An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. Highlights: AIRIM variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

From Radiological Manifestations to Pulmonary Pathogenesis of COVID-19: A Bench to Bedside Review.

In this review, we aim to assess previous radiologic studies in COVID-19 and suggest a pulmonary pathogenesis based on radiologic findings. Although radiologic features are not specific and there is heterogeneity in symptoms and radiologic and clinical manifestation, we suggest that the dominant pattern of computed tomography is consistent with limited pneumonia, followed by interstitial pneumonitis and organizing pneumonia.

Incidence and Main Determinants of Contrast-Induced Nephropathy following Coronary Angiography or Subsequent Balloon Angioplasty.

BACKGROUND/AIMS: Patient assessment by imaging studies using contrast media is currently replacing open procedures, especially in high-risk patients. However, the use of such contrast media might result in acute events and injuries after the procedure. In the present study, we first determined the incidence of contrast-induced nephropathy (CIN) in a sample of Iranian patients who candidated for coronary angiography and/or angioplasty, and then assessed major risk factors predicting the appearance of CIN following these procedures. METHODS: Two hundred and fifty consecutive, eligible patients scheduled for coronary angiography and/or angioplasty at the Afshar Hospital in Yazd between January 2009 and August 2010 were considered for enrollment. Renal function was measured at baseline and 48 h after the intervention, and CIN was defined by an increase in creatinine of >0.5 mg/dl or 25% of the initial value. The predictive role of potential risk factors was determined in a multivariate model adjusted for comorbidities, preexisting renal impairment, and angiographic data. RESULTS: CIN following coronary angiography or angioplasty appeared in 12.8% of the cases. A myocardial infarction before the procedure (OR = 2.121, p = 0.036) and a prior history of hypertension (OR = 2.789, p = 0.025) predicted the appearance of acute renal failure following angiography or subsequent angioplasty. A low estimated glomerular filtration rate at baseline slightly predicted CIN after these interventions. CONCLUSION: Transient acute renal dysfunction occurred in 12.8% of the patients within 48 h after angiography or subsequent angioplasty and could be predicted by a myocardial infarction before the procedure or by a prior history of systolic hypertension.