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Abstract Background The availability of transcriptomic data for species without a reference genome enables the construction of de novo transcriptome assemblies as alternative reference resources from RNA-Seq data. A transcriptome provides direct information about a species’ protein-coding genes under specific experimental conditions. The de novo assembly process produces a unigenes file in FASTA format, subsequently targeted for the annotation. Homology-based annotation, a method to infer the function of sequences by estimating similarity with other sequences in a reference database, is a computationally demanding procedure. Results To mitigate the computational burden, we introduce HPC-T-Annotator, a tool for de novo transcriptome homology annotation on high performance computing (HPC) infrastructures, designed for straightforward configuration via a Web interface. Once the configuration data are given, the entire parallel computing software for annotation is automatically generated and can be launched on a supercomputer using a simple command line. The output data can then be easily viewed using post-processing utilities in the form of Python notebooks integrated in the proposed software. Conclusions HPC-T-Annotator expedites homology-based annotation in de novo transcriptome assemblies. Its efficient parallelization strategy on HPC infrastructures significantly reduces computational load and execution times, enabling large-scale transcriptome analysis and comparison projects, while its intuitive graphical interface extends accessibility to users without IT skills.

Abstract Background Skeletal Stem Cells (SSCs) are required for skeletal development, homeostasis, and repair. The perspective of their wide application in regenerative medicine approaches has supported research in this field, even though so far results in the clinic have not reached expectations, possibly due also to partial knowledge of intrinsic, potentially actionable SSC regulatory factors. Among them, the pleiotropic cytokine RANKL, with essential roles also in bone biology, is a candidate deserving deep investigation. Methods To dissect the role of the RANKL cytokine in SSC biology, we performed ex vivo characterization of SSCs and downstream progenitors (SSPCs) in mice lacking Rankl (Rankl −/− ) by means of cytofluorimetric sorting and analysis of SSC populations from different skeletal compartments, gene expression analysis, and in vitro osteogenic differentiation. In addition, we assessed the effect of the pharmacological treatment with the anti-RANKL blocking antibody Denosumab (approved for therapy in patients with pathological bone loss) on the osteogenic potential of bone marrow-derived stromal cells from human healthy subjects (hBMSCs). Results We found that, regardless of the ossification type of bone, osteochondral SSCs had a higher frequency and impaired differentiation along the osteochondrogenic lineage in Rankl −/− mice as compared to wild-type. Rankl −/− mice also had increased frequency of committed osteochondrogenic and adipogenic progenitor cells deriving from perivascular SSCs. These changes were not due to the peculiar bone phenotype of increased density caused by lack of osteoclast resorption (defined osteopetrosis); indeed, they were not found in another osteopetrotic mouse model, i.e., the oc/oc mouse, and were therefore not due to osteopetrosis per se. In addition, Rankl −/− SSCs and primary osteoblasts showed reduced mineralization capacity. Of note, hBMSCs treated in vitro with Denosumab had reduced osteogenic capacity compared to control cultures. Conclusions We provide for the first time the characterization of SSPCs from mouse models of severe recessive osteopetrosis. We demonstrate that Rankl genetic deficiency in murine SSCs and functional blockade in hBMSCs reduce their osteogenic potential. Therefore, we propose that RANKL is an important regulatory factor of SSC features with translational relevance.

Abstract This work introduces a novel prescription for the expression of the thermodynamic potentials associated with the couplings of a Lanczos-Lovelock theory. These potentials emerge in theories with multiple couplings, where the ratio between them provide intrinsic length scales that break scale invariance. Our prescription, derived from the covariant phase space formalism, differs from previous approaches by enabling the construction of finite potentials without reference to any background. To do so, we consistently work with finite-size systems with Dirichlet boundary conditions and rigorously take into account boundary and corner terms: including these terms is found to be crucial for relaxing the integrability conditions for phase space quantities that were required in previous works. We apply this prescription to the first law of (extended) thermodynamics for stationary black holes, and derive a version of the Smarr formula that holds for static black holes with arbitrary asymptotic behaviour.

Abstract Additional copies of chromosome 1 long arm (1q) are frequently found in multiple myeloma (MM) and predict high-risk disease. Available data suggest a different outcome and biology of patients with amplification (Amp1q, ≥4 copies of 1q) vs. gain (Gain1q, 3 copies of 1q) of 1q. We evaluated the impact of Amp1q/Gain1q on the outcome of newly diagnosed MM patients enrolled in the FORTE trial (NCT02203643). Among 400 patients with available 1q data, 52 (13%) had Amp1q and 129 (32%) Gain1q. After a median follow-up of 62 months, median progression-free survival (PFS) was 21.2 months in the Amp1q group, 54.9 months in Gain1q, and not reached (NR) in Normal 1q. PFS was significantly hampered by the presence of Amp1q (HR 3.34 vs. Normal 1q, P

Background: Urinary tract infections (UTIs) are the most common bacterial infections in children. The high variability in pathogen susceptibility rates leads to the lack of clear guidelines for empiric and targeted therapies. In this view, local microbiological surveillance and locally adapted stewardship interventions need to be implemented. Objective: The study aims to describe the results of a pediatric antimicrobial stewardship program on antibiotic prescriptions for UTIs over 8 years in a pediatric general ward of a tertiary center. Design: This quasi-experimental study was conducted between 2015 and 2022, with two different implementations, one in 2018 and one in 2021. Methods: Demographic, clinical, microbiological, and therapeutic data were retrieved from the electronic clinical records of included patients. The primary outcomes were adherence to local guidelines for empiric therapies and the adequacy of targeted therapy. Secondary outcomes were evaluating antibiotic prescription patterns stratified by antibiotics during hospital stay and at discharge, and assessing the microbiological characteristics of UTI episodes. Results: During the study period, 7038 patients were admitted to the pediatric acute care unit (PACU), and 264 (3.7%) were included in this study. Adherence to local guidelines was highest immediately after the interventions, and it slightly decreased thereafter. Use of cephalosporins remained high throughout the 8 years but the changing microbiological scenario observed led to changing recommendations within the study period. An increase in E. coli strains resistant to co-amoxiclav was observed in the last years. Oral second-line agent consumption remained high but was adequate considering the prevalence of resistant bacteria. Conclusion: The variability of antimicrobial consumption reflects the changing resistance patterns for UTIs pathogens, underlying the importance of locally adapted, persevering antimicrobial stewardship interventions.

Antimicrobial resistance is responsible for an alarming number of deaths, estimated at 5 million per year. To combat priority pathogens, like Helicobacter pylori, the development of novel therapies is of utmost importance. Understanding the molecular alterations induced by medications is critical for the design of multi-targeting treatments capable of eradicating the infection and mitigating its pathogenicity. However, the application of bulk omics approaches for unraveling drug molecular mechanisms of action is limited by their inability to discriminate between target-specific modifications and off-target effects. This study introduces a multi-omics method to overcome the existing limitation. For the first time, the Proteome Integral Solubility Alteration (PISA) assay is utilized in bacteria in the PISA-Express format to link proteome solubility with different and potentially immediate responses to drug treatment, enabling us the resolution to understand target-specific modifications and off-target effects. This study introduces a comprehensive method for understanding drug mechanisms and optimizing the development of multi-targeting antimicrobial therapies.

A promising stream of investigations is targeting ongoing neural oscillations and whether their modulation could be related to the perception of pain. Using an electroencephalography (EEG) frequency-tagging approach, sustained periodic thermonociceptive stimuli perceived as painful have been shown to modulate ongoing oscillations in the theta, alpha and beta bands at the frequency of stimulation. Nonetheless, it remains uncertain whether these modulations are indeed linked to pain perception. To test this relationship, we modulated pain perception using a cue-based expectation modulation paradigm and investigated whether ongoing oscillations in different frequency bands mirror the changes in stimulus perception. Forty healthy participants were instructed that a visual cue can precede either a high- or low-intensity stimulation. These cues were paired with three different levels of sustained periodic thermonociceptive stimuli (low, medium and high). Despite a strong effect of expectation on perceived stimulus intensity, this effect was not reflected in the modulation of the ongoing oscillations, suggesting a potential dissociation of pain perception and these oscillatory activities. Rather, it seems that the intensity of stimulation is the primary generator of the frequency-tagged EEG responses. Importantly, these results need to be confirmed by further investigations that could allow the detection of smaller effects than originally estimated.

A novel method for the recycling of end-of-life mattresses foam, using an AIR-LAY process which employs a bi-component fiber as a binder for the polyurethane foam, have been developed and optimized. This method permits to obtain materials with the same density of the starting foam (25 kg/m3) and with a significantly lower density with respect to that obtainable with the rebonding process (above 70 kg/m3) that uses isocyanates to bond the foam particles. The obtained recycled foams have been tested by mechanical compression and recovery tests showing that compression values of 3.7 KPa, similar to that of the mattress foam (3.0 KPa), can be achieved using 20 % of bi-component fibers as binders and a density of 35 kg/m3. On the contrary, only 3 times stiffer and denser materials can be obtained using the rebonding technology, thus making them not suitable for application in mattresses. On the basis of the results of the optimization tests a set of mattresses containing a layer of the recycled foams have been prepared. The results of the tests on the prepared mattresses have shown that they have the same compression behavior, recovery time and durability (after 30,000 cycles of compression) of a standard mattress without the recycled layer, thus proving that a fully circular approach in the recycling of the foam of the mattresses is possible using the AIR-LAY process.

This paper aims to highlight the life of computer technologies to understand what kind of 'technological intentionality' is present in computers based upon the phenomenological elements constituting the objects in general. Such a study can better explain the effects of new digital technologies on our society and highlight the role of digital technologies by focusing on their activities. Even if Husserlian phenomenology rarely talks about technologies, some of its aspects can be used to address the actions performed by the digital technologies by focusing on the objects' inner 'life' thanks to the analysis of passive synthesis and phenomenological horizons in the objects. These elements can be used in computer technologies to show how digital objects are 'alive.' This paper focuses on programs developed through high-order languages like C++ and unsupervised learning techniques like 'Generative Adversarial Model.' The phenomenological analysis reveals the computer's autonomy within the programming stages. At the same time, the conceptual inquiry into the digital system's learning ability shows the alive and changeable nature of the technological object itself., Author(s): Dmytro Mykhailov [sup.1], Nicola Liberati [sup.2] Author Affiliations: (1) grid.263826.b, 0000 0004 1761 0489, School of Humanities, Southeast University, , 211189, Nanjing, China (2) grid.16821.3c, 0000 0004 0368 8293, [...]

Abstract Background Guidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres. Methods We included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution. Results We collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin–tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin–tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens. Conclusions The application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.

Abstract Extravasation is a fundamental step in the metastatic journey, where cancer cells exit the bloodstream and breach the endothelial cell barrier to infiltrate target tissues. The tactics cancer cells employ are sophisticated, closely reflecting those used by the immune system for tissue surveillance. Remarkably, tumor cells have been observed to form distinct associations or clusters with immune cells where neutrophils stand out as particularly crucial partners. These interactions are not accidental; they are critical for cancer cells to exploit the immune functions of neutrophils and successfully extravasate. In another strategy, tumor cells mimic the behavior and characteristics of immune cells. They release a suite of inflammatory mediators, which under normal circumstances, guide the processes of endothelium reshaping and facilitate the entry and movement of immune cells within tissues. In this review, we offer a new perspective on the tactics employed by cancer cells to extravasate and infiltrate target tissues. We delve into the myriad mechanisms that tumor cells borrow, adapt, and refine from the immune playbook. Video Abstract

Abstract This paper explores brain-to-brain interfaces (B2BI) as innovative human-technology interactions from a philosophical perspective to show how the implementation of this technology raises new philosophical questions about who we are and how we live in the world. More specifically, this text introduces the emergence of a collective living body through digital technologies from a phenomenological perspective to open the path to analyzing its effects on society. Few studies in the humanities have been focusing on how new human-technology interactions can connect several subjects into one living body by enabling subjects to literally “walk in the shoes of others”. This novel ability radically reframes some philosophical assumptions about what individual subjects are and how to think of them since the boundaries dividing them seem to blur. The constitution of a new type of human-technology interaction changes who we are and how we live, and we need to focus on such a change to tackle the challenges we will have to face in how we think of ourselves and live with others.

Abstract Since their proposal, Lorentz violating theories of gravity have posed a potential threat to black hole thermodynamics, as superluminal signals appeared to be incompatible with the very black hole notion. Remarkably, it was soon realized that in such theories causally disconnected regions of space-time can still exist thanks to the presence of universal horizons: causal barriers for signals of arbitrary high speed. Several investigations, sometimes with contrasting results, have been performed so to determine if these horizons can be associated with healthy thermodynamic properties similar to those associated with Killing horizons in General Relativity. In this work we offer what we deem to be the final picture emerging from this and previous studies. In summary we show that: 1) there is a thermal, and most of all species-independent, emission associated to universal horizons, determined by their surface gravity; 2) due to the modified dispersion relation of the matter fields, the low energy part of the emitted spectrum is affected by the presence of the Killing horizon, in a way similar to an effective refractive index, leading at low energies (w.r.t. the Lorentz breaking scale) to an emission that mimics a standard Hawking spectrum (i.e. one determined by the Killing horizon surface gravity); 3) the whole picture is compatible with a globally well defined vacuum state i.e. an Unruh state associated with preferred observers, which however at very low energies it is basically indistinguishable from the standard Unruh vacuum associated to metric free-falling observers. One can then conclude that Hawking radiation is remarkably resilient even within the context of gravitational theories entailing the breakdown of local Lorentz invariance.

Background/Objectives: The phyla Firmicutes and Bacteroidetes are the main constituents of the gut microbiota. An imbalance in the gut microbiota is a sign of dysbiosis, and the Firmicutes-to-Bacteroidetes ratio has been proposed to be a marker of it, especially in the context of obesity. Since Croatia is the country with one of the highest obesity rates in Europe, a pilot observational study was conducted. The aim of the study was to investigate the validity of this potential biomarker in a methodological study using sample processing, DNA sequence analysis and characterization of recruited participants, including various health factors. Methods: A study involving Croatian population was conducted. Participants age, body weight, gender, health history and lifestyle factors were recorded. Gut microbiota composition was analyzed using 16S rRNA sequencing. The F/B ratio was calculated and evaluated in the context of health factors. Statistical analysis was performed to detect the possible association of F/B ratio and excess body weight (kg) and possible impact of certain lifestyle factors. Results: No association between the F/B ratio and excess body weight (kg) was found. Excess body weight was significantly associated with higher age, male gender, and history of appendectomy. No significant health predictors of the F/B ratio were found, but weight gain was positively associated with a higher average F/B ratio. Conclusions: Although this study could not confirm the predictive value of the F/B ratio or any other phyla-related biomarker for excess body weight in the study population, it demonstrated interesting insights into the obesity-associated gut microbiota.

This analysis of the supplier relationship between Drexel University and Aramark offers a demonstration of the potential for intensifying an anchor institution's local economic inclusion strategies by leveraging the economic power of supplier partnerships. The operation of a major food service contract represents a substantial set of campus jobs and procurement, but this economic activity often remains outside the remit of economic inclusion efforts when the institution has no contractual influence over it. When an anchor institution can partner with a major supplier that shares a commitment to community impact, it offers opportunities to strengthen an anchor strategy. This article describes how Drexel University and Aramark used their campus food service relationship to deepen Drexel's anchor mission and core strategic priorities and Aramark's enterprise sustainability agenda, including the value of the negotiation process, and a set of outcomes in the form of initiatives in food insecurity, local economic inclusion and community engagement, research and technology transfer, and student co-op employment. Both the relationship building process and its outcomes offer a model for other institutions as they look to leverage the untapped economic activity of the major service suppliers.

We are pleased that the publisher of DynaMed clarified his evidence-based methodology in response to our review. We stress again how good reporting is a prerequisite for transparency. This lesson comes from the reporting of research findings but its extension to the development of information sources should be considered.

BackgroundBusy clinicians need easy access to evidence-based information to inform their clinical practice. Publishers and organizations have designed specific tools to meet doctors’ needs at the point of care. ObjectiveThe aim of this study was to describe online point-of-care summaries and evaluate their breadth, content development, and editorial policy against their claims of being “evidence-based.” MethodsWe searched Medline, Google, librarian association websites, and information conference proceedings from January to December 2008. We included English Web-based point-of-care summaries designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, evidence-based information to clinicians. Two investigators independently extracted data on the general characteristics and content presentation of summaries. We assessed and ranked point-of-care products according to: (1) coverage (volume) of medical conditions, (2) editorial quality, and (3) evidence-based methodology. We explored how these factors were associated. ResultsWe retrieved 30 eligible summaries. Of these products, 18 met our inclusion criteria and were qualitatively described, and 16 provided sufficient data for quantitative evaluation. The median volume of medical conditions covered was 80.6% (interquartile range, 68.9% - 84.2%) and varied for the different products. Similarly, differences emerged for editorial policy (median 8.0, interquartile range 5.8 - 10.3) and evidence-based methodology scores (median 10.0, interquartile range 1.0 - 12.8) on a 15-point scale. None of these dimensions turned out to be significantly associated with the other dimensions (editorial quality and volume, Spearman rank correlation r = -0.001, P = .99; evidence-based methodology and volume, r = -0.19, P = .48; editorial and evidence-based methodology, r = 0.43, P =.09). ConclusionsPublishers are moving to develop point-of-care summary products. Some of these have better profiles than others, and there is room for improved reporting of the strengths and weaknesses of these products.

Not available.

The Mostra Augustea della Romanità was inaugurated in Rome on 23 September 1937 to celebrate the Bimillenary of the birth of the Emperor Augustus. Located into the ideological-political climate of the time but nonetheless characterized by a solid scientific value, it constituted an impressive review on the culture and civilization of ancient Rome. One of its main rooms, the XVII, was dedicated to L’Esercito, preceded by that aimed at illustrate Il culto di Augusto. In the exhibition, the empire created by Augustus inevitably had to confront the new empire of Fascist Italy proclaimed on 9 May 1936, a reality that did not yet exist at the time of the conception of the exhibition but for it Imperial Rome represented the paradigm from which to draw strength and inspiration. The paper illustrates the contents of room XVII through an overview of the artworks present in it and also describes the display choices that characterized its presentation to the Italian and world public.

Cytomegalovirus causes the most common congenital infection worldwide. With most infants asymptomatic at birth, the few affected may present with variable clinical scenarios, from isolated hearing loss to severe neurologic impairment. Public health interventions include all actions at the health system, community, and individual levels that aim at reducing the burden of congenital Cytomegalovirus. This review examines the literature on maternal and neonatal screening programs in light of current evidence for treatment and the development of vaccines against Cytomegalovirus. Potential biases and benefits of these interventions are outlined, with the objective of increasing awareness about the problem and providing readers with data and critical tools to participate in this ongoing debate.