L’assetto procedurale della recente modifica delle “Normae de delictis Congregationi pro Doctrina Fidei reservatis”: esegesi e suggestioni

SOMMARIO: 1. Considerazioni preliminari - 2. Rimane ancora una preferenza (seppure sfumata) per il processo giudiziario? - 3. Imposizione di misure cautelari - 4. Requisiti per lo svolgimento di determinate mansioni - 5. Impugnabilità delle decisioni in materia di cause incidentali (scomparsa del vetus art. 25 NDR) - 6. Ancora una volta la questione della ‘calamita processuale’ - 7. Una ‘potestas sanandi’ ampliata a norma dell’art. 11 NDR? - 8. Il quadro dei mezzi d’impugnazione contro la sentenza - 9. Una questione particolare sull’appello: può sostenersi la legittimazione attiva del Promotore di Giustizia a quo per l’interposizione dell’appello? - 10. La regolamentazione del procedimento penale amministrativo - 11. Il regime di contestazione delle decisioni penali amministrative: alcuni guadagni e alcune incertezze - 12. Ampliamento della facoltà di deroga alla prescrizione? - 13. La previsione del deferimento al Romano Pontefice per la dimissione dello stato clericale assieme alla dispensa del celibato (art. 26 NDR) e il curioso diritto dell’imputato di richiedere la dispensa ab oneribus (art. 27 NDR) - 14. Conclusioni. Procedural aspects of the recent reform of the “Normae de delictis Congregationi pro Doctrina Fidei reservatis”: an interpretation and some suggestions ABSTRACT: On December 8, 2021, a new modification of the "Normae de delictis Congregationi pro Doctrina Fidei reservatis" came into force. The legal modification has affected both the substantive and the procedural part of these norms. This article examines some of the most significant aspects of this reform from a procedural-canonical perspective and suggests some possible adjustments and future lines of reflection

Conformational landscape of small ligands: a multilevel strategy to determine the conformational penalty of bioactive ligands

Determining the conformational penalty required for adopting the bioactive conformation is still a challenging question in drug design, because a small uncertainty in this free energy component can lead to significant errors in the predicted activities. Herein, we use the Multilevel strategy, a methodology recently developed by our group, to explore the conformational preferences of ligands in solution, and to estimate the conformational cost of selecting the bioactive conformation

Interplay between Ionization and Tautomerism in Bioactive β-Enamino Ester-Containing Cyclic Compounds: Study of Annulated 1,2,3,6-Tetrahydroazocine Derivatives

Depending on the chemical scaffold, the bioactive species could reflect the interplay between ionization and tautomerism, often complicated by the possibility to populate different conformational states in the case of flexible ligands. In this context, theoretical methods can be valuable to discern the role of these factors, as shown here for β-enamino esters of 1,2,3,6 tetrahydroazocino fused ring systems, some of which had proven to be suitable scaffolds for designing novel acetylcholinesterase inhibitors. The compounds investigated herein form two clusters with distinctive experimental pKa values (i.e., α,β-diesters and β-esters ranging within 6.1-7.3 and 8.2-9.0 pKa intervals, respectively), which implies a drastic difference in the most populated species at physiological conditions. While chemoinformatic tools did not provide a consistent description of the actual pKa values, the theoretical analysis performed for the protonated and neutral species of these compounds revealed a marked change in the tautomeric preference of the tetrahydroazocine moiety upon (de)protonation. Excellent agreement between calculated and experimental pKa values was found when the tautomeric preference of protonated and neutral species was considered. Overall, this study highlights the potential use of high-level computational methods to disclose the mutual influence between ionization, tautomerism and conformational preferences in multifunctional (bio)organic compounds

Searching for selective scaffolds against Plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase

Malaria is a parasitic disease caused by Plasmodium spp., being one of the major causes of death worldwide with two-hundred million new infections and hundreds of thousands of deaths in 2015. Despite the important advances in its prevention and treatment, its resistance to current drug therapies is still a serious risk in its eradication. There is urgency in finding novel targets and drugs operating by novel mechanisms, avoiding cross-resistance to classical antimalarials. In this context, the bifunctional enzyme Glucose-6- phosphate dehydrogenase 6-phosphogluconolactonase appears to be a promising therapeutic target due to its crucial role in regulating the PPP pathway (pentose phosphate pathway), which is the major source of redox potential in Plasmodium falciparum. In the last few years, our group detected a specific mutation between the human and the Plasmodium falciparum form in the binding site of Glucose-6-phosphate (G6P), the endogenous ligand of Glucose-6-phosphate dehydrogenase (G6PD). This mutation involves the substitution of an Arginine (human) by an Aspartate (parasite), which allowed us to create a validated in-house homology model of PfG6PD. Based on this result, the group has focused their efforts, through different molecular modelling techniques, in the discovery of selective scaffolds against PfG6PD. Current efforts address the development of a complete structural model of the bifunctional enzyme, which may offer novel opportunities to develop molecules capable of inhibiting this relevant enzyme

Burden of hospitalizations and outpatient visits associated with moderate and severe acute graft-versus-host disease in Finland and Sweden : a real-world data study

Purpose The aim of this study was to describe patient characteristics and quantify hospital stays and outpatient visits (H&OV) following diagnosis with moderate-to-severe acute graft-versus-host disease (aGVHD) in Finland and Sweden. Methods A retrospective chart audit collected data from patient medical records of 3 specialized centers performing allogeneic hematopoietic stem cell transplantation (HSCT; Finland, n = 2; Sweden, n = 1). Eligible patients received allogeneic HSCT (January 1, 2016-June 30, 2017) from any donor source, were diagnosed with grade II-IV aGVHD (MAGIC or modified Glucksberg criteria) at any time from transplantation to 12 months before data collection, and were >= 18 years old at diagnosis. Criteria for comparing patients graded with modified Glucksberg and MAGIC severity scales were defined. Results Fifty-five patients (Finland, n = 45; Sweden, n = 10) were included. Myeloablative conditioning was the most common conditioning regimen (81.8%); immunosuppression regimens were based on combinations of methotrexate (96.4%), in vivo T-cell depletion (80.0%), cyclosporine (63.6%), mycophenolate (40.0%), and tacrolimus (34.5%). Sixteen patients (29.1%) developed grade III/IV aGVHD; skin was the most common organ involved (80.0%). Most patients required >= 1 hospital stay (89.1%; median of 2 hospitalizations per patient); 7 patients (14.3%) required admission to an intensive care unit. Median hospitalization duration from HSCT to discharge was 26 days. Most patients also required outpatient or emergency department visits (90.9%). Subgroup analyses showed longer hospital stays for patients receiving multiple treatment lines; no clear differences in H&OV were observed between prophylactic regimens. Conclusion Based on this retrospective study, moderate-to-severe aGVHD is associated with considerable healthcare resource utilization in Finland and Sweden, particularly in patients who received multiple lines of therapy.Peer reviewe

Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors

Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer"s disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer"s related beta-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD

Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines.

We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio

Three to Tango: Inhibitory Effect of Quercetin and Apigenin on Acetylcholinesterase, Amyloid-β Aggregation and Acetylcholinesterase-Amyloid Interaction

One of the pathological hallmarks of Alzheimer's disease (AD) is the formation of amyloid-β plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid-β aggregation, hence being complementary to the palliative treatment of cholinergic decline. Anti-aggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on Aβ40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the Aβ40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a non-competitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity.

YesDual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity

Social Restrictions versus Testing Campaigns in the COVID-19 Crisis: A Predictive Model Based on the Spanish Case

The global COVID-19 spread has forced countries to implement non-pharmacological interventions (NPI) (i.e., mobility restrictions and testing campaigns) to preserve health systems. Spain is one of the most severely impacted countries, both clinically and economically. In an effort to support policy decision-making, we aimed to assess the impacts of different NPI on COVID-19 epidemiology, healthcare costs and Gross Domestic Product (GDP). A modified Susceptible-Exposed-Infectious-Removed epidemiological model was created to simulate the pandemic evolution. Its output was used to populate an economic model to quantify healthcare costs and GDP variation through a regression model which correlates NPI and GDP change from 42 countries. Thirteen scenarios combining different NPI were consecutively simulated in the epidemiological and economic models. Both increased testing and stringency could reduce cases, hospitalizations and deaths. While policies based on increased testing rates lead to higher healthcare costs, increased stringency is correlated with greater GDP declines, with differences of up to 4.4% points. Increased test sensitivity may lead to a reduction of cases, hospitalizations and deaths and to the implementation of pooling techniques that can increase throughput testing capacity. Alternative strategies to control COVID-19 spread entail differing economic outcomes. Decision-makers may utilize this tool to identify the most suitable strategy considering epidemiological and economic outcomes