LOXL2-mediated chromatin compaction is required to maintain the oncogenic properties of triple-negative breast cancer cells.

Oxidation of histone H3 at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase homolog 2 (LOXL2). This histone modification is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells and has been linked to the maintenance of compacted chromatin. However, the molecular mechanism underlying this maintenance is still unknown. Here, we show that LOXL2 interacts with RuvB-Like 1 (RUVBL1), RuvB-Like 2 (RUVBL2), Actin-like protein 6A (ACTL6A), and DNA methyltransferase 1associated protein 1 (DMAP1), a complex involved in the incorporation of the histone variant H2A.Z. Our experiments indicate that this interaction and the active form of RUVBL2 are required to maintain LOXL2-dependent chromatin compaction. Genome-wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions. In the absence of LOXL2 or RUVBL2, global levels of the heterochromatin histone mark H3K9me3 were strongly reduced, and the ATAC-seq signal in the H3K9me3 regions was increased. Finally, we observed that the interplay between these series of events is required to maintain H3K4ox-enriched heterochromatin regions, which in turn is key for maintaining the oncogenic properties of the TNBC cell line tested (MDA-MB-231).

Mediators of the association between maternal body mass index and breastfeeding duration in 3 international cohorts.

BACKGROUND: Maternal obesity has been associated with shorter breastfeeding duration, but little is known about mediating factors explaining this association. It is important to assess these relationships across diverse populations because breastfeeding is culturally patterned. OBJECTIVES: We investigated the association of prepregnancy maternal body mass index (BMI) with breastfeeding outcomes and potential mediators of this relationship in 3 culturally diverse international cohorts. METHODS: We analyzed 5120 singleton pregnancies from mother-child cohorts in Spain (INfancia y Medio Ambiente), Greece (Rhea), and the United States (Project Viva). Outcome variables were duration of any and exclusive breastfeeding. A priori hypothesized mediators in the association of maternal prepregnancy BMI with breastfeeding were birthweight (BW), maternal prenatal C-reactive protein (CRP), cesarean delivery, maternal dietary inflammatory index (DII) during pregnancy, gestational age at delivery, and gestational diabetes mellitus (GDM). We estimated the association between BMI and breastfeeding duration using linear regression adjusting for confounders. Mediation analysis estimated direct and indirect effects of maternal overweight/obesity on breastfeeding for each mediator. RESULTS: Women with overweight and obesity had shorter duration of any and exclusive breastfeeding compared with normal-weight women (any: overweight ß = -0.79 mo, 95% CI: -1.17, -0.40; obese ß = -1.75 mo 95% CI: -2.25, -1.25; exclusive: overweight ß = -0.30 mo, 95% CI: -0.42, -0.16; obese ß = -0.73 mo, 95% CI: -0.90, -0.55). Significant mediators (% change in effect estimate) of this association were higher CRP (exclusive: 5.12%), cesarean delivery (any: 6.54%; exclusive: 7.69%), and higher DII (any: 6.48%; exclusive: 7.69%). GDM, gestational age, and BW did not mediate the association of maternal weight status with breastfeeding. CONCLUSIONS: Higher prepregnancy BMI is associated with shorter duration of any and exclusive breastfeeding. Maternal dietary inflammation, systemic inflammation, and mode of delivery may be key modifiable mediators of this association. Identification of mediators provides potential targets for interventions to improve breastfeeding outcomes.

Serum levels of PCDDs, PCDFs and dl-PCBs in general population residing far and near from an urban waste treatment plant under construction in Gipuzkoa, Basque Country (Spain).

This research focused on investigating the basal serum concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in the general population residing in two urban-industrial zones near and far from an energy recovery plant under construction in Gipuzkoa, Basque Country (Spain). The study used a cross-sectional design and included 227 participants who were randomly selected from municipal censuses in both areas. The participants were stratified based on age (ranging from 18 to 70 years) and sex. Serum samples were collected from the participants and analysed following the established protocol to measure the concentrations of PCDD/Fs and dl-PCBs. The study used multiple linear regression models to assess the impact of various sociodemographic variables, lifestyle factors, reproductive history, and diet on the variability of the measured compounds in the participants' serum. The median total toxicity equivalent (TEQ) in serum, was 10.58 pg WHO-TEQ2005 g-1 lipid. Serum PCDD levels were lower in the population residing in the "far" zone than the "near" zone. Age was positively associated with both PCDD/F and dl-PCB levels, indicating that older participants had higher concentrations of these compounds in their serum. This finding might be attributed to cumulative exposure over time. In terms of sex differences, women exhibited lower levels of dl-PCBs compared to men. Among lifestyle factors, smokers showed lower levels of dl-PCBs compared to non-smokers. Furthermore, daily alcohol consumption was significantly associated with higher serum levels of these compounds, with daily drinkers showing higher levels than non-drinkers. Consumption of local poultry was associated with significantly higher serum levels and oil consumption with low levels of PCDD/Fs.

Prenatal Vitamin D Levels Influence Growth and Body Composition until 11 Years in Boys.

BACKGROUND: Gestational vitamin D levels may influence offspring growth and modulate adipogenesis. Findings from prospective studies are inconsistent, and few have evaluated the persistence of these associations into late childhood. OBJECTIVE: To examine the association between prenatal vitamin D levels and growth and adiposity in late childhood. METHODS: We included 2027 mother-child pairs from the INMA birth cohort. 25-hydroxyvitamin D3 (vitamin D3) levels were measured in serum at 13 weeks of pregnancy. Sex- and age-specific body mass index z-scores were calculated at 7 and 11 years, overweight was defined as z-score ≥ 85th percentile, and body fat mass was measured at 11 years. Z-score body mass index (zBMI) trajectories from birth to 11 years were identified using latent class growth analysis. RESULTS: The prevalence of vitamin D3 deficiency (<20 ng/mL) was 17.5%, and around 40% of the children had overweight at both ages. Associations between vitamin D levels and outcomes differed by sex. In boys, maternal vitamin D3 deficient status was associated with higher zBMI, higher fat mass percentage, higher odds of being overweight, and with an increased risk of belonging to lower birth size followed by accelerated BMI gain trajectory. In girls no associations were observed. CONCLUSION: Our results support a sex-specific programming effect of early pregnancy vitamin D3 levels on offspring body composition into late childhood observed in boys.

Methicillin-resistant and methicillin-sensitive Staphylococcus aureus in pork industry workers, Catalonia, Spain.

Background: Methicillin-resistant S. aureus (MRSA) especially ST398, is a zoonotic agent. This study aimed to determine the prevalence of methicillin-susceptible S. aureus (MSSA) and MRSA among workers in the pork production chain. Methods: 659 workers associated with 123 pig farms, livestock transporters, one pig slaughterhouse, pork transporters and 23 pork butcheries were studied for S. aureus recovery, and all isolates were characterized (antibiotic resistance, MLST and spa-typing). Results: The prevalence of S. aureus was 35.5%, 75.6% of isolates being MRSA. The prevalence of MRSA was 68.7% (149/217) among pig farm, 33.9% (19/56) livestock transporters, 2.9% (9/306) slaughterhouse, 0% in pork transporters (0/36) and butchery workers (0/44). Of the 234 S. aureus-positive workers, 100% (149/149) of pig farm workers, 82.6% (19/23) of livestock transporters, and 16.4% (9/55) of slaughterhouse workers carried MRSA isolates (p < 0.001). Of the workers who had contact with live swine, 61.8% (178/288) were S. aureus-positive, MRSA being detected in 96.1% of cases (p < 0.001). The most frequent lineage among MRSA were: ST398 (97.7%; 173/177) and ST1 (1.7%; 3/177); and among MSSA were ST30 (19.2%; 11/57) and ST5 (10.5%; 6/57). The most frequent spa-types among MRSA were t011 (93.8%, 166/177) and t1451 (2.25%, 4/177), and among MSSA: t084 (10.5%, 6/57) and t021 (7.0%, 4/57). All MRSA isolates showed resistance to tetracycline, 92.7% to clindamycin, 81.9% to erythromycin and 40.1% to cotrimoxazole. Conclusions: Pig industry workers having occupational contact with live animals present a high risk of colonization of MRSA, especially by MRSA-ST398. Prevention measures should be intensified in any employment sector involving live animals.

Characterization of PCDD/F and dl-PCB levels in air in Gipuzkoa (Basque Country, Spain).

This research examines the levels and trends of pollutants, specifically 17 congeners of PCDD/Fs and 12 dl-PCBs, in the air measured in the province of Gipuzkoa (Basque Country, Spain). The study used PCDD/Fs, dl-PCB, and the sum of dioxin-like compounds as separate response variables. A total of 113 air samples were collected and analyzed using the method described in the European Standard (EN-1948:2006) from two industrial areas. The results were analyzed using non-parametric test to assess the variability of these pollutants based on different factors (year, season and day of the week) and General Linear Models to assess the weight of each factor. The study found that the toxic equivalents (TEQs) for PCDD/Fs were 12.29 fg TEQm-3 and for dl-PCBs were 1.63 fg TEQm-3, which were in a similar range or lower than those observed in other national and international studies in industrial areas. The results showed temporal variations, with higher levels of PCDD/Fs in autumn-winter than in spring-summer and higher levels of PCDD/Fs and dl-PCBs during weekdays than on weekends. The industrial area where the energy recovery plant (ERP) will be located had higher levels of air pollutants due to the presence of two PCDD/Fs emitting industries nearby, as indicated by the Spanish Registry of Polluting Emission Sources. Both industrial areas showed similar profiles of PCDD/Fs and dl-PCBs, with the PCDD/F profiles dominated by OCDD, 1,2,3,4,6,7,8-HpCDD, and 1,2,3,4,6,7,8-HpCDF in terms of concentrations and 1,2,3,7,8-PeCDD, 2,3,4,7,8-PeCDF, and 2,3,7,8-TCDD in terms of TEQs. The dl-PCB profiles were dominated by PCB 118, PCB 105, and PCB 77 in terms of concentrations and PCB 126 in terms of TEQs. The findings of this study can serve as an indicator of the potential impact of ERP on the health of the resident population and the environment.

Exploration of thyroglobulin as a biomarker of iodine status in iodine-sufficient and mildly iodine-deficient pregnant women.

PURPOSE: Urinary iodine-to-creatinine ratio (UI/Creat) reflects recent iodine intake but has limitations for assessing habitual intake. Thyroglobulin (Tg) concentration, which increases with thyroid size, appears to be an indicator of longer-term iodine status in children and adults, however, less is known in pregnancy. This study investigated the determinants of serum-Tg in pregnancy and its use as an iodine-status biomarker in settings of iodine-sufficiency and mild-to-moderate deficiency. METHODS: Stored blood samples and existing data from pregnant women from the Netherlands-based Generation R (iodine-sufficient) and the Spain-based INMA (mildly-to-moderately iodine-deficient) cohorts were used. Serum-Tg and iodine status (as spot-urine UI/Creat) were measured at median 13 gestational weeks. Using regression models, maternal socio-demographics, diet and iodine-supplement use were investigated as determinants of serum-Tg, as well as the association between UI/Creat and serum-Tg. RESULTS: Median serum-Tg was 11.1 ng/ml in Generation R (n = 3548) and 11.5 ng/ml in INMA (n = 1168). When using 150 µg/g threshold for iodine deficiency, serum-Tg was higher in women with UI/Creat < 150 vs ≥ 150 µg/g (Generation R, 12.0 vs 10.4 ng/ml, P = 0.010; INMA, 12.8 vs 10.4 ng/ml, P < 0.001); after confounder adjustment, serum-Tg was still higher when UI/Creat < 150 µg/g (regression coefficients: Generation R, B = 0.111, P = 0.050; INMA, B = 0.157, P = 0.010). Iodine-supplement use and milk intake were negatively associated with serum-Tg, whereas smoking was positively associated. CONCLUSION: The association between iodine status and serum-Tg was stronger in the iodine-deficient cohort, than in the iodine-sufficient cohort. Serum-Tg might be a complementary (to UI/Creat) biomarker of iodine status in pregnancy but further evidence is needed.

Sedentary Behaviour and Telomere Length Shortening during Early Childhood: Evidence from the Multicentre Prospective INMA Cohort Study.

Sedentary behaviour (SB) may be related to telomere length (TL) attrition due to a possible pro-inflammatory effect. This study examined the association between parent-reported sedentary behaviour (SB) and leukocyte TL at the age of 4 and telomere tracking from 4 to 8 years. In the Spanish birth cohort Infancia y Medio Ambiente (INMA) project, we analysed data from children who attended follow-up visits at age 4 (n = 669) and 8 (n = 530). Multiple robust regression models were used to explore the associations between mean daily hours of SB (screen time, other sedentary activities, and total SB) at 4 years categorised into tertiles and TL at 4 years and difference in TL rank between age 4 and 8, respectively. At the age of 4, the results showed that children with the highest screen time (1.6-5.0 h/day) had a shorter TL of -3.9% (95% CI: -7.4, -0.4; p = 0.03) compared with children in the lowest tertile (0.0-1.0 h/day). Between 4 and 8 years, a higher screen time (highest tertile group vs. lowest tertile) was associated with a decrease in the LTL rank of -1.9% (95% CI: -3.8, -0.1; p = 0.03) from 4 to 8 years. Children exposed to a higher screen time at 4 years were more prone to have shorter TL at 4 and between 4 and 8 years of age. This study supports the potential negative effect of SB during childhood on cellular longevity.

Environmental Noise Exposure and Sleep Habits among Children in a Cohort from Northern Spain.

Environmental noise is considered the second most serious environmental risk factor in Europe. However, little evidence exists regarding its impact on health and sleep in children, and the results are inconclusive. In this study, we aim to analyse the effect of environmental noise exposure on 11-year-old children's sleep habits. Data were collected from 377 participants in the INMA-Gipuzkoa (INfancia y Medio Ambiente) cohort project using both parent-reported and actigraphic sleep measures. The results revealed that 60% of children have a day-evening-night environmental noise exposure (Lden) of above 55 dB, which is defined as a "high noise level". No differences in noise exposure were observed between different socioeconomic groups. However, no effect of environmental noise was found on sleep variables. The paper highlights the importance of studying how environmental noise may affect children's sleep.

Kinetics of immune responses elicited after three mRNA COVID-19 vaccine doses in predominantly antibody-deficient individuals.

Mass vaccination campaigns reduced COVID-19 incidence and severity. Here, we evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses. PAD patients were classified based on their immunodeficiency: unclassified primary antibody-deficiency (unPAD, n = 9), common variable immunodeficiency (CVID, n = 12), combined immunodeficiency (CID, n = 1), and thymoma with immunodeficiency (TID, n = 1). unPAD patients and healthy controls (HCs, n = 10) developed similar vaccine-induced humoral responses after two doses. However, CVID patients showed reduced binding and neutralizing titers compared to HCs. Of interest, these PAD groups showed lower levels of Spike-specific IFN-γ-producing cells. CVID individuals also presented diminished CD8+T cells. CID and TID patients developed cellular but not humoral responses. Although the third vaccine dose boosted humoral responses in most PAD patients, it had limited effect on expanding cellular immunity. Vaccine-induced immune responses in PAD individuals are heterogeneous, and should be immunomonitored to define a personalized therapeutic strategies.

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

Williams-Beuren syndrome (WBS) is a rare disorder that causes hyper-social behavior, intellectual disability, memory problems, and life-threatening overgrowth of the heart. Behavioral therapies can help improve the cognitive and social aspects of the syndrome and surgery is sometimes used to treat the effects on the heart, although often with limited success. However, there are currently no medications available to treat WBS. The endocannabinoid system ­ which consists of cannabis-like chemical messengers that bind to specific cannabinoid receptor proteins ­ has been shown to influence cognitive and social behaviors, as well as certain functions of the heart. This has led scientists to suspect that the endocannabinoid system may play a role in WBS, and drugs modifying this network of chemical messengers could help treat the rare condition. To investigate, Navarro-Romero, Galera-López et al. studied mice which had the same genetic deletion found in patients with WBS. Similar to humans, the male mice displayed hyper-social behaviors, had memory deficits and enlarged hearts. Navarro-Romero, Galera-López et al. found that these mutant mice also had differences in the function of the receptor protein cannabinoid type-1 (CB1). The genetically modified mice were then treated with an experimental drug called JZL184 that blocks the breakdown of endocannabinoids which bind to the CB1 receptor. This normalized the number and function of receptors in the brains of the WBS mice, and reduced their social and memory symptoms. The treatment also restored the animals' heart cells to a more normal size, improved the function of their heart tissue, and led to lower blood pressure. Further experiments revealed that the drug caused the mutant mice to activate many genes in their heart muscle cells to the same level as normal, healthy mice. These findings suggest that JZL184 or other drugs targeting the endocannabinoid system may help ease the symptoms associated with WBS. More studies are needed to test the drug's effectiveness in humans with this syndrome. Furthermore, the dramatic effect JZL184 has on the heart suggests that it might also help treat high blood pressure or conditions that cause the overgrowth of heart cells.

Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology.

Mutations in the GBA gene that encodes the lysosomal enzyme ß-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.

Prenatal exposure to mixtures of phthalates and phenols and body mass index and blood pressure in Spanish preadolescents.

BACKGROUND: Pregnant women are simultaneously exposed to several non-persistent endocrine-disrupting chemicals, which may influence the risk of childhood obesity and cardiovascular diseases later in life. Previous prospective studies have mostly examined single-chemical effects, with inconsistent findings. We assessed the association between prenatal exposure to phthalates and phenols, individually and as a mixture, and body mass index (BMI) and blood pressure (BP) in preadolescents. METHODS: We used data from the Spanish INMA birth cohort study (n = 1,015), where the 1st and 3rd- trimester maternal urinary concentrations of eight phthalate metabolites and six phenols were quantified. At 11 years of age, we calculated BMI z-scores and measured systolic and diastolic BP. We estimated individual chemical effects with linear mixed models and joint effects of the chemical mixture with hierarchical Bayesian kernel machine regression (BKMR). Analyses were stratified by sex and by puberty status. RESULTS: In single-exposure models, benzophenone-3 (BP3) was nonmonotonically associated with higher BMI z-score (e.g. Quartile (Q) 3: ß = 0.23 [95% CI = 0.03, 0.44] vs Q1) and higher diastolic BP (Q2: ß = 1.27 [0.00, 2.53] mmHg vs Q1). Methyl paraben (MEPA) was associated with lower systolic BP (Q4: ß = -1.67 [-3.31, -0.04] mmHg vs Q1). No consistent associations were observed for the other compounds. Results from the BKMR confirmed the single-exposure results and showed similar patterns of associations, with BP3 having the highest importance in the mixture models, especially among preadolescents who reached puberty status. No overall mixture effect was found, except for a tendency of higher BMI z-score and lower systolic BP in girls. CONCLUSIONS: Prenatal exposure to UV-filter BP3 may be associated with higher BMI and diastolic BP during preadolescence, but there is little evidence for an overall phthalate and phenol mixture effect.

Association of prenatal phthalate exposure with pubertal development in Spanish boys and girls.

BACKGROUND: Phthalates are widespread, anti-androgenic chemicals known to alter early development, with possible impact on puberty timing. AIM: To investigate the association of prenatal phthalate exposure with pubertal development in boys and girls. METHODS: Urinary metabolites of six different phthalate diesters (DEP, DiBP, DnBP, BBzP, DEHP, and DiNP) and non-phthalate plasticizer DINCH® were quantified in two urine samples collected during pregnancy from mothers participating in the INMA Spanish cohort study. Pubertal assessment of their children at age 7-10 years (409 boys, 379 girls) was conducted using the parent-reported Pubertal Development Scale. Modified Poisson and Weighted Quantile Sum (WQS) regression was employed to examine associations between prenatal phthalates and risk of puberty onset, adrenarche, and gonadarche. Effect modification by child weight status was explored by stratified analysis. RESULTS: Prenatal exposure to DEHP was associated with higher risk of puberty onset (relative risk [RR] = 1.32, 95% CI = 1.09-1.59 per each log-unit increase in concentrations) and gonadarche (RR = 1.23, 95% CI = 1.00-1.50) in boys and higher risk of adrenarche (RR = 1.25, 95% CI = 1.03-1.51) in girls at age 7-10 years. In boys, prenatal exposure to DEP, DnBP, and DEHP was also associated with higher risk of adrenarche or gonadarche (RRs = 1.49-1.80) in those with normal weight, and BBzP and DINCH® exposure with lower risk of adrenarche (RR = 0.49, 95% CI = 0.27-0.89 and RR = 0.47, 95% CI = 0.24-0.90, respectively) in those with overweight/obesity. In girls, DiBP, DnBP, and DINCH® were associated with slightly higher risk of gonadarche (RRs = 1.14-1.19) in those with overweight/obesity. In the WQS model, the phthalate mixture was not associated with puberty in boys or girls. CONCLUSION: Prenatal exposure to certain phthalates was associated with pubertal development at age 7-10 years, especially earlier puberty in boys with normal weight and girls with overweight/obesity. However, there was no evidence of effect of the phthalate mixture on advancing or delaying puberty in boys or girls.

Immune translational control by CPEB4 regulates intestinal inflammation resolution and colorectal cancer development.

Upon tissue injury, cytokine expression reprogramming transiently remodels the inflammatory immune microenvironment to activate repair processes and subsequently return to homeostasis. However, chronic inflammation induces permanent changes in cytokine production which exacerbate tissue damage and may even favor tumor development. Here, we address the contribution of post-transcriptional regulation, by the RNA-binding protein CPEB4, to intestinal immune homeostasis and its role in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) development. We found that intestinal damage induces CPEB4 expression in adaptive and innate immune cells, which is required for the translation of cytokine mRNA(s) such as the one encoding interleukin-22. Accordingly, CPEB4 is required for the development of gut-associated lymphoid tissues and to maintain intestinal immune homeostasis, mediating repair and remodeling after acute inflammatory tissue damage and promoting the resolution of intestinal inflammation. CPEB4 is chronically overexpressed in inflammatory cells in patients with IBD and in CRC, favoring tumor development.

Clinical and Epidemiological Characteristics of Streptococcus suis Infections in Catalonia, Spain.

Introduction: Streptococcus suis (S. suis) is a human zoonotic pathogen of occupational origin, with infection acquired through contact with live pigs or pig meat. Pig farming is one of Catalonia's biggest industries and as a result this region of Spain has one of the highest density pig populations per km2. The aim of our study was to describe the infections caused by S. suis occurring in that area over a 9-year period. Materials and Methods: A retrospective, multi-center study was carried out by searching records from 15 hospitals in Catalonia for the period between 2010 and 2019. Results: Over the study period altogether nine cases of S. suis infection were identified in five hospitals, with five of these cases occurring in the 2018-2019 period. The mean age of patients was 48 ± 8.9 years and all of them were males. Five patients (55.6%) worked in pig farms. The most frequent manifestation of infection was meningitis (5 cases; 55.6%) followed by septic arthritis (3 cases; 33.3%). None of the patients died at 30 days; nonetheless, 4 developed hearing loss as a long-term complication. Conclusion: The most commonly identified S. suis infection was meningitis. Over 50% of the episodes occurred in the last 2 years and have affected pig farm workers. Further surveillance is needed in order to know its prevalence.

Sea Bass Primary Cultures versus RTgill-W1 Cell Line: Influence of Cell Model on the Sensitivity to Nanoparticles.

Determination of acute toxicity to vertebrates in aquatic environments is mainly performed following OECD test guideline 203, requiring the use of a large number of fish and with mortality as endpoint. This test is also used to determine toxicity of nanomaterials in aquatic environments. Since a replacement method for animal testing in nanotoxicity studies is desirable, the feasibility of fish primary cultures or cell lines as a model for nanotoxicity screenings is investigated here. Dicentrarchus labrax primary cultures and RTgill-W1 cell line were exposed to several concentrations (0.1 to 200 ug/mL) of different nanoparticles (TiO2, polystyrene and silver), and cytotoxicity, metabolic activity and reactive oxygen species formation were investigated after 24 and 48 h of exposure. Protein corona as amount of protein bound, as well as the influence of surface modification (-COOH, -NH2), exposure media (Leibovitz's L15 or seawater), weathering and cell type were the experimental variables included to test their influence on the results of the assays. Data from all scenarios was split based on the significance each experimental variable had in the result of the cytotoxicity tests, in an exploratory approach that allows for better understanding of the determining factors affecting toxicity. Data shows that more variables significantly influenced the outcome of toxicity tests when the primary cultures were exposed to the different nanoparticles. Toxicity tests performed in RTgill-W1 were influenced only by exposure time and nanoparticle concentration. The whole data set was integrated in a biological response index to show the overall impact of nanoparticle exposures.

Episodic Vestibulocerebellar Ataxia Associated with a CACNA1G Missense Variant.

Episodic vestibulocerebellar ataxias are rare diseases, frequently linked to mutations in different ion channels. Our objective in this work was to describe a kindred with episodic vestibular dysfunction and ataxia, associated with a novel CACNA1G variant. Two individuals from successive generations developed episodes of transient dizziness, gait unsteadiness, a sensation of fall triggered by head movements, headache, and cheek numbness. These were suppressed by carbamazepine (CBZ) administration in the proband, although acetazolamide and topiramate worsened instability, and amitriptyline and flunarizine did not prevent headache spells. On examination, the horizontal head impulse test (HIT) yielded saccadic responses bilaterally and was accompanied by cerebellar signs. Two additional family members were asymptomatic, with normal neurological examinations. Reduced vestibulo-ocular reflex gain values, overt and covert saccades were shown by video-assisted HIT in affected subjects. Hearing acuity was normal. Whole-exome sequencing demonstrated the heterozygous CACNA1G missense variant c.6958G>T (p.Gly2320Cys) in symptomatic individuals. It was absent in 1 unaffected member (not tested in the other asymptomatic individual) and should be considered likely pathogenic. CACNA1G encodes for the pore-forming, α1G subunit of the T-type voltage-gated calcium channel (VGCC), in which currents are transient owing to fast inactivation, and tiny, due to small conductance. Mutations in CACNA1G cause generalized absence epilepsy and adult-onset, dominantly inherited, spinocerebellar ataxia type 42. In this kindred, the aforementioned CACNA1G variant segregated with disease, which was consistent with episodic vestibulocerebellar ataxia. CBZ proved successful in bout prevention and provided symptomatic benefit in the proband, probably as a result of interaction of this drug with VGCC. Further studies are needed to fully determine the vestibular and neurological manifestations of this form of episodic vestibulocerebellar ataxia. This novel disease variant could be designated episodic vestibulocerebellar ataxia type 10.

The role of liver steatosis as measured with transient elastography and transaminases on hard clinical outcomes in patients with COVID-19.

Liver injury has been widely described in patients with Coronavirus disease 2019 (COVID-19). We aimed to study the effect of liver biochemistry alterations, previous liver disease, and the value of liver elastography on hard clinical outcomes in COVID-19 patients. We conducted a single-center prospective observational study in 370 consecutive patients admitted for polymerase chain reaction (PCR)-confirmed COVID-19 pneumonia. Clinical and laboratory data were collected at baseline and liver parameters and clinical events recorded during follow-up. Transient elastography [with Controlled Attenuation Parameter (CAP) measurements] was performed at admission in 98 patients. All patients were followed up until day 28 or death. The two main outcomes of the study were 28-day mortality and the occurrence of the composite endpoint intensive care unit (ICU) admission and/or death. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at admission in 130 patients (35%) and 167 (45%) patients, respectively. Overall, 14.6% of patients presented the composite endpoint ICU and/or death. Neither ALT elevations, prior liver disease, liver stiffness nor liver steatosis (assessed with CAP) had any effect on outcomes. However, patients with abnormal baseline AST had a higher occurrence of the composite ICU/death (21% versus 9.5%, p = 0.002). Patients ⩾65 years and with an AST level > 50 U/ml at admission had a significantly higher risk of ICU and/or death than those with AST ⩽ 50 U/ml (50% versus 13.3%, p < 0.001). In conclusion, mild liver damage is prevalent in COVID-19 patients, but neither ALT elevation nor liver steatosis influenced hard clinical outcomes. Elevated baseline AST is a strong predictor of hard outcomes, especially in patients ⩾65 years.

Implications for First-Order Cosmological Phase Transitions from the Third LIGO-Virgo Observing Run.

We place constraints on the normalized energy density in gravitational waves from first-order strong phase transitions using data from Advanced LIGO and Virgo's first, second, and third observing runs. First, adopting a broken power law model, we place 95% confidence level upper limits simultaneously on the gravitational-wave energy density at 25 Hz from unresolved compact binary mergers, Ω_{CBC}<6.1×10^{-9}, and strong first-order phase transitions, Ω_{BPL}<4.4×10^{-9}. The inclusion of the former is necessary since we expect this astrophysical signal to be the foreground of any detected spectrum. We then consider two more complex phenomenological models, limiting at 25 Hz the gravitational-wave background due to bubble collisions to Ω_{pt}<5.0×10^{-9} and the background due to sound waves to Ω_{pt}<5.8×10^{-9} at 95% confidence level for phase transitions occurring at temperatures above 10^{8} GeV.