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IntroductionTherapeutic Alliance (TA) is a fundamental aspect of clinical practice, in particular with psychotic patients. In this population, TA has been associated with better clinical outcomes, such as symptomatic and functional impairment reduction and greater life quality. Several aspects have been suggested to negatively interfere with this patient-therapist relationship, including different beliefs about mental health/disease, the role of mental health systems or mental disease-associated stigma. Showing empathy, stimulating metacognition, searching for shared meaning and working as a team seem to be an adequate way to surpass these obstacles - just like we do when we enter an escape room.ObjectivesTo understand the importance of TA in the successful clinical management of psychotic patients; and to propose an original hierarchical framework of TA with these patients.MethodsReview of the scientific literature on the subject and proposal of an original framework of TA with psychotic patients doing an analogy with escape room dynamics.ResultsIn an escape room, a team works together to solve a series of mysteries, each leading to another, thus accomplishing one final goal. To do such, every element must agree on the solution to proceed; and there is no access to one level without successfully completing the former.In a clinical environment with a psychotic patient, such rules may also apply. Although the starting level in each patient-therapist relationship may vary, it is here proposed that proceeding to the next level without at least partial agreement in the previous one may be inefficacious or even counterproductive for the intentions of the therapist.So, shall we begin?Level 0 - Who am I? Prior to the encounter with the patient, it is important that the therapist knows himself reasonably well, specially regarding his beliefs, shortcomings and biases in his clinical practice.Level 1 - What is this? The teamwork starts here. Both therapist and patient must discover why this encounter is happening, what does it mean to be in this medical facility or to be mentally ill, in general.Level 2 - What is wrong? Trying to understand what is detrimental in the patient’s mental health.Level 3 - What to do? Tailoring a therapeutic intervention to the impairments of the patient.Level 4 - How to do it? Finding a way to suit the therapeutic intervention to patient’s personal preferences and availability.Level 5 - The way out. Helping the patient escape this room and fulfill his maximum potential in all of the other “rooms” of his life.ConclusionsTA is indispensable to therapeutic success when dealing with psychotic patients.There is a need for shared meaning and understanding in multiple aspects of the therapist-patient relationship; an approach that only focus some of these aspects while ignoring others may be ineffective or even detrimental to clinical outcomes.Disclosure of InterestNone Declared

Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group); BPA treated mice that also ate a normal chow diet (BPA); vehicle treated animals that had a high fat diet (HFD) and BPA treated animals that were fed HFD (HFD-BPA). The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA) in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity.

Mineralized and sound dentin matrices contain inactive preforms of proteolytic enzymes that may be activated during the demineralization cycle. In this study, we tested the hypothesis that protease inhibitors (PI) preserve demineralized collagen fibrils and other constituents of the dentin matrix and thereby affect the potential for remineralization. Artificial carious lesions with lesion depths of 140 μm were created with acetate buffer (pH = 5.0, 66 hours), and remineralized using a polymer-induced-liquid-precursor (PILP) process (pH = 7.4, 14 days) containing poly(aspartic acid) (pAsp) as the process-directing agent. De- and remineralizing procedures were performed in the presence or absence of PI. Ultrastructure and mechanical recovery of demineralized dentin following PILP remineralization were examined and measured in water with atomic force microscopy (AFM) and nanoindentation. Nanomechanical properties of hydrated artificial lesions had a low elastic modulus (ER <0.4 GPa) extending about 100 μm into the lesion, followed by a sloped region of about 140 μm depth where values reached those of normal dentin (18.0-20.0 GPa). Mapping of mineral content by both micro-FTIR and micro x-ray computed tomography correlated well with modulus profiles obtained by nanoindentation. Tissue demineralized in the presence of PI exhibited higher elastic moduli (average 2.8 GPa) across the lesion and comprised a narrow zone in the outer lesion with strongly increased modulus (up to 8 GPa; p < 0.05), which might be related to the preservation of non-collagenous proteins that appear to induce calcium phosphate mineral formation even under demineralizing physical-chemical conditions. However, mechanical aspects of remineralization through the elastic modulus change, and the micromorphological aspects with SEM and TEM observation were almost identical with PILP treatments being conducted in the presence or absence of PI. Thus, the application of the protease inhibitors (PI) seemed to be less effective in promoting the remineralization of demineralized dentin.

Nature uses extracellular matrix scaffolds to organize biominerals into hierarchical structures over various length scales. This has inspired the design of biomimetic mineralization scaffolds, with DNA nanostructures being among the most promising. DNA nanotechnology makes use of molecular recognition to controllably give 1D, 2D and 3D nanostructures. The control we have over these structures makes them attractive templates for the synthesis of mineralized tissues, such as bones and teeth. In this Review, we first summarize recent work on the crystallization processes and structural features of biominerals on the nanoscale. We then describe self-assembled DNA nanostructures and come to the intersection of these two themes: recent applications of DNA templates in nanoscale biomineralization, a crucial process to regenerate mineralized tissues. DNA is a promising scaffold for guiding biomineralization. This Review describes how DNA nanostructures template calcium-based and silica biominerals, with applications envisioned in biomedicine, electronics and engineering.

Nonlinear optical materials have been investigated recently due to their potential technological applications in information storage and communications. In this context, semi-organic crystals can effectively combine the desired nonlinear optical properties of amino acids with the promising mechanical and thermal properties of inorganic materials. In this work, we have synthesized and characterized a semi-organic crystal of the amino acid l -histidine and hydrofluoric acid and investigated the chemical interactions between the organic and inorganic moieties. The crystal of l -histidine bis(fluoride) has been produced by slow solvent evaporation and characterized by X-ray diffraction (XRD) crystallography and thermogravimetric and differential thermal analyses. The XRD conducted using the Rietveld method shows that the unit cell is orthorhombic with the P2 1 2 1 2 space group and contains four l -histidine bis(fluoride) units. Both differential thermal analysis and temperature-dependent XRD show that the crystals are thermally stable up to 191°C and do not undergo phase transition. The computational Hirshfeld surface analysis of the crystal structure reveals the main intermolecular interactions. Density functional theory has been employed to calculate the ionic interaction energy and electrostatic potential maps and confirm the spontaneity of ionic association at 191°C. The combined experimental and computational results show that the thermal stability of the semi-organic l -histidine bis(fluoride) crystal makes it suitable for nonlinear optical applications in optical sensing and communication systems. Graphical abstract

The role played by the metal − support (MSI) and metal − metal (MMI) interactions on two important processes in controlling the catalyst performance — nucleation and molecular adsorption — has been investigated using density functional theory (DFT), by means of B3LYP functional, combined with localized molecular orbital energy decomposition analysis (LMOEDA), and natural bond orbital (NBO) calculations, with aid of a Pd 4 /γ-alumina (110D) model (Pd 4 /Al 13 O 23 H 7 ). Our results indicate the occurrence of an electronic metal − support interaction (EMSI) which induces a most intense charge transfer in the Pd 4  → γ-alumina backdonation direction, most expressive in Pd → Al, promoting an electronic redistribution within the units and attenuating the MMI. Nevertheless, the MSI/MMI synergistic effect seems to favor slightly the nucleation of a fifth palladium atom, leading to a distorted square pyramidal arrangement for Pd 5 . The LMOEDA analysis points to a mostly covalent character in the Pd − Al bonds, whereas the Pd − O bonds are mainly electrostatic in nature. The palladium atoms deposited on oxygen anions are the acid centers, where both NO molecule and an additional palladium atom anchor more strongly. In addition, the MSI/MMI effect, through the electronic and geometric contributions, drives the adsorption of the NO molecule to the mode which most favors the Pd → NO ( 4d z 2  →  2π * ) backdonation (bridge mode). Graphical Abstract MSI and MMI effects on the nature of the Pd − O (electrostatic) and Pd − Al (covalent) bonds, charge transfer into Pd 4 /γ-Al 2 O 3 (110D) interface (back donation) and preferential site for adsorption of a single NO molecule and an additional Pd atom (Pd − O).

Hemolytic diseases include a variety of conditions with diverse etiologies in which red blood cells are destroyed and large amounts of hemeproteins are released. Heme has been described as a potent proinflammatory molecule that is able to induce multiple innate immune responses, such as those triggered by TLR4 and the NLRP3 inflammasome, as well as necroptosis in macrophages. The mechanisms by which eukaryotic cells respond to the toxic effects induced by heme to maintain homeostasis are not fully understood, however. Here we describe a previously uncharacterized cellular response induced by heme: the formation of p62/SQTM1 aggregates containing ubiquitinated proteins in structures known as aggresome-like induced structures (ALIS). This action is part of a response driven by the transcription factor NRF2 to the excessive generation of reactive oxygen species induced by heme that results in the expression of genes involved in antioxidant responses, including p62/SQTM1. Furthermore, we show that heme degradation by HO-1 is required for ALIS formation, and that the free iron released on heme degradation is necessary and sufficient to induce ALIS. Moreover, ferritin, a key protein in iron metabolism, prevents excessive ALIS formation. Finally, in vivo, hemolysis promotes an increase in ALIS formation in target tissues. Our data unravel a poorly understood aspect of the cellular responses induced by heme that can be explored to better understand the effects of free heme and free iron during hemolytic diseases such as sickle cell disease, dengue fever, malaria, and sepsis.

Autophagy facilitates host defense against invading bacteria. Philpott and colleagues show that Nod1 and Nod2 link pathogen sensing to autophagy by recruiting the autophagy protein AGT16L1 to the site of pathogen entry. Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. By a mechanism independent of the adaptor RIP2 and transcription factor NF-κB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. In cells homozygous for the Crohn's disease–associated NOD2 frameshift mutation, mutant Nod2 failed to recruit ATG16L1 to the plasma membrane and wrapping of invading bacteria by autophagosomes was impaired. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.

Though new targeted therapies for colorectal cancer, which progresses from local intestinal tumors to metastatic disease, are being developed, tumor specificity remains an important problem, and side effects a major concern. Here, we show that the protein-fatty acid complex BAMLET ( b ovine a lpha-lactalbumin m ade le thal to t umor cells) can act as a peroral treatment for colorectal cancer. Apc Min/ + mice, which carry mutations relevant to hereditary and sporadic human colorectal cancer, that received BAMLET in the drinking water showed long-term protection against tumor development and decreased expression of tumor growth-, migration-, metastasis- and angiogenesis-related genes. BAMLET treatment via drinking water inhibited the Wnt/β-catenin and PD-1 signaling pathways and prolonged survival without evidence of toxicity. Systemic disease in the lungs, livers, spleens, and kidneys, which accompanied tumor progression, was inhibited by BAMLET treatment. The metabolic response to BAMLET included carbohydrate and lipid metabolism, which were inhibited in tumor prone Apc Min/ + mice and weakly regulated in C57BL/6 mice, suggesting potential health benefits of peroral BAMLET administration in addition to the potent antitumor effects. Together, these findings suggest that BAMLET administration in the drinking water maintains antitumor pressure by removing emergent cancer cells and reprogramming gene expression in intestinal and extra-intestinal tissues.

Enamel, the outermost layer of teeth, is an acellular mineralized tissue that cannot regenerate; the mature tissue is composed of high aspect ratio apatite nanocrystals organized into rods and inter-rod regions. Amelogenin constitutes 90% of the protein matrix in developing enamel and plays a central role in guiding the hierarchical organization of apatite crystals observed in mature enamel. To date, a convincing link between amelogenin supramolecular structures and mature enamel has yet to be described, in part because the protein matrix is degraded during tissue maturation. Here we show compelling evidence that amelogenin self-assembles into an amyloid-like structure in vitro and in vivo . We show that enamel matrices stain positive for amyloids and we identify a specific region within amelogenin that self-assembles into β-sheets. We propose that amelogenin nanoribbons template the growth of apatite mineral in human enamel. This is a paradigm shift from the current model of enamel development.