Quantifying cell cycle regulation by tissue crowding.

The spatiotemporal coordination and regulation of cell proliferation is fundamental in many aspects of development and tissue maintenance. Cells have the ability to adapt their division rates in response to mechanical constraints, yet we do not fully understand how cell proliferation regulation impacts cell migration phenomena. Here, we present a minimal continuum model of cell migration with cell cycle dynamics, which includes density-dependent effects and hence can account for cell proliferation regulation. By combining minimal mathematical modeling, Bayesian inference, and recent experimental data, we quantify the impact of tissue crowding across different cell cycle stages in epithelial tissue expansion experiments. Our model suggests that cells sense local density and adapt cell cycle progression in response, during G1 and the combined S/G2/M phases, providing an explicit relationship between each cell-cycle-stage duration and local tissue density, which is consistent with several experimental observations. Finally, we compare our mathematical model's predictions to different experiments studying cell cycle regulation and present a quantitative analysis on the impact of density-dependent regulation on cell migration patterns. Our work presents a systematic approach for investigating and analyzing cell cycle data, providing mechanistic insights into how individual cells regulate proliferation, based on population-based experimental measurements.

Swarms of Enzyme-Powered Nanomotors Enhance the Diffusion of Macromolecules in Viscous Media.

Over the past decades, the development of nanoparticles (NPs) to increase the efficiency of clinical treatments has been subject of intense research. Yet, most NPs have been reported to possess low efficacy as their actuation is hindered by biological barriers. For instance, synovial fluid (SF) present in the joints is mainly composed of hyaluronic acid (HA). These viscous media pose a challenge for many applications in nanomedicine, as passive NPs tend to become trapped in complex networks, which reduces their ability to reach the target location. This problem can be addressed by using active NPs (nanomotors, NMs) that are self-propelled by enzymatic reactions, although the development of enzyme-powered NMs, capable of navigating these viscous environments, remains a considerable challenge. Here, the synergistic effects of two NMs troops, namely hyaluronidase NMs (HyaNMs, Troop 1) and urease NMs (UrNMs, Troop 2) are demonstrated. Troop 1 interacts with the SF by reducing its viscosity, thus allowing Troop 2 to swim more easily through the SF. Through their collective motion, Troop 2 increases the diffusion of macromolecules. These results pave the way for more widespread use of enzyme-powered NMs, e.g., for treating joint injuries and improving therapeutic effectiveness compared with traditional methods.

Sensitization to textile dyes in Spain: Epidemiological situation (2019-2022).

BACKGROUND: Current frequency and features for positivity to textile dye mix (TDM) in Spain are unknown. OBJECTIVES: To study the frequency, clinical features and simultaneous positivity between TDM, para-phenylenediamine (PPD) and specific disperse dyes. MATERIALS AND METHODS: We analysed all consecutive patients patch-tested with TDM from the Spanish Contact Dermatitis Registry (REIDAC), from 1 January 2019 to 31 December 2022. Within this group, we studied all selected patients patch-tested with a textile dye series. RESULTS: Out of 6128 patients analysed, 3.3% were positive to the TDM and in 34% of them, the sensitization was considered currently relevant. TDM positivity was associated with working as a hairdresser/beautician and scalp, neck/trunk and arm/forearm dermatitis. From TDM-positive patients, 57% were positive to PPD. One hundred and sixty-four patients were patch-tested with the textile dye series. Disperse Orange 3 was the most frequent positive dye (16%). One of every six cases positive to any dye from the textile dye series would have been missed if patch-tested with the TDM alone. CONCLUSIONS: Positivity to TDM is common in Spain and often associated with PPD sensitization. TDM is a valuable marker of disperse dyes allergy that should be part of the Spanish and European standard series.

2-Hydroxyethyl methacrylate (2-HEMA) sensitization, a global epidemic at its peak in Spain?

BACKGROUND: A global epidemic of allergic contact dermatitis to (meth)acrylates has been described in relation to the widespread use of manicure products. OBJECTIVES: To evaluate the frequency of sensitization to 2-hydroxyethyl methacrylate (2-HEMA) among consecutively patch tested patients with eczema in Spain; the percentage of current relevance; the MOAHLFA index; and, the potential sources of exposure to (meth)acrylates. METHODS: From January 2019 to December 2022, 2-HEMA 2% pet. was prospectively patch tested in 24 REIDAC (Spanish Allergic Contact Dermatitis Registry) centres. RESULTS: Six thousand one hundred thirty-four patients were consecutively patch tested with 2-HEMA 2% pet. 265/6134 (4.3%) were positive. Positive reactions of current relevance were identified to involve 184/265 (69%). The efficiency (number of patch tests needed to detect relevant positive patch test reactions) was 34 (6134/184). The variable 'occupational' was found to be significantly associated with a higher risk for relevant positive reactions to 2-HEMA (OR: 10.9; 95% CI: 8.1-14.9). CONCLUSION: (Meth)acrylate sensitization is a prevalent health issue in Spain. 2-HEMA 2% pet. has been identified to be a highly effective (meth)acrylate allergy marker in the GEIDAC baseline series. The responsible authorities should implement policies guaranteeing accurate labelling of industrial, medical, and consumer materials while ensuring the enforcement of said labelling through appropriate legal means.

Detecting reading difficulties in Spanish in older elementary students in the context of the Response to Intervention model.

Detecting students with reading difficulties (RD) is particularly important in the context of the Response to Intervention (RTI) model, in terms of both research and professional practice. However, there is no unanimous agreement on the best procedure to carry it out. In addition, most of the research in this field has been carried out in the English language, and there is little evidence on how these measures behave in other languages. This study focuses on identifying the best procedure for detecting RD in Spanish in older elementary students, comparing the validity, accuracy and goodness of fit of three different universal screening assessment approaches-the Psychometric Assessment Approach, the Curriculum-Based Assessment Approach and the Teacher Detection Approach-using RTI as a criterion to determine the goodness of fit of the different approaches. A total of 154 fifth-year primary students participated in this study. The results reveal that the multivariate inclusion of the evaluation approaches used is the best means of ensuring an efficient, valid assessment when attempting to identify RD among fifth graders. This finding has practical implications for the implementation of the RTI model in the field of RD.

Sensitization to isothiazolinones in the Spanish Contact Dermatitis Registry (REIDAC): 2019-2021 epidemiological situation.

BACKGROUND: Current frequency and risk factors for sensitization to methylisothiazolinone (MI), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in Spain are not well known. OBJECTIVES: To study the frequency of sensitization, risk factors and simultaneous sensitization between the four isothiazolinones. MATERIALS AND METHODS: We analysed all 2019-2021 consecutive patients patch-tested with MI (0.2% aq.), MCI/MI (0.02% aq.), BIT (0.1% pet.) and OIT (0.1% pet) within the Spanish Contact Dermatitis Registry (REIDAC). RESULTS: A total of 2511 patients were analysed. Frequencies of sensitization were: any isothiazolinone 15.7%, MI 6.8%, MCI/MI 4.8%, BIT 3.5% and OIT 0.5%. MI and MCI/MI sensitization was associated with being occupationally active, hand dermatitis, detergents and age over 40. BIT sensitization was associated with leg dermatitis and age over 40. About one in nine MI-positive patients were positive to BIT, whereas one in five BIT-positive patients were positive to MI. CONCLUSIONS: Sensitization to MI, MCI/MI and BIT is still common in Spain, while sensitization to OIT is rare. Currently, sensitization to MI and MCI/MI seems to be occupationally related. Although its origin is unknown, sensitization to BIT is more frequent in patients aged over 40 years. Simultaneous sensitization between MI and BIT is uncommon.

Particulate cartilage and platelet-rich plasma treatment for knee chondral defects in sheep.

PURPOSE: Articular cartilage is vulnerable to multiple types of damage and it has limited reparative and regenerative capacities due to its absence of vascularity. Although a large number of therapeutic strategies exist to treat chondral defects, they have some limitations, such as fibrocartilage formation. Therefore, the goal of the present study was to evaluate the chondrogenic regenerative properties of an autologous-made matrix of particulated cartilage and platelet-rich plasma (PACI + PRP) implantation for the treatment of full-thickness chondral defects in sheep. METHODS: A full-thickness 8 mm diameter cartilage defect was created in the weight-bearing area of the medial femoral condyle in both knees of 16 sheep. The right knees of all animals were treated with particulated autograft cartilage implantation and platelet-rich plasma, while the left knees were injected with Ringer's lactate solution or hyaluronic acid. The sheep were killed 9 or 18 months after surgery. Macroscopic evaluations were performed using three different scoring systems, and histopathological evaluations were performed using a modified scoring system based on different scoring systems. RESULTS: The PACI + PRP groups showed statistically significant differences in the percentage of defect repair and chondrocytes in the newly formed cartilage tissue at 18 months compared to 9 months. CONCLUSIONS: The results suggest that macroscopic appearance, histological structure and chondrocyte repair were improved when using PACI + PRP treatment for chondral defects, producing an outcome similar to the surrounding healthy cartilage. PACI + PRP is a totally autologous, easy, and unexpensive treatment that can be performed in one-step procedure and is useful as a therapeutic option for knee chondral defects.

Factors associated with suicidal ideation among medical students during the initial phase of the COVID-19 pandemic in Peru: A multicenter study.

We aimed to describe the prevalence and factors associated with suicidal ideation in a sample of 1238 medical students from different medical schools in Peru based on question 9 of the Patient Health Questionnaire (PHQ-9). Our results revealed that 17.9% of the participants had suicidal ideation. Furthermore, using logistic regression, we found that not practicing any religion, the presence of clinically significant depression, and the presence of clinically significant anxiety were statistically related to the presence of suicidal ideation. Our results indicate that suicidal ideation was highly prevalent in the sample of medical students studied.

Immunohistochemical Analysis of Knee Chondral Defect Repair after Autologous Particulated Cartilage and Platelet-Rich Plasma Treatment in Sheep.

This study performs an analysis that will enable the evaluation of the quality, durability, and structure of repaired cartilaginous extracellular matrix tissue using an autologous-based particulated autograft cartilage and platelet-rich plasma treatment (PACI + PRP). A single-blind controlled experiment was conducted on 28 sheep to evaluate the efficacy of the PACI + PRP treatment for cartilage defects. Full-thickness 8 mm diameter defects were created in the weight-bearing area of both knees. The right knees received PACI + PRP. The left knees were treated with Ringer's lactate solution (RLS) or hyaluronic acid (HA) injections. Sheep were euthanized at 9- or 18-months post-surgery. An extensive immunohistochemical analysis was performed to assess collagen types (I, II, III, V, VI, IX, X, XI) and aggrecan positivity. A semiquantitative scoring system provided a detailed evaluation of immunostaining. Collagens and aggrecan scores in the PACI + PRP groups were similar to healthy cartilage. Significant differences were found in collagens associated with matrix maturity (II and V), degradation (IX), structure and mechanics (VI), and hypertrophy (X) between healthy cartilage and RLS- or HA-repaired cartilage. The PACI + PRP treatment advanced the repair cartilage process in chondral defects with mature hyaline cartilage and enhanced the structural and mechanical qualities with better consistent cartilage, less susceptible to degradation and without hypertrophic formation over time.

Multivariate Prognostic Models for Patients with Stages I and Ii Colon Carcinoma: a Strobe-Compliant Retrospective Cohort Study.

Background: Colorectal cancer is the most frequent gastrointestinal malignancy worldwide. The value of adjuvant treatment is controversial in Stages I and II. Objective: The aim of this study was to construct post-operative prognostic models applicable to patients with stages I-II colon carcinoma (CC). Methods: This is a retrospective cohort study of patients with Stage I-II CC treated over a 25-year period. Exposure was defined as clinical, histopathological, and immunohistochemical factors (including CDX2 and MUC2 expression). Patients were randomly allocated to either a "modeling set" or a "validation set". Factors associated with recurrence, disease-free survival (DFS), and overall survival (OS) were defined in the "modeling set". Their performances were tested in the "validation set". Results: From a total of 556 recruited patients, 339 (61%) were allocated to the "modeling set" and 217 (39%) to the "validation set". Three models explaining recurrence, DFS, and OS were described. Tumor location in the left colon (Hazards ratio [HR] = 1.57; 95% Confidence interval [CI] 0.99-2.48), lymphocyte (HR = 0.46; 96% CI 0.27-0.88) and monocyte (HR = 0.99; 95% CI 0.99-1) counts, neutrophil/platelet ratio (HR = 1.3; 95% CI 0.74-2.3, and HR = 2.3; 95% CI 1.3-4.1; for second and third category, respectively), albumin/monocyte ratio (HR = 0.43; 95% CI 0.21-0.87), and microscopic residual disease after surgery (HR = 8.7; 95% CI 3.1-24) were independently associated with OS. T classification and expression of CDX2 and/or MUC2 were not independently associated with recurrence or prognosis. Conclusion: These models are simple and readily available, and distinguish the risk and prognosis in patients with CC stages I and II; these models require cheaper processes than the use of more sophisticated molecular biology techniques. They may guide either the need for adjuvant therapy versus post-operative surveillance only, as well as aid in the design of clinical trials.

The Detection of Resilience in Families Grieving Over a Suicide.

The study, conducted in 2021, describes the relationship between resilience development factors and dimensions and the grief processes of persons affected by the suicide of a family member. The objective was to analyze whether the loved ones of suicide victims had developed resilient behaviors and how these were manifested during the mourning process. To achieve this, two instruments were used: the Brief Resilience Coping Scale (BRCS), and in-depth interviews, in both cases applied to a sample of 21 individuals from whom narratives of their experiences were obtained as elements for analysis. These narratives were operationalized, coded and analyzed according to the theoretical framework advanced by the authors Edith Grotberg and Cecily Knight. The behaviors detected took the form, among others, of artistic expression and/or the provisioning of support services to people affected by suicide, generally through participation in associations and self-help groups dedicated to the care and facilitation of emotional expression resulting from the traumatic event.

LKB-1 Expression and High-Risk Histopathology are Independent Prognostic Factors for Patients with Oral Cavity Carcinoma.

BACKGROUND: The expression of liver kinase B1 (LKB-1) has been associated with prognosis in squamous cell carcinoma of the oral cavity (SCCOC). This study aimed to define the prognostic role of LKB-1 expression for patients with SCCOC and the suitability of its integration into a multivariate prognostic model. METHODS: A retrospective cohort study of patients with SCCOC was conducted in a cancer center. Expression of LKB-1 was evaluated by immunohistochemistry, and multivariate analysis defined prognostic factors associated with recurrence, recurrence-free survival (RFS), and overall survival (OS). The logistic regression model was used to construct a predictive computer software program. RESULTS: Of the 201 patients in this study, 104 (51.7%) experienced recurrence of their disease. Lower expression of LKB-1, high-risk histopathology, and advanced tumor-node-metastasis (TNM) stages were independent factors via multivariate analysis associated with the increased recurrence risk, poor RFS, and poor OS. If lack of LKB-1 expression is considered the reference category, the factors independently associated with recurrence were low (odds ratio [OR], 0.157; 95% confidence interval [CI], 0.044-0.557), intermediate (OR, 0.073; 95% CI, 0.017-0.319), and intense (OR, 0.047; 95% CI, 0.007-0.304) expression of LKB-1. This model permitted construction of a computer software program capable of prediction with receiver operating characteristic analysis (area under the curve, 0.925) and led to the definition of five prognostic groups with a biologic gradient. CONCLUSION: These results suggest that LKB-1 expression in patients with SCCOC is of robust prognostic value and complements the TNM staging system. The proposed model requires external validation in prospective observational studies.

Unmet Needs in the Management of Moderate-to-Severe Psoriasis in Spain: A Multidimensional Evaluation.

Psoriasis is a chronic, systemic inflammatory disease that affects the skin, with a high impact on patients' quality of life. The aim of this study was to identify and determine the relative importance of unmet needs in the management of moderate-to-severe psoriasis in Spain, from a multi-stakeholder perspective. A mixed method-approach was used to collect information, design a questionnaire and a discrete-choice exercise, and elicit the unmet needs through a multidisciplinary committee composed of 12 experts. A total of 65 unmet needs were identified and categorized into 4 areas: clinical, patient-related, decision-making process, and social. Decision-making process unmet needs were perceived as the most pressing ones, followed by social, clinical and patient-related. Individually, the need to incorporate outcomes that are important to the patients and to have treatments that achieve total clearance with a rapid onset of action and long-term persistence were the most important unmet needs.

Evolution of a structured cell population endowed with plasticity of traits under constraints on and between the traits.

Confronted with the biological problem of managing plasticity in cell populations, which is in particular responsible for transient and reversible drug resistance in cancer, we propose a rationale consisting of an integro-differential and a reaction-advection-diffusion equation, the properties of which are studied theoretically and numerically. By using a constructive finite volume method, we show the existence and uniqueness of a weak solution and illustrate by numerical approximations and their simulations the capacity of the model to exhibit divergence of traits. This feature may be theoretically interpreted as describing a physiological step towards multicellularity in animal evolution and, closer to present-day clinical challenges in oncology, as a possible representation of bet hedging in cancer cell populations.

Noise-driven bifurcations in a neural field system modelling networks of grid cells.

The activity generated by an ensemble of neurons is affected by various noise sources. It is a well-recognised challenge to understand the effects of noise on the stability of such networks. We demonstrate that the patterns of activity generated by networks of grid cells emerge from the instability of homogeneous activity for small levels of noise. This is carried out by analysing the robustness of network activity patterns with respect to noise in an upscaled noisy grid cell model in the form of a system of partial differential equations. Inhomogeneous network patterns are numerically understood as branches bifurcating from unstable homogeneous states for small noise levels. We show that there is a phase transition occurring as the level of noise decreases. Our numerical study also indicates the presence of hysteresis phenomena close to the precise critical noise value.

Psychometric properties of the Spanish version of the fear of COVID-19 scale in Peruvian medical students.

The Coronavirus Disease 2019 (COVID-19) pandemic continues to produce significant emotional consequences at the individual, community, societal, and global levels. This study describes the psychometric properties of the Spanish version of the Fear of COVID-19 Scale (FCV-19S) in Peruvian medical students. Data were collected by a convenience sampling method, resulting in a total of 1238 medical students from different medical schools in Peru. Our analyses suggest that a two-factor model explains the underlying two-dimensional structure of the FCV-19S. The results indicated that the Spanish version of the FCV-19S scale was found to have adequate psychometric properties.

Correction: Vidal et al. From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment. Int. J. Mol. Sci. 2021, 22, 6740.

In the original publication [...].

Role of Micronutrients and Gut Microbiota-Derived Metabolites in COVID-19 Recovery.

A balanced and varied diet provides diverse beneficial effects on health, such as adequate micronutrient availability and a gut microbiome in homeostasis. Besides their participation in biochemical processes as cofactors and coenzymes, vitamins and minerals have an immunoregulatory function; meanwhile, gut microbiota and its metabolites coordinate directly and indirectly the cell response through the interaction with the host receptors. Malnourishment is a crucial risk factor for several pathologies, and its involvement during the Coronavirus Disease 2019 pandemic has been reported. This pandemic has caused a significant decline in the worldwide population, especially those with chronic diseases, reduced physical activity, and elder age. Diet and gut microbiota composition are probable causes for this susceptibility, and its supplementation can play a role in reestablishing microbial homeostasis and improving immunity response against Coronavirus Disease 2019 infection and recovery. This study reviews the role of micronutrients and microbiomes in the risk of infection, the severity of disease, and the Coronavirus Disease 2019 sequelae.

Resiniferatoxin promotes adult worm expulsion in Trichinella spiralis-infected rats by Th2 immune response modulation.

BACKGROUND: The immune response during T spiralis infection is characterized by an increase in eosinophils and mast cells, as well as Th2 cytokine production, such as interleukin (IL)-4, IL-10 and IL-13, promoting T spiralis expulsion from the host. However, this response damages the host, favouring the parasite survival. In the search for new pharmacological strategies that protect against T spiralis infection, a recent study showed that treatment with resiniferatoxin (RTX) modulates the Th1 cytokines production, reducing muscle parasite burden. OBJECTIVE: To evaluate the effect of RTX treatment on the Th2 cytokines production, the number of eosinophils, mast cells and the intestinal expulsion of T spiralis. METHODS: Serum levels of IL-4, IL-10 and IL-13 were quantified by ELISA; the number of eosinophils, mast cells and the adult worms of T spiralis in the small intestine was quantified. RESULTS: RTX treatment increased serum levels of IL-4, IL-10 and IL-13, and it decreases intestinal eosinophilia, however, favours the mastocytosis, promoting T spiralis intestinal expulsion. CONCLUSIONS: These findings suggest that RTX is capable to modulate the Th2 immune response, promoting T spiralis expulsion, which contributes to the defence against T spiralis infection, placing the RTX as a potential immunomodulatory drug.

Identification of a novel differentially methylated region adjacent to ATG16L2 in lung cancer cells using methyl-CpG binding domain protein-enriched genome sequencing.

Lung cancer is the most common cancer worldwide. Epigenetic modifications like DNA methylation play fundamental roles in the dynamic process of lung cancer. The objective of this study was to use methyl-CpG binding domain protein-enriched genome sequencing (MBD-Seq) to identify novel and high-confidence DNA methylation in lung tumor. We first compared the whole-genome DNA methylation of three lung cancer cell lines, including A549, H1299, and SK-MES-1, against BEAS-2B, a lung/bronchial normal epithelial cell line. We then used pyrosequencing and OneStep qMethyl kit methods to verify the results in the cell line specimens. MBD-Seq identified 279, 8046, and 22 887 differentially methylated regions (DMRs), respectively, with 120 common DMRs among three comparison groups. Three DMRs were consistent with the MBD-Seq results by both pyrosequencing and OneStep qMethyl validations. Furthermore, OneStep qMethyl kit was also performed for functional validation of these three potential DMRs in sputum DNA from clinical participants. We successfully identified one new DMR adjacent to ATG16L2. The novel DMR might have an important function in lung carcinogenesis. Further validation of the finding in clinical specimens of lung cancer patients and functional analysis of this novel DMR in the development of lung cancer through transcriptional silencing of ATG16L2 are warranted.