The evolutionary history of hepaciviruses.

In the search for natural reservoirs of hepatitis C virus (HCV), a broad diversity of non-human viruses within the Hepacivirus genus has been uncovered. However, the evolutionary dynamics that shaped the diversity and timescale of hepaciviruses evolution remain elusive. To gain further insights into the origins and evolution of this genus, we screened a large dataset of wild mammal samples (n = 1,672) from Africa and Asia, and generated 34 full-length hepacivirus genomes. Phylogenetic analysis of these data together with publicly available genomes emphasizes the importance of rodents as hepacivirus hosts and we identify 13 rodent species and 3 rodent genera (in Cricetidae and Muridae families) as novel hosts of hepaciviruses. Through co-phylogenetic analyses, we demonstrate that hepacivirus diversity has been affected by cross-species transmission events against the backdrop of detectable signal of virus-host co-divergence in the deep evolutionary history. Using a Bayesian phylogenetic multidimensional scaling approach, we explore the extent to which host relatedness and geographic distances have structured present-day hepacivirus diversity. Our results provide evidence for a substantial structuring of mammalian hepacivirus diversity by host as well as geography, with a somewhat more irregular diffusion process in geographic space. Finally, using a mechanistic model that accounts for substitution saturation, we provide the first formal estimates of the timescale of hepacivirus evolution and estimate the origin of the genus to be about 22 million years ago. Our results offer a comprehensive overview of the micro- and macroevolutionary processes that have shaped hepacivirus diversity and enhance our understanding of the long-term evolution of the Hepacivirus genus.

Organizational design: the case of SARS-CoV-2 vaccination in a healthcare centre.

Background: Only recently Anti-Covid-19 strategies have been applied through specific vaccines, that are a decisive support to modify the evolution of the disease and to reduce the contagion curve. Along vaccination campaigns, the necessity to guarantee rapidity and effectiveness is a critical challenge for all health organizations; their operative capability is applied to carry out govern plans, to ensure safety of the procedures, to adopt good clinical practices, to help with adhesion to vaccine administration and to monitor adverse effects. Study design: The "Centro Clinico Morgagni" is a private accredited diagnosis and treatment Centre with high specialty departments and several hospital beds. The challenge for its administration was to complete the vaccination of all the staff, so a COVID19 crisis unit was established to assure the control of all activities in the center throughout the pandemic. The goal was to complete the vaccination plan following the guidelines with no risks or harm. Methods: An original organizational model, based on different planning methodologies was developed, its task was to define a standard procedure and to give operational instructions based on ISO 9001 for monitoring the entire vaccination process. Also, the model had to define every responsibility role and it had to follow Joint Commission International's methodologies as far as error barriers, drug conservation risks, drug transport and drug administration were concerned.Furthermore, in agreement with the HACCP system, critical control points were highlighted during all the process. The results have been processed in the form of quick references and illustrative panels based on relevant process aspects, which were given to the staff involved in the operations as reference tools for prompt consultation. Results: The vaccination operations at the Centro Clinico Morgagni took place quickly in only four days: 800 staff units were vaccinated - first and second doses with Covid19 mRNA BNT162b2 (Cominraty) - in three different vaccination centers without highlighting significant events that did not comply with the guidelines, nor deviations from the established goals. More precisely, starting from 277 bottles corresponding to six doses each, only 0.2% was wasted, while ADR monitoring reported a prevalence of adverse effects in females (78%) compared to males (22%). Adhesion for vaccination of qualified personnel, thanks to the activities of the Medical College set up for this purpose, reached 100% of the candidate staff through repeated personalized interviews with only one opposition, compared to the 30 communicated at the beginning. Conclusions: It was necessary to ensure the efficiency of the entire process and the model was tested positively. This model can also provide a security control of all the vaccinated personnel; its schematization allows an easy application and flexibility, thus making it an organizational tool that could be reproduced and transferred to other contexts.

New Minimally Invasive Intraoral Procedure for Condylar Fractures: Clinical Presentation and Considerations on Current Techniques.

ABSTRACT: Mandibular fractures are the third most prevalent maxillofacial traumatic events. Surgical approaches to the condyle are a debated topic. This study describes a mini-invasive technique for condylar fracture reduction. The patient of this study suffered multiple traumatic injuries including a carotid artery dissecting aneurysm, which contraindicated the standard open reduction and internal fixation technique. The novel minimally invasive technique involves intraoral access and fracture fragment realignment using a periosteal elevator, a molar occlusal splint, and intermaxillary fixation after intraoperative radiologic imaging confirmation of condyle reposition.The approach avoids skin incisions and tissue dissection, with good aesthetic outcomes and facial nerve preservation. This technique proved to be safe and simple to be less demanding for the patient, with a shorter recovery time than experienced with other techniques.The results suggest this technique is a good option for the surgical treatment of condylar neck fractures showing favorable rim morphology with primary stability after reduction.

Mutations in the estrogen receptor alpha hormone binding domain promote stem cell phenotype through notch activation in breast cancer cell lines.

The detection of recurrent mutations affecting the hormone binding domain (HBD) of estrogen receptor alpha (ERα/ESR1) in endocrine therapy-resistant and metastatic breast cancers has prompted interest in functional characterization of these genetic alterations. Here, we explored the role of HBD-ESR1 mutations in influencing the behavior of breast cancer stem cells (BCSCs), using various BC cell lines stably expressing wild-type or mutant (Y537 N, Y537S, D538G) ERα. Compared to WT-ERα clones, mutant cells showed increased CD44+/CD24- ratio, mRNA levels of stemness genes, Mammosphere Forming Efficiency (MFE), Self-Renewal and migratory capabilities. Mutant clones exhibited high expression of NOTCH receptors/ligands/target genes and blockade of NOTCH signaling reduced MFE and migratory potential. Mutant BCSC activity was dependent on ERα phosphorylation at serine 118, since its inhibition decreased MFE and NOTCH4 activation only in mutant cells. Collectively, we demonstrate that the expression of HBD-ESR1 mutations may drive BC cells to acquire stem cell traits through ER/NOTCH4 interplay. We propose the early detection of HBD-ESR1 mutations as a challenge in precision medicine strategy, suggesting the development of tailored-approaches (i.e. NOTCH inhibitors) to prevent disease development and metastatic spread in BC mutant-positive patients.

Rare-earth nickelates RNiO3: thin films and heterostructures.

This review stands in the larger framework of functional materials by focussing on heterostructures of rare-earth nickelates, described by the chemical formula RNiO3 where R is a trivalent rare-earth R = La, Pr, Nd, Sm, …, Lu. Nickelates are characterized by a rich phase diagram of structural and physical properties and serve as a benchmark for the physics of phase transitions in correlated oxides where electron-lattice coupling plays a key role. Much of the recent interest in nickelates concerns heterostructures, that is single layers of thin film, multilayers or superlattices, with the general objective of modulating their physical properties through strain control, confinement or interface effects. We will discuss the extensive studies on nickelate heterostructures as well as outline different approaches to tuning and controlling their physical properties and, finally, review application concepts for future devices.

Conditional expression of Ki-RasG12V in the mammary epithelium of transgenic mice induces estrogen receptor alpha (ERα)-positive adenocarcinoma.

Appropriate 'in vivo' models are crucial for studying breast cancer biology and evaluating the efficacy of therapeutic agents. Thus we engineered a novel transgenic mouse line expressing the human Ki-Ras bearing an activating mutation (Ki-Ras(G12V)) selectively in the mammary epithelium after lactation. These mice develop invasive ductal adenocarcinomas with 100% incidence within 3-9 months after Ki-Ras(G12V) induction. Immunophenotyping revealed that the mammary tumors express luminal markers, are positive for estrogen and progesterone receptors, negative for HER2 and have a low proliferation index. Moreover, cell lines derived from such tumors are estrogen-responsive and, when transplanted into nude mice, form tumors that respond to the antiestrogen ICI 182780. In conclusion, the mammary tumors of these transgenic mice and the derived cell lines exhibit key features of the major form of human breast cancer, that is, luminal A subtype and thus have a high potential for breast cancer research and treatment.

Multiple Supersonic Phase Fronts Launched at a Complex-Oxide Heterointerface.

Selective optical excitation of a substrate lattice can drive phase changes across heterointerfaces. This phenomenon is a nonequilibrium analogue of static strain control in heterostructures and may lead to new applications in optically controlled phase change devices. Here, we make use of time-resolved nonresonant and resonant x-ray diffraction to clarify the underlying physics and to separate different microscopic degrees of freedom in space and time. We measure the dynamics of the lattice and that of the charge disproportionation in NdNiO_{3}, when an insulator-metal transition is driven by coherent lattice distortions in the LaAlO_{3} substrate. We find that charge redistribution propagates at supersonic speeds from the interface into the NdNiO_{3} film, followed by a sonic lattice wave. When combined with measurements of magnetic disordering and of the metal-insulator transition, these results establish a hierarchy of events for ultrafast control at complex-oxide heterointerfaces.

Striped nanoscale phase separation at the metal-insulator transition of heteroepitaxial nickelates.

Nucleation processes of mixed-phase states are an intrinsic characteristic of first-order phase transitions, typically related to local symmetry breaking. Direct observation of emerging mixed-phase regions in materials showing a first-order metal-insulator transition (MIT) offers unique opportunities to uncover their driving mechanism. Using photoemission electron microscopy, we image the nanoscale formation and growth of insulating domains across the temperature-driven MIT in NdNiO3 epitaxial thin films. Heteroepitaxy is found to strongly determine the nanoscale nature of the phase transition, inducing preferential formation of striped domains along the terraces of atomically flat stepped surfaces. We show that the distribution of transition temperatures is a local property, set by surface morphology and stable across multiple temperature cycles. Our data provide new insights into the MIT of heteroepitaxial nickelates and point to a rich, nanoscale phenomenology in this strongly correlated material.

Interlayer coupling through a dimensionality-induced magnetic state.

Dimensionality is known to play an important role in many compounds for which ultrathin layers can behave very differently from the bulk. This is especially true for the paramagnetic metal LaNiO3, which can become insulating and magnetic when only a few monolayers thick. We show here that an induced antiferromagnetic order can be stabilized in the [111] direction by interfacial coupling to the insulating ferromagnet LaMnO3, and used to generate interlayer magnetic coupling of a nature that depends on the exact number of LaNiO3 monolayers. For 7-monolayer-thick LaNiO3/LaMnO3 superlattices, negative and positive exchange bias, as well as antiferromagnetic interlayer coupling are observed in different temperature windows. All three behaviours are explained based on the emergence of a (»,»,»)-wavevector antiferromagnetic structure in LaNiO3 and the presence of interface asymmetry with LaMnO3. This dimensionality-induced magnetic order can be used to tailor a broad range of magnetic properties in well-designed superlattice-based devices.

Erratum to: Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter.

Erratum to: Breast Cancer Res Treat (2012), 134:569­581, DOI 10.1007/s10549-012-2090-9. Uunfortunately, authors could not find the original film from which the figure was drawn. Therefore, as suggested by the Editor, they have repeated the relative experiment, and ask to publish this new figure as a correction. The authors apologize for any inconvenience that it may cause.

Interfacial Control of Magnetic Properties at LaMnO3/LaNiO3 Interfaces.

The functional properties of oxide heterostructures ultimately rely on how the electronic and structural mismatches occurring at interfaces are accommodated by the chosen materials combination. We discuss here LaMnO3/LaNiO3 heterostructures, which display an intrinsic interface structural asymmetry depending on the growth sequence. Using a variety of synchrotron-based techniques, we show that the degree of intermixing at the monolayer scale allows interface-driven properties such as charge transfer and the induced magnetic moment in the nickelate layer to be controlled. Further, our results demonstrate that the magnetic state of strained LaMnO3 thin films dramatically depends on interface reconstructions.

The impact of drug interactions and polypharmacy on antimicrobial therapy in the elderly.

Infectious diseases are more prevalent in older people than in younger adults, and represent a major healthcare issue in older populations. Indeed, infections in the elderly are often associated with higher morbidity and mortality, and may present atypically. Additionally, older patients are generally treated with polypharmacy regimens, which increase the likelihood of drug-drug interactions when the prescription of an antimicrobial agent is needed. A progressive impairment in the functional reserve of multiple organs may affect either pharmacokinetics or pharmacodynamics during aging. Changes in body composition occurring with advancing age, reduced liver mass and perfusion, and reduced renal excretion may affect either pharmacokinetics or pharmacodynamics. These issues need to be taken into account when prescribing antimicrobial agents to older complex patients taking multiple drugs. Interventions aimed at improving the appropriateness and safety of antimicrobial prescriptions have been proposed. Educational interventions targeting physicians may improve antimicrobial prescriptions. Antimicrobial stewardship programmes have been found to reduce the length of hospital stay and improve safety in hospitalized patients, and their use in long-term care facilities is worth testing. Computerized prescription and decision support systems, as well as interventions aimed at improving antimicrobial agents dosage in relation to kidney function, may also help to reduce the burden of interactions and inherent costs.

Assessment of the gastrointestinal helminth fauna of mountain hares (Lepus timidus varronis) from the northwestern Italian Alps, with new records of parasite occurrence.

We describe the gastrointestinal parasite community of Lepus timidus varronis, a subspecies of the mountain hare (L. timidus) living in the Alps. Two nematode species are reported for the first time in L. timidus.

Invasive species and their parasites: eastern cottontail rabbit Sylvilagus floridanus and Trichostrongylus affinis (Graybill, 1924) from Northwestern Italy.

The eastern cottontail Sylvilagus floridanus is a native American lagomorph. Within the genus Sylvilagus, the eastern cottontail is the species with the widest distribution. From 1950s, the species was introduced to several European countries. A rapid territorial expansion of the introduced eastern cottontails has been observed in many areas of Italy. The eastern cottontail has been demonstrated to play a main role as carrier of exotic parasites. To date, three nematode species, exotic in Italian ecosystems, have been reported from introduced S. floridanus. However, its parasite fauna biodiversity is richer in native populations of the American continent. The aim of this work was to further investigate the gastrointestinal parasites of S. floridanus, to evaluate the potential presence of other exotic species. During 2010, 101 hosts were examined, and three nematodes were collected from their digestive tract. Two parasite species (Obeliscoides cuniculi, Trichostrongylus calcaratus) were already reported in Italy; the isolation of Trichostrongylus affinis is instead the first report of this nematode in Italy and in Europe as a whole. This study wants to highlight the great risks related to the introduction of allochthonous species. The impact of the invasion by alien animal species may be particularly severe for public and animal health, due to the potential introduction of new pathogens. The good number of exotic parasites found in introduced eastern cottontails, together with the few sanitary surveys carried out, suggests that an epidemiological survey, with specimens from multiple localities on a wider geographic range, could lead to interesting findings on parasites of native and alien lagomorphs in Europe.

DAX-1, as an androgen-target gene, inhibits aromatase expression: a novel mechanism blocking estrogen-dependent breast cancer cell proliferation.

Sexual hormones, estrogens and androgens, determine biological response in a tissue- and gender-specific manner and have a pivotal role in endocrine-mediated tumorigenesis. In situ estrogen production by aromatase is a critical determinant for breast cancer growth and progression. On the contrary, clinical and in vitro studies indicate that androgens have a protective role in mammary carcinogenesis. Here, we demonstrated, in hormone-dependent breast cancer cells, the existence of a functional interplay between the androgen receptor (AR), the orphan nuclear receptor DAX-1 and the aromatase enzyme involved in the inhibition of the estrogen-dependent breast cancer cell proliferation exerted by androgen signaling. Indeed, our results revealed, in MCF-7 cells, that ligand-activated AR induces the expression of the orphan nuclear receptor DAX-1 by direct binding to a newly identified androgen-response-element within the DAX-1 proximal promoter. In turn, androgen-induced DAX-1 is recruited, in association with the corepressor N-CoR, within the SF-1/LRH-1 containing region of the aromatase promoter, thereby repressing aromatase expression and activity. In elucidating a novel mechanism by which androgens, through DAX-1, inhibit aromatase expression in breast cancer cell lines, these findings reinforce the theory of androgen- opposing estrogen-action, opening new avenues for therapeutic intervention in estrogen-dependent breast tumors.

Bergapten induces ER depletion in breast cancer cells through SMAD4-mediated ubiquitination.

ERα function is crucial for the development of normal mammary gland as well as in the process of progression of breast cancer cells. Signals that target receptor levels contribute to regulate estrogens effects in the cells. An intricate cross-regulation has been documented between ERα and TGF-ß down-stream molecules: SMAD2, SMAD3, and SMAD4, that can bind ERα and regulate their signaling. Thus, identification of natural anticancer drugs able to influence the latter molecule might provide alternative choices for breast cancer treatment. Taking into account our previous published data we wanted to study the effect of 5-Methoxypsoralen (bergapten) on ERα and on TGF-ß pathway. We reported that bergapten, a coumarin containing compound, effectively depletes ERα in MCF-7 breast cancer sensitive cells and in tamoxifen-resistant clone. The decrease of ERα protein after bergapten treatment results from the ubiquitine-proteasome pathway as demonstrated by the use of MG-132. IP experiments with ER antibody, demonstrated that the protein has physical interaction with SMAD4 and poly-ubiquitine and the amount of ubiquitinated receptor, linked to SMAD4, is greater under bergapten. The crucial role played by SMAD4, in this process, emerges from the observation that in breast cancer cells, silencing of SMAD4, resulted in increased expression of endogenous ERα in both control and bergapten-treated cells, compared to wild- type cells. The same results were confirmed in siRNA TGF-ß RII cells. The results suggest a novel negative regulation of ERα by TGF-ß/SMAD4 in breast cancer cells and indicate that the SMAD4 protein is involved in the degradation of ERα induced by bergapten. We propose that bergapten may efficiently act as a natural antitumoral agent, able to deplete ERα from breast cancer tamoxifen-sensitive and resistant cells, thereby retraining the effect of membrane signals targeting ERα and in such way its mitogenic potentiality.

Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter.

Human estrogen receptors alpha and beta are crucially involved in the regulation of mammary growth and development. Normal breast tissues display a relative higher expression of ER beta than ER alpha, which drastically changes during breast tumorogenesis. Thus, it is reasonable to suggest that a dysregulation of the two estrogen receptor subtypes may induce breast cancer development. However, the molecular mechanisms underlying the potential opposing roles played by the two estrogen receptors on tumor cell growth remain to be elucidated. In the present study, we have demonstrated that ER beta overexpression in breast cancer cells decreases cell proliferation and down-regulates ER alpha mRNA and protein content, along with a concomitant repression of estrogen-regulated genes. Transient transfection experiments, using a vector containing the human ER alpha promoter region, showed that elevated levels of ER beta down-regulated basal ER alpha promoter activity. Furthermore, site-directed mutagenesis and deletion analysis revealed that the proximal GC-rich motifs at -223 and -214 are critical for the ER beta-induced ER alpha down-regulation in breast cancer cells. This occurred through ER beta-Sp1 protein-protein interactions within the ER alpha promoter region and the recruitment of a corepressor complex containing the nuclear receptor corepressor NCoR, accompanied by hypoacetylation of histone H4 and displacement of RNA-polymerase II. Silencing of NCoR gene expression by RNA interference reversed the down-regulatory effects of ER beta on ER alpha gene expression and cell proliferation. Our results provide evidence for a novel mechanism by which overexpression of ER beta through NCoR is able to down regulate ER alpha gene expression, thus blocking ER alpha's driving role on breast cancer cell growth.

Simultaneously mapping and superimposing landmark configurations with parsimony as optimality criterion.

All methods proposed to date for mapping landmark configurations on a phylogenetic tree start from an alignment generated by methods that make no use of phylogenetic information, usually by superimposing all configurations against a consensus configuration. In order to properly interpret differences between landmark configurations along the tree as changes in shape, the metric chosen to define the ancestral assignments should also form the basis to superimpose the configurations. Thus, we present here a method that merges both steps, map and align, into a single procedure that (for the given tree) produces a multiple alignment and ancestral assignments such that the sum of the Euclidean distances between the corresponding landmarks along tree nodes is minimized. This approach is an extension of the method proposed by Catalano et al. (2010. Phylogenetic morphometrics (I): the use of landmark data in a phylogenetic framework. Cladistics. 26:539-549) for mapping landmark data with parsimony as optimality criterion. In the context of phylogenetics, this method allows maximizing the degree to which similarity in landmark positions can be accounted for by common ancestry. In the context of morphometrics, this approach guarantees (heuristics aside) that all the transformations inferred on the tree represent changes in shape. The performance of the method was evaluated on different data sets, indicating that the method produces marked improvements in tree score (up to 5% compared with generalized superimpositions, up to 11% compared with ordinary superimpositions). These empirical results stress the importance of incorporating the phylogenetic information into the alignment step.

Hiperplasia pseudoepiteliomatosa: uma reação rara à tatuagem / Pseudoepitheliomatous hyperplasia: a rare reaction to tattoo

Atualmente, as reações cutâneas à tatuagem não são incomuns e diferentes padrões histológicos são descritos. Relata-se caso de paciente do sexo masculino de 51 anos, com múltiplas lesões pápulo-verrucosas surgidas na tatuagem após retoque com tinta guache na cor vermelha. Seu exame anatomopatológicore velou o raro padrão de hiperplasia pseudoepiteliomatosa (AU)

Currently, skin reactions to tattoo are not uncommon and several histological patterns are described. It is presented a case of a male patient of 51 years old with multiple papular warty lesions that arisen on his tattoo after a refinishing with red gouach. His histopathological examination revealed a rare pattern of pseudoepitheliomatous hyperplasia (AU)