Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis.

Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease.

Precision Low-Cost Compact Micro-Displacement Sensors Based on a New Arrangement of Cascaded Levers with Flexural Joints.

Existing displacement sensors of micrometers to sub-micron precision are expensive and have various limitations. This paper reports the design and development of a new contact type compact micro-displacement sensor of sub-micron precision for a fraction of the cost of commercial devices. The basic concept of the new sensor system applies a mechanical magnifying mechanism to magnify a displacement at sub-micron to micron level and uses a low-cost Hall sensor to measure the magnified displacement. Various conceptual designs for the mechanical magnifying mechanism based on cascaded levers with flexural joints were studied and a final design, featuring side-by-side placement of lever structures in a multi-planar layout with adjacent levers coupled by L-shaped coupling foils, was devised. Prototypes of two different sizes and constructions with mechanical magnification ratios over 100 were made and tested. Measurement repeatability and accuracy to sub-micrometer level and a resolution down to hundredths of a micrometer were demonstrated by a compact Alpha Model prototype. Design modification of parts and a corresponding small lot size production procedure were devised to provide an estimated bill of material cost per unit under US$100.

Higher Levels of Early Childhood Caries (ECC) Is Associated with Developing Psychomotor Deficiency: The Cross- Sectional Bi-Township Analysis for The New Hypothesis.

The aim of this study was to reassess and confirm the relationship between early childhood caries (ECC) and manifestations of psychomotor deficiency in 4-6-yr-old kindergarteners, which has remained elusive to date. A cross-sectional study with bi-township analysis was designed whereby 353 kindergarteners, aged 4-6 whose caries were greater (dmft (decayed, missing and filled teeth, dmft index) = 5.25) than that of the national average, located in a rural township of central Taiwan were recruited using simple random-selection. Besides the personal, demographic, and dietary information, the measurements for caries and the amended comprehensive scales (CCDI) of children's psychomotor development were used to address their relationship. One-way ANOVA vs. multiple linear regression were employed to compare the differences of variables between age, gender, BMI (Body Mass Index), and dmft scores vs. relationships among all variables, respectively. The results confirmed that there was a positive relationship between severe ECC (dmft > 3~8) and psychomotor deficiency (i.e., expressive language and comprehension-concept scales, etc.) amongst the kindergarteners analyzed. Our cross-sectional bi-township analysis has confirmed that there is indeed an association between severe ECC and psychomotor deficiency in kindergarteners, and we suggest that this may arise through critical stages of growth, not only via personal language communications, but psycho-social engagements as well. Therefore, a new hypothesis is proposed.

Elimination profile of triamcinolone in urine following oral administration.

Triamcinolone (T) is a glucocorticoid commonly used to relieve inflammation and treat arthritis, severe allergies, and asthma; however, it is banned by the World Anti-Doping Agency in competition for athletes when administered orally, intravenously, intramuscularly, or rectally. The minimum required performance limit (MRPL) for urinary T is 30 ng/mL. However, the data about the urinary excretion of T after oral administration is limited. We investigate the elimination profile and determine whether single-dose administration of T would cause a positive doping result. Twelve healthy volunteers received a single-dose of 4-mg T rally, and urine samples were collected for 24 hours. A validated liquid chromatography-tandem mass spectrometry method was used to determine urinary T levels. Non-compartmental modeling was used to estimate the pharmacokinetic parameters. All the urinary T concentrations were much higher than the MRPL. The peak urinary T concentration was 3211.4 ± 860.3 ng/mL (mean ± SD), time to peak concentration was 1.7 ± 0.9 hours, and the estimated elimination half-life was 4.4 ± 2.8 hours. About 27.76% of the consumed dose was eliminated via urine within 24 hours of intake. After a single-dose oral administration, urinary T concentrations still exceeded the MRPL after 24 hours. This information could be useful for limiting the misuse of T. Athletes should be aware when using T in competition and acquire approval for a therapeutic use exemption prior to use. Moreover, the elimination profile of orally administered T may be crucial information for distinguishing different dosage routes.

Acute Garcinia mangostana (mangosteen) supplementation does not alleviate physical fatigue during exercise: a randomized, double-blind, placebo-controlled, crossover trial.

BACKGROUND: The purple mangosteen (Garcinia mangostana), known as the "queen of fruit," is widely consumed and unique not only because of its outstanding appearance and flavor but also its remarkable and diverse pharmacological effects. The aim of the present study is to evaluate the effect of acute mangosteen supplementation on physical fatigue during exercise. METHODS: A randomized, double-blind, placebo-controlled, crossover study was carried out by 12 healthy adults. The participants were randomly assigned to receive acute oral administration of either 250 mL of the mangosteen-based juice (supplementation treatment; 305 mg of α-mangostin and 278 mg of hydroxycitric acid) or a placebo (control treatment) 1 h before cycle ergometer exercise. Time to exhaustion, heart rate, Borg Rating of Perceived Exertion score, blood biochemical markers (namely ammonia, cortisol, creatine kinase, aspartate aminotransferase, alanine aminotransferase, glucose, and lactate), muscle dynamic stiffness, and Profile of Mood States (POMS) were evaluated and recorded. RESULTS: The results showed all parameters we examined were significantly altered by the exercise challenge, which demonstrated they directly reflected the condition of fatigue. However, there were no differences between the two treatments besides a positive impact on the POMS examination. CONCLUSIONS: The occurrence of physical fatigue depends on multiple underlying mechanisms. We concluded that acute mangosteen supplementation had no impact on alleviating physical fatigue during exercise.

Experience of Early Childhood Caries May Positively Correlate with Psychomotor Development.

PURPOSE: To examine the as yet unknown relationship between dental caries and the child's psychomotor development. MATERIALS AND METHODS: A cross-sectional study was designed by screening the kindergartens from urban areas of two cities in southern Taiwan. Besides the personal, demographic and dietary information, the common measures for caries (dmft) and the amended comprehensive scales (CCDI) for psychomotor development were used to assess their relationship(s). A power analysis showed that 334 subjects would be required. One-way ANOVA vs multiple linear regression analysis were used to compare the differences of variables between gender, age and dmft scales, vs the relationship among all variables tested, respectively. RESULTS: A total of 433 children completed the study. The results demonstrated that there was a positive relationship between higher (i.e. dmft≥4 and 5) but not lower or extremely high caries experience and aspects of psychomotor development (i.e. personal-social and expressive language) in children aged 4 to 6 years. CONCLUSION: The present results are important for paediatric dentists, as they suggest a positive correlation between caries experience (dmft 3 to 6) and psychomotor development in pre-school children and that such a correlation may occur more significantly as an attribute of the most affected teeth (incisors and molars) during the critical stage of personal-social and expressive language development (speech-communication).

Positive doping results caused by the single-dose local injection of triamcinolone acetonide.

Triamcinolone acetonide (TA) is classified as an S9 glucocorticoid in the 2014 Prohibited List published by the World Anti-Doping Agency, which caused it to be prohibited in-competition when administered orally, intravenously, intramuscularly or rectally. The Minimum Required Performance Level (MRPL) for the detection and identification of glucocorticoids is 30 ng/mL. Other common local injection routes, such as intraarticular, intratendinous, or intrabursal injection, are not prohibited. The purpose of this study was to analyze the TA and triamcinolone (T) concentrations in urine after a single injection of TA in patients to determine if it would produce a positive result. This study was performed on 40 patients with sports injuries or joint pains. TA was administered locally (doses varied from 12 to 80 mg). Samples were extracted using a solid-phase extraction column, followed by hydrolysis and liquid extraction using diethyl ether. The elution solvents were collected and dried. The dried residue was reconstituted and assayed by performing liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive ionization mode using electrospray ionization and multiple-reaction monitoring as the acquisition mode. The results demonstrated that the concentrations of both TA and T in urine exceeded the MRPL (30 ng/mL) after a single local injection. We obtained positive results for TA in 25 patients, and a positive result for T in one patient. Furthermore, the metabolic situation of TA, a long-acting glucocorticoid, was not an exact linear model. The highest concentrations of TA and T appeared 1-4h after injection. This information could be useful for limiting the misuse of TA by athletes. We suggest that athletes be aware when using TA injections during a competition period and obtain approval for therapeutic use exemption prior to using TA.