Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes.

Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA2, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKß-NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.

Dendritic cells (cross)dress for success.

The relevance of cross-dressing as an antigen presentation mechanism in antitumor responses is not fully understood. In this issue of Immunity, MacNabb et al. (2022) report that dendritic cells use cross-dressing as an effective mechanism to trigger CD8+ T cell antitumor immunity.

Epithelial colonization by gut dendritic cells promotes their functional diversification.

Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population composed of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Here, we show that the small intestine included two pools of cDC2s originating from common pre-DC precursors: (1) lamina propria (LP) CD103+CD11b+ cDC2s that were mature-like proinflammatory cells and (2) intraepithelial cDC2s that exhibited an immature-like phenotype as well as tolerogenic properties. These phenotypes resulted from the action of food-derived retinoic acid (ATRA), which enhanced actomyosin contractility and promoted LP cDC2 transmigration into the epithelium. There, cDC2s were imprinted by environmental cues, including ATRA itself and the mucus component Muc2. Hence, by reaching distinct subtissular niches, DCs can exist as immature and mature cells within the same tissue, revealing an additional mechanism of DC functional diversification.

Gut immune cells and intestinal niche imprinting.

The intestine comprises the largest proportion of immune cells in the body. It is continuously exposed to new antigens and immune stimuli from the diet, microbiota but also from intestinal pathogens. In this review, we describe the main populations of immune cells present along the intestine, both from the innate and adaptive immune system. We later discuss how intestinal niches significantly impact the phenotype and function of gut immune populations at steady state and upon infection.

Disorders of gut-brain interaction are common diagnoses among infants and toddlers in gastroenterology practices in Latin-America.

OBJECTIVES: To assess the relative frequency and associated factors of disorders of gut-brain interaction (DGBIs) in outpatient gastrointestinal (GI) clinics in young children of Latin America. METHODS: Cross-sectional study in 10 pediatric GI outpatient clinics (private and public) in five countries of Latin America (El Salvador, México, Colombia, Panamá, and Nicaragua). Parents of patients 1 month 4 years of age from outpatient clinics complete/d a diagnostic questionnaire for DGBIs per Rome IV criteria (QPGS-IV, Spanish version). We conducted descriptive analysis, two-sample t-tests and chi-square tests, univariate analyses, and logistic regression to evaluate risk factors. RESULTS: We collected data from 783 children. In total, 34.5% had a DGBI. Overall, functional constipation (FC) was the most common diagnosis (23.4%) in children of all ages (infants, 16.1%, 1-4-years-old, 32.7%). In infants, the second most common DGBI was regurgitation (6.6%) and in 1-4-years-old and cyclic vomiting syndrome (4.1%). The diagnosis of a DGBI was significantly associated with a family history of DGBIs (odds ratio [OR] 2.97, 95% confidence interval [CI] 1.61-5.57, p = 0.0001). Patients who identified as black (OR 2.25, 95% CI 1.28-3.92, p = 0.0021) or mixed race (OR 1.76, 95% CI 1.25-2.48, p = 0.0006) were also significantly associated with a higher likelihood of DGBIs. CONCLUSIONS: DGBIs are a common diagnosis in pediatric GI clinics of Latin America. Overall, FC was the most common DGBI.

Macropinocytosis and Cell Migration: Don't Drink and Drive .

Macropinocytosis is a nonspecific mechanism by which cells compulsively "drink" the surrounding extracellular fluids in order to feed themselves or sample the molecules therein, hence gaining information about their environment. This process is cell-intrinsically incompatible with the migration of many cells, implying that the two functions are antagonistic. The migrating cell uses a molecular switch to stop and explore its surrounding fluid by macropinocytosis, after which it employs the same molecular machinery to start migrating again to examine another location. This cycle of migration/macropinocytosis allows cells to explore tissues, and it is key to a range of physiological processes. Evidence of this evolutionarily conserved antagonism between the two processes can be found in several cell types-immune cells, for example, being particularly adept-and ancient organisms (e.g., the social amoeba Dictyostelium discoideum). How macropinocytosis and migration are negatively coupled is the subject of this chapter.

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

Initial Contraceptive Choices of Women Enrolled in a Cluster-Randomized Trial in Southwest Trifinio, Guatemala.

INTRODUCTION: The aim of this analysis is to present initial contraceptive choices of women offered postpartum contraception in rural Guatemala. METHODS: We trained community nurses participating in the delivery of a home-based antepartum and postpartum care program in rural Guatemala in contraceptive implant placement and had them offer condoms, pills, an injection, or an implant at women's home-based 40-day postpartum visit in intervention clusters of a non-blinded, cluster-randomized trial. Women who had already started postpartum contraception or were over the age of 35 were excluded from participation. The primary outcome of the trial was contraceptive use at 3 months postpartum, so this initial analysis describes immediate preferences in the population. RESULTS: Of 208 women enrolled in the study, 108 were in intervention clusters and 100 lived in control clusters. In the intervention group, 32 women declined contraception, 36 women received the injectable, 30 women had an implant placed, 5 women started pills, 2 women chose condoms, and data on 3 women were missing. In the control clusters, 43 women were planning on the injectable, 11 planned on the implant, 10 did not want to start a method, 5 planned on sterilization, 2 aimed for natural family planning, 2 wanted a copper IUD, 1 woman wanted condoms, 18 did not know, and data on 8 women were missing. DISCUSSION: The contraceptive implant, which was not previously available in this community, had high uptake at 27.8% in the intervention group. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04005391; Retrospectively Registered 7/2/2019, https://clinicaltrials.gov/ct2/show/NCT04005391 Protocol: https://doi.org/10.1186/s13063-019-3735-3.

Interpregnancy Interval in a Rural Guatemalan Population: Results from a Quality Improvement Database.

OBJECTIVE: This analysis describes the interpregnancy interval (time from livebirth to subsequent conception) in a convenience sample of women living in Southwest Guatemala and the association of antepartum characteristics and postpartum outcomes with a short interpregnancy interval (< 24 months). METHODS: This is an observational study of a convenience sample of women enrolled in the Madres Sanas community antenatal/postnatal nursing program supported by the Center for Human Development in Southwest Trifinio, Guatemala, between October 1, 2018 and October 1, 2019. We observed the distribution of interpregnancy intervals among the population of women with a reported date of last live birth, and used bivariate comparisons to compare women with a short interpregnancy interval (< 24 months) to those with an optimal interval ([Formula: see text] 24 months) by antepartum, obstetric and delivery, and postpartum outcomes. RESULTS: 171 parous women enrolled in the Madres Sanas program between October 1, 2018 and October 1, 2019, and reported the date of their last live birth. One hundred-forty-one (82.5%) women delivered and 130 of those women (92.2%) were seen for their 40-day postpartum visit. The mean interval was 37.1 months with a 22.1-month standard deviation. The median interval was 33.7 months with an interquartile range of 19.6-49.5 months. Among these women, 113 (66.1%) the interpregnancy interval was at least 24 months. The only covariate of all sociodemographic, obstetric and antepartum, delivery, and postpartum characteristics that differed between women who achieved an interval ([Formula: see text] 24 months) compared to those that did not (< 24 months), was age (median 22.9, interquartile range (IQR) [19.1,27.0] vs median 24.8, IQR [21.6,27.9], respectively, p = 0.006). A regression model found that with each increasing year of age, the interpregnancy interval increases by 1.08 months, p = 0.025. CONCLUSION: Among parous women, two-thirds of women space pregnancies at least 24 months. Older women were more likely to have a longer interval between live births.

Primary and secondary three-month outcomes of a cluster-randomized trial of home-based postpartum contraceptive delivery in southwest Trifinio, Guatemala.

DESIGN: This a cluster-randomized parallel arm pragmatic trial to observe the association of home-based postpartum contraceptive provision, including the contraceptive implant, with implant utilization rates at 3 months post-enrollment. METHODS: In a region of rural Guatemala referred to as the Southwest Trifinio, twelve communities are served by a community-based antenatal and postnatal care program. The communities were combined into eight clusters based on 2017 birth rates and randomized to receive the home-based contraceptive delivery (condoms, pills, injection, implant) during the routine 40-day postpartum visit. All participants receive comprehensive contraceptive counseling beginning at the first antenatal visit, so control clusters received this as part of routine care; this education preceded the study intervention. RESULTS: Once the 12 communities were combined into 8 clusters by expected birth volume and nurse team, which we expected to translate to eventual postpartum visits, the allocation sequence was generated in SAS. Of 208 women enrolled in the study, 108 were in four intervention and 100 in four control clusters. We used descriptive statistics to produce counts and percentages of characteristics of the study population overall and by intervention arm followed by univariate modeling using a mixed effects regression adjusted for cluster. Three-month contraceptive initiation rates were 56.0% in the control clusters compared to 76.8% in the intervention clusters, p < 0.001. Women in control clusters overwhelmingly opted for the injectable contraceptive (94.6%) while women in intervention clusters chose both the injection (61.5%) and the implant (33.7%), p < 0.001. Implant use by 3 months, the primary outcome of the study, was significantly higher in the intervention arm (25.9%) compared to the control arm (3.6%), p < 0.001, RR 1.3 CI [1.2, 1.4]. CONCLUSION: Our study was designed to respond to previously identified barriers to contraceptive uptake, and it was successful. Not only did it increase overall use of contraception by 3 months, but it shifted that contraceptive use away from short-acting methods in favor of longer-acting methods, with high continuation and satisfaction rates and no adverse outcomes reported. TRIAL REGISTRATION: clinicaltrials.gov , NCT04005391 ; Retrospectively Registered 7/2/2019.

[Pediatric acute liver failure]. / Falla hepática aguda en pediatría.

Acute liver failure (ALF) is a rare and life-threatening entity in pediatrics which requires a multidis ciplinary approach for early diagnosis and treatment. The objective of this article is to update defi nitions, management, and available treatments. We obtained the articles by reviewing the literature available between 2000 and 2020 in different databases (Pubmed, LILACS, BIREME, Google Scholar, and UpToDate), using terms such as "acute liver failure" in Pubmed, and in other databases "pedia tric acute liver failure" and "falla hepática aguda en pediatría" using filters such as age, publication date, and types of study (clinical trials, review articles, systematic reviews, and case-control studies). We chose those articles with the highest number of citations and with recent data. The ALF requires support in the pediatric intensive care unit and its early diagnosis favors the beginning of treatment. In pediatric patients with ALF, it is recommended to focus on age-specific diagnostic testing. There is no agreement regarding the liver transplantation in pediatric cases of ALF.

Personal networks, social media, and community cohesion in the strategies of peace-building agents in Colombia to counteract the segregation of displaced populations.

As part of the "Colombian Peace Process," victim assistance programs, actions for the reincorporation into civilian life of ex-combatants, and demobilized persons of the armed conflict have been developed as well as innovative instances of intervention in cases of posttraumatic stress. In this study, we surveyed 143 community leaders from the Department of Atlántico (Colombia), participants in a program for capacity building in rehabilitation and mediation strategies. With a mixed design in which we combine the analysis of personal networks, psychometric scales, and qualitative interviews, we describe the use that community mediators make of their personal skills, their personal network, and social media in their actions to confront social trauma and promote coexistence in the local community. The results show a significant relationship between the density of personal networks and the psychological sense of community. Paradoxically, the high social cohesion of the communities of people displaced by political violence seems to pose objective difficulties in reducing trauma. In the discussion, we indicate that the sociogeographic segregation derived from housing policies becomes an obstacle to the effective functioning of the coexistence and reintegration programs of victims and demobilized persons of the armed conflict. In this context, social media such as Facebook, Twitter, and WhatsApp are little used by community mediators in the development of their activities, which they perceive as reinforcing largely the dynamics of segregation of the displaced population.

Comparative Reduction of Egg Yolk Cholesterol Using Anionic Chelating Agents.

Egg yolk is used as an emulsifying agent. Nevertheless, its high concentration of cholesterol is linked to chronic degenerative diseases that cause cardiovascular disease. In this study, three methods for reducing the level of cholesterol in egg yolks were studied. The first method consisted of physical separation of the granules contained in the yolk (NaG). The second method applied was the use of anionic chelating biopolymers, such as arabic gum solution (AG) and mesquite gum solution (MG), and the third method was extraction with a solvent (SA). For this purpose, the cholesterol present in egg yolks, the microstructure, particle size, zeta potential, and its emulsifying capacity were determined. The amount of cholesterol removed was 97.24% using 1% mesquite gum (MG1%), and 93.26% using 1% Arabic gum (AG1%). The zeta potential was determined, and the isoelectric point (ζ = 0) of egg yolk was identified as pH 4.6. While, at this pH, the zeta potential of mesquite gum was -14.8 mV, the zeta potential for the arabic gum was -16 mV. The emulsifying capacity of MG1% was 62.95%, while the emulsifying capacity of AG1% was 63.57%. The complex obtained can be used in the development of functional foods reduced in cholesterol.

Which green way: description of the intervention for mobilising against Aedes aegypti under difficult security conditions in southern Mexico.

BACKGROUND: Community mobilisation for prevention requires engagement with and buy in from those communities. In the Mexico state of Guerrero, unprecedented social violence related to the narcotics trade has eroded most community structures. A recent randomised controlled trial in 90 coastal communities achieved sufficient mobilisation to reduce conventional vector density indicators, self-reported dengue illness and serologically proved dengue virus infection. METHODS: The Camino Verde intervention was a participatory research protocol promoting local discussion of baseline evidence and co-design of vector control solutions. Training of facilitators emphasised community authorship rather than trying to convince communities to do specific activities. Several discussion groups in each intervention community generated a loose and evolving prevention plan. Facilitators trained brigadistas, the first wave of whom received a small monthly stipend. Increasing numbers of volunteers joined the effort without pay. All communities opted to work with schoolchildren and for house-to-house visits by brigadístas. Children joined the neighbourhood vector control movements where security conditions permitted. After 6 months, a peer evaluation involved brigadista visits between intervention communities to review and to share progress. DISCUSSION: Although most communities had no active social institutions at the outset, local action planning using survey data provided a starting point for community authorship. Well-known in their own communities, brigadistas faced little security risk compared with the facilitators who visited the communities, or with governmental programmes. We believe the training focus on evidence-based dialogue and a plural community ownership through multiple design groups were key to success under challenging security conditions. TRIAL REGISTRATION: ISRCTN27581154 .

Experiential-sensorial adaptive system model for hospitality based on 360° VR videos and case-based reasoning.

In this work, an adaptive software architecture is proposed for the generation of experiences for hotel promotion and marketing, based on Case-based Reasoning (CBR) that uses the attributes and user characteristics and immersive 360° videos. Considering that immersion in virtual reality (VR) environments can trigger responses in various dimensions, such as affective, cognitive, attitudinal, and behavioral dimensions, these dimensions are evaluated in immersive environments with 360° videos. To validate the results obtained with the software architecture, a quasi-experimental study was conducted through the evaluation of the experience, consisting in the visualization of the environments of a boutique hotel, with a sample of a randomly selected group of young people. The contribution of this work lies in the use of 360° VR videos, for the visualization of the hotel characteristics and environments according the user profiles, to evaluate the affective, cognitive and attitudinal and behavioral responses and their influence on the booking intention and attitude. Finally, conclusions and recommendations for future work have been established.

Adaptive immunity to retroelements promotes barrier integrity.

Maintenance of tissue integrity is a requirement of host survival. This mandate is of prime importance at barrier sites that are constitutively exposed to the environment. Here, we show that exposure of the skin to non-inflammatory xenobiotics promotes tissue repair; more specifically, mild detergent exposure promotes the reactivation of defined retroelements leading to the induction of retroelement-specific CD8+ T cells. These T cell responses are Langerhans cell dependent and establish tissue residency within the skin. Upon injury, retroelement-specific CD8+ T cells significantly accelerate wound repair via IL-17A. Collectively, this work demonstrates that tonic environmental exposures and associated adaptive responses to retroelements can be coopted to preemptively set the tissue for maximal resilience to injury.

Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis.

Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncovered a dominant role for type 2 innate lymphoid cells (ILC2s) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2s by androgens leads to a reduction in dendritic cell accumulation and activation in males, along with reduced tissue immunity. Collectively, our results reveal a role for the androgen-ILC2-dendritic cell axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.

Predictors and clinical complications associated with antiphospholipid antibodies in sickle cell disease.

Although a higher prevalence of antiphospholipid autoantibodies (aPL) has been observed in some cohorts of sickle cell disease (SCD) patients, the clinical risk factors for the development of aPL and its associated complications remain unclear. In a retrospective study of 63 SCD patients, a lower hemoglobin concentration and higher white blood cell count were independently associated with an elevated aPL. SCD patients with elevated aPL had increased pregnancy complications (≥3 miscarriages, preterm delivery, pre-eclampsia) and venous thrombotic events. Our findings suggest that SCD may predispose to the generation of aPL and that aPL itself may contribute to the vasculopathy of SCD. Prospective testing for aPL is warranted in patients with SCD.

Inclusion4EU: Co-Designing a Framework for Inclusive Software Design and Development.

Digital technology is now pervasive, however, not all groups have uniformly benefitted from technological changes and some groups have been left behind or digitally excluded. Comprehensive data from the 2017 Current Population Survey shows that older people and persons with disabilities still lag behind in computer and internet access. Furthermore unique ethical, privacy and safety implications exist for the use of technology for older persons and people with disabilities and careful reflection is required to incorporate these aspects, which are not always part of a traditional software lifecycle. In this paper we present the Inclusion4EU project that aims to co-design a new framework, guidelines and checklists for inclusive software design and development with end-users from excluded categories, academics with expertise in human-computer interaction and industry practitioners from software engineering.

Perspectives of Obstetricians and Women with a History of Prior Cesarean Birth Regarding Subsequent Mode of Birth in Trifinio and Coatepeque, Guatemala.

BACKGROUND: The decision regarding delivery in the context of a prior cesarean birth is complex because both trial of labor after cesarean and elective repeat cesarean birth have risks and benefits. PURPOSE: Our research objective was to understand the perspective of women and obstetricians regarding factors influencing mode of birth for women with a history of prior cesarean. METHODS: In February 2020, qualitative data was collected at Coatepeque Hospital in Coatepeque, Guatemala. In-depth interviews were conducted with obstetricians and women at the Center for Human Development in the Southwest Trifinio region. Interviews were recorded, transcribed, translated, and analyzed using conceptual content analysis of key informant interviews to analyze the meaning of themes and concepts related to mode of delivery for women with a history of prior cesarean birth. RESULTS: Women described feeling conflicted about their preferences on the location and attendant of their future births, but suggested that the hospital setting, and physician providers were more capable of managing complications. Physicians felt trial of labor after cesarean was the safer option but described multiple reasons that made repeat cesarean birth the more common mode of birth. CONCLUSIONS: There is a need for innovative approaches to patient messaging and education around mode of delivery after a prior cesarean in the Southwest Region in Guatemala. Findings from this study underscore the need to improve the quality and dissemination of the educational information given, medical history collected during prenatal care, and pain control during labor. Finally, there is a need for obstetric training to support vaginal birth in the facility setting for the successful implementation of evidence-based practices around trial of labor after cesarean at Coatepeque Hospital.