new electrons perform atomic transitions to the already filled fundamental level of copper. This work analyzes the set of the VIP-2 data corresponding to a test run of 68 days in a current modulated regime alternating no current with current data-taking in short periods (50 s each), instead the usual alternating months-long data-taking of each of these two phases. We propose an analysis method to improve the experiment's sensitivity: a spectral analysis constraint with the Discrete Fourier Transformation of the data. Compared to the spectrum-only analysis, about a factor of 1.5 of improvement to the limit for the probability of PEP violation for electrons was obtained., Competing Interests: Conflict of interestThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© The Author(s) 2024.)

Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3β,5α,6β-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3β,5α,6β-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: In normal pregnancies, a hypoxic intrauterine environment seems necessary for early trophoblast development. In this context, maternal serum levels of ischemia-modified albumin (IMA) are elevated, reflecting the oxidative stress associated with placental development. The aim of this study was to evaluate IMA and pregnancy-associated plasma protein A (PAPP-A) in mothers bearing small-for-gestational-age (SGA) fetuses compared to normal pregnancies., Study Design: A prospective study was performed between June 2010 and June 2011. Serum total albumin, IMA and PAPP-A concentrations were determined in 81 pregnant women in three different periods: 1st trimester, 2nd trimester and postpartum. Two groups of subjects were retrospectively identified: Group (1) mothers bearing appropriate-for-gestational-age (AGA) fetuses, and Group (2) mothers bearing SGA fetuses. Serum total albumin and IMA concentrations were determined in 198 non-pregnant women as controls., Results: Serum IMA concentrations increase during gestation. IMA/albumin serum levels in the 1st trimester were significantly higher in subjects of Group (2) (p<0.05), whereas values of serum PAPP-A MoM were significantly lower (p<0.05)., Conclusions: Elevated IMA serum levels together with low levels of PAPP-A were detected in the 1st trimester in mothers bearing SGA fetuses, and this may reflect early placental changes occurring before clinical manifestation of SGA., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Recent data suggest that vitamin A modulates the expression of type I interferon receptor enhancing the antireplication effect of interferon-α on hepatitis C virus (HCV). This study aimed to investigate the prevalence of vitamin A deficiency among patients with chronic HCV infection and to assess whether vitamin A deficiency could be associated with unresponsiveness to interferon-based antiviral therapy. The analysis included 199 consecutive treatment-naïve chronic HCV patients in whom pretreatment serum vitamin A and 25-OH vitamin D were measured; 119 healthy blood donors were used as controls. Median (interquartile range) serum vitamin A in HCV-positive patients was significantly lower than in controls: 256 ng/mL (128-440) versus 742 (624-942, P<0.0001). Overall sustained viral response was achieved in 122/199 patients, 46/109 infected by difficult to treat HCV genotypes. In these latter, 39/104 (37.5%) were nonresponders. At multivariate analysis, nonresponse to antiviral therapy was predicted by carriage of interleukin (IL)-28B T/* genotypes, baseline serum levels of γGT>60 IU/mL, of HCV RNA>600,000 IU/mL, of vitamin A≤100 ng/mL, and a cumulative dose of ribavirin≤80%. Seventeen patients (9.0%) had both serum levels of vitamin A≤100 ng/mL and of vitamin D≤20 ng/mL; the presence of a combined vitamin A and D deficiency was found to be a strong independent predictor of nonresponse to antiviral therapy., Conclusion: A high percentage of patients with chronic HCV infection have serum vitamin A deficiency. This condition is associated with nonresponse to antiviral therapy., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: In recent years, a number of technological advancements started to modify the long standing appearance and functionalities of traditional optical microscopes used in Pathology and other medical fields. In fact, at present many new tools for microscopical visualization exist that are based on digital imaging, robotization, and remote communication. Such tools are typically adopted in activities ranging from education to telediagnosis to remote consultation. Present paper describes the features of a basic digital microscope that has been tested to verify its performance for occasional remote consultation inside an international project between Italy and Slovenija, funded by Interreg initiative of the European Regional Development Fund., Methods: The system is composed by a pair of digital microscopes (Leica DMD108, Leitz Microsystems, Wetzlar, Germany) associated to a high resolution videoconferencing systems (Tandberg 990, Lysaker, Norway). The systems are connected through the Internet. Sixty histology and cytology cases have been collaboratively diagnosed between two Pathology Institutes to verify the diagnostic performance of the system, regarding the image quality point of view as well as time needed for diagnosis. The system has also been tested for compatibility with standard videoconferencing software., Results: No discrepancies between local and remote diagnoses have been identified, with diagnosis time reasonably close to typical microscope observation times. Time needed for most operations is not far from that needed on a traditional microscope, except for startup., Conclusions: The system can be considered usable as a standard microscope, and also for occasional remote consultations.

The present paper will present a survey on features of a number of non-specialized off-the-shelf JPEG2000 viewers, seen from the point of view of digital microscopy. Selected viewers were tested within a number of usage scenarios, including: i) open a conformance test JPEG2000 file; ii) open a large JPEG2000 file; iii) moving from one point to another; iv) changing resolution/magnification. For each scenario, data recorded included: successful or unsuccessful operation; time needed for conclusion; occasional problems.Preliminary results demonstrate that JPEG2000 conformance as stated by many viewers is only limited to some of the possibilities of the JPEG2000 standard, in particular for what regards file size.

Background/aims: Hepatic iron may act as an important co-morbid factor in non-hemochromatotic liver diseases, but whether it may favour fibrogenesis after liver transplantation is not known. To verify whether the hepatic iron concentration of the graft might play a role in the rapid fibrotic progression frequently observed after liver transplantation for chronic hepatitis C., Methods: The hepatic iron concentration, measured at the time of the donor operation, was retrospectively related to the histological follow-up data of 68 recipients (49 males, 19 females), of whom 38 were hepatitis C virus positive., Results: The hepatic iron concentration in donor liver biopsies ranged from 25 to 7,100 microg/gdw. After a median follow-up of 19 months, nine patients (five HCV positive) had a staging score >3. There was a significant association between a higher frequency of increasing staging and donor age >50 years. In female HCV-positive recipients, a graft hepatic iron concentration >1,200 microg/gdw was associated with fibrosis progression >0.15 fibrosis units per month (4/4 vs. 1/7, p<0.01)., Conclusions: The graft hepatic iron concentration may be one of the factors involved in early fibrosis progression due to recurrent hepatitis C in female recipients.

Upon separation of a crude preparation of beta subunit ("beta fraction") from mitochondrial F(1)-ATPase containing one equivalent of Fe(III) in the nucleotide-independent site (1Fe(III)-loaded MF(1)), Fe(III) is almost completely recovered. CD spectra show that "beta fraction" maintains the structural changes induced by Fe(III) in the whole enzyme. In accordance, EPR reveals that the Fe(III) site geometry is conserved in "beta fraction." Moreover, the EPR spectra of 1Fe(III)-loaded MF(1) and its "beta fraction" undergo similar changes of the line-shape upon Pi binding at the catalytic site, indicating that the Pi and Fe(III) are proximal on beta. Highly purified beta in nucleotide-free form binds 1mol of Fe(III)/mol of protein. MF(1) "freezed" by inhibitors with two beta in closed conformation and one beta in open or half-closed conformation binds 1mol of Fe(III)/mol of enzyme. Therefore, the Fe(III) site location in the unique beta subunit not adopting the closed conformation is proposed.