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Polyunsaturated fatty acids (PUFAs) play an important role in the establishment and the maintenance of the skin barrier function. However, the impact of their derived lipid mediators remains unclear. Skin substitutes were engineered according to the self-assembly method with a culture medium supplemented with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA). We show that supplementation with ALA and LA decreased testosterone absorption through a tissue-engineered reconstructed skin model, thus indicating an improved skin barrier function following supplementation. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes. Indeed, the dual supplementation increased the levels of eicosapentaenoic acid (15-fold), docosapentaenoic acid (DPA) (3-fold), and LA (1.5-fold) in the epidermal phospholipids while it increased the levels of ALA (>20-fold), DPA (3-fold) and LA (1.5-fold) in the epidermal triglycerides. The bioactive lipid mediator profile of the skin substitutes, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols, was next analyzed using liquid chromatography-tandem mass spectrometry. The lipid supplementation further modulated bioactive lipid mediator levels of the reconstructed skin substitutes, leading to a lipid mediator profile more representative of the one found in normal human skin. These findings show that an optimized supply of PUFAs via culture media is essential for the establishment of improved barrier function in vitro. Statement of significance : Supplementation of the culture medium with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA) improved the skin barrier function of a tissue-engineered skin model. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes and further modulated bioactive lipid mediator levels, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols. These findings highlight the important role of ALA and LA in skin homeostasis and show that an optimized supply of polyunsaturated fatty acids via culture media is essential for the establishment of improved barrier function in vitro.

Analizamos los efectos de la pandemia de covid-19 sobre las desigualdades sociales y las prácticas de convivialidad en la interacción entre el trabajo remunerado y el de cuidados no remunerado en la Ciudad de México. A partir de una encuesta estratificada original y cuatro grupos focales, estudiamos las diferencias de estos efectos entre hombres y mujeres, y también entre mujeres con características distintas. Respecto al trabajo remunerado, mostramos que la precarización se profundizó: observamos las afectaciones más severas en las personas adultas mayores, las que laboraban en empresas grandes y medianas, y entre las mujeres que trabajaban por cuenta propia. Respecto al trabajo de cuidados no remunerado, las mujeres experimentaron una sobrecarga considerable. La contribución principal de esta investigación es que muestra que la pandemia profundizó las brechas entre grupos de mujeres en perjuicio de las desaventajadas que, en general, disponen de menos recursos para negociar dentro y fuera de los hogares.

Background Gut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex system of bioactive lipid mediators, has been reported to play a role in various physio-pathological processes such as inflammation, immune responses and energy metabolism. The eCBome and the gut microbiome (miBIome) are closely linked and form the eCBome - miBIome axis, which may be of special relevance to colitis. Methods Colitis was induced in conventionally raised (CR), antibiotic-treated (ABX) and germ-free (GF) mice with dinitrobenzene sulfonic acid (DNBS). Inflammation was assessed by Disease Activity Index (DAI) score, body weight change, colon weight-length ratio, myeloperoxidase (MPO) activity and cytokine gene expression. Colonic eCBome lipid mediator concentrations were measured by HPLC-MS /MS. Results GF mice showed increased levels of anti-inflammatory eCBome lipids (LEA, OEA, DHEA and 13- HODE-EA) in the healthy state and higher MPO activity. DNBS elicited reduced inflammation in GF mice, having lower colon weight/length ratios and lower expression levels of Il1b, Il6, Tnfa and neutrophil markers compared to one or both of the other DNBS-treated groups. Il10 expression was also lower and the levels of several N-acyl ethanolamines and 13-HODE-EA levels were higher in DNBS-treated GF mice than in CR and ABX mice. The levels of these eCBome lipids negatively correlated with measures of colitis and inflammation. Conclusions These results suggest that the depletion of the gut microbiota and subsequent differential development of the gut immune system in GF mice is followed by a compensatory effect on eCBome lipid mediators, which may explain, in part, the observed lower susceptibility of GF mice to develop DNBS-induced colitis.

Molecular multiplex assays (MPAs) for simultaneous detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza and respiratory syncytial virus (RSV) in a single RT-PCR reaction reduce time and increase efficiency to identify multiple pathogens with overlapping clinical presentation but different treatments or public health implications. Clinical performance of XpertXpress® SARS-CoV-2/Flu/RSV (Cepheid, GX), TaqPath™ COVID−19, FluA/B, RSV Combo kit (Thermo Fisher Scientific, TP), and PowerChek™ SARS-CoV-2/Influenza A&B/RSV Multiplex RT-PCR kit II (KogeneBiotech, PC) was compared to individual Standards of Care (SoC). Thirteen isolates of SARS-CoV-2, human seasonal influenza, and avian influenza served to assess limit of detection (LoD). Then, positive and negative residual nasopharyngeal specimens, collected under public health surveillance and pandemic response served for evaluation. Subsequently, comparison of effectiveness was assessed. The three MPAs confidently detect all lineages of SARS-CoV-2 and influenza viruses. MPA-LoDs vary from 1 to 2 Log10 differences from SoC depending on assay and strain. Clinical evaluation resulted in overall agreement between 97 and 100%, demonstrating a high accuracy to detect all targets. Existing differences in costs, testing burden and implementation constraints influence the choice in primary or community settings. TP, PC and GX, reliably detect SARS-CoV-2, influenza and RSV simultaneously, with reduced time-to-results and simplified workflows. MPAs have the potential to enhance diagnostics, surveillance system, and epidemic response to drive policy on prevention and control of viral respiratory infections.

Background. One of the central debates in health policy is related to the fragmentation of health systems. Fragmentation is perceived as a major obstacle to UHC. This article presents the results of a consultation to a group of actors of the Mexican policy arena on the origins and impacts of the fragmentation of the Mexican health system.Methods. We used a consultation to nine key actors to collect thoughts on the fragmentation of the Mexican health system. The group included national and local decision makers with experience in health care issues and researchers with background in health systems and/or public policies. The sessions were recorded, transcribed verbatim and analyzed thematically.Results. Participants defined the term ‘fragmentation’ as the separation of the various groups of the population based on characteristics which define their access to healthcare services. This is a core characteristic of health systems in Latin America. In general, those affiliated to social security institutions have a higher per capita expenditure than those without social security, which translate into differential health benefits. According to the actors in this consultation, fragmentation is the main structural problem of the Mexican health system. Actors agreed that the best way to end fragmentation is through the creation of a universal health system. De-fragmentation plans should include a research component to document the impacts of fragmentation, and design and test the instruments needed for the integration process.Conclusions. First, health system fragmentation in Mexico has created problems of equity since different population groups have unequal access to public resources and different health benefits. Second, Mexico needs to move beyond the fragmentation of its health system and guarantee, through its financial integration, access to the same package of health services to all its citizens. Third, de-fragmentation plans should include a research component to document the impacts of fragmentation, and design and test the instruments needed for the integration process. Fourth, de-fragmentation of health systems is not an easy task because there are vested interests that oppose its implementation. Political strategies to meet the resistance of these groups are an essential component of any de-fragmentation plan.

Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for detecting RNA modifications transcriptome wide, researchers have uncovered a diverse epitranscriptome that serves as an additional layer of gene regulation beyond simple RNA sequence. Here, we review the proteins that write, read, and erase these marks, with a particular focus on the most abundant internal modification, N 6-methyladenosine (m6A). We first describe the discovery of the key enzymes that deposit and remove m6A and other modifications and discuss how our understanding of these proteins has shaped our views of modification dynamics. We then review current models for the function of m6A reader proteins and how our knowledge of these proteins has evolved. Finally, we highlight important future directions for the field and discuss key questions that remain unanswered. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Human herpesviruses 6A and 6B are betaherpesviruses that can integrate their genomes into the telomeres of latently infected cells. Integration can also occur in germ cells, resulting in individuals who harbor the integrated virus in every cell of their body and can pass it on to their offspring. This condition is termed inherited chromosomally integrated HHV-6 (iciHHV-6) and affects about 1% of the human population. The integrated HHV-6A/B genome can reactivate in iciHHV-6 patients and in rare cases can also cause severe diseases including encephalitis and graft-versus-host disease. Until now, it has remained impossible to prevent virus reactivation or remove the integrated virus genome. Therefore, we developed a system that allows the removal of HHV-6A from the host telomeres using the CRISPR/Cas9 system. We used specific guide RNAs (gRNAs) targeting the direct repeat region at the ends of the viral genome to remove the virus from latently infected cells generated in vitro and iciHHV-6A patient cells. Fluorescence-activated cell sorting (FACS), quantitative PCR (qPCR), and fluorescence in situ hybridization (FISH) analyses revealed that the virus genome was efficiently excised and lost in most cells. Efficient excision was achieved with both constitutive and transient expression of Cas9. In addition, reverse transcription-qPCR (RT-qPCR) revealed that the virus genome did not reactivate upon excision. Taken together, our data show that our CRISPR/Cas9 approach allows efficient removal of the integrated virus genome from host telomeres.

Supplementary Data from Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer

Latin America has experienced a rise in noncommunicable diseases (NCDs) which is having repercussions on the structuring of healthcare delivery and social protection for vulnerable populations. We examined catastrophic (CHE) and excessive (EHE, impoverishing and/or catastrophic) health care expenditures in Mexican households with and without elderly members (≥65 years), by gender of head of the households, during 2000-2020. We analyzed pooled cross-sectional data for 380,509 households from eleven rounds of the National Household Income and Expenditure Survey. Male- and female-headed households (MHHs and FHHs) were matched using propensity scores to control for gender bias in systematic differences regarding care-seeking (demand for healthcare) preferences. Adjusted probabilities of positive health expenditures, CHE and EHE were estimated using probit and two-stage probit models, respectively. Quintiles of EHE by state among FHHs with elderly members were also mapped. CHE and EHE were greater among FHHs than among MHHs (4.7% vs 3.9% and 5.5% vs 4.6%), and greater in FHHs with elderly members (5.8% vs 4.9% and 6.9% vs 5.8%). EHE in FHHs with elderly members varied geographically from 3.9% to 9.1%, being greater in less developed eastern, north-central and southeastern states. Compared with MHHs, FHHs face greater risks of CHE and EHE. This vulnerability is exacerbated in FHHs with elderly members, because of gender intersectional vulnerability. The present context, marked by a growing burden of NCDs and inequities amplified by COVID-19, makes key interlinkages across multiple Sustainable Development Goals (SDGs) apparent, and calls for urgent measures that strengthen social protection in health.