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Quantum mechanics is arguably our most successful physical theory, yet the nature of the quantum state still constitutes an ongoing controversy. This paper proposes, articulates, and defends a metaphysical interpretation of the quantum state that is fictionalist in spirit since it regards quantum states as representing a fictional ontology. Such an ontology is therefore not physical, and yet it provides a reference for the language used in quantum mechanics and has explanatory power. In this sense, this view, akin to Allori’s recent account of wavefunctionalism, combines elements of the representationalist and anti-representationalist camps and aims to be the best of both worlds. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression. Methods: We measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children. Results: We found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007). Conclusions/interpretation: This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Abstract The discovery of the Ten‐Eleven‐Translocation (TET) oxygenases that catalyze the hydroxylation of 5‐methylcytosine (5mC) to 5‐hydroxymethylcytosine (5hmC) has triggered an avalanche of studies aiming to resolve the role of 5hmC in gene regulation if any. Hitherto, TET1 is reported to bind to CpG‐island (CGI) and bivalent promoters in mouse embryonic stem cells, whereas binding at DNAseI hypersensitive sites (HS) had escaped previous analysis. Significant enrichment/accumulation of 5hmC but not 5mC can indeed be detected at bivalent promoters and at DNaseI‐HS. Surprisingly, however, 5hmC is not detected or present at very low levels at CGI promoters notwithstanding the presence of TET1. Our meta‐analysis of DNA methylation profiling points to potential issues with regard to the various methodologies that are part of the toolbox used to detect 5mC and 5hmC. Discrepancies between published studies and technical limitations prevent an unambiguous assignment of 5hmC as a ‘true’ epigenetic mark, that is, read and interpreted by other factors and/or as a transiently accumulating intermediary product of the conversion of 5mC to unmodified cytosines.

The purpose of this contribution is to examine the current state of the de Broglie-Bohm theory (dBB) in light of Bohm’s vision as he explicitly set it out in his book Quantum theory [In Bohm, D., Quantum theory, Courier corporation, (1961b)]. In particular, two programmes that differ in many crucial respects are currently being pursued. On the one hand, the Bohmian mechanics school, founded by Dürr Goldstein and Zanghì, considers the theory to be Galilean invariant, regards particles’ motion as determined by a nomological entity, the universal wave function, upholds the quantum equilibrium hypothesis and explains probabilities in terms of typicality. On the other hand, the Pilot-wave school advocated by Valentini considers the theory to be based on Aristotelian dynamics, regards the wave function as a physical field displaying a contingent nature, and explains quantum equilibrium as the result of a process of relaxation from quantum non-equilibrium. Looking at Bohm’s work [In Bohm, D., Quantum theory, Courier corporation, (1961b)], it is clear that his intention was to construct a theory that was empirically different from standard quantum mechanics, so that it would be testable and falsifiable. Only this way could he defend dBB from the criticism that accused the theory of being 'metaphysical'. These methodological concerns about the falsifiability of the theory constitute, in my opinion, a strong reason for regarding Valentini's programme as methodologically valuable, even if it might turn out to be wrong. Indeed, the programme of the Pilot-wave school aims to be falsifiable with respect to standard quantum mechanics and can in principle defend the empirical status of particle trajectories. [ABSTRACT FROM AUTHOR]

Background: Dried blood spot (DBS) testing is a well-known method of bio-sampling by which blood samples are blotted and dried on filter paper. The dried samples can then be analyzed by several techniques such as DNA amplification and HPLC. We have developed a non-invasive sampling followed by an alternative protocol for genomic DNA extraction from a drop of blood adsorbed on paper support. This protocol consists of two separate steps: (1) organic DNA extraction from the DBS, followed by (2) DNA amplification by polymerase chain reaction (PCR). The PCR-restriction fragment length polymorphism (PCR-RFLP) is an advantageous and simple approach to detect single nucleotide polymorphisms (SNPs). Results: We have evaluated the efficiency of our method for the extraction of genomic DNA from DBS by testing its performance in genotyping mouse models of obesity and herein discuss the specificity and feasibility of this novel procedure. Conclusions: Our protocol is easy to perform, fast and inexpensive and allows the isolation of pure DNA from a tiny amount of sample. [ABSTRACT FROM AUTHOR]

Astrophysicist Abraham Loeb suggests that the interstellar interloper 1I/2017 ‘Oumuamua, detected in our solar system in 2017, is alien space debris or even an alien operational probe (Bialy and Loeb 2018; Sheerin & Loeb 2020). Does this conjecture have significant epistemic support, such that it can be justified as a viable hypothesis? In this paper, I propose that the meta-empirical confirmation approach, developed and defended by philosopher and physicist Dawid (2006, 2013, 2018, 2019), provides an appropriate framework to answer this question. I defend this proposal by elucidating how meta-empirical confirmation applies to the ‘Oumuamua case and what specific meta-empirical arguments could support Loeb’s hypothesis. Even though Loeb would not himself endorse meta-empirical confirmation, because it is not traditional empiricism, this case shows that meta-empirical confirmation is not in fact a threat to empiricism. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We assessed the levels of blood circulating immune checkpoint molecules (ICMs) at diagnosis of type 1 diabetes, and determined their association with the risk of developing an additional autoimmune disorder over time. Methods: Children with new-onset type 1 diabetes (n = 143), without biological and/or clinical signs of additional autoimmune disorders, and healthy children (n = 75) were enrolled, and blood circulating levels of 14 ICMs were measured. The children with type 1 diabetes were divided into two groups on the basis of the development of an additional autoimmune disease in the 5 years after diabetes onset. Differences in soluble ICM levels between the groups were assessed, and a Cox regression analysis was used to evaluate their association with the risk of development of an additional autoimmune disease over time. To validate the data, circulating ICMs were measured in an independent cohort of 60 children with new-onset type 1 diabetes stratified into two groups. Results: We found that the levels of circulating ICMs were significantly higher in children with new-onset diabetes compared with healthy children. Further, we observed that children with type 1 diabetes who developed a second autoimmune disease over time (T1D-AAD+ children) had higher levels of soluble ICMs than children with type 1 diabetes who did not (T1D-AAD− children). Cox regression models revealed that high circulating levels of CD137/4-1BB and PD-1 molecules at diabetes diagnosis were associated with the risk of developing an additional autoimmune disease in both type 1 diabetes cohorts. Conclusions/interpretation: Our findings suggest that soluble CD137/4-1BB and PD-1 molecules may be used as prognostic biomarkers in children with type 1 diabetes, and may pave the way for novel immunological screening at diabetes onset, allowing early identification of children at higher risk of developing other autoimmune conditions over time. [ABSTRACT FROM AUTHOR]

Deoxycytidine kinase (dCK) and 5' deoxynucleotidase (NT5C2) are involved in metabolism of cladribine (2CdA), the immunomodulatory drug for multiple sclerosis; by mediating phosphorylation (activation) or phosphorolysis (deactivation) of 2CdA, respectively, these enzymes promote or prevent its accumulation in the cell, which leads to cell death. In particular, lymphocytes which present with a high intracellular dCK/NT5C2 ratio are more sensitive to 2CdA than other immune cells. We aim at determining if the expression of these enzymes and/or their activity differ in specific progenitor and mature immune cells and are influenced by cellular activation and/or exposure to 2CdA. Flow cytometry analysis showed no difference in dCK/NT5C2 ratio in progenitor and mature immune cells. 2CdA induced apoptosis in stimulated T and B cells and unstimulated B cells. dCK expression was enhanced by 2CdA at mRNA and protein levels in activated T cells and mRNA level in activated B cells. dCK activity, measured through an in-house luminescence release enzyme assay was higher in activated T and B cells, and such an increase was abrogated in activated B cells, but not T cells, upon exposure to 2CdA. These results reveal an important relationship between dCK activity and the effect of 2CdA on B and T cells, according to their activation status. Further study is warranted to evaluate whether dCK activity could, in the future, be a suitable predictive biomarker of lymphocyte response to 2CdA. [ABSTRACT FROM AUTHOR]

Gene expression, lipidomic and growth impairment findings suggest that the natural history of celiac disease (CD) starts before the gluten-induced immune response. Gluten intake in the first years of life is a controversial risk factor. We aimed to estimate the risk of developing CD associated with the amount of gluten intake and the serum inflammatory profile in genetically predisposed infants. From an Italian cohort of children at risk for CD, we enrolled 27 children who developed CD (cases) and 56 controls matched by sex and age. A dietary interview at 9, 12, 18, 24 and 36 months was performed. Serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10 IL12p70, IL17, and TNFα) were analysed at 4 and 36 months. Infants who developed CD by 6 years showed an increase in serum cytokines (INFγ, IL1β, IL2, IL6, IL10, IL12p70 and TNFα) at 4 months of age before gluten introduction. CD cases ate significantly more gluten in the second year of life than controls, and gluten intake in the second year of life was strongly correlated with serum cytokines (INFγ, IL2, IL4, IL12p70, IL17) at 36 months only in CD cases. The dietary pattern of infants who developed CD was characterized by high consumption of biscuits and fruit juices and low intake of milk products, legumes, vegetables and fruits. Genetically predisposed infants who developed CD showed a unique serum cytokine profile at 4 months before gluten consumption. The amount of gluten was strongly correlated with an inflammatory profile in serum cytokines at 36 months only in infants who developed CD. [ABSTRACT FROM AUTHOR]

Humeanism started life as a metaphysical program that could turn out to be false if our best physical theories were to postulate ontological features at odds with Humean ones. However, even if this has arguably already happened, Humeanism is still considered one of the strongest and most appealing metaphysical theories for describing the physical world. What is even more surprising is that a radical Humean thesis—Super-Humeanism—which posits an extremely parsimonious ontology including nothing more than propertyless matter points and their distance relations, is said by its proponents to follow from an attentive reading of our best physical theories. Given its close relationship with physics, Super-Humeans argue that their doctrine (i) conforms to Scientific Realism, (ii) offers the ontology that best explains physics' empirical evidence, and (iii) is a naturalistic theory. This paper investigates the strategies that Super-Humeans have adopted to defend these three claims and, more generally, its alleged closeness to physics. I will show that, contrary to what advocates of Super-Humeanism claim, some of its commitments have inevitably created a gap between itself and physics that is difficult to overcome. While it is laudable that Super-Humeans have adopted various strategies to close this gap, no strategy has yet fully succeeded. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated and compared the effectiveness of a phytotherapeutic drug composed of herbal extracts on postsurgical discomfort after mandibular third molar surgery. Materials and methods: Eighty-two patients requiring the surgical removal of a mandibular third molar were randomly assigned to receive placebo (group 1), ibuprofen (group 2), and a phytotherapeutic drug (composed of baicalin, 190 mg; bromelain, 50 mg; escin, 30 mg) (group 3). Drugs were administered after tooth extraction twice a day for 5 days. The primary outcome, pain, was evaluated using a visual analogue scale at 2 h, 6 h, 12 h, 24 h, 48 h, and 7 and 10 days after surgery. The secondary outcomes were the changes in maximum mouth opening and facial contours (mm) between baseline and at 24 h, 72 h, and 7 and 10 days after surgery. Results: Compared to the baseline, all treatments demonstrated an improvement in the primary and secondary outcomes. Moreover, compared to groups 1 and 2, patients in group 3 yielded a significant reduction of the postoperative pain score at 12 h (p < 0.001), 24 h (p = 0.010), and 48 h (p = 0.048) after surgery. The mean reduction of the swelling and trismus was similar between groups. Conclusions: The results of this study suggest that a postoperative administration of a phytotherapeutic drug was found to be effective in postoperative pain management after the surgical removal of impacted mandibular third molars. Clinical relevance: The phytotherapeutic drug composed of herbal extract determined a decrease in the severity of postoperative pain compared to ibuprofen and placebo. [ABSTRACT FROM AUTHOR]

Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression. Methods: Plasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost <10% of C-peptide; those showing an intermediate C-peptide loss. To evaluate the modulation of plasma circulating miRNAs during the course of type 1 diabetes, logistic regression models were implemented and the correlation between miRNAs and immunometabolic factors was also assessed. Results were then validated in an independent cohort of children with recent-onset type 1 diabetes (n = 18). The prognostic value of the identified plasma signature was tested by a neural network-based model. Results: Plasma circulating miR-23~27~24 clusters (miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27a-3p and miR-27b-3p) were upmodulated upon type 1 diabetes progression, showed positive correlation with osteoprotegerin (OPG) and were negatively correlated with soluble CD40 ligand, resistin, myeloperoxidase and soluble TNF receptor in children with type 1 diabetes but not in healthy children. The combination of plasma circulating miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27b-3p and OPG, quantified at disease onset, showed a significant capability to predict the decline in insulin secretion 12 months after disease diagnosis in two independent cohorts of children with type 1 diabetes. Conclusions/interpretations: We have pinpointed a novel miR-23a-3p/miR-23b-3p/miR-24-3p/miR-27b-3p/OPG plasma signature that may be developed into a novel blood-based method to better stratify patients with type 1 diabetes and predict C-peptide loss. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates1–3. However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy4,5, is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB—unlike other substrates of mTORC1, such as S6K and 4E-BP1— is strictly dependent on the amino-acid-mediated activation of RagC and RagD GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt–Hogg–Dubé syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin (FLCN) and is characterized by benign skin tumours, lung and kidney cysts and renal cell carcinoma6,7. We found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt–Hogg–Dubé syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. Our findings identify a mechanism that enables differential phosphorylation of mTORC1 substrates, the dysregulation of which leads to kidney cysts and cancer. Dysregulation of an mTORC1 substrate-specific mechanism leads to constitutive activation of TFEB, and promotes kidney cystogenesis and tumorigenesis in a mouse model of Birt–Hogg–Dubé syndrome. [ABSTRACT FROM AUTHOR]

According to the doctrine of Super-Humeanism (Esfeld in Synthese. 10.1007/s11229-017-1426-8, 2017), the world's mosaic consists only of permanent matter points and changing spatial relations, while all the other entities and features figuring in scientific theories are nomological parameters, whose role is merely to build the best law system. In this paper, I develop an argument against Super-Humeanism by pointing out that it is vulnerable to and does not have the resources to solve the well-known problem of immanent comparisons. Firstly, I show that it cannot endorse a fundamentalist solution à la Lewis, since its two pillars—a minimalist ontology and a best system account of lawhood—would generate, together, a tedious problem of internal coherence. Secondly, I consider anti-fundamentalist strategies, proposed within Humeanism, and find them inapplicable to the Super-Humean doctrine. The concern is that, since it is impossible to choose the best law system within Super-Humeanism, this doctrine may be charged with incoherence. [ABSTRACT FROM AUTHOR]

Purpose: Patients with advanced cancer are likely to face increasing levels of care dependence. Adult patients who become care dependent on others can experience this condition as one of suffering and humiliation. The nurse-patient relationship plays a key role in the experience of dependence. Understanding patients' and nurses' perceptions of care dependence is crucial to addressing the impact it has on the lives of both. The aim of this study is to explore the experiences of patients with cancer and nurses caring for them. Methods: A multicentre qualitative study was conducted in Italy using semi-structured interviews with patients with advanced cancer admitted to 3 hospitals, and 9 focus groups with nurses working in oncology wards of 2 hospitals. Data were analysed with inductive content analysis. Results: Thirty-two patients and 44 nurses participated in the study. Three common themes were identified: within dependence, the relationship is a lifeline; dependence is influenced by internal and external factors and dependence generates changes. Dependence impacts on patients' and nurses' lives and implies a process of personal maturing for both. Patients learn the humility to ask for help by exposing their vulnerability. Nurses become aware that a trusting relationship helps patients to accept dependence, and they learn to self-transcend in order to build it. Conclusions: Striving to build positive relationships implies a change in nurses' and patients' lives. In this way, they come to understand important aspects of life and find meaning in difficult situations. Further studies should explore also homecare settings and patients' families. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the present cross-sectional study was to investigate the association between serum glycosylated haemoglobin (HbA1c) levels and periodontal status in patients with periodontitis (CP) and periodontally healthy controls. Furthermore, the objectives were to determine if the periodontitis influenced the serum HbA1c levels. Materials and methods: A total of 93 patients with CP and 95 periodontally healthy subjects were enrolled in the present study using a cross-sectional design. At baseline, patients were examined and characterized on a regular basis for blood serum parameters and non-fasting blood samples levels. In all patients, a full periodontal examination was performed and clinical attachment loss (CAL) was the primary outcome variable chosen. The spearman correlation, a stepwise multivariable linear regression, and Jonckheere-Terpstra tests were applied in order to assess the relationship between HbA1c levels and periodontitis. Results: Patients in the CP group presented a significantly higher median serum level of HbA1c [40.9 (31.2; 45.6) mmol/mol)] compared to patients in the healthy control group [35.3 (29.6; 38.6) mmol/mol)] (p < 0.001). HbA1c levels were negatively correlated with the number of teeth and positively correlated with C-reactive protein levels and all periodontal parameters (p < 0.001). Moreover, there was a significant decrease in the number of teeth when HbA1c levels increased (P-trend < 0.001), while there was a significant increase in periodontal parameters (CAL, p = 0.002); PD, p = 0.008; BOP, p < 0.001) when levels of HbA1c increased. Conclusions: Patients with CP and undiagnosed diabetes presented significantly higher serum levels of HbA1c compared to periodontally healthy controls. Moreover, the presence of periodontitis was positively correlated with serum HbA1c levels before diabetes onset. Clinical relevance: HbA1c levels were positively correlated with the severity of periodontitis before diabetes onset. [ABSTRACT FROM AUTHOR]

Objectives: To identify, summarize, and aggregate the quantitative and qualitative evidence on the use of mindfulness-based programs in people with chronic obstructive pulmonary disease (COPD), to describe the possible barriers and facilitators and derive recommendations for the implementation of mindfulness-based programs in people with COPD. Methods: A mixed methods review was conducted following the Joanna Briggs Institute methodology. After a systematic search in eight relevant databases, seven papers presenting five studies were included. Two researchers independently extracted the data and assessed the methodological quality of the studies. Results: No significant changes in levels of anxiety, stress, respiratory symptoms, or other physiological outcomes were found, despite the perception of most participants that mindfulness had a positive influence on their psychological and physical well-being. Only one study showed the effectiveness of mindfulness-based programs in reducing depressive symptoms when combined with pulmonary rehabilitation. Participation in and completion of mindfulness-based programs were hampered by personal beliefs, psychological factors, and practical aspects. Furthermore, the characteristics of the mindfulness-based protocols and the different methods of provision could encourage or discourage program attendance. Conclusions: The limited published studies to date have not demonstrated the efficacy of mindfulness-based programs in COPD. Further methodologically sound studies with bigger sample sizes and with consistent outcome measures are needed to verify their effectiveness. Due to the fluctuations in symptoms of the disease, and patients' difficulties in leaving the house, home-based, web-delivered, and shorter protocols could be further tested as they could facilitate the adherence of people with COPD to mindfulness practice. [ABSTRACT FROM AUTHOR]

The National Training and Technical Assistance Center for Child, Youth, and Family Mental Health (NTTAC) supports the development and implementation of systems of care (SOC) for youth with serious emotional disorders (SED) and their families. This article presents results from a process evaluation of NTTAC, conducted to support the Center's quality improvement and contribute to the knowledge base around provision of technical assistance (TA). The evaluation used a mixed methods approach with data collection focused on a defined subset of NTTAC TA recipients-recipients of federal Comprehensive Community Mental Health Services for Children SOC grants. Data sources included coded administrative records from SOC grant sites, administrative data from NTTAC, standardized measures of SOC development, and stakeholder survey data. Results indicate that TA dosage matched needs and goals of TA recipients (SOC sites), overall levels of satisfaction with TA were high, and TA content was generally aligned with need. TA recipients reported significant progress on indicators of SOC development over time. Together, these findings suggest that it is possible to develop TA methods that reflect the level and type of TA recipients' goals and needs, and, in turn, positively impact SOC development and behavioral health service delivery. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance. Methods: A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines. Results: miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines. Conclusions: We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a multi-system disorder that can have significant adverse effects on the health of the mouth. The aim of this study was to investigate the associations between the disease characteristics of SSc, periodontal disease (PD), and tooth loss. Fifty-four patients affected by SSc and 55 non-diseased controls were matched for age and gender. SSc was characterized in subtypes and with the mean duration of disease and the Modified Rodnan Skin Score [mRSS]. Patients were surveyed and examined through the evaluation of the periodontal parameters and the number of teeth. A logistic regression analysis showed that patients with SSc presented a higher number of missing teeth ( p = 0.001) and a significant median increased odds 2.95 (95% CI 1.26 to 6.84) of PD (defined as clinical attachment loss, CAL) compared to nondiseased controls (6.83, 95% CI 1.94 to 24.36). Moreover, the fewer values of PD was correlated with mRSS in the total SSc group and with the mean duration of disease in patients with limited SSc ( p = 0.007), even after adjusting this correlation with the presence of the major organ involvement. This study showed that patients with SSc presented increased odds of PD and tooth loss compared to non-diseased controls. In SSc patients, the magnitude of PD was strongly associated with the mRSS and with the mean duration of the disease. The clinicians should be aware of the potential systemic health problems related to PD. [ABSTRACT FROM AUTHOR]

Knowledge of glass trading in protohistoric Southern Italy has been limited by a lack of archeometrical data available to date, preventing comparison with the well-known Northern Italian context. The aim of the present work is to help fill the data gap for Southern Bronze-Iron Age vitreous items and enable a general overview of protohistoric Italian glass supply routes. The paper presents physical-chemical data for 61 vitreous items from 11 Southern Italian sites, dated from the beginning of the Bronze Age up to the Archaic period (22nd–6th century BC), ensuring a complete diachronic analysis. SEM-EDS, EMPA, LA-ICPMS, and XRD analyses permitted definition of the raw materials and manufacturing techniques employed, as well as determination of item provenance. The sample set exhibits great variability of glass chemical types, including plant ash glass, mixed alkali, and natron samples. A complex picture emerges, mostly as regards the different natron glass typologies (High-Zr, Low-Zr, Black, etc.) and their rapid technological evolution in the early 1st millennium BC. Taking into account the data reported in this study and those available in literature for both Northern and Southern Italian Bronze-Iron Ages items, this work demonstrates the existence of different trade routes for the first time. This is especially true for the Early/Middle Bronze Age periods, with Northern Italy involved in trade with Central Europe, and South already involved in Mediterranean trade circuits. [ABSTRACT FROM AUTHOR]

In this paper, I discuss whether the results of loop quantum gravity (LQG) constitute a fatal blow to Humeanism. There is at least a prima facie reason for believing so: while Humeanism regards spatiotemporal relations as fundamental, LQG describes the fundamental layer of our reality in terms of spin networks, which are not in spacetime. However, the question should be tackled more carefully. After explaining the importance of the debate on the tenability of Humeanism in light of LQG, and having presented the Humean doctrine, I review two cases which present serious threats to Humeanism, one concerning the fundamentality of vectorial quantities and the other concerning quantum entanglement. In particular, I recall the strategies that are usually employed in these two cases in order to save Humeanism: in the first case, the strategy consists in amending the characterization of the Humean mosaic; in the second case, it consists in adopting a realist or nomological interpretation of the wave function. These solutions will turn out to be helpful in my discussion of LQG where, after describing LQG, I show that Humeans might save their doctrine either by endorsing a realist interpretation of spin networks, or by giving them a nomological status and, at the same time, by revisiting the characterization of the Humean mosaic. However, I conclude that both solutions are wanting. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to assess the influence of anxiety and depression on the physical and mental quality of life (QoL) in patient with chronic obstructive pulmonary disease (COPD) and caregiver dyads, detect the simultaneous effect of anxiety and depression of each partner on the other's QoL and determine the dyadic patterns.Methods: A cross-sectional descriptive design was used. The actor-partner interdependence model estimated by structural equation modeling was used for the dyadic analysis. Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and 12-Item Short-Form Health Survey (SF-12) were used to measure depression, anxiety and QoL, respectively.Results: Eighty COPD dyads were enrolled in the study. Patients presented higher depression symptoms and poorer physical and mental QoL than their caregivers, whereas comparable levels of anxiety were found in patients and caregivers. The model exploring the effects of depression and anxiety on mental QoL found that patients' depressive symptoms negatively influence their mental QoL, and caregivers' anxiety and depression symptoms negatively impact their mental QoL. The model exploring the effects of anxiety and depression on physical QoL detected one statistically significant actor effect with patients' depressive symptoms negatively influencing their physical QoL, and two partner effects with caregivers' anxiety worsening patients' physical QoL and caregivers' depression improving patients' physical QoL.Conclusions: The results suggest that caregivers' psychological distress influences caregivers' mental QoL and patients' physical QoL. Therefore, health-care professionals should assess and treat anxiety and depression in both members of the COPD dyad to improve their QoL. [ABSTRACT FROM AUTHOR]

Information on the phenology and distribution of fish larvae is critical to understanding recruitment dynamics of populations. Larvae of the family Bathymasteridae (ronquils) are an abundant component of the ichthyoplankton community in the eastern North Pacific Ocean and Bering Sea, but cannot be readily identified to the species level using morphological or meristic approaches. We developed a restriction fragment length polymorphism (RFLP) protocol based upon variation in the mitochondrial (COI) gene to identify larvae of three species in the genus Bathymaster: smallmouth ronquil (B. leurolepis), Alaskan ronquil (B. caeruleofasciatus) and searcher (B. signatus). A subsample of larvae from annual ichthyoplankton surveys was screened using the RFLP protocol, and 259 of 260 individuals were correctly identified to species, providing the first data on the seasonal occurrence of early life-history stages in ichthyoplankton surveys for these species. Peak abundance for two species in surveys conducted from 2006 to 2014 occurred in spring. Larvae of smallmouth ronquil were absent from spring surveys and occurred as only 8% of the total numbers collected in later seasons. Our results indicate that larvae of Alaskan ronquil (B. caeruleofasciatus) were more likely to occur at deeper sampling stations (bottom depth > 180 m) in spring, while searcher (B. signatus) larvae were more common at shallower stations (bottom depth ≤ 100 m). [ABSTRACT FROM AUTHOR]

During starvation the transcriptional activation of catabolic processes is induced by the nuclear translocation and consequent activation of transcription factor EB (TFEB), a master modulator of autophagy and lysosomal biogenesis. However, how TFEB is inactivated upon nutrient refeeding is currently unknown. Here we show that TFEB subcellular localization is dynamically controlled by its continuous shuttling between the cytosol and the nucleus, with the nuclear export representing a limiting step. TFEB nuclear export is mediated by CRM1 and is modulated by nutrient availability via mTOR-dependent hierarchical multisite phosphorylation of serines S142 and S138, which are localized in proximity of a nuclear export signal (NES). Our data on TFEB nucleo-cytoplasmic shuttling suggest an unpredicted role of mTOR in nuclear export. [ABSTRACT FROM AUTHOR]

Objective: Chemotherapeutic agents have been widely used as adjuncts for the treatment of chronic periodontitis (CP). This study investigated and compared a desiccant agent as an adjunct to scaling and root planing (SRP) versus SRP alone for the treatment of CP.Materials and methods: Thirty-six patients with CP were studied. Using a split-mouth design, the maxillary right and left quadrants were randomly assigned to SRP plus desiccant (Hybenx® EPIEN Medical, Inc. St. Paul, MN, USA) or SRP alone. Patients were examined on a regular basis for clinical, microbiological, and inflammatory mediator changes over a 1-year period. Clinical attachment level (CAL) was the primary outcome variable. In addition, the red complex bacteria and gingival crevicular fluid (GCF) inflammatory mediators were monitored.Results: Compared to baseline, both treatments demonstrated an improvement in periodontal parameters. Compared to SRP alone, SRP plus desiccant yielded a significant improvement in probing depth (PD) (SRP: 2.23 ± 0.31 mm vs. desiccant: 3.25 ± 0.57 mm, p < 0.05), CAL (SRP: 3.16 ± 0.29 mm vs. desiccant: 4.21 ± 0.34 mm, p < 0.05 mm) and bleeding on probing (BOP) (SRP: 4.56 ± 1.5% vs. desiccant: 34.23 ± 4.2%, p < 0.001) at 12 months. Similarly, in the SRP plus desiccant group, the bacteria of the red complex were significantly reduced (p < 0.05); and the level of inflammatory mediators was significantly reduced (p < 0.003) compared to SRP alone.Conclusions: SRP plus the desiccant resulted in a greater reduction in clinical, microbial and inflammatory mediators compared to SRP alone.Clinical relevance: Desiccant, when combined to SRP, was demonstrated as a significant approach to control the levels of certain periodontal pathogens, inflammatory mediators in patients with CP. [ABSTRACT FROM AUTHOR]

Identification of fish larvae in Arctic marine waters is problematic as descriptions of early-life-history stages exist for few species. Our goal in this study is to provide descriptions that enable researchers to distinguish larvae of righteye flounders (family Pleuronectidae) of the genus Limanda that are among the most abundant fishes and frequently collected pleuronectid larvae in the northern Bering, Chukchi, and Beaufort seas. Three species of Limanda are represented: L. aspera (yellowfin sole), L. proboscidea (longhead dab), and L. sakhalinensis (Sakhalin sole). Partial descriptions of L. aspera and L. proboscidea larvae have been previously published, but content and illustrations are inadequate for making positive identifications; therefore, each species is redescribed here with updated illustrations. Larvae of L. sakhalinensis are described for the first time. Descriptions of meristic, morphometric, and pigment characteristics with species comparisons of larvae are presented. Primary characters that distinguish the three species are pigmentation, body depth, and length of larvae and early juveniles at developmental stage landmarks. Pigment characters during the early and late larval stages of L. proboscidea and its large size at transformation are different compared to L. aspera and L. sakhalinensis. These disparate larval characters described for L. proboscidea in comparison to the other two species provide additional evidence suggesting the genus Limanda may be paraphyletic, as has been proposed in other studies. Results presented here have potential utility in future Arctic fisheries oceanography research. [ABSTRACT FROM AUTHOR]

This qualitative study examined caregivers' perceptions of Parent Peer Support (PPS) services, embedded in the Wraparound service delivery model for youth with severe emotional and behavioral disturbances (SEBD), to identify potential engagement facilitators and barriers. Wraparound is a holistic process involving multiple formal and informal providers to collectively implement an individualized, family-centered plan of care focused on maintaining youth with SEBD within the community. PPS are frequently referred to caregivers involved in Wraparound to provide additional support. Caregivers ( n = 35) previously involved in an evaluation of one state's Wraparound model participated in a single 30-60-min interview. Interview questions examined caregivers' expectations about PPS, reasons for accepting or refusing PPS, and caregivers' perceived impact of PPS. Transcribed interviews were analyzed using strategies from grounded theory methodology. Perceived need, as well as desire for shared experiences, knowledge, and assistance in accessing resources, facilitated accepting the PPS service. Barriers included inaccurate expectations of PPS, time limitations on Wraparound services, escalating youth behavior requiring more restrictive placements, scheduling difficulties, perceived unresponsiveness, and caregivers feeling overwhelmed by the number of providers. Caregivers indicated that PPS provided several benefits for themselves, youth in the care, and their families. However, potential barriers to ongoing engagement included perceived intrusiveness, as well as misalignment between services offered and caregivers' needs. [ABSTRACT FROM AUTHOR]

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders. [ABSTRACT FROM AUTHOR]

Recent evidence emphasized that transglutaminase 2 (TG2), a protein cross-linking enzyme, may play a role in the early phase of inflammation. High levels of TG2 have been associated with the constitutive activation of nuclear factor-kappa B (NF-κB) that is considered the main regulator of inflammation. In this context, the receptor activator of NF-kappa B ligand (RANKL) and receptor activator of NF-κB have extensive functions in the regulation of cytokine secretion associated with different pathological conditions. The human periodontal ligament (HPDL) cells, which express and secrete osteoprotegerin (OPG) and RANKL, represent an useful 'ex vivo' model for monitoring cell response in inflammatory microenvironments, such as periodontitis-dependent tissue response. Thus, we evaluated TG2 expression and alterations in RANKL/OPG ratio occurring in cultured HPDL cells. The HPDL cells were obtained from patients with chronic periodontitis (CP) and healthy subjects. We observed the up-regulation of some inflammatory markers, such as IL-6, TNF-α, and HMGB-1, and at the same time an increase in TG2 mRNA levels in HPDL cells from CP patients compared with healthy subjects. We found a positive correlation between RANKL/OPG ratio and TG2 mRNA levels in HPDL cells from CP patients. In the parallel experiments, we demonstrated that TG2 inhibition reduced RANKL expression in both HPDL cells from CP patients and monocytes differentiated to macrophages by tetradecanoyl phorbol acetate treatment. Given the RANKL key role in NF-κB pathway and the observed up-regulation of pro-inflammatory cytokines, our data suggest that TG2 may be involved in molecular mechanisms of inflammatory response occurring in periodontal disease. [ABSTRACT FROM AUTHOR]

Human regulatory T cells (Treg cells) that develop from conventional T cells (Tconv cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced Treg cells (iTreg cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iTreg cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iTreg cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of Treg cells in health and in autoimmunity. [ABSTRACT FROM AUTHOR]