Sahlcummings5323

Splicing minigene reporter assay revealed that c.1326A>C causes exon 11 or exon 11 and 12 skipping during NIS pre-mRNA splicing leading to the NIS pathogenic variants p.G415_P443del and p.G415L

*32, respectively. Significantly, the frameshift variant p.G415L

*32 is predicted to be subjected to degradation by nonsense-mediated decay.

We identified the first exonic synonymous

gene variant causing aberrant NIS pre-mRNA splicing, thus expanding the mutational landscape of the

gene leading to dyshormonogenic congenital hypothyroidism.

We identified the first exonic synonymous SLC5A5 gene variant causing aberrant NIS pre-mRNA splicing, thus expanding the mutational landscape of the SLC5A5 gene leading to dyshormonogenic congenital hypothyroidism.Since their initial description by Enrico Sertoli in 1865, Sertoli cells have continued to enchant testis biologists. Testis size and germ cell carrying capacity are intimately tied to Sertoli cell number and function. One critical Sertoli cell function is signaling from Sertoli cells to germ cells as part of regulation of the spermatogenic cycle. Sertoli cell signals can be endocrine or paracrine in nature. Here we review recent advances in understanding the interplay of Sertoli cell endocrine and paracrine signals that regulate germ cell state. Although these findings have long-term implications for treating male infertility, recent breakthroughs in Sertoli cell transplantation have more immediate implications. We summarize the surge of advances in Sertoli cell ablation and transplantation, both of which are wedded to a growing understanding of the unique Sertoli cell niche in the transitional zone of the testis.A fundamental question in cell biology underlies how nutrients are regenerated to maintain and renew tissues. Physiologically, the canonical Wnt signaling is a vital pathway for cell growth, tissue remodeling, and organ formation; pathologically, Wnt signaling contributes to the development of myriad human diseases such as cancer. Despite being the focus of intense research, how Wnt intersects with the metabolic networks to promote tissue growth and remodeling has remained mysterious. Our understanding of metabolism has been revolutionized by technological advances in the fields of chemical biology, metabolomics, and live microscopy that have now made it possible to visualize and manipulate metabolism in living cells and tissues. The application of these toolsets to innovative model systems have propelled the Wnt field into new realms at the forefront answering the most pressing paradigms of cell metabolism in health and disease states. Elucidating the basis of Wnt signaling and metabolism in a cell-type and tissue-specific manner will provide a powerful base of knowledge for both basic biomedical fields and clinician scientists, and has the promise to generate new, transformative therapies in disease and even processes of aging.Several publications have raised the issue that the development of diabetes precedes the alteration of the microbiome (dysbiosis) and the role of environmental factors. Antibiotic use induces dysbiosis, and we wanted to estimate the associations between the consumption of antibiotics and the prevalence of diabetes (both types 1 and 2; T1D and T2D, respectively) in European countries. If such an association exists, the dominant use antibiotic classes might be reflected in the prevalence rates of T1D and T2D in different countries. Comparisons were performed between the prevalence of diabetes estimated for 2019 and featured in the Diabetes Atlas and the average yearly consumption of antibiotic classes between 2010 and 2109, calculated from the European Centre for Disease Prevention and Control (ECDC) yearly reports on antibiotic consumption in Europe. Pearson's correlation and variance analyses were used to estimate the possible relationship. Strong positive (enhancer) associations were found between the preval beta-lactamase-resistant, combination penicillin (p = 0.005); cephalosporin (p = 0.036); and quinolone (p = 0.003)]. Countries with high prevalence rates of T2D consumed more cephalosporin (p = 0.084) and quinolone (p = 0.054) and less broad-spectrum, beta-lactamase-sensitive penicillin (p = 0.012) than did other countries. The development of diabetes-related dysbiosis might be related to the higher consumption of specific classes of antibiotics, showing positive (enhancer) associations with the prevalence of diabetes, and the low consumption of other classes of antibiotics, those showing negative (inhibitory) associations. These groups of antibiotics are different in T1D and T2D.Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD+ levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD+ decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD+ levels can be lowered experimentally in chronologically young adult males. We therefore developed a transgenic mouse model of acquired niacin dependency (ANDY), in which NAD+ levels can be experimentally lowered using a niacin-deficient, chemically defined diet. Using ANDY mice, this report demonstrates for the first time that decreasing body-wide NAD+ levels in young adult mice, including in the testes, to levels that match or exceed the natural NAD+ decline observed in old mice, results in the disruption of spermatogenesis with small testis sizes and reduced sperm counts. ANDY mice are dependent on dietary vitamin B3 (niacin) for NAD+ synthesis, similar to humans. NAD+-deficiency the animals develop on a niacin-free diet is reversed by niacin supplementation. Providing niacin to NAD+-depleted ANDY mice fully rescued spermatogenesis and restored normal testis weight in the animals. The results suggest that NAD+ is important for proper spermatogenesis and that its declining levels during aging are functionally linked to declining spermatogenesis and male fertility. Functions of NAD+ in retinoic acid synthesis, which is an essential testicular signaling pathway regulating spermatogonial proliferation and differentiation, may offer a plausible mechanism for the hypospermatogenesis observed in NAD+-deficient mice.Adipose tissues perform physiological functions such as energy storage and endocrine, whose dysfunction will lead to severe metabolic disorders. Accumulating evidences show that exosomes can meditate communications between different tissues by transporting nucleic acids, proteins and other biological factors. More importantly, exosomes secreted by adipose tissue function as critical contributing factors that elucidate specific mechanisms in metabolic disturbance such as obesity, adipose inflammation and diabetes etc. Adipose tissue is the major source of circulating exosomal miRNAs. Nemtabrutinib supplier miRNA secreted from adipose tissues not only altered in patients with metabolic disease, but also result in an increase in metabolic organ talk. Here we have reviewed the latest progress on the role of adipose tissue derived exosomes roles in metabolic disorders. Moreover, the current obstacles hindering exosome-based therapeutic strategies have also been discussed.

Vitamin D-dependant rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by pathogenic variants in the

gene. This gene is essential for vitamin D activation. Although VDDR1A is a rare condition worldwide, its prevalence is high in the Saguenay-Lac-Saint-Jean (SLSJ) region due to a founder effect. Daily intake of calcitriol before the onset of clinical manifestations can prevent them in affected children.

A genetic screening test was developed and validated for the

gene c.262del pathogenic variant. Newborn screening was implemented in the SLSJ region for this variant, and the feasibility and acceptability were assessed. Sixteen medical records of children affected with VDDR1A were reviewed to document the consequences of the disease at diagnosis.

A total of 2000 newborns were tested for VDDR1A. Most families (96.5%) accepted the genetic test. We found a carrier rate of 1/29 for the c.262delG variant in our cohort, which is suggestive of a founder effect. We identified one child af health perspective.Lipodystrophy includes a heterogeneous group of rare diseases characterized by different amounts of adipose tissue loss and several metabolic complications, including hypertriglyceridemia, steatohepatitis and particularly insulin resistance, that may lead to severe morbidity and, sometimes, mortality. Therefore, therapy for lipodystrophy primarily consists of a conventional approach that involves standard treatments of metabolic abnormalities. Given the evidence of leptin deficiency in lipodystrophy syndromes, leptin replacement therapy has been considered as a treatment option. Long-term studies on the use of therapy with a methionylated analog of human leptin, metreleptin, first on animals and subsequently on human patients, demonstrated enormous improvements of patients' clinical features and metabolic conditions. Recently, metreleptin was approved by Food and Drug Administration (FDA) for the treatment of generalized lipodystrophy and by European Medicines Agency (EMA) for the treatment of both generalized and partial lipodystrophy. However, further research is being conducted for new and different therapeutic agents, especially helpful for the treatment of patients with partial lipodystrophy, as some of them do not have access to metreleptin therapy or show poor response.Obesity is defined as overaccumulation of white adipose tissue in the body, mainly under the skin (subcutaneous adiposity) or in the abdominal cavity (visceral adiposity). It could be the origin of various metabolic disorders including hypertension, hyperlipidemia, type 2 diabetes, cardiovascular diseases etc. Active adipose tissue was discovered in humans through 18F-fluorodeoxyglucose Positron Emission Tomography coupled with Computer Tomography (18F FDG-PET/CT), which was initially performed for tumor scanning. Since human active adipose tissue is probably composed of brown and beige adipose tissues and they burn white adipose tissue to generate heat, targeting human brown/beige adipose tissue to induce their thermogenic function is considered significant to combat obesity. In this review, we describe the latest advancements on promising therapeutic strategies to combat obesity by targeting human thermogenic adipose tissues to achieve further metabolic balance in humans.

Glycosylated hemoglobin A1c (HbA1c) is an important means of monitoring blood glucose and diagnosing diabetes. High-performance liquid chromatography (HPLC) is the most widely used method to detect HbA1c in clinical practice. However, the results of HbA1c by HPLC are susceptible to hemoglobinopathy. Here, we report a case of discordantly low HbA1c with an abnormal chromatogram caused by rare β-thalassemia.

A 36-year-old Tujia Chinese woman presented with an abnormally low HbA1c level of 3.4% by HPLC in a health check-up. The chromatogram of HbA1c showed an abnormal peak. Fasting blood glucose, routine blood tests and serum bilirubin were normal. Her body mass index was 27.86 kg/m

. Hemoglobin electrophoresis showed low hemoglobin A and abnormal hemoglobin β-chain variants. The thalassemia gene test suggested a rare type of β-thalassemia (gene sequencing HBB c.170G>A, Hb J-Bangkok (GGC->GAC at codon 56) in a beta heterozygous mutation). Glycated albumin (GA) was slightly increased. Oral glucose tolerance tests (OGTT) and insulin release tests indicated impaired glucose tolerance and insulin resistance.