COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.

Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role but also via the oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis and shed light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations.

New variants expand the neurological phenotype of COQ7 deficiency.

The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.

SARS-CoV-2 infection in early first-trimester miscarriages: a prospective observational study.

RESEARCH QUESTION: Is there an association between SARS-CoV-2 infection and first-trimester miscarriage? DESIGN: This multicentre prospective study included a cohort of women with first-trimester miscarriages registered consecutively by seven Spanish hospitals where universal PCR screening for SARS-CoV-2 infection was implemented with both miscarriages and deliveries. The incidence of SARS-CoV-2 infection among women with first-trimester miscarriages was compared with the rate registered in women on admission to the delivery ward within the same time frame using a mixed-effects Poisson regression analysis, considering 'hospital' as random effect. The characteristics of SARS-CoV-2 positive and negative patients who miscarried were compared through two-sided univariable analyses. RESULTS: A total of 301 miscarriages were registered, 11 (3.7%) to SARS-CoV-2 infected and 290 to non-infected women. In the same time frame as the miscarriages, 1936 deliveries were registered, 44 [2.3%] of them were SARS-CoV-2 infected. No differences in terms of SARS-CoV-2 infection incidence were observed between infected miscarriages and infected deliveries (P = 0.233). Regarding the differences observed between miscarriages in SARS-CoV-2 positive and negative women, more inevitable miscarriages occurred in the group of infected women (36.4% versus 16.5% in non-infected women; P = 0.004), and there was greater surgical management of miscarriages (27.3% versus 8.2% in non-infected women; P = 0.036), probably in line with the greater number of inevitable miscarriages observed in this group. CONCLUSIONS: No association between SARS-CoV-2 infection and risk of first-trimester miscarriage was observed; however, the type of miscarriage seems to differ between SARS-CoV-2 positive and negative women, with inevitable miscarriage being more frequent among infected women.

High coenzyme Q10 plasma levels improve stress and damage markers in professional soccer players during competition.

Ubiquinol, the reduced form of Coenzyme Q10 (CoQ10), is a key factor in bioenergetics and antioxidant protection. During competition, professional soccer players suffer from considerable physical stress causing high risk of muscle damage. For athletes, supplementation with several antioxidants, including CoQ10, is widely recommended to avoid oxidative stress and muscle damage. We performed an observational study of plasma parameters associated with CoQ10 levels in professional soccer players of the Spanish First League team Athletic Club de Bilbao over two consecutive seasons (n = 24-25) in order determine their relationship with damage, stress and performance during competition. We analyzed three different moments of the competition: preterm, initial phase and mid phase. Metabolites and factors related with stress (testosterone/cortisol) and muscle damage (creatine kinase) were determined. Physical activity during matches was analyzed over the 2015/16 season in those players participating in complete matches. In the mid phase of competition, CoQ10 levels were higher in 2015/16 (906.8 ± 307.9 vs. 584.3 ± 196.3 pmol/mL, p = 0.0006) High levels of CoQ10 in the hardest phase of competition were associated with a reduction in the levels of the muscle-damage marker creatine kinase (Pearsons' correlation coefficient (r) = - 0.460, p = 0.00168) and a trend for the stress marker cortisol (r = -0.252, p = 0.150). Plasma ubiquinol was also associated with better kidney function (r = -0.287, p = 0.0443 for uric acid). Furthermore, high CoQ10 levels were associated with higher muscle performance during matches. Our results suggest that high levels of plasma CoQ10 can prevent muscle damage, improve kidney function and are associated with higher performance in professional soccer players during competition.

Depressed indurated plaque with elastorrhexis as a distinctive lesion in Buschke-Ollendorff syndrome.

Buschke-Ollendorff syndrome (BOS) is a rare autosomal dominant genodermatosis caused by heterozygous mutations in LEMD3 and characterized by connective tissue nevi and sclerotic bone lesions known as osteopoikilosis. We report a family with three individuals affected by BOS, two of whom manifested clinical and histopathological peculiarities, presenting with a depressed indurated plaque as the main cutaneous manifestation instead of the classic connective tissue nevi. Notable elastorrhexis was present in both biopsies.

High-pressure and -temperature spinning capillary cell for in situ synchrotron X-ray powder diffraction.

In situ research of materials under moderate pressures (hundreds of bar) is essential in many scientific fields. These range from gas sorption to chemical and biological processes. One industrially important discipline is the hydration of oil well cements. Existing capillary cells in this pressure range are static as they are easy to design and operate. This is convenient for the study of single-phase materials; however, powder diffraction quantitative analyses for multiphase systems cannot be performed accurately as a good powder average cannot be attained. Here, the design, construction and commissioning of a cost-effective spinning capillary cell for in situ powder X-ray diffraction is reported, for pressures currently up to 200 bar. The design addresses the importance of reducing the stress on the capillary by mechanically synchronizing the applied rotation power and alignment on both sides of the capillary while allowing the displacement of the supports needed to accommodate different capillaries sizes and to insert the sample within the tube. This cell can be utilized for multiple purposes allowing the introduction of gas or liquid from both ends of the capillary. The commissioning is reported for the hydration of a commercial oil well cement at 150 bar and 150°C. The quality of the resulting powder diffraction data has allowed in situ Rietveld quantitative phase analyses for a hydrating cement containing seven crystalline phases.

Competitive Swimming and Racial Disparities in Drowning.

This paper provides compelling evidence of an inverse relationship between competitive swimming rates and drowning rates using Centers for Disease Control and Prevention (CDC) data on fatal drowning rates and membership rates from USA Swimming, the governing organization of competitive swimming in the United States. Tobit and Poisson regression models are estimated using panel data by state from 1999-2007 separately for males, females, African Americans and whites. The strong inverse relationship between competitive swimming rates and unintentional deaths through fatal drowning is most pronounced among African Americans males.

COQ7 defect causes prenatal onset of mitochondrial CoQ10 deficiency with cardiomyopathy and gastrointestinal obstruction.

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10 levels, and reduced basal and maximal respiration in patients' fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.

Mutations of GEMIN5 are associated with coenzyme Q10 deficiency: long-term follow-up after treatment.

GEMIN5 exerts key biological functions regulating pre-mRNAs intron removal to generate mature mRNAs. A series of patients were reported harboring mutations in GEMIN5. No treatments are currently available for this disease. We treated two of these patients with oral Coenzyme Q10 (CoQ10), which resulted in neurological improvements, although MRI abnormalities remained. Whole Exome Sequencing demonstrated compound heterozygosity at the GEMIN5 gene in both cases: Case one: p.Lys742* and p.Arg1016Cys; Case two: p.Arg1016Cys and p.Ser411Hisfs*6. Functional studies in fibroblasts revealed a decrease in CoQ10 biosynthesis compared to controls. Supplementation with exogenous CoQ10 restored it to control intracellular CoQ10 levels. Mitochondrial function was compromised, as indicated by the decrease in oxygen consumption, restored by CoQ10 supplementation. Transcriptomic analysis of GEMIN5 patients compared with controls showed general repression of genes involved in CoQ10 biosynthesis. In the rigor mortis defective flies, CoQ10 levels were decreased, and CoQ10 supplementation led to an improvement in the adult climbing assay performance, a reduction in the number of motionless flies, and partial restoration of survival. Overall, we report the association between GEMIN5 dysfunction and CoQ10 deficiency for the first time. This association opens the possibility of oral CoQ10 therapy, which is safe and has no observed side effects after long-term therapy.

The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.

We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes.

Recent Advances in C-S-H Nucleation Seeding for Improving Cement Performances.

Reducing cement CO2 footprint is a societal need. This is being achieved mainly by replacing an increasing amount of Portland clinker by supplementary cementitious materials. However, this comes at a price: lower mechanical strengths at early ages due to slow pozzolanic reaction(s). This is being addressed by using accelerator admixtures. In this context, calcium silicate hydrate nucleation seeding seems to have a promising future, as it can accelerate cement and pozzolanic reactions at early ages, optimising their microstructures, without compromising late strength and durability performances. In fact, these features could even be improved. Moreover, other uses are low temperature concreting, precasting, shotconcrete, etc. Here, we focus on reviewing recent reports on calcium silicate hydrate seeding using commercially available admixtures. Current knowledge on the consequences of nucleation seeding on hydration reactions and on early and late mechanical strengths is discussed. It is noted that other features, in addition to the classic alite hydration acceleration, are covered here including the enhanced ettringite precipitation and the very efficient porosity refinement, which take place in the seeded binders. Finally, because the seeded binders seem to be denser, durability properties could also be enhanced although this remains to be properly established.

Mid-term symptomatic relief after platelet-rich plasma infiltration in vulvar lichen sclerosus.

PURPOSE: Vulvar lichen sclerosus (LS) is a chronic, progressive, autoimmune dermatologic condition that causes cutaneous changes accompanied by pruritus and pain. There remains a small population with vulvar LS refractory to topical corticosteroids. Injection of platelet-rich plasma (PRP) has been reported to have positive effects on tissue repair. The aim of this pilot study was to evaluate changes in symptom scores during and after PRP vulvar infiltration. METHODS: Three PRP infiltrations were administered to 28 female postmenopausal patients with biopsy-proved LS with unsatisfactory response to steroid therapy. Change in score according to the Clinical Scoring System for Vulvar Lichen Sclerosus (CSS) was measured on six occasions over the course of a year. We used growth curve modeling to measure change over the period of the study. RESULTS: Women in our study experienced a statistically significant improvement in auto-assessed symptoms of vulvar lichen sclerosus, and this improvement appears to be maintained throughout the monitoring year. CONCLUSION: Platelet-rich plasma may have a role in symptom relief in certain cases of patients with LS that do not respond to first-line therapy.

4D nanoimaging of early age cement hydration.

Despite a century of research, our understanding of cement dissolution and precipitation processes at early ages is very limited. This is due to the lack of methods that can image these processes with enough spatial resolution, contrast and field of view. Here, we adapt near-field ptychographic nanotomography to in situ visualise the hydration of commercial Portland cement in a record-thick capillary. At 19 h, porous C-S-H gel shell, thickness of 500 nm, covers every alite grain enclosing a water gap. The spatial dissolution rate of small alite grains in the acceleration period, ∼100 nm/h, is approximately four times faster than that of large alite grains in the deceleration stage, ∼25 nm/h. Etch-pit development has also been mapped out. This work is complemented by laboratory and synchrotron microtomographies, allowing to measure the particle size distributions with time. 4D nanoimaging will allow mechanistically study dissolution-precipitation processes including the roles of accelerators and superplasticizers.

Intercultural Differences between Spain and Italy Regarding School Bullying, Gender, and Age.

The objectives of this research were to establish the differences between Spain and Italy regarding the presence of bullying in primary and secondary schools, as well as to determine whether there are differences between experiencing or perpetrating bullying and gender and age in the practice of school bullying. To assess the EBIPQ scores in terms of country and gender, the chi-squared test was used, and ANOVA was applied for age. A total of 1536 students from primary and secondary schools in Spain and Italy participated in the study. Their ages ranged from 10 to 19 years (mean = 13.01, standard deviation = 2.19). The results revealed statistically significant differences in terms of bullying categories concerning the country of origin and gender, with a higher number of Italian participants in the role of "no victim aggress" and Spanish participants in the roles of "victim" and "victim and aggress". Additionally, there were more boys in the role of "victim and aggress" and girls in the role of "no victim aggress". Regarding age, statistically significant differences were found, with older students taking on the role of "aggress" on average, while younger students assumed the role of "victim".

Psychometric Analysis of an Academic Self-Attribution Questionnaire in Middle and High School Students in Italy: Implications of Gender and Age.

This research aimed to validate the Academic Success and Failure Attribution Questionnaire (ASFAQ) and analyze gender and age differences in middle and high school students in Italy. Methods: From the ASFAQ questionnaire validated with Spanish students, an analysis of the psychometric characteristics of the scale was carried out using a Confirmatory Factor Analysis (CFA). To compare ASFAQ scores by gender and school year, the independent samples parametric t-test and Pearson's coincidence test were used. (3) Results: in total, 976 students participated in the research, of which 515 were middle school students and 461 were high school students. The results showed a validity of the ASFAQ for Italian students, in addition to statistically significant differences between males and females, and school year. (4) Conclusions: The ASFAQ is reliable and valid to assess the attributional styles of academic success and failure in an Italian context. There are significant differences in sex and school year, and a consequence with age.

The Influence of Bullying on Positive Emotions and Their Effect as Mediators between Controllable Attributions of Success and Academic Performance.

Academic performance (AP) is a topic of particular interest in the academic context. Attributions for academic success (AAS) have been shown to have a significant impact on AP, and more specifically internal controllable attributions (ICA) are closely linked to academic success. Similarly, positive emotions (PE) have a significant influence on AP and may in turn be influenced by bullying. This study examines the connections between ICA of academic success and AP mediated through PE in late primary and early secondary school students and analyzes the relationships between PE and bullying categories. Students (N = 562, 49.46% female, Mage = 11.6 SD = 1.2) reported on their perceptions of ICA and PE in relation to exams and their relationship with bullying through validated questionnaires. The AP was obtained as the average mark of all subjects in the immediately preceding assessment. First, a multiple linear regression analysis considering ICA and PE as predictor variables was carried out, which showed a significantly positive link between ICA and PE, between ICA and AP, and between PE and AP. Subsequently, using the SPSS macro PROCESS, a simple mediation model was implemented to quantify the effect of ICA on AP through PE in exams, and finally an ANOVA between the categories of bullying and PE was performed. The results showed a significant indirect relationship with a positive predictive relationship for AP. The model shows that PE proves to be a significant mediator between ICA and AP, and it is shown that students disengaged from bullying score higher in PE.

COQ4 is required for the oxidative decarboxylation of the C1 carbon of Coenzyme Q in eukaryotic cells.

Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role, but also via oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis, and shed new light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations.