Molecular Insights of Cholestasis in MDR2 Knockout Murine Liver Organoids.

MDR3 (multidrug resistance 3) deficiency in humans (MDR2 in mice) causes progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 is a lethal disease characterized by an early onset of intrahepatic cholestasis progressing to liver cirrhosis, a preneoplastic condition, putting individuals at risk of hepatocellular carcinoma (HCC). Hepatocyte-like organoids from MDR2-deficient mice (MDR2KO) were used in this work to study the molecular alterations caused by the deficiency of this transporter. Proteomic analysis by mass spectrometry allowed characterization of 279 proteins that were differentially expressed in MDR2KO compared with wild-type organoids. Functional enrichment analysis indicated alterations in three main cellular functions: (1) interaction with the extracellular matrix, (2) remodeling intermediary metabolism, and (3) cell proliferation and differentiation. The affected cellular processes were validated by orthogonal molecular biology techniques. Our results point to molecular mechanisms associated with PFIC3 that may drive the progression to liver cirrhosis and HCC and suggest proteins and cellular processes that could be targeted for the development of early detection strategies for these severe liver diseases.

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.

Comparative study of the glistening between four intraocular lens models assessed by OCT and deep learning.

PURPOSE: To evaluate the glistening in 4 different models of intraocular lenses (IOLs) using optical coherence tomography (OCT) and deep learning (DL). SETTING: Centro Internacional de Oftalmología Avanzada (Madrid, Spain). DESIGN: Cross-sectional study. METHODS: 325 eyes were assessed for the presence and severity of glistening in 4 IOL models: ReSTOR+3 SN6AD1 (n = 41), SN60WF (n = 110), PanOptix TFNT (n = 128) and Vivity DFT015 (n = 46). The presence of glistening was analyzed using OCT, identifying the presence of hyperreflective foci (HRF) in the central area of the IOL. A manual and an original DL-based quantification algorithm designed for this purpose was applied. RESULTS: Glistening was detected in 22 (53.7%) ReSTOR SN6AD1, 44 (40%) SN60WF, 49 (38.3%) PanOptix TFNT, and 4 (8.7%) Vivity DFT015 IOLs, when any grade was considered. In the comparison of the different types of IOLs, global glistening measured as total HRF was 17.3 ± 25.9 for the ReSTOR+3; 9.3 ± 15.7 for the SN60WF; 6.9 ± 10.5 for the PanOptix; and 1.2 ± 2.6 for the Vivity ( P < .05). There was excellent agreement between manual and DL-based quantification (≥0.829). CONCLUSIONS: It is possible to quantify, classify and compare the glistening severity in different IOL models using OCT images in a simple and objective manner with a DL algorithm. In the comparative study, the Vivity presented the lowest severity of glistening.

A Virtual National Diversity Mentoring Initiative to Promote Inclusion in Emergency Medicine.

INTRODUCTION: Trainees underrepresented in medicine (URiM) face additional challenges seeking community in predominantly white academic spaces, as they juggle the effects of institutional, interpersonal, and internalized racism while undergoing medical training. To offer support and a space to share these unique experiences, mentorship for URiM trainees is essential. However, URiM trainees have limited access to mentorship from URiM faculty. To address this gap, we developed a national virtual mentoring program that paired URiM trainees interested in emergency medicine (EM) with experienced mentors. METHODS: We describe the implementation of a virtual Diversity Mentoring Initiative (DMI) geared toward supporting URiM trainees interested in EM. The program development involved 1) partnering of national EM organizations to obtain funding; (2) identifying a comprehensive platform to facilitate participant communication, artificial intelligence-enabled matching, and ongoing data collection; 3) focusing on targeted recruitment of URiM trainees; and (4) fostering regular leadership meeting cadence to customize the platform and optimize the mentorship experience. CONCLUSION: We found that by using a virtual platform, the DMI enhanced the efficiency of mentor-mentee pairing, tailored matches based on participants' interests and the bandwidth of mentors, and successfully established cross-institutional connections to support the mentorship needs of URiM trainees.

Neurocognitive Suicide and Homicide Markers in Patients with Schizophrenia Spectrum Disorders: A Systematic Review.

Suicide and homicide are considered important problems in public health. This study aims to identify the cognitive performance of suicidal and homicidal behaviors in people with schizophrenia spectrum disorders, as well as examining whether there are shared neuropsychological mechanisms. A systematic review of the recent literature was carried out from September 2012 to June 2022 using the Medline (via PubMed), Scopus, Embase, and Cochrane databases. Among the 870 studies initially identified, 23 were finally selected (15 related to suicidal behaviors and 8 to homicidal behaviors). The results evidenced a relationship between impairment of cognitive performance and homicidal behavior; meanwhile, for suicidal behaviors, no consistent results were found. High neuropsychological performance seems to act as a protective factor against violent behavior in people with schizophrenia spectrum disorders, but not against suicidal behavior; indeed, it can even act as a risk factor for suicidal behavior. To date, there is insufficient evidence that shared neurocognitive mechanisms exist. However, processing speed and visual memory seem to be affected in the presence of both behaviors.

Mapping early serum proteome signatures of liver regeneration in living donor liver transplant cases.

The liver is the only solid organ capable of regenerating itself to regain 100% of its mass and function after liver injury and/or partial hepatectomy (PH). This exceptional property represents a therapeutic opportunity for severe liver disease patients. However, liver regeneration (LR) might fail due to poorly understood causes. Here, we have investigated the regulation of liver proteome and phosphoproteome at a short time after PH (9 h), to depict a detailed mechanistic background of the early LR phase. Furthermore, we analyzed the dynamic changes of the serum proteome and metabolome of healthy living donor liver transplant (LDLT) donors at different time points after surgery. The molecular profiles from both analyses were then correlated. Insulin and FXR-FGF15/19 signaling were stimulated in mouse liver after PH, leading to the activation of the main intermediary kinases (AKT and ERK). Besides, inhibition of the hippo pathway led to an increased expression of its target genes and of one of its intermediary proteins (14-3-3 protein), contributing to cell proliferation. In association with these processes, metabolic reprogramming coupled to enhanced mitochondrial activity cope for the energy and biosynthetic requirements of LR. In human serum of LDLT donors, we identified 56 proteins and 13 metabolites statistically differential which recapitulate some of the main cellular processes orchestrating LR in its early phase. These results provide mechanisms and protein mediators of LR that might prove useful for the follow-up of the regenerative process in the liver after PH as well as preventing the occurrence of complications associated with liver resection.

Primary neonatal and pediatric ECMO transport: First experience in Spain.

INTRODUCTION: The organization of primary Extracorporeal membrane oxygenation (ECMO) transport is highly variable. METHODS: To present the experience of the first mobile pediatric ECMO program in Spain, we designed a prospective descriptive study of all primary neonatal and pediatric (0-16 years) ECMO transports carried out over 10 years. The main variables recorded include demographic information, patient background, clinical data, ECMO indications, adverse events, and main outcomes. RESULTS: 39 primary ECMO transports were carried out with a 66.7% survival to hospital discharge. The median age was 1.24 months[IQR: 0.09-96]. Cannulation was mostly peripheral venoarterial (33/39). The mean response time from the call from the sending center to the departure of the ECMO team was 4 h[2.2-8]. The median inotropic score at the time of cannulation was 70[17.2-206.5], with a median oxygenation index of 40.5[29-65]. In 10% of the cases, ECMO-CPR was performed. Adverse events occurred in 56.4%, mostly related to the means of transport (40% overall). On arrival at the ECMO center, 44% of the patients underwent interventions. The median PICU stay was 20.5 days[11-32]. 5 patients developed neurological sequels. Statistically significant differences between survivors and deceased patients were not found. CONCLUSIONS: A good survival rate, with a low prevalence of serious adverse events, suggests a clear benefit of primary ECMO transport when conventional therapeutic measures are exhausted and the patient is too unstable to undergo conventional transport. A nationwide primary ECMO-transport program must therefore be offered to all patients regardless of their location.

Work preferences and Animal Welfare Perception of Veterinary Medicine and Animal Science Students in Northeastern Mexico.

Veterinary medicine and animal science (VMAS) students coexist in asocial, geographic, and economic context that influences personal and career decisions. The goal of this study was to analyze students' perceptions of Animal Welfare (AW) and World Organization for Animal Health (OIE) topics by gender, religion, and stage of study at the school of veterinary medicine in the northeastern Mexican border area. Survey response rate was 60% of VMAS student enrollment, which was divided in basic, intermediate, and advanced academic levels. Student respondents reported animal production followed by animals for companionship and wildlife appreciation as their job placement expectations after graduation. Students in the basic training stage rated AW in general practice to be more important compared with those in intermediate and advanced training (p < 0.005). Compared with intermediate and advanced level students, students at the basic level considered bioethics, sustainable food production, and OIE animal welfare topics more important (p < 0.05). Regarding gender differences, compared with male students, their female counterparts rated AW more important, depending on areas of work practice and OIE topics (p < 0.05).

Ras-transfected human mammary tumour cells are resistant to photodynamic therapy by mechanisms related to cell adhesion.

AIMS: Photodynamic therapy (PDT) is a treatment modality for several cancers involving the administration of a tumour-localising photosensitiser (PS) and its subsequent activation by light, resulting in tumour damage. Ras oncogenes have been strongly associated with chemo- and radio-resistance. Based on the described roles of adhesion and cell morphology on drug resistance, we studied if the differences in shape, cell-extracellular matrix and cell-cell adhesion induced by Ras transfection, play a role in the resistance to PDT. MATERIALS AND METHODS: We employed the human normal breast HB4a cells transfected with H-RAS and a panel of five PSs. KEY FINDINGS: We found that resistance to PDT of the HB4a-Ras cells employing all the PSs, increased between 1.3 and 2.5-fold as compared to the parental cells. There was no correlation between resistance and intracellular PS levels or PS intracellular localisation. Even when Ras-transfected cells present lower adherence to the ECM proteins, this does not make them more sensitive to PDT or chemotherapy. On the contrary, a marked gain of resistance to PDT was observed in floating cells as compared to adhesive cells, accounting for the higher ability conferred by Ras to survive in conditions of decreased cell-extracellular matrix interactions. HB4a-Ras cells displayed disorganisation of actin fibres, mislocalised E-cadherin and vinculin and lower expression of E-cadherin and ß1-integrin as compared to HB4a cells. SIGNIFICANCE: Knowledge of the mechanisms of resistance to photodamage in Ras-overexpressing cells may lead to the optimization of the combination of PDT with other treatments.

Effectiveness of a Two-Year Multicomponent Intervention for the Treatment of Overweight and Obesity in Older People.

This study aimed to assess the effectiveness of a two-year intervention based on the Mediterranean diet for the treatment of overweight and obesity in a sample of 51 older people from the Mediterranean city of Alicante (Spain). We also examined the effects of the intervention on psychological well-being. The participants were randomly assigned to the experimental and control groups. The experimental group received group nutritional education sessions, an individualized dietary-nutritional treatment based on a Mediterranean diet, and a physical activity program; the control group received Mediterranean nutritional education in a written format. The experimental group showed a greater loss in weight (p = 0.017) and percentage of fat mass (p = 0.049), and a greater reduction in body mass index (BMI) (p = 0.014) and waist circumference (p = 0.010). Both groups improved their depression scores using the PHQ-9; however, no significant improvement was seen in adherence to the Mediterranean diet (PREDIMED) and anxiety level (GAD-7). These results suggest that a two-year intervention based on the Mediterranean diet allows an older population with overweight or obesity to achieve greater weight loss and a greater decrease in BMI, waist circumference, and fat mass percentage. In relation to psychological well-being, depression levels improved at the end of said intervention.

Self-Organizing Maps to Multidimensionally Characterize Physical Profiles in Older Adults.

The aim of this study is to automatically analyze, characterize and classify physical performance and body composition data of a cohort of Mexican community-dwelling older adults. Self-organizing maps (SOM) were used to identify similar profiles in 562 older adults living in Mexico City that participated in this study. Data regarding demographics, geriatric syndromes, comorbidities, physical performance, and body composition were obtained. The sample was divided by sex, and the multidimensional analysis included age, gait speed over height, grip strength over body mass index, one-legged stance, lean appendicular mass percentage, and fat percentage. Using the SOM neural network, seven profile types for older men and women were identified. This analysis provided maps depicting a set of clusters qualitatively characterizing groups of older adults that share similar profiles of body composition and physical performance. The SOM neural network proved to be a useful tool for analyzing multidimensional health care data and facilitating its interpretability. It provided a visual representation of the non-linear relationship between physical performance and body composition variables, as well as the identification of seven characteristic profiles in this cohort.

Reliability and Usability Analysis of an Embedded System Capable of Evaluating Balance in Elderly Populations Based on a Modified Wii Balance Board.

This paper analyzes the reliability and usability of a portable electronic instrument that measures balance and balance impairment in older adults. The center of pressure (CoP) metrics are measured with a modified Wii Balance Board (mWBB) platform. In the intra- and inter-rater testing, 16 and 43 volunteers (mean 75.66 and standard deviation (SD) of 7.86 years and 72.61 (SD 7.86) years, respectively) collaborated. Five volunteer raters (5.1 (SD 3.69) years of experience) answered the System Usability Scale (SUS). The most reliable CoP index in the intra-examiner tests was the 95% power frequency in the medial-lateral displacement of the CoP with closed-eyes. It had excellent reliability with an intraclass correlation coefficient ICC = 0.948 (C.I. 0.862-0.982) and a Pearson's correlation coefficient PCC = 0.966 (p < 0.001). The best index for the inter-rater reliability was the centroidal frequency in the anterior-posterior direction closed-eyes, which had an ICC (2,1) = 0.825. The mWBB also obtained a high usability score. These results support the mWBB as a reliable complementary tool for measuring balance in older adults. Additionally, it does not have the limitations of laboratory-grade systems and clinical screening instruments.

C apsicum fruits as functional ingredients with antimicrobial activity: an emphasis on mechanisms of action.

Capsicum spp. fruits (CFs) are a basic ingredient in the diet and have been used as active ingredients in the pharmaceutical, cosmetic, and food products, due to their antioxidant, anti-inflammatory, antiseptic, and antimicrobial properties. The antimicrobial activity is the most studied property due to its effectiveness against pathogenic species, however, few studies have focused on the mechanisms of action involved. Therefore, this review discusses the effects generated by the CFs compounds on the viability and metabolism of microorganisms, highlighting the mechanisms by which these compounds exert their antimicrobial effects. The information provided shows that CFs are mainly source of capsaicinoids and phenolic compounds responsible for the inhibition of bacteria, yeasts, and fungi, through an increase in the permeabilization of the membrane and cell wall. Also, these compounds show an antiviral effect associated with the inactivation of virus binding proteins, preventing their replication and infection. Despite this, there is still a lack of information about the mechanisms that regulate the interactions between CFs compounds and food-important-microorganisms. Therefore, future research should focus on new antimicrobial compounds from CFs for their subsequent use against novel infectious agents, mainly virus of importance in health such as SARS-CoV-2.

The Application of Ultrasound in Honey: Antioxidant Activity, Inhibitory Effect on α-amylase and α-glucosidase, and In Vitro Digestibility Assessment.

In the present study, the effects of ultrasound (10, 20, and 30 min) on the bioactive compounds, antioxidant capacity, enzymatic inhibition, and in vitro digestion of six honey extracts from the Oaxaca state, Mexico, were analyzed. Significant differences were found in each honey extract with respect to the ultrasonic treatment applied (p < 0.05). In the honey extract P-A1 treated with 20 min of ultrasound, the phenols reached a maximum concentration of 29.91 ± 1.56 mg EQ/100 g, and the flavonoids of 1.92 ± 0.01 mg EQ/100 g; in addition, an inhibition of α-amylase of 37.14 ± 0.09% was noted. There were also differences in the phases of intestinal and gastric digestion, presenting a decrease in phenols (3.92 ± 0.042 mg EQ/100 g), flavonoids (0.61 ± 0.17 mg EAG/100 mg), antioxidant capacity (8.89 ± 0.56 mg EAG/100 mg), and amylase inhibition (9.59 ± 1.38%). The results obtained from this study indicate that, in some honeys, the processing method could increase the concentration of bioactive compounds, the antioxidant capacity, and the enzymatic inhibition; however, when subjected to in vitro digestion, the properties of honey are modified. The results obtained could aid in the development of these compounds for use in traditional medicine as a natural source of bioactive compounds.

Patterns of Muscle-Related Risk Factors for Sarcopenia in Older Mexican Women.

Early detriment in the muscle mass quantity, quality, and functionality, determined by calf circumference (CC), phase angle (PA), gait time (GT), and grip strength (GSt), may be considered a risk factor for sarcopenia. Patterns derived from these parameters could timely identify an early stage of this disease. Thus, the present work aims to identify those patterns of muscle-related parameters and their association with sarcopenia in a cohort of older Mexican women with neural network analysis. Methods: Information from the functional decline patterns at the end of life, related factors, and associated costs study was used. A self-organizing map was used to analyze the information. A SOM is an unsupervised machine learning technique that projects input variables on a low-dimensional hexagonal grid that can be effectively utilized to visualize and explore properties of the data allowing to cluster individuals with similar age, GT, GSt, CC, and PA. An unadjusted logistic regression model assessed the probability of having sarcopenia given a particular cluster. Results: 250 women were evaluated. Mean age was 68.54 ± 5.99, sarcopenia was present in 31 (12.4%). Clusters 1 and 2 had similar GT, GSt, and CC values. Moreover, in cluster 1, women were older with higher PA values (p < 0.001). From cluster 3 upward, there is a trend of worse scores for every variable. Moreover, 100% of the participants in cluster 6 have sarcopenia (p < 0.001). Women in clusters 4 and 5 were 19.29 and 90 respectively, times more likely to develop sarcopenia than those from cluster 2 (p < 0.01). Conclusions: The joint use of age, GSt, GT, CC, and PA is strongly associated with the probability women have of presenting sarcopenia.

Mapping the Serum Proteome of COVID-19 Patients; Guidance for Severity Assessment.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whose outbreak in 2019 led to an ongoing pandemic with devastating consequences for the global economy and human health. According to the World Health Organization, COVID-19 has affected more than 481 million people worldwide, with 6 million confirmed deaths. The joint efforts of the scientific community have undoubtedly increased the pace of production of COVID-19 vaccines, but there is still so much uncharted ground to cover regarding the mechanisms of SARS-CoV-2 infection, replication and host response. These issues can be approached by proteomics with unprecedented capacity paving the way for the development of more efficient strategies for patient care. In this study, we present a deep proteome analysis that has been performed on a cohort of 72 COVID-19 patients aiming to identify serum proteins assessing the dynamics of the disease at different age ranges. A panel of 53 proteins that participate in several functions such as acute-phase response and inflammation, blood coagulation, cell adhesion, complement cascade, endocytosis, immune response, oxidative stress and tissue injury, have been correlated with patient severity, suggesting a molecular basis for their clinical stratification. Eighteen protein candidates were further validated by targeted proteomics in an independent cohort of 84 patients including a group of individuals that had satisfactorily resolved SARS-CoV-2 infection. Remarkably, all protein alterations were normalized 100 days after leaving the hospital, which further supports the reliability of the selected proteins as hallmarks of COVID-19 progression and grading. The optimized protein panel may prove its value for optimal severity assessment as well as in the follow up of COVID-19 patients.

Cordyceps mexicana sp. nov., parasitizing Paradirphia sp. moths: A new sister species of the Cordyceps militaris complex, distributed in central Mexican Quercus-Pinus mixed forests.

Cordyceps s.l. is a paraphyletic group of ascomycete fungi that exhibit multifunctional lifestyles, that is, as saprotrophs, endophytes, and pathogens of insects, spiders, fungi, and grasses. The family Cordycipitaceae includes macroscopically similar species that have been erroneously considered to be conspecific with Cordyceps militaris. In this study, we describe a new species within the C. militaris complex that is distributed in the Quercus-Pinus forests of central Mexico on the basis of its morphology, phylogenetic relationships, and life cycle. Phylogenetically, Cordyceps mexicana is a well-supported new sister species of the C. militaris complex. It is distinguished by the morphology of its conidiophore, host association, and geographic distribution. This species parasitizes pupae of Paradirphia sp. (Lepidoptera: Saturniidae: Hemileucinae) and might be macroscopically confused with C. militaris. Its stromata are large, can measure up to 10 cm in length, and the fertile part is always bright yellow. This species develops whitish mycelial cords that emerge from the stromata and grow toward the host. Microscopically, it develops asci with filiform ascospores disarticulating in part-spores. Its life cycle and geographic distribution are also discussed.

Does imbalance in chest X-ray datasets produce biased deep learning approaches for COVID-19 screening?

BACKGROUND: The health crisis resulting from the global COVID-19 pandemic highlighted more than ever the need for rapid, reliable and safe methods of diagnosis and monitoring of respiratory diseases. To study pulmonary involvement in detail, one of the most common resources is the use of different lung imaging modalities (like chest radiography) to explore the possible affected areas. METHODS: The study of patient characteristics like sex and age in pathologies of this type is crucial for gaining knowledge of the disease and for avoiding biases due to the clear scarcity of data when developing representative systems. In this work, we performed an analysis of these factors in chest X-ray images to identify biases. Specifically, 11 imbalance scenarios were defined with female and male COVID-19 patients present in different proportions for the sex analysis, and 6 scenarios where only one specific age range was used for training for the age factor. In each study, 3 different approaches for automatic COVID-19 screening were used: Normal vs COVID-19, Pneumonia vs COVID-19 and Non-COVID-19 vs COVID-19. The study was validated using two public chest X-ray datasets, allowing a reliable analysis to support the clinical decision-making process. RESULTS: The results for the sex-related analysis indicate this factor slightly affects the system in the Normal VS COVID-19 and Pneumonia VS COVID-19 approaches, although the identified differences are not relevant enough to worsen considerably the system. Regarding the age-related analysis, this factor was observed to be influencing the system in a more consistent way than the sex factor, as it was present in all considered scenarios. However, this worsening does not represent a major factor, as it is not of great magnitude. CONCLUSIONS: Multiple studies have been conducted in other fields in order to determine if certain patient characteristics such as sex or age influenced these deep learning systems. However, to the best of our knowledge, this study has not been done for COVID-19 despite the urgency and lack of COVID-19 chest x-ray images. The presented results evidenced that the proposed methodology and tested approaches allow a robust and reliable analysis to support the clinical decision-making process in this pandemic scenario.

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling.

The balance between laminin isoforms containing the α5 or the α4 chain in the endothelial basement membrane determines the site of leukocyte diapedesis under inflammatory conditions. Extracellular superoxide dismutase (SOD3) induces laminin α4 expression in tumor blood vessels, which is associated with enhanced intratumor T cell infiltration in primary human cancers. We show now that SOD3 overexpression in neoplastic and endothelial cells (ECs) reduces laminin α5 in tumor blood vessels. SOD3 represses the laminin α5 gene (LAMA5), but LAMA5 expression is not changed in SOD1-overexpressing cells. Transcriptomic analyses revealed SOD3 overexpression to change the transcription of 1682 genes in ECs, with the canonical and non-canonical NF-κB pathways as the major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as NF-κB-driven promoter activity in ECs stimulated with tumor necrosis factor (TNF)-α, an NF-κB signaling inducer. SOD3 inhibited the phosphorylation and degradation of IκBα (nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor alpha), an NF-κB inhibitor. Finally, TNF-α was found to be a transcriptional activator of LAMA5 but not of LAMA4; LAMA5 induction was prevented by SOD3. In conclusion, SOD3 is a major regulator of laminin balance in the basement membrane of tumor ECs, with potential implications for immune cell infiltration into tumors.

Physical capability in a rural birth cohort at the age of 52: association with early environmental, nutritional, and developmental factors.

INTRODUCTION: Midlife physical capability (PC) is associated with developmental factors in the populations of economically developed countries. As far as we know, there is no information for rural populations of low- and middle-income countries. The aim of the study was to investigate the influence of pre- and postnatal factors on midlife objective measures of PC in a 1966-67 birth cohort from a Mexican rural community. The hypothesis was that adverse developmental conditions are associated with low midlife PC. METHODS: In 1966-67, a birth cohort of all children from a poor Mexican rural community was assembled. Data on family socioeconomic status (SES), parental health and nutritional status, birth weight, postnatal growth and feeding patterns were registered. In 2018, out of the 336 cohort members, 118 were living in the community, and eighty-two of them underwent a comprehensive clinical evaluation. The evaluation included grip strength, gait velocity and chair-stand PC tests. In multivariable linear models, PC tests were the dependent variables, and prenatal, birth and postnatal factors were the independent variables. Adjustment for confounding was made with adult anthropometric, body composition, clinical and ageing status variables. RESULTS: Independent of adult health status and other ageing indicators, lower PC was associated with family organization and SES, parental nutritional status, birth weight, infant postnatal growth velocity, and weaning time. These results indicate that adverse family and environmental conditions that are prevalent in poor rural communities are associated with low midlife PC.