BACKGROUND:Congenital cytomegalovirus infection (CMVc) affects 0.7%–6% of recent births. Among its clinical manifestations are low weight and length at birth.
OBJECTIVE:Describe the growth patterns ...of children with CMVc in their early years.
METHODS:Observational, multicenter study of patients with CMVc. Anthropometric data were collected during the first 2 years of life and compared with World Health Organization standards.
RESULTS:Anthropometric characteristics of 383 children with CMVc were studied, of which 198 (51%) were symptomatic at birth. At birth, 9% were small for gestational age (SGA) in terms of their weight and length and 17% had microcephaly. At 24 ± 3 months, 10% had a weight and length ≤2 SD, and 13% a head circumference ≤2 SD. Of those who were SGA at birth, at 24 ± 3 months >20% remained at ≤2 SD of their weight and length. Conversely, 75% of children with low weight or length at 24 ± 3 had not been SGA at birth. 20% of infants with microcephaly at birth remained with microcephaly, and 10% of those without microcephaly developed it at 24 ± 3 months. The average growth rate in length and weight was normal. Patients who were symptomatic at birth, premature and with motor and neurocognitive impairment had a significantly higher risk of low weight and length at 24 ± 3 months.
CONCLUSION:Around 10% of children with CMVc are at ≤2 SD in weight, length and head circumference at 24 ± 3 months. The lack of adequate growth is associated with symptoms at birth, prematurity and motor and neurocognitive impairment. Growth impairment could be incorporated into the symptomatic spectrum of CMVc.
In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).
Following next-generation ...sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.
All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients’ fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.
Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
Abstract
Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine ...palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive.
Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila.
Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila.
These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.
Srivastava et al. identify monoallelic missense and biallelic frameshift variants in SPTSSA, encoding a subunit of serine palmitoyltransferase (SPT), in three individuals with a new complex hereditary spastic paraplegia. The variants disrupt ORMDL-mediated regulation of SPT resulting in excessive sphingolipid synthesis.
In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, ...endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
Squamous cell carcinoma (SCC) lesions were confirmed by histopathology in 94% of 176 carcasses condemned for SCC during 8-hour shifts at four different processing plants. Lesions in the remaining ...carcasses were diagnosed as focal ulcerative dermatitis. SCC lesions were confined to the skin; no metastasis or invasion of underlying muscle was present. Monthly prevalence of SCC condemnations at processing was obtained from two plants for a 1-year period and from two additional plants for 3-year periods. Overall study prevalence of SCC varied between 0.03% and 0.09% of total condemnations. Servicemen were found not to have an effect on SCC condemnations for the only company that had these data available. Chronological trends were evaluated for SCC condemnations. A trigonometric model predicted 6-month cycles for one processing plant over a 3-year period. The same model was used to describe 6-month cycles present in the last 12 months of a 3-year observation period in a different processing plant. Chronologic trends were evaluated qualitatively for the two other processing plants
The packaging nets used for bell peppers act as a form of protection. However, the manufacturing is based on polymers that cause serious environmental problems. The effects of nets made of ...biodegradable materials, such as poly(lactic) acid (PLA), poly(butylene adipate-co-terephthalate) (PBAT), and cactus stem residues, were evaluated on four different colors of 'California Wonder' bell peppers stored over a 25-day storage period under controlled and ambient temperature conditions. Compared to commercial polyethylene nets, the bell peppers kept in the biodegradable nets did not show notable differences with respect to color, weight loss, total soluble solids, and titratable acidity. However, there were significant differences (
< 0.05) in terms of phenol content, carotenoids (orange bell peppers), anthocyanins, and vitamin C, with an overall tendency to show a higher content in those kept in PLA 60%/PBTA 40%/cactus stem flour 3% compared to commercial packaging. In addition, the same net notably reduced the development of bacteria, fungi, and yeasts during the storage of red, orange, and yellow bell peppers. As postharvest packaging for bell peppers, this net could be considered a viable option for the storage of this product.
The concept of corporate social responsibility (CSR) has a long tradition in business, but it is relatively new in public administration. Recently, there has been general consensus that there is a ...need to promote CSR in public administrations so as to improve transparency, governance, and the efficient allocation of public resources. We develop a new scale for measuring local public corporate responsibility (LPCR) based on CSR international standards and inputs from experts and academics, who evaluate whether the selected indicators are relevant, useful, adequate and practical for measuring LPCR. We test the tool empirically by analysing the CSR practices of 24 municipal councils in a Spanish territory. The result is a scale that allows us to determine the extent to which the municipal councils are socially responsible. This tool gives citizens access to information about CSR in their municipal councils and enables the identification of areas where municipal councils face challenges and require improvement.
A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged ...as top candidates, and after visual analyses of the predicted structures of their complexes with Mpro, 17 were chosen for evaluation in a kinetic assay for Mpro inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC50 values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1′, and P2 pockets of Mpro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.
The existence of G protein-coupled receptor (GPCR) dimers and/or oligomers has been demonstrated in heterologous systems using a variety of biochemical and biophysical assays. While these ...interactions are the subject of intense research because of their potential role in modulating signaling and altering pharmacology, evidence for the existence of receptor interactions in vivo is still elusive because of a lack of appropriate methods to detect them. Here, we adapted and optimized a proximity ligation assay (PLA) for the detection in brain slices of molecular proximity of two antigens located on either the same or two different GPCRs. Using this approach, we were able to confirm the existence of dopamine D2 and adenosine A2A receptor complexes in the striatum of mice ex vivo.
Spermatozoa motility is a key parameter during the fertilization process. In this context, spermatozoa tyrosine protein phosphorylation and an appropriate cytoskeleton α‐tubulin distribution are some ...of the most important physiological events involved in motility. However, the relationship between these two biomarkers remains poorly defined. Here, we characterized simultaneously by immunocytochemistry the α‐tubulin (TUBA4A) distribution and the tyrosine phosphorylation at flagellum before capacitation, during different capacitation times (1 and 4 hr), and after acrosome reaction induction in human spermatozoa. We found that the absence of spermatozoa phosphorylation in tyrosine residues positively and significantly correlated (p < 0.05) with the terminal piece α‐tubulin flagellar distribution in all physiological conditions. Conversely, we observed a positive significant correlation (p < 0.01) between phosphorylated spermatozoa and continuous α‐tubulin distribution in spermatozoa flagellum, independently of the physiological condition. Similarly, the subpopulation of spermatozoa with tyrosine phosphorylated and continuous α‐tubulin increases with longer capacitation times and after the acrosome reaction induction. Overall, these findings provide novel insights into the post‐transcriptional physiological events associated to α‐tubulin and the tyrosine phosphorylation during fertilization, which present potential implications for the improvement of spermatozoa selection methods.
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