Thermally Triggered Triazolinedione-Tyrosine Bioconjugation with Improved Chemo- and Site-Selectivity.

A bioconjugation strategy is reported that allows the derivatization of tyrosine side chains through triazolinedione-based "Y-clicking". Blocked triazolinedione reagents were developed that, in contrast to classical triazolinedione reagents, can be purified before use, can be stored for a long time, and allow functionalization with a wider range of cargoes and labels. These reagents are bench-stable at room temperature but steadily release highly reactive triazolinediones upon heating to 40 °C in buffered media at physiological pH, showing a sharp temperature response over the 0 to 40 °C range. This conceptually interesting strategy, which is complementary to existing photo- or electrochemical bioorthogonal bond-forming methods, not only avoids the classical synthesis and handling difficulties of these highly reactive click-like reagents but also markedly improves the selectivity profile of the tyrosine conjugation reaction itself. It avoids oxidative damage and "off-target" tryptophan labeling, and it even improves site-selectivity in discriminating between different tyrosine side chains on the same protein or different polypeptide chains. In this research article, we describe the stepwise development of these reagents, from their short and modular synthesis to small-molecule model bioconjugation studies and proof-of-principle bioorthogonal chemistry on peptides and proteins.

Comprehensive Two-Dimensional Gas Chromatography-Mass Spectrometry as a Tool for the Untargeted Study of Hop and Their Metabolites.

Since hop secondary metabolites have a direct correlation with the quality of beer and other hop-based beverages, and the volatile fraction of hop has a complex composition, requiring effective separation, here we explore the application of headspace solid-phase microextraction as a sample preparation method, coupled with comprehensive two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) analysis. The methodology involved the use of a DVB/PDMS fibre with 500 mg of hop cone powder, extracted for 40 min at 50 °C, for both GC-MS and GC×GC-MS. The varieties Azacca, Cascade, Enigma, Loral, and Zappa were studied comprehensively. The results demonstrate that GC×GC-MS increases the number of peaks by over 300% compared to classical GC-MS. Overall, 137 compounds were identified or tentatively identified and categorised into 10 classes, representing between 87.6% and 96.9% of the total peak area. The composition revealed the highest concentration of sesquiterpene hydrocarbons for Enigma, whilst Zappa showed a relatively significant concentration of monoterpene hydrocarbons. Principal component analysis for all compounds and classes, along with hierarchical cluster analysis, indicated similarities between Zappa and Cascade, and Azacca and Loral. In conclusion, this method presents an optimistic advancement in hop metabolite studies with a simple and established sample preparation procedure in combination with an effective separation technique.

Thermosensitive polymer prodrug nanoparticles prepared by an all-aqueous nanoprecipitation process and application to combination therapy.

Despite their great versatility and ease of functionalization, most polymer-based nanocarriers intended for use in drug delivery often face serious limitations that can prevent their clinical translation, such as uncontrolled drug release and off-target toxicity, which mainly originate from the burst release phenomenon. In addition, residual solvents from the formulation process can induce toxicity, alter the physico-chemical and biological properties and can strongly impair further pharmaceutical development. To address these issues, we report polymer prodrug nanoparticles, which are prepared without organic solvents via an all-aqueous formulation process, and provide sustained drug release. This was achieved by the "drug-initiated" synthesis of well-defined copolymer prodrugs exhibiting a lower critical solution temperature (LCST) and based on the anticancer drug gemcitabine (Gem). After screening for different structural parameters, prodrugs based on amphiphilic diblock copolymers were formulated into stable nanoparticles by all-aqueous nanoprecipitation, with rather narrow particle size distribution and average diameters in the 50-80 nm range. They exhibited sustained Gem release in human serum and acetate buffer, rapid cellular uptake and significant cytotoxicity on A549 and Mia PaCa-2 cancer cells. We also demonstrated the versatility of this approach by formulating Gem-based polymer prodrug nanoparticles loaded with doxorubicin (Dox) for combination therapy. The dual-drug nanoparticles exhibited sustained release of Gem in human serum and acidic release of Dox under accelerated pathophysiological conditions. Importantly, they also induced a synergistic effect on triple-negative breast cancer line MDA-MB-231, which is a relevant cell line to this combination.

Soft-tissue, non-osteogenic distraction of the mandible and lower face in bilateral hemifacial microsomia-technical report.

The aim of this study is to present a sequential strategy of soft-tissue, non-osteogenic distraction with a novel device, followed by microvascular bony reconstruction for severe cases of mandibular hypoplasia. The case of a 21-year-old woman with Goldenhar syndrome is presented, whose mandible remained severely hypoplastic despite previous attempts at distraction and was not suitable for further osteogenic distraction. Soft tissue deficiency and pin track scarring prevented free fibular transfers. A personalized distractor, anchored to the cranium and the mandibular symphysis, was designed to expand the soft tissues while allowing for physiological temporomandibular joint (TMJ) movement without compression forces. Internal distractors were placed along the osteotomies to prevent condylar luxation. After completion of the soft tissue distraction, the native mandible was resected except for the condyles and reconstructed with two free fibula flaps. This report represents the proof of concept of a sequential approach to severe lower face soft-tissue and bone deficiency, which preserves TMJ function and avoids the transfer of poorly matched skin to the face.

Towards scaling up the sonochemical synthesis of Pt-nanocatalysts.

Large scale production of electrocatalysts for electrochemical energy conversion devices such as proton exchange membrane fuel cells must be developed to reduce their cost. The current chemical reduction methods used for this synthesis suffer from problems with achieving similar particle properties such as particle size and catalytic activity when scaling up the volume or the precursor concentration. The continuous production of reducing agents through the sonochemical synthesis method could help maintain the reducing conditions (and also the particle properties) upon increasing the reactor volume. In this work we demonstrate that the reducing conditions of Pt-nanoparticles are indeed maintained when the reactor volume is increased from 200 mL to 800 mL. Similar particle sizes, 2.1(0.3) nm at 200 mL and 2.3(0.4) nm at 800 mL, and catalytic activities towards the oxygen reduction reaction (ORR) are maintained as well. The reducing conditions were assessed through TiOSO4 dosimetry, sonochemiluminesence imaging, acoustic power measurements, and Pt(II) reduction rate measurements. Cyclic voltammetry, CO-stripping, hydrogen evolution measurements, ORR measurements, and electron microscopy were used to evaluate the catalytic activity and particle size. The similar particle properties displayed from the two reactor volumes suggest that the sonochemical synthesis of Pt-nanoparticles is suitable for large scale production.

Passaging of gingival fibroblasts from periodontally healthy and diseased sites upregulates osteogenesis-related genes.

To investigate biological processes of the periodontium, in vitro primary cell models have been established. To study the biology of the gingiva, primary gingival fibroblast cell models are widely used. For such experiments, cells need to be expanded and passaged. A key assumption is that primary cells maintain most of their original characteristics they have in situ. The aim of this research is to explore the impact of early passaging on selected gene expression of human gingival fibroblast cells. For this purpose, gene expression from the outgrowth of the resected tissues until the fourth passage was followed for nine tissue samples, from both healthy and diseased sites. Micrographs were taken from the cultures, RNA was extracted from the samples of each passage and quantitative PCR was performed for selected genes representing various biological processes. Epithelial cells were present during the first outgrowth, but were no longer present in the second passage. Our results indicate that the morphology of the gingival fibroblast cells does not change with passaging and that passages 2-4 contain only gingival fibroblasts. Gene expression of M-CSF, TNF-α, TLR4, POSTN and FAPα was unchanged by passaging, the expression of IL-6, IL-1ß and TLR2 decreased due to passaging and the expression of in particular the selected osteogenesis genes (ALP, RUNX2, Osteonectin, COL1A), OPG and MKI67 increased with passaging. Worldwide, use of the same passage in laboratory experiments using primary cell cultures is the standard. Our results support this, since for certain genes, in particular osteogenesis genes, expression may alter solely due to passaging.

Promotion of hydrogen evolution from seawater via poly(aniline-co-4-nitroaniline) combined with 3D nickel nanoparticles.

This work reports the synthesis of poly (aniline-co-4-nitroaniline) deposited on a three-dimensional nanostructured nickel (3D-Ni) film, where both layers were fabricated via potentiostatic electrodeposition. The obtained electrocatalyst exhibited excellent electrochemical activity for the Hydrogen Evolution Reaction (HER) with small overpotentials of - 195 and - 325 mV at - 10 and - 100 mAcm-2, respectively, and a low Tafel slope of 53.3 mV dec-1 in seawater. Additionally, the electrocatalyst exhibited good stability after 72 h operation under a constant potential of - 1.9 V vs. RHE. The efficient HER performance of the as-prepared catalyst was found to originate from the synergy between the conducting polymer and three-dimensional nickel nanoparticles with a large electrochemical active surface area. Moreover, the results obtained from electrochemical impedance spectroscopy (EIS) measurements revealed that the presence of 3D-Ni layer improved the kinetics of HER by reducing the charge transfer resistance for the electrocatalyst.

Periodontitis and risk of cancer: Mechanistic evidence.

This review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low-grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro-aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non-indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor-associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor-infiltrating T cells) and the increased expression of pro-inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors.

Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives.

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of ß-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

Willingness for Medical Screening in a Dental Setting-A Pilot Questionnaire Study.

An important way to manage noncommunicable diseases (NCDs) is to focus on prevention, early detection, and reducing associated risk factors. Risk factors can be detected with simple general health checks, which can also be performed in dental clinics. The purpose of this study was to investigate participants' willingness to participate in general health checks at the dentist, in particular the difference in opinion between medical patients and random healthy dental attendees. A total of 100 medical patients from an outpatient internal medicine clinic and 100 dental clinic attendees were included (total of 200 participants). The participants were asked for their opinion using six closed-ended questions. Overall, 91.0% of participants were receptive to information about the risk of diabetes mellitus (DM) and cardiovascular diseases (CVD). The majority (80-90%) was receptive to screening for DM and CVD risk, such as weight and height measurements, blood pressure measurement, saliva testing for CVD and to measure glucose and cholesterol via finger stick. No significant differences were found in the frequencies of the responses between the different groups based on health status, age, sex, or cultural background. This study shows that most participants are willing to undergo medical screening at the dentist for early detection and/or prevention of common NCDs.

A preclinical platform for assessing long-term drug efficacy exploiting mechanically tunable scaffolds colonized by a three-dimensional tumor microenvironment.

BACKGROUND: Long-term drug evaluation heavily relies upon rodent models. Drug discovery methods to reduce animal models in oncology may include three-dimensional (3D) cellular systems that take into account tumor microenvironment (TME) cell types and biomechanical properties. METHODS: In this study we reconstructed a 3D tumor using an elastic polymer (acrylate-endcapped urethane-based poly(ethylene glycol) (AUPPEG)) with clinical relevant stiffness. Single cell suspensions from low-grade serous ovarian cancer (LGSOC) patient-derived early passage cultures of cancer cells and cancer-associated fibroblasts (CAF) embedded in a collagen gel were introduced to the AUPPEG scaffold. After self-organization in to a 3D tumor, this model was evaluated by a long-term (> 40 days) exposure to a drug combination of MEK and HSP90 inhibitors. The drug-response results from this long-term in vitro model are compared with drug responses in an orthotopic LGSOC xenograft mouse model. RESULTS: The in vitro 3D scaffold LGSOC model mimics the growth ratio and spatial organization of the LGSOC. The AUPPEG scaffold approach allows to test new targeted treatments and monitor long-term drug responses. The results correlate with those of the orthotopic LGSOC xenograft mouse model. CONCLUSIONS: The mechanically-tunable scaffolds colonized by a three-dimensional LGSOC allow long-term drug evaluation and can be considered as a valid alternative to reduce, replace and refine animal models in drug discovery.

Periodontitis is associated with multimorbidity in a large dental school population.

AIM: To investigate whether and which diseases co-occur with periodontitis (PD) to assess the prevalence of comorbidities and multimorbidity and to identify patterns and profiles of comorbidity and multimorbidity and the influence of demographic and lifestyle factors to identify distinct groups of multimorbid patients. MATERIALS AND METHODS: A database from the Academic Centre of Dentistry Amsterdam (ACTA) with 37,801 adult individuals containing information about demographic (age, sex, socio-economic position [SEP]) and lifestyle factors (smoking, alcohol use and addictive substance use) and PD and systemic diseases was constructed. PD assessment was based on clinical information by the use of claim codes and systemic diseases data were derived from self-reported medical history. For analyses, univariable and multivariable (adjusted for age, sex, SEP, smoking, alcohol use and addictive substance use) logistic regression analyses and cluster analysis were used. RESULTS: Individuals with PD more often had one or multiple diseases. The adjusted odds ratio (OR) for PD patients having up to four systemic diseases ranged from 1.46 to 1.20. Co-occurrence of PD with several systemic diseases and a higher prevalence of multimorbidity was found (adjusted OR comorbidity = 1.36; 95% confidence interval (CI): 1.30-1.43; multimorbidity = 1.18; 95% CI: 1.11-1.25). Four clusters existed: cluster 1 was defined as a periodontal and systemically healthy group and cluster 4 as burdened with PD but not containing any systemic diseases. Individuals in cluster 1 were of the lowest age (44.9 [SD: 15.5]) and had the lowest prevalence of the lifestyle factors of smoking (13.6%) and alcohol use (3.9%). Clusters 2 and 3 contained both PD and had several systemic diseases but were different from each other. Cluster 2 contained 34.5% of PD individuals and had mainly respiratory tract, immune system and digestive system diseases. Cluster 3 contained 45.9% of PD individuals and had mainly cardiometabolic diseases. Cluster 2 had the highest prevalence of females (63.1%) and the highest prevalence of smokers (23.8%) and addictive substance users (8.9%). Cluster 3 included individuals of the highest age (63.5 [SD: 11.9]), and had highest prevalence of alcohol users (17.7%) and lowest prevalence of addictive substance users (3.8%). CONCLUSIONS: This study shows that individuals with PD are more often burdened with comorbidity and multimorbidity. Presence of distinct clusters suggests overlap in pathophysiology between certain types of PD and specific systemic diseases. Therefore, PD can be considered as part of multimorbidity, as one of the systemic diseases co-occurring in certain groups of individuals.

Lipid Nanoparticle Delivery Alters the Adjuvanticity of the TLR9 Agonist CpG by Innate Immune Activation in Lymphoid Tissue.

Pharmacological strategies to activate innate immune cells are of great relevance in the context of vaccine design and anticancer immune therapy, to mount broad immune responses able to clear infection and malignant cells. Synthetic CpG oligodeoxynucleotides (CpG-ODNs) are short single-stranded DNA molecules containing unmethylated CpG dinucleotides and a phosphorothioate backbone. Class B CpG ODNs activate robust innate immune responses through a TLR9-dependent NF-κB signaling pathway. This feature is attractive to exploit in the context of vaccine design and cancer immunotherapy. Soluble CpG-ODNs cause hepatic toxicity, which reduces its therapeutic applicability. The formulation of class B CpG ODN1826 in lipid nanoparticles (LNPs) containing an ionizable cationic lipid that complexes CpG through electrostatic interaction is reported. Upon local administration, LNP-formulated CpG drains to lymph nodes and triggers robust innate immune activation. Unformulated, soluble, CpG, by contrast, is unable to induce robust innate activation in draining lymph nodes and is distributed systemically. In a vaccination setting, LNP-formulated CpG, admixed with a protein antigen, induces higher antigen-specific antibody titers and T cell responses than antigen admixed with unformulated soluble CpG.

Association of the human gut microbiota with vascular stiffness.

Gut microbiota metabolites have been mechanistically linked to inflammatory pathway activation and atherosclerosis, which are major causes of vascular stiffness (VS). Aiming to investigate if the gut microbiome might be involved in VS development, we performed a cross-sectional study (n = 3,087), nested within the population-based European Prospective Investigations into Cancer and Nutrition (EPIC) Potsdam. We investigated the correlation of the gut microbiota (alpha diversity and taxa abundance) with 3 vascular stiffness measures: carotid-femoral (PWV), aortic augmentation index (AIX) and ankle-brachial index (ABI). Shannon index was not significantly associated with VS but the number of observed Amplicon Sequence Variants (ASV) was positively associated with PWV and AIX. We found a total of 19 ASVs significantly associated with at least one VS measure in multivariable-adjusted models. One ASV (classified as Sutterella wadsworthensis) was associated with 2 VS measures, AIX (- 0.11 ± 0.04) and PWV (-0.14 ± 0.03). Other examples of ASVs associated with VS were Collinsella aerofaciens, previously reported to be affected by diet and Bacteroides uniformis, commercially available as probiotics. In conclusion, our study suggests a potential role of individual components of the gut microbiota in the aetiology of VS.

Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing.

Recruiting endogenous antibodies to the surface of cancer cells using antibody-recruiting molecules has the potential to unleash innate immune effector killing mechanisms against antibody-bound cancer cells. The affinity of endogenous antibodies is relatively low, and many currently explored antibody-recruiting strategies rely on targeting over-expressed receptors, which have not yet been identified in most solid tumors. Here, both challenges are addressed by functionalizing poly(propyleneimine) (PPI) dendrimers with both multiple dinitrophenyl (DNP) motifs, as anti-hapten antibody-recruiting motifs, and myristoyl motifs, as universal phospholipid cell membrane anchoring motifs, to recruit anti-hapten antibodies to cell surfaces. By exploiting the multivalency of the ligand exposure on the dendrimer scaffold, it is demonstrated that dendrimers featuring ten myristoyl and six DNP motifs exhibit the highest antibody-recruiting capacity in vitro. Furthermore, it is shown that treating cancer cells with these dendrimers in vitro marks them for phagocytosis by macrophages in the presence of anti-hapten antibodies. As a proof-of-concept, it is shown that intratumoral injection of these dendrimers in vivo in tumor-bearing mice results in the recruitment of anti-DNP antibodies to the cell surface in the tumor microenvironment. These findings highlight the potential of dendrimers as a promising class of novel antibody-recruiting molecules for use in cancer immunotherapy.

A Direct Immunoassay Based on Surface-Enhanced Spectroscopy Using AuNP/PS-b-P2VP Nanocomposites.

A biosensor was developed for directly detecting human immunoglobulin G (IgG) and adenosine triphosphate (ATP) based on stable and reproducible gold nanoparticles/polystyrene-b-poly(2-vinylpyridine) (AuNP/PS-b-P2VP) nanocomposites. The substrates were functionalized with carboxylic acid groups for the covalent binding of anti-IgG and anti-ATP and the detection of IgG and ATP (1 to 150 µg/mL). SEM images of the nanocomposite show 17 ± 2 nm AuNP clusters adsorbed over a continuous porous PS-b-P2VP thin film. UV-VIS and SERS were used to characterize each step of the substrate functionalization and the specific interaction between anti-IgG and the targeted IgG analyte. The UV-VIS results show a redshift of the LSPR band as the AuNP surface was functionalized and SERS measurements showed consistent changes in the spectral features. Principal component analysis (PCA) was used to discriminate between samples before and after the affinity tests. Moreover, the designed biosensor proved to be sensitive to different concentrations of IgG with a limit-of-detection (LOD) down to 1 µg/mL. Moreover, the selectivity to IgG was confirmed using standard solutions of IgM as a control. Finally, ATP direct immunoassay (LOD = 1 µg/mL) has demonstrated that this nanocomposite platform can be used to detect different types of biomolecules after proper functionalization.

Antagonism of P2X7 receptors enhances lorazepam action in delaying seizure onset in an in vitro model of status epilepticus.

Approximately 30% of patients with status epilepticus (SE) become refractory to two or more antiseizure medications (ASMs). There is thus a real need to identify novel targets against which to develop new ASMs for treating this clinical emergency. Among purinergic receptors, the ionotropic ATP-gated P2X7 receptor (P2X7R) has received attention as a potential ASM target. This study evaluated the effect of the selective P2X7R antagonist A740003 on acute seizures in the dentate gyrus (DG) of hippocampal brain slices, where P2X7Rs are highly expressed, with a view to establishing the potential of P2X7R antagonists as a therapy or adjunct with lorazepam (LZP) in refractory SE. Extracellular electrophysiological recordings were made from the DG of male mouse hippocampal slices. Spontaneous seizure-like events (SLEs) were induced by removing extracellular Mg2+ and sequentially adding the K+ channel blocker 4-aminopyridine and the adenosine A1 receptor antagonist 8-cyclopentyltheophylline, during which the early and late application of A740003 and/or lorazepam was evaluated. Our study revealed that, in the absence of changes in mRNA for P2X7Rs or inflammatory markers, P2X7R antagonism did not reduce the frequency of SLEs. However, A740003 in conjunction with LZP delayed the onset of seizures. Furthermore, our results support the need for employing LZP before seizures become refractory during SE as delayed application of LZP increased seizure frequency. These studies reveal possible sites of intervention that could have a positive impact in patients with high risk of suffering SE.

Contexto, ser humano y epigenética / Context, human being and epigenetics

Resumen Los últimos años de investigación científica han visto un crecimiento en los estudios que relacionan situaciones de vulnerabilidad (particularmente, durante la vida temprana) con el desarrollo de psicopatologías. Tales disfuncionalidades en la salud mental y en las emociones entienden una sinergia entre factores contextuales y la biología del organismo. Lo que da en llamarse "puente" entre ambas instancias es estudiado por un área de la investigación científica relativamente nueva: la epigenética. La epigenética fue establecida como un interesante factor que permite relacionar, desde un punto de vista biológico, el contexto en que se desarrollan las personas con sus estados emocionales. Este artículo se propone revisar algunos trabajos e integrarlos dentro de una concepción compleja del ser humano, que lo entiende como un sistema de relaciones entre diversas dimensiones que incluyen las esferas genéticas, epigenéticas, neurológicas, emocionales, interaccionales, cognitivas y socioculturales enmarcadas en un contexto particular.

Abstract The discovery of the whole sequence of the human genome in 2001 promised to be a revolution in terms of dealing with diseases and understanding what makes us a "different" species from other animals. However, the scope of this promising discovery was more limited than expected. The information carried by DNA is complex and, furthermore, it does not explain the vast repertoire of functions and dysfunctions that organisms present. For this reason, it began to be thought that it was necessary to change the focus to understand how individuals are formed and develop, and turn the attention paid to DNA to what surrounds that DNA: the environment of the organism (both internal and external). In this way, the studies began to focus on the influence of the context to which organisms are exposed to understand the characteristics of the body and its actions. In thinking about the concept of the body in development, this renewed focus in the environmental influence allows an understanding of it as a permeable and complex system, where dysregulations (diseases) may also be triggered by exogenous events and not only from the endogenous factors. Therefore, in a recursive way, the influence of the human being on the environment transforms the environment that returns to influence the human being. Here is the history of mankind. There are contexts that offer a healthy framework for the growth of its inhabitants and there are others that make life vulnerable and produce lifetime consequences. However, while some people are and feel vulnerable to contexts of adversity, other people are resilient and manage to positively live and growth despite the difficulties that might appear throughout life. Epigenetics has been proposed as one of the molecular mechanisms that explain how those contexts "get under the skin" and trigger phenotypic characteristics. Although the regulation of gene expression by epigenetic mechanisms occurs naturally and constantly in the developing organism, it can also be influenced by environmental factors, such as age, lifestyle, health conditions or social relationships. Epigenetics is sensitive to environmental changes allowing organisms to adapt their physiology and behavior. Unlike the changes that occur in the DNA sequence, epigenetic processes are reversible. One of the most known examples of epigenetic action in determining phenotypes according to the environment is the stress response through the hypothalamus-pituitary-adrenal (HPA) axis. The functioning of the HPA axis and the response to stress can be related to the concepts of vulnerability and trauma. If an emotionally sensitive event is disturbing, it becomes a stressful situation, with the activation of the HPA axis, flooding the bloodstream with cortisol. This allostatic process is the basis of the mechanism of adaptability of humans to traumatic impacts. But if the situation continues to impact, allostasis is systematized and generates an allostatic circuit that produces a residual charge that ends up creating dysfunction in the organism. In this article the involvement of epigenetics in this regulation is discussed and some seminal studies in rodents and humans are presented. The last few years of scientific research have seen an explosive growth of studies linking situations of vulnerability (particularly, during early life) with the development of psychopathologies. Epigenetics was established as an interesting factor that allows to relate, from a biological point of view, the context in which people develop with their emotional states. This article proposes a review of some of these works in order to integrate them into a complex conception of the human being, which understands it as a system of relationships between various dimensions, including genetics, epigenetics, neurology, emotions, social interactions, cognition, and socio-culture, framed in a particular context.

Visible Light Conjugation with Triazolinediones as a Route to Degradable Poly(ethylene glycol)-Lipids for mRNA Lipid Nanoparticle Formulation.

Polyethylene glycol (PEG) is considered as the gold standard for colloidal stabilization of nanomedicines, yet PEG is non-degradable and lacks functionality on the backbone. Herein, we introduce concomitantly PEG backbone functionality and degradability via a one-step modification with 1,2,4-triazoline-3,5-diones (TAD) under green light. The TAD-PEG conjugates are degradable in aqueous medium under physiological conditions, with the rate of hydrolysis depending on pH and temperature. Subsequently, a PEG-lipid is modified with TAD-derivatives and successfully used for messenger RNA (mRNA) lipid nanoparticle (LNP) delivery, thereby improving mRNA transfection efficiency on multiple cell cultures in vitro. In vivo, in mice, mRNA LNP formulation exhibited a similar tissue distribution as common LNPs, with a slight decrease in transfection efficiency. Our findings pave the road towards the design of degradable, backbone-functionalized PEG for applications in nanomedicine and beyond.