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Nursing retention is a major challenge globally. Ongoing workforce instability across countries underscores the need to understand the factors influencing turnover and nursing retention. Trust is a crucial element in managing workplace relationships between nurse managers and nurses. Existing studies have shown the direct impact of trust on employees’ intention to leave their job but have not explored the effects of potential mediators such as organizational commitment. The aim of this study was to examine the impact of trust in the leader on nurses’ intention to leave their job through the mediation of organizational commitment. A cross-sectional study was conducted in Italy. A convenience sample of 1853 nurses completed a self-report survey. The study tested a hypothesis-based mediation model using structural equation modeling, which showed good fit indices. The results indicated that trust in the leader had a significant impact on nurses’ intention to leave, and this relationship was partially mediated by organizational commitment. Nurses who trust their leader are more likely to demonstrate higher levels of organizational commitment, resulting in a lower intention to leave their job. Furthermore, organizational commitment and trust emerge as critical factors in reducing nurses’ intention to leave their current positions. Therefore, managers can reduce nurses’ intention to leave by building trustful relationships that enhance organizational commitment.This study was not registered.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through in vitro and in vivo experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects in vivo were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In in vitro, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1-/-, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.

Abstract Microbial diversity of caves is largely understudied and its possible applications are still unknown. Autochthonous fungi, in particular, may have the potential to biomineralize metals and may be used as promising agents for bioremediation of polluted sites; thus, unearthing the fungal diversity in hypogean ecosystems is nowadays of utmost importance. To start addressing this knowledge gap, the cultivable mycobiota of two neighbouring caves—one natural and one exploited for touristic purposes—were characterised and compared by studying fungi isolated from sediments collected at increasing distances from the entrance. Overall, 250 fungal isolates ascribable to 69 taxa (mainly Ascomycota) were found, a high percentage of which was reported in caves for the first time. The sediments of the touristic cave displayed a richer and more diversified community in comparison with the natural one, possibly due to visitors carrying propagules or organic material. Considering that these environments are still poorly explored, chances to detect new fungal lineages are not negligible.

BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.

Introduction: Recently, a flow cytometric (FC) based test has been developed for detection of circulating fetal cells to replace the less accurate and reproducible Kleihauer-Betke test.FC test is easier to perform, it can distinguish the origin of fetal cells, but it is expensive and available in highly specialized laboratories. We evaluated the introduction of high-performance liquid chromatography (HPLC) approach as initial screening to identify patients who need an additional FC test to better discriminate the nature of haemoglobin-F (HbF) positive cells. Methods: Blood samples from 130 pregnant women suspected to have fetomaternal haemorrhage were analysed with HPLC and FC methods. The cut-off for HbF HPLC concentration was calculated. Statistical analyses for the evaluation of HPLC as a screening method were performed. The positivity cut-off of HbF to be used as decision-making value to continue the investigation was calculated. Results: An excellent agreement (R2 > 0.90) was observed between the percentage of HbF obtained by HPLC and the percentage of fetal cells detected by FC. Results obtained from each assay were compared to define the HPLC threshold below which it is not necessary to continue the investigations, confirming the maternal nature of the HbF positive cells detected. Our study demonstrated that a cut-off of 1.0 % HbF obtained by HPLC was associated with the lowest rate of false negative results in our patient cohort. Conclusions: This study provides a new FMH investigation approach that possibly leads to a reduction in times and costs of the analysis.

Questions about how closure is achieved in disputes involving new observational or experimental claims have highlighted the role of bodily knowledge possibly irreducible to written experimental protocols and instructions how to build and operate instruments. This essay asks similar questions about a scenario that is both related and significantly different: the replication of an invention, not of an observation or the instrument through which it produced. Furthermore, the machine considered here—Galileo’s compass or sector—was not a typical industrial invention (like a spinning jenny), but a mathematical invention (a calculator), that is, a machine that produces numbers, not yarn. This case study describes some of the similarities and differences between replicating experiments, traditional machines producing material outputs, and mathematical inventions yielding calculations or information. This comparison indicates that, as in other kinds of replication, the replication of mathematical inventions involves texts (the calculator’s instructions) but that in this case bodily knowledge cannot be properly described as either tacit or explicit. It rather takes the shape of memory—muscle memory—that may be recalled from reading the instructions.

This essay is about the unique role of proper nouns at the intersection of knowledge and property, both tangible and intangible. Nouns are central to any form of property and credit, from a person's name listed on a property deed or copyright registration, to the name of an artist to whom a work is attributed, or that of a scientist after whom a discovery or theory is named. And names can also be found on the other end of the property spectrum, not as the names of authors and owners but as objects of property, as in the case of brand names. Here I trace some of the functions of these names as they move across different scenarios of knowledge-making and property-making, focusing on some of the effects those trajectories are having in the contemporary technosciences as they bring together the function of the author and that of the brand.

Rooted in the traditional peer review model, the conceptualization of dialogue informing this collection may in fact constrain the ambitious rethinking of the process of editorial review we have been encouraged to pursue here. After suggesting ways to enhance the dialogical dimensions of the traditional peer review model, I will propose a substantially different conceptualization of dialogue, one framed by the more recent practice of post-publication review

Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease with no approved therapies. The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival. Several candidate drugs are currently being developed. The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor. Other agents that target bile acid metabolism are ASTB/IBAP inhibitors and fibroblasts growth factor (FGF)19 analogues. Cholangiocytes, the epithelial bile duct cells, play a role in PSC development. Recent studies have revealed that these cells undergo a downregulation of GPBAR1 (TGR5), a bile acid receptor involved in bicarbonate secretion and immune regulation. Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein–coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota.

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.

Abstract Background Randomized controlled trials (RCTs) reported contrasting results about reverse left ventricular remodeling (LVR) after sodium-glucose co-transporter-2 inhibitors (SGLT2i) therapy in patients with heart failure (HF). Methods and results We performed a metanalysis of RCTs of SGLT2i administration in HF outpatients published until June 2022 searching four electronic databases. The protocol has been published in PROSPERO. Primary LVR outcome was change in absolute LV end-diastolic (LVEDV) and end-systolic volume (LVESV) from baseline to study endpoint. Secondary outcomes included changes in LVEDV and LVESV indexed to body surface area, LV Mass index (LVMi), LV ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide (NTproBNP). Mean differences (MDs) with 95% CIs were pooled. A total of 9 RCTs (1385 patients) were analyzed. All of them reported data on LVEF. Six trials reported data on LVESV and LVEDV (n = 951); LVMi was available in 640. SGLT2i treatment significantly reduced LVEDV [MD= -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD= -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD= -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], while LVEF significantly increased [MD = + 1.98% (0.67; 0.306), P = 0.0031]. By subgroup analysis, the beneficial effects of SGLT2i on LVEF did not differ by imaging method used, time to follow-up re-evaluation, or HF phenotype. Reduction in LV volumes tended to be greater in HF with reduced EF (HFrEF) than in those with preserved EF (HFpEF), while the opposite was observed for LVMi. Conclusions Treatment with SGLT2i significantly reversed cardiac volumes, improving LV systolic function and LV mass, particularly in HFrEF patients.

The histories of patent law and medical practice in the United States have intersected in various ways over the past 150 years, beginning with the professional campaign against “patent medicines” in the late nineteenth century, and culminating, for now, in attempts to patent the diagnostic procedures discussed in this article. The patenting of diagnostic procedures provokes a set of fundamental questions about the episteme of patent law. These questions are not new. They emerged at the very origins of patent jurisprudence, centered on the question of what distinguished an invention from a law of nature, and this question of patentability has persistently reemerged over the past century in the contexts of plant breeding, biotechnology, and now diagnostic medicine. So far, the question has been addressed in terms that imagine the invention as a machine, understood in the figurative sense of a transformative organization of forces and elements. But diagnostic procedures, because they address the body informationally, as a system based on the recursive patterning of signals rather than a linear transformation of inputs into outputs, stretch the figure of the machine to the point at which it ceases to be effective. How then should one define and delimit invention?.

Background Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid–activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown. Methods and Results Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and Gpbar1−/−, Fxr−/−, and dual Gpbar1−/‐Fxr−/− mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking Fxr and Gpbar1−/−/Fxr−/− display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by Gpbar1 and Fxr gene ablation. In apolipoprotein E−/− and wild‐type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low‐density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti‐inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists. Conclusions FXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.

This study outlines a multi-year collaboration journey between academics in two widely disparate disciplines: art/design and business/management. Eventually this culminated in co-designing and co-developing a folded paper zine, and related processes, to improve private reflective practice, particularly of managers and students of management. This zine co-design journey was articulated through the lens of Schumpeter's hybridity perspective 'new combinations', in the context of transdisciplinarity. As both commercial and social organisations face increasing complexity and uncertainty, the rationally oriented tools developed for planning and decision-making in more stable times need to be augmented by those which assume or even welcome ambiguity and not-knowing. This creates an opportunity to draw on art-based methods such as zines, given that the arts acknowledge, value and address such uncertainty.

Abstract Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids are signaling molecules acting on two main receptors the Farnesoid-x-receptor (FXR) and G protein coupled receptor GPB AR1. Clinical trials have shown that FXR agonism might result in side effects along with lack of efficacy in restoring liver histopathology. For these reasons a multi-targets therapy combined FXR agonists with agent targeting additional molecular mechanisms might have improved efficacy over selective FXR agonists. In the present study we have compared the effects of BAR502, a dual FXR/GPBAR1 ligand) alone or in combination with ursodeoxycholic acid (UDCA) in a model of NAFLD/NASH induced by feeding mice with a Western diet for 10 weeks. The results demonstrated that while BAR502 and UDCA partially protected against liver damage caused by Western diet, the combination of the two, reversed the pro-atherogenic lipid profile and completely reversed the histopathology damage, attenuating liver steatosis, ballooning, inflammation and fibrosis. Additionally, while both agents increased insulin sensitivity and bile acid signaling, the combination of the two, modulated up top 85 genes in comparison of mice feed a Western diet, strongly reducing expression of inflammatory markers such as chemokines and cytokines. Additionally, the combination of the two agents redirected the bile acid metabolism toward bile acid species that are GPBAR1 agonist while reduced liver bile acid content and increased fecal excretion. Together, these data, highlight the potential role for a combinatorial therapy based on BAR502 and UDCA in treating of NAFLD.

Abstract To date, the highly adapted cave microbial communities are challenged by the expanding anthropization of these subterranean habitats. Although recent advances in characterizing show-caves microbiome composition and functionality, the anthropic effect on promoting the establishment, or reducing the presence of specific microbial guilds has never been studied in detail. This work aims to investigate the whole microbiome (Fungi, Algae, Bacteria and Archaea) of four Italian show-caves, displaying different environmental and geo-morphological conditions and one recently discovered natural cave to highlight potential human-induced microbial traits alterations. Results indicate how show-caves share common microbial traits in contrast to the natural one; the first are characterized by microorganisms related to outdoor environment and/or capable of exploiting extra inputs of organic matter eventually supplied by tourist flows (i.e. Chaetomium and Phoma for fungi and Pseudomonas for bacteria). Yet, variation in microalgae assemblage composition was reported in show-caves, probably related to the effect of the artificial lighting. This study provides insights into the potential microbiome cave contamination by human-related bacteria (e.g. Lactobacillus and Staphylococcus) and commensal/opportunistic human associated fungi (e.g. Candida) and dermatophytes. This work is critical to untangle caves microbiome towards management and conservation of these fragile ecosystems.

Alternative splicing (AS) appears to be altered in Huntington's disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, a significant proportion (36%) of the aberrantly spliced isoforms are not-functional and meant to non-sense mediated decay (NMD). The expanded Htt CAG repeats further reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Integrative transcriptomic analyses unveil a network of transcriptionally altered micro-RNAs and RNA-binding proteins (Celf, hnRNPs, Ptbp, Srsf, Upf1, Ythd2) which might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might alter neural fitness, contributing to HD pathogenesis.

"Word-processing software, SCIgen, or Photoshop have increased fraudulent output, but … they have also changed the very form of fraud. Photoshop and similar tools are thus enabling something that is categorically new: recursive fraud, that is, the serial digital reproduction and dissemination of more fraud." Read more in the Guest Editorial by M. Biagioli.

While the initial reception of Alfred Hitchcock’s Vertigo (1958) was unspectacular, it made its presence felt in a host of other films - from Chris Marker’s Sans Soleil (1983), to Brian De Palma’s Obsession (1976), and David Lynch’s Mulholland Dr. (1999). What seemed to have eluded the critics at the time is that Vertigo is a film about being haunted: by illusive images, turbulent emotions, motion and memory, the sound and feeling of falling into the past, into a nightmare. But it is also a shrewdly reflexive film that haunts filmmakers, critics, and artists alike, raising fundamental questions about the ontology of moving images and the regime of fascination (exemplified by Hollywood) that churns them out. Douglas Gordon’s Feature Film (1999), D.N. Rodowick’s The Wanderers (2016), and Lynn Hershman’s VertiGhost (2017) are contemporary examples of how the appropriation and contemplation of some the film’s most iconic motifs (the figures of Madeleine, the spiral, the copy or fake, and the fetish), themes (liebestod, obsession, the uncanny) and strategies (mirroring, duplicity, and disorientation) ask us to rethink the relation of fetishism to fabulation, and supplementarity to dissimulation and social engineering. Feature Film, The Wanderers, and VertiGhost are supplementary works, but like the original film they are about duplicity, doppelgänger, and dissimulation. What interests us is how they challenge the authority over, or even proximity to, that which returns in the form of the supplement. And ultimately, attaching themselves to the chain of forgers and forgeries, these supplementary works take their place in the vertiginous sequence of substitutions the film established: a neat allegory for a reign of the digital ghosting that Hitchcock could never have anticipated.

A new trend in scientific misconduct involves listing fake coauthors on one's publication. I trace some of the incentives behind faking coauthors, using them to highlight important changes in global science publishing like the increasingly important source of credibility provided by institutional affiliations, which may begin to function like ‘brands’.

Historians of science and technology and STS practitioners have always taken intellectual property very seriously but, with some notable exceptions, they have typically refrained from looking "into" it. There is mounting evidence, however, that they can open up the black box of IP as effectively as they have done for the technosciences, enriching their discipline while making significant contributions to legal studies. One approach is to look at the technologies through which patent law construes its object - the invention - in specific settings and periods by examining procedures, classifications, archives, models, repositories, patent specifications (in both their linguistic and pictorial dimensions), and the highly specialized language of patent claims. More ambitiously, we could treat intellectual property as a technology itself. Patent law does not evolve either by merely articulating its doctrine in response to technological developments. The line between what does and does not count as invention may be redrawn with the emergence of new objects and technologies, but is not determined by them. It is this constructive feature of the law that we are trying to capture with the notion of law as technology. We hope that thinking about the technologies of the law and the law as technology will bring into question what we mean by both "technology" and "law".

The scale is the most famous emblem of the law, including intellectual property (IP). Because IP rights impose social costs on the public by limiting access to protected work, the law can be justified only to the extent that, on balance, it encourages enough creation and dissemination of new works to offset those costs. The scale is thus a potent rhetorical trope of fairness and objectivity, but also an instrument the law thinks with - one that is constantly invoked to justify or to question the extent of available IP protection. The balancing act that underlies the legitimacy of IP is, however, literally impossible to perform. Because we are unable to measure the benefits that IP has for inventors or the costs it has for the public, the scale has nothing to weigh. It conveys a clear sense that IP law can be balanced, but in fact propagates only a visible simulacrum of balance - one that is as empty as it is powerful.