The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.

Cilia are important cellular organelles for signaling and motility and are constructed via intraflagellar transport (IFT). RabL2 is a small GTPase that localizes to the basal body of cilia via an interaction with the centriolar protein CEP19 before downstream association with the IFT machinery, which is followed by initiation of IFT. We reconstituted and purified RabL2 with CEP19 or IFT proteins to show that a reconstituted pentameric IFT complex containing IFT81/74 enhances the GTP hydrolysis rate of RabL2. The binding site on IFT81/74 that promotes GTP hydrolysis in RabL2 was mapped to a 70-amino-acid-long coiled-coil region of IFT81/74. We present structural models for RabL2-containing IFT complexes that we validate in vitro and in cellulo and demonstrate that Chlamydomonas IFT81/74 enhances GTP hydrolysis of human RabL2, suggesting an ancient evolutionarily conserved activity. Our results provide an architectural understanding of how RabL2 is incorporated into the IFT complex and a molecular rationale for why RabL2 dissociates from anterograde IFT trains soon after departure from the ciliary base.

Biochemically validated structural model of the 15-subunit intraflagellar transport complex IFT-B.

Cilia are ubiquitous eukaryotic organelles impotant for cellular motility, signaling, and sensory reception. Cilium formation requires intraflagellar transport of structural and signaling components and involves 22 different proteins organized into intraflagellar transport (IFT) complexes IFT-A and IFT-B that are transported by molecular motors. The IFT-B complex constitutes the backbone of polymeric IFT trains carrying cargo between the cilium and the cell body. Currently, high-resolution structures are only available for smaller IFT-B subcomplexes leaving > 50% structurally uncharacterized. Here, we used Alphafold to structurally model the 15-subunit IFT-B complex. The model was validated using cross-linking/mass-spectrometry data on reconstituted IFT-B complexes, X-ray scattering in solution, diffraction from crystals as well as site-directed mutagenesis and protein-binding assays. The IFT-B structure reveals an elongated and highly flexible complex consistent with cryo-electron tomographic reconstructions of IFT trains. The IFT-B complex organizes into IFT-B1 and IFT-B2 parts with binding sites for ciliary cargo and the inactive IFT dynein motor, respectively. Interestingly, our results are consistent with two different binding sites for IFT81/74 on IFT88/70/52/46 suggesting the possibility of different structural architectures for the IFT-B1 complex. Our data present a structural framework to understand IFT-B complex assembly, function, and ciliopathy variants.

Experimental structure based drug design (SBDD) applications for anti-leishmanial drugs: A paradigm shift?

Leishmaniasis is a group of neglected tropical diseases caused by at least 20 species of Leishmania protozoa, which are spread by the bite of infected sandflies. There are three main forms of the disease: cutaneous leishmaniasis (CL, the most common), visceral leishmaniasis (VL, also known as kala-azar, the most serious), and mucocutaneous leishmaniasis. One billion people live in areas endemic to leishmaniasis, with an annual estimation of 30,000 new cases of VL and more than 1 million of CL. New treatments for leishmaniasis are an urgent need, as the existing ones are inefficient, toxic, and/or expensive. We have revised the experimental structure-based drug design (SBDD) efforts applied to the discovery of new drugs against leishmaniasis. We have grouped the explored targets according to the metabolic pathways they belong to, and the key achieved advances are highlighted and evaluated. In most cases, SBDD studies follow high-throughput screening campaigns and are secondary to pharmacokinetic optimization, due to the majoritarian belief that there are few validated targets for SBDD in leishmaniasis. However, some SBDD strategies have significantly contributed to new drug candidates against leishmaniasis and a bigger number holds promise for future development.

Full-length 16S rRNA gene sequencing by PacBio improves taxonomic resolution in human microbiome samples.

BACKGROUND: Sequencing variable regions of the 16S rRNA gene (≃300 bp) with Illumina technology is commonly used to study the composition of human microbiota. Unfortunately, short reads are unable to differentiate between highly similar species. Considering that species from the same genus can be associated with health or disease it is important to identify them at the lowest possible taxonomic rank. Third-generation sequencing platforms such as PacBio SMRT, increase read lengths allowing to sequence the whole gene with the maximum taxonomic resolution. Despite its potential, full length 16S rRNA gene sequencing is not widely used yet. The aim of the current study was to compare the sequencing output and taxonomic annotation performance of the two approaches (Illumina short read sequencing and PacBio long read sequencing of 16S rRNA gene) in different human microbiome samples. DNA from saliva, oral biofilms (subgingival plaque) and faeces of 9 volunteers was isolated. Regions V3-V4 and V1-V9 were amplified and sequenced by Illumina Miseq and by PacBio Sequel II sequencers, respectively. RESULTS: With both platforms, a similar percentage of reads was assigned to the genus level (94.79% and 95.06% respectively) but with PacBio a higher proportion of reads were further assigned to the species level (55.23% vs 74.14%). Regarding overall bacterial composition, samples clustered by niche and not by sequencing platform. In addition, all genera with > 0.1% abundance were detected in both platforms for all types of samples. Although some genera such as Streptococcus tended to be observed at higher frequency in PacBio than in Illumina (20.14% vs 14.12% in saliva, 10.63% vs 6.59% in subgingival plaque biofilm samples) none of the differences were statistically significant when correcting for multiple testing. CONCLUSIONS: The results presented in the current manuscript suggest that samples sequenced using Illumina and PacBio are mostly comparable. Considering that PacBio reads were assigned at the species level with higher accuracy than Illumina, our data support the use of PacBio technology for future microbiome studies, although a higher cost is currently required to obtain an equivalent number of reads per sample.

Efficacy and safety of hydroxychloroquine for treatment of mild SARS-CoV-2 infection and prevention of COVID-19 severity in pregnant and postpartum women: A randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Pregnant women have an increased risk of severe COVID-19. Evaluation of drugs with a safety reproductive toxicity profile is a priority. At the beginning of the pandemic, hydroxychloroquine (HCQ) was recommended for COVID-19 treatment. MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted in eight teaching hospitals in Spain to evaluate the safety and efficacy of HCQ in reducing viral shedding and preventing COVID-19 progression. Pregnant and postpartum women with a positive SARS-CoV-2 PCR (with or without mild COVID-19 signs/symptoms) and a normal electrocardiogram were randomized to receive either HCQ orally (400 mg/day for 3 days and 200 mg/day for 11 days) or placebo. PCR and electrocardiogram were repeated at day 21 after treatment start. Enrollment was stopped before reaching the target sample due to low recruitment rate. Trial registration EudraCT #: 2020-001587-29, on April 2, 2020. CLINICAL TRIALS: gov # NCT04410562, registered on June 1, 2020. RESULTS: A total of 116 women (75 pregnant and 41 post-partum) were enrolled from May 2020 to June 2021. The proportion of women with a positive SARS-CoV-2 PCR at day 21 was lower in the HCQ group (21.8%, 12/55) than in the placebo group (31.6%, 18/57), although the difference was not statistically significant (P = 0.499). No differences were observed in COVID-19 progression, adverse events, median change in QTc, hospital admissions, preeclampsia or poor pregnancy and perinatal outcomes between groups. CONCLUSIONS: HCQ was found to be safe in pregnant and postpartum women with asymptomatic or mild SARS-CoV-2 infection. Although the prevalence of infection was decreased in the HCQ group, the statistical power was insufficient to confirm the potential beneficial effect of HCQ for COVID-19 treatment.

Politicizing Children's Play: A Community Photovoice Process to Transform a School Playground.

IMPORTANCE:  Contextual elements at school playgrounds compromise the right to play. An occupation-based social transformation project to foster occupational justice in play at a school playground was conducted. OBJECTIVE:  To better understand barriers to and facilitators of children's participation in occupations at the school playground to co-create actions that enable play.  Design: A participatory methodology-Photovoice-was used. The research consisted of four phases: involving the community in the research design, community-led data generation and analysis, discussion of findings to increase the community's awareness, and a community agenda for changing the playground. SETTING: Public primary school playground in northwest Spain. PARTICIPANTS: All children (n = 450, ages 3-12 yr), families (n = 12), and teachers (n = 15) participated. A thematic analysis of visual, textual, and oral material was conducted, including member checking.  Results: The study revealed several barriers to play, including the short recess duration, poor floor (surface) conditions, jail-like atmosphere, and violence. However, participants identified an ad hoc lending games system and playground murals advocating for children's rights as facilitators. These findings have direct implications for improving the play environment. CONCLUSIONS AND RELEVANCE:  Conflicting priorities between children's and adults' desires and needs for the playground were unveiled, displaying the relevance of invisible contexts (i.e., social or institutional contexts) in shaping play opportunities. A critical occupational stance combined with a participatory and playful methodology generated space to unveil these conflicting priorities, reconcile agendas, raise awareness, and propose collective actions to transform the playground. Plain-Language Summary: Playing is fundamental to children's development and inclusion. This study focused on making school playgrounds better places for kids to play. Researchers found that things such as short playtimes, bad playground conditions, and violence made it tough for kids to enjoy playing, but they also discovered some good things, such as a system for borrowing games and colorful murals promoting children' rights. These findings show that changing the playground's physical and social environment can make a big difference for kids. By listening to kids and working together, adults and children can create playgrounds where all kids can play meaningfully and safely. Occupational therapists can promote such processes.

Differential utility of various frailty diagnostic tools in non-geriatric hospital departments of several countries: A longitudinal study.

BACKGROUND: There is limited knowledge on the performance of different frailty scales in clinical settings. We sought to evaluate in non-geriatric hospital departments the feasibility, agreement and predictive ability for adverse events after 1 year follow-up of several frailty assessment tools. METHODS: Longitudinal study with 667 older adults recruited from five hospitals in three different countries (Spain, Italy and United Kingdom). Participants were older than 75 years attending the emergency room, cardiology and surgery departments. Frailty scales used were Frailty Phenotype (FP), FRAIL scale, Tilburg and Groningen Frailty Indicators, and Clinical Frailty Scale (CFS). Analyses included the prevalence of frailty, degree of agreement between tools, feasibility and prognostic value for hospital readmission, worsening of disability and mortality, by tool and setting. RESULTS: Emergency Room and cardiology were the settings with the highest frailty prevalence, varying by tool between 40.4% and 67.2%; elective surgery was the one with the lowest prevalence (between 13.2% and 38.2%). The tools showed a fair to moderate agreement. FP showed the lowest feasibility, especially in urgent surgery (35.6%). FRAIL, CFS and FP predicted mortality and readmissions in several settings, but disability worsening only in cardiology. CONCLUSIONS: Frailty is a highly frequent condition in older people attending non-geriatric hospital departments. We recommend that based upon their current feasibility and predictive ability, the FRAIL scale, CFS and FP should be preferentially used in these settings. The low concordance among the tools and differences in prevalence reported and predictive ability suggest the existence of different subtypes of frailty.

Phase angle as a marker of outcome in hospitalized pediatric patients. A systematic review of the evidence (GRADE) with meta-analysis.

Phase angle (PhA) is a valuable tool for evaluating the nutritional and inflammatory status, which can accompany acute and severe disorders. PhA is a cellular health biomarker, whose value is particularly substantial due to the negative consequences of these situations in the pediatric population. Relevant literature was collected with the aim of comprehensively analysing the evidence on the association between an altered PhA can serve as a predictive-marker for mortality and poor-outcomes in at-risk-pediatric patients. Understanding this relationship could have significant implications for identifying high-risk individuals and implementing timely interventions. A systematic review with meta-analysis was conducted in the primary electronic databases from inception until January 2023. Overall, four studies with a total of 740 patients were eligible for our analysis. Evidence demonstrates that PhA is associated with nutritional status, reflecting undernutrition and changes in body composition related to illness. This review suggests that PhA can indeed be used as an indicator of nutritional status and a tool for predicting prognosis, including mortality and poor-outcomes, in hospitalized pediatric patients. A low PhA was associated with a significant mortality risk [RR:1.51;95%CI (1.22-1.88),p = 0.0002;I2 = 0%,(p = 0.99)] and an increased complications risk [OR:8.17;95%CI (2.44-27.4),p = 0.0007;I2 = 44%,(p = 0.18)]. These findings highlight the importance of taking a comprehensive approach to clinical nutrition, integrating multiple evaluation aspects to establish an accurate diagnosis and personalized therapeutic plans. While PhA emerges as a valuable tool for assessing the risk of malnutrition and as a prognostic-indicator for poor-outcomes in pediatric patients. Further future studies are needed to focus on investigating this relationship in larger and diverse population to strengthen the evidence base.

DKK1 drives immune suppressive phenotypes in intrahepatic cholangiocarcinoma and can be targeted with anti-DKK1 therapeutic DKN-01.

BACKGROUND AND AIMS: Dickkopf-1 (DKK1) is associated with poor prognosis in intrahepatic cholangiocarcinoma (iCCA), but the mechanisms behind this are unclear. Here, we show that DKK1 plays an immune regulatory role in vivo and inhibition reduces tumour growth. METHODS: Various in vivo GEMM mouse models and patient samples were utilized to assess the effects of tumour specific DKK1 overexpression in iCCA. DKK1-driven changes to the tumour immune microenvironment were characterized by immunostaining and gene expression analysis. DKK1 overexpressing and damage-induced models of iCCA were used to demonstrate the therapeutic efficacy of DKK1 inhibition in these contexts using the anti-DKK1 therapeutic, DKN-01. RESULTS: DKK1 overexpression in mouse models of iCCA drives an increase in chemokine and cytokine signalling, the recruitment of regulatory macrophages, and promotes the formation of a tolerogenic niche with higher numbers of regulatory T cells. We show a similar association of DKK1 with FOXP3 and regulatory T cells in patient tissue and gene expression data, demonstrating these effects are relevant to human iCCA. Finally, we demonstrate that inhibition of DKK1 with the monoclonal antibody mDKN-01 is effective at reducing tumour burden in two distinct mouse models of the disease. CONCLUSION: DKK1 promotes tumour immune evasion in iCCA through the recruitment of immune suppressive macrophages. Targeting DKK1 with a neutralizing antibody is effective at reducing tumour growth in vivo. As such, DKK1 targeted and immune modulatory therapies may be an effective strategy in iCCA patients with high DKK1 tumour expression or tolerogenic immune phenotypes.

Edible plant by-products as source of polyphenols: prebiotic effect and analytical methods.

Polyphenols with high chemical diversity are present in vegetables both in the edible parts and by-products. A large proportion of them remains unabsorbed along the gastrointestinal tract, being accumulated in the colon, where they are metabolized by the intestinal microbiota. These polyphenols have been found to have "prebiotic-like" effects. The edible plant industry generates tons of residues called by-products, which consist of unutilized plant tissues (peels, husks, calyxes and seeds). Their disposal requires special and costly treatments to avoid environmental complications. Reintroducing these by-products into the value chain using technological and biotechnological practices is highly appealing since many of them contain nutrients and bioactive compounds, such as polyphenols, with many health-promoting properties. Edible plant by-products as a source of polyphenols highlights the need for analytical methods. Analytical methods are becoming increasingly selective, sensitive and precise, but the great breakthrough lies in the pretreatment of the sample and in particular in the extraction methods. This review shows the importance of edible plant by-products as a source of polyphenols, due to their prebiotic effect, and to compile the most appropriate analytical methods for the determination of the total content of phenolic compounds as well as the detection and quantification of individual polyphenols.

Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease: A Survey-Based Study.

OBJECTIVE: To characterize Parkinson's disease (PD) symptoms based on the presence, onset time, and severity of rapid eye movement sleep behavior disorder (RBD) and their association with impulse control disorders (ICD). BACKGROUND: RBD is a frequent non-motor symptom in PD, usually described as prodromal. The severity of RBD according to the start time and its relationship with ICD in PD needs further clarification. METHODS: A survey-based study was performed to determine the presence of RBD symptoms, their severity, and the temporal relationship with the PD onset. The survey included RBD1Q, the Mayo Sleep, and the RBDQ-HK questionnaires and questions about clinical characteristics, including ICD. Only PD patients with care partners spending night hours in the same room were included. RESULTS: 410 PD patients were included: 206 with RBD (50.2%) and 204 non-RBD (49.8%). The PD-RBD patients were younger and their daily levodopa dose was higher than the non-RBD group. Most of these patients developed RBD symptoms after the onset of clinical PD were younger at motor symptom onset and had higher scores in the hallucinations and psychosis subsection of MDS-UPDRS-I. RBD group had a more severe non-motor phenotype, including more ICD than those without RBD, mainly due to higher compulsive eating. CONCLUSIONS: In our study, most patients recognized RBD symptoms after the onset of the PD motor symptoms and the clinical features of PD with and without RBD were distinctive, supporting the hypothesis that PD-RBD might represent a variant pattern of neurodegeneration.

"SARCOPENIA MEASURED BY ULTRASOUND IN HOSPITALIZED OLDER ADULTS" (ECOSARC): multi-centre, prospective observational study protocol.

BACKGROUND: Measurement of muscle mass and function, and thereafter, screening and diagnosis of sarcopenia, is a challenge and a need in hospitalized older adults. However, it is difficult in complex real-world old patients, because usually they are unable to collaborate with clinical, functional, and imaging testing. Ultrasound measurement of quadriceps rectus femoris (QRF) provides a non-invasive, real-time assessment of muscle quantity and quality, and is highly acceptable to participants with excellent inter-rater and intra-rater variability. However, normative data, protocol standardization, and association with longitudinal outcomes, needs further research and consensus. METHODS: Prospective exploratory multicenter study in older adults admitted to Acute Geriatric Units (AGUs) for medical reasons. 157 subjects from 7 AGUs of Spain were recruited between May 2019 and January 2022. Muscle ultrasound measurements of the anterior vastus of the QRF were acquired on admission and on discharge, using a previously validated protocol, using a Chieson model ECO2 ultrasound system (Chieson Medical Technologies, Co. Ltd, Wimxu District Wuxi, Jiangsu, China). Measurements included the cross-sectional area, muscle thickness in longitudinal view, intramuscular central tendon thickness, echogenicity, and the presence or absence of edema and fasciculations. Functional, nutritional, and DXA measurements were provided. Clinical follow-up was completed at discharge, and 30 and 90 days after discharge. Variations between hospital admission and discharge ultrasound values, and the relationship with clinical variables, will be analyzed using paired t-tests, Wilcoxon tests, or Mc Nemar chi-square tests when necessary. Prevalence of sarcopenia will be calculated, as well as sensitivity and specificity of ultrasound measurements to determine sarcopenia. Kappa analysis will be used to analyze the concordance between measurements, and sensitivity analysis will be conducted for each participating center. DISCUSSION: The results obtained will be of great interest to the scientific geriatric community to assess the utility and validity of ultrasound measurements for the detection and follow-up of sarcopenia in hospitalized older adults, and its association with adverse outcomes. TRIAL REGISTRATION: NCT05113758. Registration date: November 9th 2021. Retrospectively registered.

Biotechnological potential of microorganisms isolated from the salar del hombre muerto, Argentina.

Bacterial strains were isolated from soil and aqueous solution samples from the Salar del Hombre Muerto, Argentina. A total of 141 strains were characterized and the tolerance to sodium chloride was evaluated. We performed a screening to search for molecules of biotechnological interest: carotenoids (11%), emulsifiers (95%), and exopolysaccharides (6%), and to assess the production of enzymes, including proteolytic (39%), lipolytic (26%), hemolytic (50%), and catalase activities (99%); 25 bacterial strains were selected for further studies. Some of them produced biofilms, but only Bacillus sp. HA120b showed that ability in all the conditions assayed. Although 21 strains were able to form emulsions, the emulsifying index Kocuria sp. M9 and Bacillus sp. V3a cultures were greater than 50% and, emulsions were more stable when the bacteria grew in higher salt concentrations. Only pigmented Kocuria sp. M9 showed lipolytic activity on olive oil medium and was able to produce biofilms when cultured without and with 4 M of NaCl. Yellow pigments, lipase activity, and biosurfactant production were observed for Micrococcus sp. SX120. Summarizing, we found that the selected bacteria produced highly interesting molecules with diverse industrial applications and, many of them are functional in the presence of high salt concentrations.

Plasma rich in growth factors versus corticosteroid injections for management of chronic rotator cuff tendinopathy: a prospective double-blind randomized controlled trial with 1 year of follow-up.

BACKGROUND: Rotator cuff tendinopathy (RCT) is a painful and dysfunctional shoulder condition traditionally considered as a degenerative pathology. However, evidence is pointing to immunocompetent cells and activated stromal fibroblasts as the drivers of a nonresolved inflammatory condition in RCT. As potent anti-inflammatory agents, corticosteroid injections have been among the first-line and the most common therapeutic strategies. Recently, another adjuvant therapy to treat musculoskeletal inflammation-driven painful conditions, namely, platelet-rich plasma (PRP), has emerged as safe and effective. The aim of this study was to compare the clinical efficacy of intratendinous injections of plasma rich in growth factors (PRGF) with conventional intratendinous corticosteroid injections on patients with chronic RCT using patient-reported outcome measures. METHODS: A total of 39 patients received PRGF treatment (3 infiltrations, 1 every other week), whereas 40 patients, as a control group, received corticosteroid (3 infiltrations, 1 every other week). Patients were evaluated before treatment and at 3, 6, and 12 months of follow-up using the University of California Los Angeles (UCLA) scale, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), and Constant test. The primary outcome of the study was a 15% superior improvement of the PRGF group compared with the corticosteroid group in the UCLA scale and QuickDASH test at 6 months of follow-up, considering this difference to be clinically relevant. RESULTS: Both PRGF and corticosteroid groups showed significant clinical improvement in the 3 scores at all time points of the study compared with baseline. However, at 6 and 12 months of follow-up, the PRGF group had 22.1% and 21.2% superior improvement of the UCLA test, 14.3% and 13.5% for QuickDASH, and 16.4% and 20.2% for the Constant-Murley test, respectively, compared to the corticosteroid group. CONCLUSIONS: Three PRGF intratendinous injections every other week in patients with chronic rotator cuff tendinopathy show significantly superior and sustained pain-relieving and functional improvements compared with corticosteroid intratendinous injections assessed by 3 patient-reported outcome scales at 6 and 12 months of follow-up.

Genotype and Phenotype Influence the Personal Response to Prostaglandin Analogues and Beta-Blockers in Spanish Glaucoma and Ocular Hypertension Patients.

Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). The MD values presented significant differences between wildtype rs3766355 (-2 ± 2.2 dB), HT (-3.87 ± 4 dB), and HM carriers (-9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (-6.1 ± 8.67 dB), HT (-9.02 ± 8.63 dB), and HM carriers (-9.51 ± 7.44 dB) (p = 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.

Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study.

Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non-HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD.

Priming effects in soils across Europe.

Land use is a key factor driving changes in soil carbon (C) cycle and contents worldwide. The priming effect (PE)-CO2 emissions from changed soil organic matter decomposition in response to fresh C inputs-is one of the most unpredictable phenomena associated with C cycling and related nutrient mobilization. Yet, we know very little about the influence of land use on soil PE across contrasting environments. Here, we conducted a continental-scale study to (i) determine the PE induced by 13 C-glucose additions to 126 cropland and seminatural (forests and grasslands) soils from 22 European countries; (ii) compare PE magnitude in soils under various crop types (i.e., cereals, nonpermanent industrial crops, and orchards); and (iii) model the environmental factors influencing PE. On average, PEs were negative in seminatural (with values ranging between -60 and 26 µg C g-1 soil after 35 days of incubation; median = -11) and cropland (from -55 to 27 µC g-1 soil; median = -4.3) soils, meaning that microbial communities preferentially switched from soil organic C decomposition to glucose mineralization. PE was significantly less negative in croplands compared with seminatural ecosystems and not influenced by the crop type. PE was driven by soil basal respiration (reflecting microbial activity), microbial biomass C, and soil organic C, which were all higher in seminatural ecosystems compared with croplands. This cross European experimental and modeling study elucidated that PE intensity is dependent on land use and allowed to clarify the factors regulating this important C cycling process.

Selecting the best non-invasive matrix to measure mercury exposure in human biomonitoring surveys.

Exposure to mercury, even at low doses, can affect human health, well-being and life quality at a broad scale. Human biomonitoring is the most straightforward approach to measure and quantify mercury exposure in humans. The objective of the present study is to compare and discuss the relationships between Hg levels in the most used matrices, hair, urine and blood, with the aim to ascertain to what extent mercury exposure and internal mercury levels could be predicted by monitoring non-invasive matrices. The study population (n = 527) is a subsample from Spanish BIOAMBIENT. ES study (18-65 y, both sexes), with data of Hg levels in blood, hair, and urine from the same individuals. We found strong inter-matrix Spearman correlations between blood and hair mercury (r2 = 0.84), while the correlations for urine and blood mercury (r2=0.64) and urine and hair mercury (r2=0.65) were weaker. The geometric mean of the ratios between matrices were (GM, 95%CI): Hair/Blood 280 (271-290), Urine/Blood 0.174 (0.163-0.186) and Hair/Urine 2070 (1953-2194) and Urine/Blood 0.135 (0.128-0.144) for urine corrected by creatinine. High individual variation was observed particularly in those ratios involving urine. Considering the wide range of values observed in the ratios, we do not recommend applying them at individual level. The predictive models indicate that hair Hg was a more accurate predictor than urine. The inclusion of urine values did not increase the predictive accuracy, so, we recommend a cautious interpretation of urine mercury levels. Our study presents clear evidence that in a population highly exposed to food-borne mercury, a large portion of urinary mercury primarily emanates from methylmercury demethylation. We conclude that urine, as a non-invasive matrix, can be used as a reliable qualitative biomarker for Hg exposure when hair measurements not are available. For quantitative individual assessments, still blood measurements are to be preferred.

European interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for the analysis of bisphenol A, S and F in human urine: Results from the HBM4EU project.

The Human Biomonitoring for Europe initiative (HBM4EU) aims to study the exposure of citizens to chemicals and potentially associated health effects. One objective of this project has been to build a network of laboratories able to answer to the requirements of European human biomonitoring studies. Within the HBM4EU quality assurance and quality control scheme (QA/QC), a number of interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) were organized to ensure data consistency, comparability and reliability. Bisphenols are among the prioritized substance groups in HBM4EU, including bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) in human urine. In four rounds of ICI/EQUAS, two target concentration levels were considered, related to around P25 and P95 of the typical exposure distribution observed in the European general population. Special attention was paid to the conjugated phase II metabolites known to be most dominant in samples of environmentally exposed individuals, through the analysis of both native samples and samples fortified with glucuronide forms. For the low level, the average percentage of satisfactory results across the four rounds was 83% for BPA, 71% for BPS and 62% for BPF. For the high level, the percentages of satisfactory results increased to 93% for BPA, 89% for BPS and 86% for BPF. 24 out of 32 participating laboratories (75%) were approved for the analyses of BPA in the HBM4EU project according to the defined criterion of Z-scores for both low and high concentration levels in at least two ICI/EQUAS rounds. For BPS and BPF, the number of qualified laboratories was 18 out of 27 (67%) and 13 out of 28 (46%), respectively. These results demonstrate a strong analytical capability for BPA and BPS in Europe, while improvements may be needed for BPF.

Personal care product use and lifestyle affect phthalate and DINCH metabolite levels in teenagers and young adults.

Humans are widely exposed to phthalates and their novel substitutes, and considering the negative health effects associated with some phthalates, it is crucial to understand population levels and exposure determinants. This study is focused on 300 urine samples from teenagers (aged 12-17) and 300 from young adults (aged 18-37) living in Czechia collected in 2019 and 2020 to assess 17 plasticizer metabolites as biomarkers of exposure. We identified widespread phthalate exposure in the study population. The diethyl phthalate metabolite monoethyl phthalate (MEP) and three di (2-ethylhexyl) phthalate metabolites were detected in the urine of >99% of study participants. The highest median concentrations were found for metabolites of low-molecular-weight (LMW) phthalates: mono-n-butyl phthalate (MnBP), monoisobutyl phthalate (MiBP) and MEP (60.7; 52.6 and 17.6 µg/L in young adults). 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) metabolites were present in 68.2% of the samples with a median of 1.24 µg/L for both cohorts. Concentrations of MnBP and MiBP were similar to other European populations, but 5-6 times higher than in populations in North America. We also observed large variability in phthalate exposures within the study population, with 2-3 orders of magnitude differences in urinary metabolites between high and low exposed individuals. The concentrations varied with season, gender, age, and lifestyle factors. A relationship was found between high levels of MEP and high overall use of personal care products (PCPs). Cluster analysis suggested that phthalate exposures depend on season and multiple lifestyle factors, like time spent indoors and use of PCPs, which combine to lead to the observed widespread presence of phthalate metabolites in both study populations. Participants who spent more time indoors, particularly noticeably during colder months, had higher levels of high-molecular weight phthalate metabolites, whereas participants with higher PCP use, particularly women, tended to have higher concentration of LMW phthalate metabolites.