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Human MD2 deficiency-an inborn error of immunity with pleiotropic features.
No full textBACKGROUND: Toll-like receptors (TLRs) are important pattern recognition receptors that sense microbes and control host defense. Myeloid differentiation protein 2 (MD2) is the indispensable coreceptor for TLR4, facilitating the binding to the gram-negative bacterial cell wall component LPS and activation of downstream signaling. OBJECTIVE: We sought to provide phenotypic and mechanistic insights into human MD2 deficiency. METHODS: To elucidate the genetic cause in a patient with very early onset inflammatory bowel disease, we performed whole-exome sequencing and studied the functional consequences of the identified mutation in LY96 (encoding for MD2) in genetically engineered induced pluripotent stem cell-derived macrophages with knockout of MD2 or knockin of the patient-specific mutation, including TLR4-mediated signaling, cytokine production, and bacterial handling. RESULTS: Whole-exome sequencing identified a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. Induced pluripotent stem cell-derived macrophages with knockout of MD2 or expression of the Thr116del mutation showed impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling as well as TLR4 endocytosis on challenge with LPS or bacteria. In addition, MD2-deficient macrophages showed decreased cytokine expression (eg, IL-6, TNF, and IL-10) in response to LPS or gram-negative but not gram-positive bacteria. CONCLUSIONS: Human MD2 deficiency causes defective TLR4 signaling in response to LPS or gram-negative bacteria. The clinical manifestations and expressivity might be variable due to unknown secondary risk factors. Because TLR4 represents a therapeutic target for multiple inflammatory conditions, our study may provide insights into potential side effects of pharmacological TLR4 targeting
Genome editing and protein energy malnutrition.
No full textProtein-energy malnutrition is a state of disordered catabolism resulting from metabolic derangements or starvation. It is associated with chronic disease, hypoglycemia, hypothermia, serious infections, and even an increased prevalence of morbidity and mortality in countries with poor socioeconomic or environmental factors. Adequate food administration is essential to satisfy the main caloric and nutritional demands of humans. The most significant factors seen in the development of protein-energy malnutrition in areas of high incidence, such as underdeveloped countries, are inadequate food and nutrient supplies. It has been well established that one of the strategies to alleviate undernourishment is the biofortification of staple crops. This is because vegetables and plants are significant sources of crucial nutrients for human growth and development. To enhance plant nutrition, recent tactics aim to formulated balanced and diverse diets with acceptable levels of vitamins and minerals that benefit human health. New advances in plant biotechnology and animal productivity could control key enzymes in several metabolic pathways, enriching important nutrients such as iron and vitamins and decreasing the content of disadvantageous compounds such as acrylamide-forming amino acids and phytic acids. Numerous biofortified crops such as rice, maize, and wheat have been created to resolve the problem of nutrition deficiencies. Some examples of these methodologies are genome editing engineered nucleases, transcriptional activator-like effector nucleases, zinc finger nucleases, and clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease which have been created and widely studied for their application, efficiency, and specificity
The UCSC genome browser database: 2023 update.
No full textThe UCSC Genome Browser (https://genome.ucsc.edu) is an omics data consolidator, graphical viewer, and general bioinformatics resource that continues to serve the community as it enters its 23rd year. This year has seen an emphasis in clinical data, with new tracks and an expanded Recommended Track Sets feature on hg38 as well as the addition of a single cell track group. SARS-CoV-2 continues to remain a focus, with regular annotation updates to the browser and continued curation of our phylogenetic sequence placing tool, hgPhyloPlace, whose tree has now reached over 12M sequences. Our GenArk resource has also grown, offering over 2500 hubs and a system for users to request any absent assemblies. We have expanded our bigBarChart display type and created new ways to visualize data via bigRmsk and dynseq display. Displaying custom annotations is now easier due to our chromAlias system which eliminates the requirement for renaming sequence names to the UCSC standard. Users involved in data generation may also be interested in our new tools and trackDb settings which facilitate the creation and display of their custom annotations
Root-induced fungal growth triggers macroaggregation in forest subsoils.
No full textSubsoils are characterized by low concentrations of organic carbon (OC). Nevertheless, they contain more than half of the global soil OC because of their large volume. This discrepancy suggests that subsoils might further sequester carbon (C), thus acting as potential sinks for atmospheric C. Plant roots and associated rhizodeposits are a major OC input source to subsoils. However, whether and how increased OC inputs via plant roots to subsoils affect soil C sequestration mechanisms remains unclear. Here we set up a pot experiment with European Beech (Fagus sylvatica L.) seedlings to investigate the effect of tree roots and associated rhizosphere development on soil aggregation and C allocation in topsoil vs. subsoil material collected from three forest sites of different parent materials. Over a 5-month growth period, the seedlings developed a dense root system transforming the whole soil volume into root-affected (i.e., rhizosphere) soil. We found that roots and the associated rhizosphere development increased the amount of macroaggregates in the two finest-textured subsoils. The most C-poor and fine-textured subsoil had a 15% increase in bulk OC concentration, indicating a potential for C sequestration in subsoils by enhanced macroaggregation. Across subsoils, rooting strongly enhanced microbial abundance and was especially correlated with fungal abundance and a shift in the fungal-to-bacterial- ratio. The strong fungal growth was likely the cause for the enhanced macroaggregation in these subsoils. In topsoils, however, rooting treatment decreased macroaggregate abundance, potentially through the disruption of preexisting aggregates, as indicated by the concomitant increase in microaggregates. Our study supports the growing awareness that OC dynamics may be governed by different mechanisms in top- and subsoils, respectively. It demonstrates that the enhanced addition of OM via plant roots to subsoils boosts fungal growth and thereby increases macroaggregate formation, potentially facilitating C sequestration by occlusion
EURADOS intercomparison on the usage of the ICRP/ICRU adult reference computational phantoms.
No full textThe European Radiation Dosimetry Group, EURADOS, has organised an intercomparison study on the usage of the ICRP/ICRU voxel reference computational phantoms together with radiation transport codes. Voluntary participants have been invited to solve specific tasks and provide solutions to the organisers before a certain deadline. The tasks to be solved are of practical interest in occupational, environmental and medical dosimetry. The aims of this training activity were to investigate if the phantoms have been correctly implemented in the radiation transport codes and to give the participants the opportunity to check their own calculations against quality-assured master solutions and improve their approach, if needed
Detrimental effects of microplastic exposure on normal and asthmatic pulmonary physiology.
No full textConcerns that airborne microplastics (MP) may be detrimental to human health are rising. However, research on the effects of MP on the respiratory system are limited. We tested the effect of MP exposure on both normal and asthmatic pulmonary physiology in mice. We show that MP exposure caused pulmonary inflammatory cell infiltration, bronchoalveolar macrophage aggregation, increased TNF-alpha level in bronchoalveolar lavage fluid (BALF), and increased plasma IgG1 production in normal mice. MP exposure also affected asthma symptoms by increasing mucus production and inflammatory cell infiltration with notable macrophage aggregation. Further, we found co-labeling of macrophage markers with MP incorporating fluorescence, which indicates phagocytosis of the MP by macrophages. A comparative transcriptomic analysis showed that MP exposure altered clusters of genes related to immune response, cellular stress response, and programmed cell death. A bioinformatics analysis further uncovered the molecular mechanism whereby MP stimulated production of tumor necrosis factor and immunoglobulins to activate a group of transmembrane B-cell antigens, leading to the modulation of cellular stress and programmed cell death in the asthma model. In summary, we show that MP exposure had detrimental effects on the respiratory system in both healthy and asthmatic mice, which calls for urgent discourse and action to mitigate environmental microplastic pollutants
Depressive symptoms mediate the longitudinal association between diabetes and subjective cognitive decline. Findings from a semirural multi-ethnic older population in Malaysia.
No full textThe potential role of psychological distress as the pathway linking diabetes and subjective cognitive decline (SCD) is still unclear. This study aims to investigate whether depressive symptoms mediate the relationship between diabetes and SCD in older adults. Baseline data from 3428 adults (55-94 years) of the South East Asia Community Observatory (SEACO), Malaysia were utilized. Subjective cognitive complaints (SCC) were recorded at baseline and five years later. Mediation analyses with non-parametric bootstrapping methods were employed. A proportion of 20% of participants without SCC at baseline reported a decline in SCC after 5 years of follow-up. Known diabetes (β = -0.13, SE = 0.05, p = 0.02) and depressive symptoms (ß = -0.18, SE = 0.05, p = 0.001) were independently associated with SCD. Previously diagnosed diabetes was associated with depressive symptoms at baseline (ß = 0.04, SE = 0.02, p = 0.01), and greater SCD at follow-up (β = -0.19, SE = 0.06, p = 0.001). Mediation analyses revealed that 9% of the association between diabetes and SCD was attributable to an indirect effect through depressive symptoms (ß = -0.01, 95% CI 0.02-0.001, p < 0.0001). This study provides further evidence of the detrimental effects of diabetes and depression on subjective cognitive decline. Our findings also suggest that depression is an important pathway linking previously diagnosed diabetes with subjective cognitive decline in older adulthood
Changes in sleep duration and sleep difficulties from adolescence to young adulthood and the risk of obesity: Bidirectional evidence in the GINIplus and LISA studies.
No full textOBJECTIVE: This study aimed to assess the association of changes in sleep behaviors from adolescence to young adulthood with the risk of overweight/obesity, and the reverse relationship. METHODS: Data of 1978 participants was obtained from the 15- and 20-year follow-ups of the GINIplus and LISA birth cohorts. Insufficient sleep was defined as reported sleep duration <8 h for adolescents, <7 h for adults, and sleep difficulties as reported having sleeping difficulties. Logistic regression models were used to assess bidirectional associations of changes in insufficient sleep and sleep difficulties with overweight/obesity. The polygenic risk scores (PRS) for body mass index (BMI) was tested in a sub-sample (n = 918). RESULTS: Compared with sufficient sleep in both adolescence and young adulthood, insufficient sleep only in young adulthood was associated with an increased risk of overweight/obesity (odds ratio = 1.85, 95%confidence interval = [1.27-2.69]). Compared with no sleep difficulties at both time-points, only persistent sleep difficulties was associated with a higher risk of overweight/obesity (2.15 [1.22-3.77]). The PRS for BMI was associated with overweight/obesity (1.41 [1.17-1.70]), but no significant gene-sleep interaction effect was observed. Reversely, only persistent overweight/obesity was associated with increased risks of insufficient sleep (1.81 [1.21-2.70]), and sleep difficulties (1.77 [1.18-2.66]), respectively. CONCLUSIONS: Insufficient sleep only presented a cross-sectional association with overweight/obesity in young adulthood, while long-term sleep difficulties from adolescence to young adulthood was associated with young adult overweight/obesity. Reversely, long-term overweight/obesity from adolescence to young adulthood was associated with insufficient sleep and sleep difficulties in young adulthood
Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients.
No full textAdrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking.This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options
2-year results with a sirolimus-eluting self-expanding stent for femoropopliteal lesions: The first-in-human ILLUMINA study.
No full textOBJECTIVES: The aim of the study was to assess 24-month efficacy and safety of a novel drug-eluting stent (DES) for femoropopliteal interventions with an innovative stent design and abluminal reservoir technology releasing the amphilimus formulation (sirolimus plus fatty acid) for efficient drug transfer and optimized release kinetics. BACKGROUND: DES releasing paclitaxel exhibited good patency rates after femoropopliteal interventions. No benefit has been reported when sirolimus or everolimus were used for antiproliferative stent coating. METHODS: Within a multicenter, first-in-man, single-arm study, 100 patients with symptomatic femoropopliteal disease (Rutherford category 2-4, mean lesion length 5.8 ± 3.9 cm, 35.0% total occlusions) were treated with the NiTiDES stent (Alvimedica). Two-year follow-up included assessment of primary patency (defined as absence of clinically driven target lesion revascularization or binary restenosis with a peak systolic velocity ratio >2.4 by duplex ultrasound), safety, functional, and clinical outcomes. RESULTS: At 24 months, Kaplan-Meier estimates of primary patency and freedom from clinically driven target lesion revascularization were 83.4% (95% CI: 73.9%-89.6%) and 93.1% (95% CI: 85.3%-96.9%), respectively. Over the study period, 3 deaths were reported with no major limb amputation. Functional and clinical benefits were sustained, as 82.1% of patients fell into Rutherford category 0 or 1 at 24 months, which was associated with preserved improvements in all walking disability questionnaire scores. CONCLUSIONS: The 2-year results of the ILLUMINA (Innovative siroLimus seLf expanding drUg-eluting stent for the treatMent of perIpheral disease: evaluation of safety aNd efficAcy) study demonstrate a sustained treatment benefit with a novel sirolimus-eluting stent that also compares favorably to other femoropopliteal intervention trials. Head-to-head comparisons of NiTiDES with a paclitaxel-based DES are warranted. (The ILLUMINA Study [ILLUMINA]; NCT03510676)