Assessment of access and outcomes of kidney transplantation through the reforms of the Swiss organ allocation system.

Introduction: The Swiss allocation system for kidney transplantation has evolved over time to balance medical urgency, immunological compatibility, and waiting time. Since the introduction of the transplantation law in 2007, which imposed organ allocation on a national level, the algorithm has been optimized. Initially based on waiting time, HLA compatibility, and crossmatch performed by cell complement-dependent cytotoxicity techniques, the system moved in 2012 to a score including HLA compatibility, waiting time, anti-HLA antibodies detected by the Luminex technology, and a virtual crossmatch.

Disrupted protein interaction dynamics in a genetic neurodevelopmental disorder revealed by structural bioinformatics and genetic code expansion.

Deciphering the structural effects of gene variants is essential for understanding the pathophysiological mechanisms of genetic diseases. Using a neurodevelopmental disorder called Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) as a genetic disease model, we applied structural bioinformatics and Genetic Code Expansion (GCE) strategies to assess the pathogenic impact of human NR2F1 variants and their binding with known and novel partners. While the computational analyses of the NR2F1 structure delineated the molecular basis of the impact of several variants on the isolated and complexed structures, the GCE enabled covalent and site-specific capture of transient supramolecular interactions in living cells.

Pathophysiological Heterogeneity of the BBSOA Neurodevelopmental Syndrome.

The formation and maturation of the human brain is regulated by highly coordinated developmental events, such as neural cell proliferation, migration and differentiation. Any impairment of these interconnected multi-factorial processes can affect brain structure and function and lead to distinctive neurodevelopmental disorders. Here, we review the pathophysiology of the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722; ORPHA 401777), a recently described monogenic neurodevelopmental syndrome caused by the haploinsufficiency of gene, a key transcriptional regulator of brain development.

Antibody-mediated rejection after kidney transplantation in children; therapy challenges and future potential treatments.

Antibody-mediated rejection (AMR) remains one of the most critical problems in renal transplantation, with a significant impact on patient and graft survival. In the United States, no treatment has received FDA approval jet. Studies about treatments of AMR remain controversial, limited by the absence of a gold standard and the difficulty in creating large, multi-center studies.

Structural and Functional Aspects of the Neurodevelopmental Gene : From Animal Models to Human Pathology.

The assembly and maturation of the mammalian brain result from an intricate cascade of highly coordinated developmental events, such as cell proliferation, migration, and differentiation. Any impairment of this delicate multi-factorial process can lead to complex neurodevelopmental diseases, sharing common pathogenic mechanisms and molecular pathways resulting in multiple clinical signs. A recently described monogenic neurodevelopmental syndrome named Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is caused by haploinsufficiency.

The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1.

Increasing evidence suggests that neurodevelopmental alterations might contribute to increase the susceptibility to develop neurodegenerative diseases. We investigate the occurrence of developmental abnormalities in dopaminergic neurons in a model of Parkinson's disease (PD). We monitor the differentiation of human patient-specific neuroepithelial stem cells (NESCs) into dopaminergic neurons.

Pathogenic variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously.

Optimized Immunostaining of Embryonic and Early Postnatal Mouse Brain Sections.

The mammalian neocortex, the outer layer of the cerebrum and most recently evolved brain region, is characterized by its unique areal and laminar organization. Distinct cortical layers and areas can be identified by the protein expression of graded transcription factors and molecular determinants that define the identity of different projection neurons. Thus, specific detection and visualization of protein expression is crucial for assessing the identity of neocortical neurons and, more broadly, for understanding early and late developmental mechanisms and function of this complex system.

Dynamic expression of NR2F1 and SOX2 in developing and adult human cortex: comparison with cortical malformations.

The neocortex, the most recently evolved brain region in mammals, is characterized by its unique areal and laminar organization. Distinct cortical layers and areas can be identified by the presence of graded expression of transcription factors and molecular determinants defining neuronal identity. However, little is known about the expression of key master genes orchestrating human cortical development.

COUP-TFI/Nr2f1 Orchestrates Intrinsic Neuronal Activity during Development of the Somatosensory Cortex.

The formation of functional cortical maps in the cerebral cortex results from a timely regulated interaction between intrinsic genetic mechanisms and electrical activity. To understand how transcriptional regulation influences network activity and neuronal excitability within the neocortex, we used mice deficient for Nr2f1 (also known as COUP-TFI), a key determinant of primary somatosensory (S1) area specification during development. We found that the cortical loss of Nr2f1 impacts on spontaneous network activity and synchronization of S1 cortex at perinatal stages.

A perspective view on the nanomotion detection of living organisms and its features.

The insurgence of newly arising, rapidly developing health threats, such as drug-resistant bacteria and cancers, is one of the most urgent public-health issues of modern times. This menace calls for the development of sensitive and reliable diagnostic tools to monitor the response of single cells to chemical or pharmaceutical stimuli. Recently, it has been demonstrated that all living organisms oscillate at a nanometric scale and that these oscillations stop as soon as the organisms die.

Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome.

Optic nerve atrophy represents the most common form of hereditary optic neuropathies leading to vision impairment. The recently described Bosch-Boonstra-Schaaf optic atrophy (BBSOA) syndrome denotes an autosomal dominant genetic form of neuropathy caused by mutations or deletions in the NR2F1 gene. Herein, we describe a mouse model recapitulating key features of BBSOA patients-optic nerve atrophy, optic disc anomalies, and visual deficits-thus representing the only available mouse model for this syndrome.

The microRNA miR-21 Is a Mediator of FGF8 Action on Cortical COUP-TFI Translation.

The morphogen FGF8 plays a pivotal role in neocortical area patterning through its inhibitory effect on COUP-TFI/Nr2f1 anterior expression, but its mechanism of action is poorly understood. We established an in vitro model of mouse embryonic stem cell corticogenesis in which COUP-TFI protein expression is inhibited by the activation of FGF8 in a time window corresponding to cortical area patterning. Interestingly, overexpression of the COUP-TFI 3'UTR reduces the inhibitory effect of FGF8 on COUP-TFI translation.

The pleiotropic transcriptional regulator COUP-TFI plays multiple roles in neural development and disease.

Transcription factors are expressed in a dynamic fashion both in time and space during brain development, and exert their roles by activating a cascade of multiple target genes. This implies that understanding the precise function of a transcription factor becomes a challenging task. In this review, we will focus on COUP-TFI (or NR2F1), a nuclear receptor belonging to the superfamily of the steroid/thyroid hormone receptors, and considered to be one of the major transcriptional regulators orchestrating cortical arealization, cell-type specification and maturation.

Nanomotion Detection Method for Testing Antibiotic Resistance and Susceptibility of Slow-Growing Bacteria.

Infectious diseases are caused by pathogenic microorganisms and are often severe. Time to fully characterize an infectious agent after sampling and to find the right antibiotic and dose are important factors in the overall success of a patient's treatment. Previous results suggest that a nanomotion detection method could be a convenient tool for reducing antibiotic sensitivity characterization time to several hours.

Rn7SK small nuclear RNA is involved in neuronal differentiation.

Rn7SK-mediated global transcriptional regulation, key function of this small nuclear RNA (snRNA), is mediated by inhibition of the positive transcription elongation factor b (P-TEFb). Recently, we have identified a potential anti-proliferative and tumor-suppressive function of Rn7SK. However, its possible regulatory role in development and cell programming has not been investigated so far.

COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal Cxcr4 expression.

Development of the dentate gyrus (DG), the primary gateway for hippocampal inputs, spans embryonic and postnatal stages, and involves complex morphogenetic events. We have previously identified the nuclear receptor COUP-TFI as a novel transcriptional regulator in the postnatal organization and function of the hippocampus. Here, we dissect its role in DG morphogenesis by inactivating it in either granule cell progenitors or granule neurons.

RISC-mediated control of selected chromatin regulators stabilizes ground state pluripotency of mouse embryonic stem cells.

Background: Embryonic stem cells are intrinsically unstable and differentiate spontaneously if they are not shielded from external stimuli. Although the nature of such instability is still controversial, growing evidence suggests that protein translation control may play a crucial role.

Results: We performed an integrated analysis of RNA and proteins at the transition between naïve embryonic stem cells and cells primed to differentiate.

Current practice in Latin America of flexible ureterorenoscopy with laser for treating kidney stones.

Introduction: The use of flexible ureterorenoscopy for treating kidney stones has increased in recent years, with considerable worldwide variation in the surgical technique and indications.

Objectives: To determine the current practice, technique variations, use and indications of flexible ureterorenoscopy for treating kidney stones in Latin American.

Methods: We sent (by email and web link) an anonymous questionnaire with 30 questions on flexible ureterorenoscopy for treating kidney stones to Latin American urologists from January 2015 to July 2015.

Activin/Nodal Signaling Supports Retinal Progenitor Specification in a Narrow Time Window during Pluripotent Stem Cell Neuralization.

Retinal progenitors are initially found in the anterior neural plate region known as the eye field, whereas neighboring areas undertake telencephalic or hypothalamic development. Eye field cells become specified by switching on a network of eye field transcription factors, but the extracellular cues activating this network remain unclear. In this study, we used chemically defined media to induce in vitro differentiation of mouse embryonic stem cells (ESCs) toward eye field fates.

The double inhibition of endogenously produced BMP and Wnt factors synergistically triggers dorsal telencephalic differentiation of mouse ES cells.

Embryonic stem (ES) cells are becoming a popular model of in vitro neurogenesis, as they display intrinsic capability to generate neural progenitors that undergo the known steps of in vivo neural development. These include the acquisition of distinct regional fates, which depend on growth factors and signals that are present in the culture medium. The control of the intracellular signaling that is active at different steps of ES cell neuralization, even when cells are cultured in chemically defined medium, is complicated by the endogenous production of growth factors.

From pluripotency to forebrain patterning: an in vitro journey astride embryonic stem cells.

Embryonic stem cells (ESCs) have been used extensively as in vitro models of neural development and disease, with special efforts towards their conversion into forebrain progenitors and neurons. The forebrain is the most complex brain region, giving rise to several fundamental structures, such as the cerebral cortex, the hypothalamus, and the retina. Due to the multiplicity of signaling pathways playing different roles at distinct times of embryonic development, the specification and patterning of forebrain has been difficult to study in vivo.