Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability

DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G>A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short statur

Early vs late histological confirmation of coeliac disease in children with new-onset type 1 diabetes

AIM Screening for coeliac disease in asymptomatic children with new-onset type 1 diabetes is controversial. The aim of this study was to analyse whether the confirmation of coeliac disease in children with new-onset type 1 diabetes and positive screening results can be postponed. METHODS This was a multicentre population-based cohort study based on the German/Austrian/Swiss/Luxembourgian Prospective Diabetes Follow-up Registry (Diabetes Patienten Verlaufsdokumentation [DPV]). Participants aged ≤18 years diagnosed with type 1 diabetes between 1995 and June 2021 and with elevated IgA tissue transglutaminase antibodies (anti-tTGA) at diabetes onset on screening for coeliac disease were included. We compared outcomes of participants with a diabetes duration of more than 1 year between those in whom coeliac disease was confirmed histologically within the first 6 months and those in whom coeliac disease was confirmed between 6 and 36 months after diabetes diagnosis. RESULTS Of 92,278 children and adolescents with a diagnosis of type 1 diabetes, 26,952 (29.2%) had documented anti-tTGA data at diabetes onset. Of these, 2340 (8.7%) had an elevated anti-tTGA level. Individuals who screened positive were younger (median age 9.0 vs 9.8 years, p<0.001) and more often female (53.1% vs 44.4%, p<0.001). A total of 533 participants (22.8% of those who screened positive) had a documented biopsy, of whom 444 had documented histological confirmation of coeliac disease. Of 411 participants with biopsy-proven coeliac disease within the first 36 months of diabetes and follow-up data, histological confirmation was performed in 264 (64.2%) within the first 6 months and in 147 (35.8%) between 6 and 36 months after diabetes onset. At follow-up (median diabetes duration 5.3 years and 5.1 years, respectively), estimated median HbA1c levels (62.8 mmol/mol vs 62.2 mmol/mol [7.9% vs 7.8%]), cardiovascular risk markers (lipids, rate of microalbuminuria, blood pressure), rates of acute diabetes complications (diabetic ketoacidosis, severe hypoglycaemia) and the proportions of participants reaching anti-tTGA levels within the normal range did not differ between groups. Participants with delayed histological confirmation of coeliac disease showed no negative effects on growth or weight gain during the observation period. CONCLUSIONS Our study suggests that the histological confirmation of coeliac disease in asymptomatic individuals with new-onset type 1 diabetes could be postponed

Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women

OBJECTIVE: The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution. METHOD: We genotyped and measured the serum leptin levels of the NP-Y rs16147 polymorphism in 1,097 Caucasian subjects in the context of a population-based, case-control multicenter study. We measured weight, height and waist circumference, from which we then calculated BMI and waist-to-hip ratio (WHR). RESULTS: We found the CT-genotype of the SNP rs16147 to be significantly associated with lower WHRs and higher serum leptin levels in women, compared to homozygote gene carriers. No association between rs16147, WHR and serum leptin levels was found in men. CONCLUSION: Our results provide evidence that the functionally relevant SNP in the NP-Y promoter gene affects body fat distribution and serum leptin levels in women, pointing towards possible behavioral effects of NPY in obesity

A sonic theory unsuitable for human consumption

The past decade has seen the proliferation of scholarly work on audio culture by philosophers, sociologists, ethnographers, musicologists, anthropologists, and others. There is now a range of histories and ethnographies on listening and on the soundscape, and a proliferation of epistemological, methodological, and cultural investigations of the sonic. At the same time, as John Kieffer notes, sound art is fast becoming “the new kid on the cultural block” (2010). Different writers have engineered different conceptual approaches for studying the sonic. These voices are symptomatic of a body of work that has developed as a way of reacting against the primacy of Cartesian reason, looking for ways of escaping the Western tendency to measure, calculate and represent everything. They offer strategies for defending and resurrecting the nullified senses, like hearing, which must no longer surrender to the tyranny of ocularcentrism. However, the belated recognition of sound as a valid academic object of study and art discipline, often risks fetishizing the sonic and repeating the same ideological separations between sound and image, body and mind. Moreover, refreshing as they may be, they are too often confined within a human-centred position and interested in predominantly addressing the phenomenal experience of sound. This article wishes to discuss alternative schemas daring to go beyond the audiophile anthropocentric angle. It mainly draws on Kodwo Eshun’s unconventional method of ‘sonic fiction’ (1998), in order to argue for the value of developing a sound theory that brings together speculative philosophy, science fiction, and experimental audio art. Ultimately, it attempts to explore how such ‘a sonic intervention into thought’ (Goodman, 2010) can drag us away from the sociopolitical and historical organisation of sound and toward the vicinity of a more ‘unreal state’, where the boundaries between fiction and theory are provisional and utterly permeable

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Vitamin D Receptor Deficiency and Low Vitamin D Diet Stimulate Aortic Calcification and Osteogenic Key Factor Expression in Mice

Low levels of 25-hydroxy vitamin D (25(OH)D) are associated with cardiovascular diseases. Herein, we tested the hypothesis that vitamin D deficiency could be a causal factor in atherosclerotic vascular changes and vascular calcification. Aortic root sections of vitamin D receptor knockout (VDR−/−) mice that were stained for vascular calcification and immunostained for osteoblastic differentiation factors showed more calcified areas and a higher expression of the osteogenic key factors Msx2, Bmp2, and Runx2 than the wild-type mice (P<0.01). Data from LDL receptor knockout (LDLR−/−) mice that were fed western diet with either low (50 IU/kg), recommended (1,000 IU/kg), or high (10,000 IU/kg) amounts of vitamin D3 over 16 weeks revealed increasing plasma concentrations of 25(OH)D (P<0.001) with increasing intake of vitamin D, whereas levels of calcium and phosphorus in plasma and femur were not influenced by the dietary treatment. Mice treated with the low vitamin D diet had more calcified lesions and a higher expression of Msx2, Bmp2, and Runx2 in aortic roots than mice fed recommended or high amounts of vitamin D (P<0.001). Taken together, these findings indicate vitamin D deficiency as a risk factor for aortic valve and aortic vessel calcification and a stimulator of osteogenic key factor expression in these vascular areas

Avaliação do tratamento de percolado de aterro sanitário pelo processo de peroxicoagulação eletroquímica utilizando eletrodos híbridos de ferro e alumínio

The decomposition of residues in landfills generates a dark colored liquid known as leachate, which has in its composition harmful pollutants to the environment. Advanced electro- oxidative processes are presented as a form of treatment of this effluent mainly due to the degradation capacity of these compounds. This work consists of an investigation about the treatment of the leachate by means of the process of electrochemical peroxicoagulation (EPC) using a hybrid electrode composed of two aluminum plates and two plates of iron. A response surface methodology (RSM) based on 10 experimental runs was used, considering the initial concentration H 2 O 2 (mg L -1 ) and current intensity (A) as independent variables, the variables being response to % removal of 254 nm absorbance and turbidity. The pH of the solution was kept constant ~ 4, at an air addition rate of 1.6 L min -1 . The best EPC process conditions were observed in 1283 mg H 2 O 2 L -1 and current intensity of 1.6 A, obtaining 83.2% removal for absorbance and 91.3% for turbidity at electrolysis time of 60 minutes. Within this proposal, it is possible to point out that PCE presented an efficient technique and with prospects of minimizing the environmental impacts caused by the discharge of landfill leachate into water bodies, in compliance with current legislation.A decomposição de resíduos em aterros sanitários gera um líquido de cor escura conhecido como percolado, que possui em sua composição características poluentes prejudiciais ao meio ambiente. Processos eletro-oxidativos avançados se apresentam como uma forma de tratamento deste efluente devido principalmente a capacidade de degradação destes compostos. O presente trabalho se constitui em uma investigação a cerca do tratamento do percolado por meio do processo de peroxicoagulação eletroquímica (PCE) utilizando um eletrodo híbrido composto por duas placas de alumínio e duas placas de ferro. Foi aplicada uma metodologia de superfície de resposta (MSR) baseada em 10 corridas experimentais, considerando como variáveis independentes, a concentração inicial H 2 O 2 (mg L -1 ) e a intensidade de corrente (A), sendo as variáveis resposta a porcentagem de remoção de absorbância 254 nm e a turbidez. O pH da solução foi mantido constante ~ 4, a uma taxa de injeção de ar de 1,6 L min -1 . As melhores condições do processo PCE foram observadas em 1283 mg H 2 O 2 L -1 e intensidade de corrente de 1,6 A, obtendo-se 83 % de remoção para absorbância e 91 % para a turbidez em tempo de eletrólise de 60 minutos. Dentro desta proposta, pode-se salientar que a PCE apresentou-se uma técnica eficiente e com perspectivas de minimizar os impactos ambientais ocasionados pelo descarte de percolado de aterros sanitários em corpos hídricos, atendendo as legislações vigentes

Exploring the advancements of Australian OPAT

Outpatient parenteral antimicrobial therapy (OPAT) in Australia has evolved from modest beginnings to a well-established health service with proven benefits in patient outcomes. This is a comprehensive review of the current state of art Australian OPAT with vignettes of the types of OPAT models of care, antimicrobial prescribing and antimicrobial use. In addition, we highlight the similarities and differences between OPAT to other countries and describe Australian OPAT experiences with COVID-19 and paediatrics. Australian OPAT continues to advance with OPAT antifungals, novel treatment options and upcoming high-impact research

Migratory blackcaps can use their magnetic compass at 5 degrees inclination, but are completely random at 0 degrees inclination

It is known that night-migratory songbirds use a magnetic compass measuring the magnetic inclination angle, i.e. the angle between the Earth's surface and the magnetic field lines, but how do such birds orient at the magnetic equator? A previous study reported that birds are completely randomly oriented in a horizontal north-south magnetic field with 0° inclination angle. This seems counter-intuitive, because birds using an inclination compass should be able to separate the north-south axis from the east-west axis, so that bimodal orientation might be expected in a horizontal field. Furthermore, little is known about how shallow inclination angles migratory birds can still use for orientation. In this study, we tested the magnetic compass orientation of night-migratory Eurasian blackcaps (Sylvia atricapilla) in magnetic fields with 5° and 0° inclination. At 5° inclination, the birds oriented as well as they did in the normal 67° inclined field in Oldenburg. In contrast, they were completely randomly oriented in the horizontal field, showing no sign of bimodality. Our results indicate that the inclination limit for the magnetic compass of the blackcap is below 5° and that these birds indeed seem completely unable to use their magnetic compass for orientation in a horizontal magnetic field

DAMPs Released from Proinflammatory Macrophages Induce Inflammation in Cardiomyocytes via Activation of TLR4 and TNFR

Cardiac dysfunction is a life-threatening complication in sepsis. Upon infection and cardiac stress, the cardiac macrophage population expands. Recruited macrophages exhibit a predominantly proinflammatory phenotype and release danger-associated molecular patterns (DAMPs) that contribute to cardiac dysfunction. However, the underlying pathomechanisms are highly complex and not fully understood. Here, we utilized an indirect macrophage–cardiomyocyte co-culture model to study the effects of proinflammatory macrophages on the activation of different cardiac receptors (TLR3, TLR4, and TNFR) and their role in cardiac inflammation and caspase-3/7 activation. The stimulation of cardiomyocytes with conditioned medium of LPS-stimulated macrophages resulted in elevated IL-6 protein concentrations and relative IL-6 and TNFα mRNA levels. Conditioned medium from LPS-stimulated macrophages also induced NFκB translocation and increased caspase-3/7 activation in cardiomyocytes. Analyzing the role of different cardiac receptors, we found that TLR4 and TNFR inhibition reduces cardiac inflammation and that the inhibition of TNFR prevents NFκB translocation into the nuclei of cardiomyocytes, induced by exposure to conditioned medium of proinflammatory macrophages. Moreover, we demonstrated that TLR3 inhibition reduces macrophage-mediated caspase-3/7 activation. Our results suggest that the immune response of macrophages under inflammatory conditions leads to the release of DAMPs, such as eRNA and cytokines, which in turn induce cardiomyocyte dysfunction. Thus, the data obtained in this study contribute to a better understanding of the pathophysiological mechanisms of cardiac dysfunction