Disease-causing mutations in genes encoding transcription factors critical for photoreceptor development

Photoreceptor development of the vertebrate visual system is controlled by a complex transcription regulatory network. OTX2 is expressed in the mitotic retinal progenitor cells (RPCs) and controls photoreceptor genesis. CRX that is activated by OTX2 is expressed in photoreceptor precursors after cell cycle exit. NEUROD1 is also present in photoreceptor precursors that are ready to specify into rod and cone photoreceptor subtypes. NRL is required for the rod fate and regulates downstream rod-specific genes including the orphan nuclear receptor NR2E3 which further activates rod-specific genes and simultaneously represses cone-specific genes. Cone subtype specification is also regulated by the interplay of several transcription factors such as THRB and RXRG. Mutations in these key transcription factors are responsible for ocular defects at birth such as microphthalmia and inherited photoreceptor diseases such as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and allied dystrophies. In particular, many mutations are inherited in an autosomal dominant fashion, including the majority of missense mutations i

Disease-causing mutations in genes encoding transcription factors critical for photoreceptor development

Photoreceptor development of the vertebrate visual system is controlled by a complex transcription regulatory network. OTX2 is expressed in the mitotic retinal progenitor cells (RPCs) and controls photoreceptor genesis. CRX that is activated by OTX2 is expressed in photoreceptor precursors after cell cycle exit. NEUROD1 is also present in photoreceptor precursors that are ready to specify into rod and cone photoreceptor subtypes. NRL is required for the rod fate and regulates downstream rod-specific genes including the orphan nuclear receptor NR2E3 which further activates rod-specific genes and simultaneously represses cone-specific genes. Cone subtype specification is also regulated by the interplay of several transcription factors such as THRB and RXRG. Mutations in these key transcription factors are responsible for ocular defects at birth such as microphthalmia and inherited photoreceptor diseases such as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and allied dystrophies. In particular, many mutations are inherited in an autosomal dominant fashion, including the majority of missense mutations in CRX and NRL. In this review, we describe the spectrum of photoreceptor defects that are associated with mutations in the above-mentioned transcription factors, and summarize the current knowledge of molecular mechanisms underlying the pathogenic mutations. At last, we deliberate the outstanding gaps in our understanding of the genotype–phenotype correlations and outline avenues for future research of the treatment strategies

Essential functions of MLL1 and MLL2 in retinal development and cone cell maintenance

MLL1 (KMT2A) and MLL2 (KMT2B) are homologous members of the mixed-lineage leukemia (MLL) family of histone methyltransferases involved in epigenomic transcriptional regulation. Their sequence variants have been associated with neurological and psychological disorders, but little is known about their roles and mechanism of action in CNS development. Using mouse retina as a model, we previously reported MLL1\u27s role in retinal neurogenesis and horizontal cell maintenance. Here we determine roles of MLL2 and MLL1/MLL2 together in retinal development using conditional knockout (CKO) mice. Deletin

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here, we us

Smart Meters Integration in Distribution System State Estimation with Collaborative Filtering and Deep Gaussian Process

The problem of state estimations for electric distribution system is considered. A collaborative filtering approach is proposed in this paper to integrate the slow time-scale smart meter measurements in the distribution system state estimation, in which the deep Gaussian process is incorporated to infer the fast time-scale pseudo measurements and avoid anomalies. Numerical tests have demonstrated the higher estimation accuracy of the proposed method

Nonlinear flow in low permeability reservoirs: Modelling and experimental verification

The low-permeability reservoirs are of heavy heterogeneity, low permeability, fine oil-water passages, strong resistance during flow, and the significant interaction between solid and liquid interfaces causes the flow of fluid in reservoir deviating from the Darcy’s law. There is no agreement on the interaction between the various factors in seepage process and the influence of seepage law. The boundary layer exists when liquid flow in micro-tubes and nano-tubes, and the boundary layer decreases with the increase of driving force, and the maximum value of boundary layer ratio is equal to 1. Based on the capillary boundal model and the boundary layer theory, a new exponential seepage model for low permeability reservoirs was proposed. Some experiments of water flow with different pressure gradient were carried out in low permeability cores with permeability of 4 to 8 milidarcy in natural rock cores from an oilfield in China, and the nonlinear model is of good agreement with the single-phase water flooding experiments of these cores. The results demonstrate that the physical meaning of each parameter of the new model is clear and it can be applied to describe the nonlinear characteristics of low permeability reservoirs. The large driving force can overcome disadvantages in the developments of low permeability reservoirs.Cited as: Song, F., Bo, L., Zhang, S., Sun, Y. Nonlinear flow in low permeability reservoirs: Modelling and experimental verification. Advances in Geo-Energy Research, 2019, 3(1): 76-81, doi: 10.26804/ager.2019.01.0

Topography, structural and exhumation history of the Admiralty Mountains region, northern Victoria Land, Antarctica

International audience; The Admiralty Mountains region forms the northern termination of the northern Victoria Land, Antarctica. Few quantitative data are available to reconstruct the Cenozoic morpho-tectonic evolution of this sector of the Antarctic plate, where the Admiralty Mountains region forms the northern termination of the western shoulder of the Mesozoic-Cenozoic West Antarctica Rift System. In this study we combine new low-temperature thermochronological data (apatite fission-track and (U-Th-Sm)/He analyses) with structural and topography analysis. The regional pattern of the fission-track ages shows a general tendency to older ages (80–60 Ma) associated with shortened mean track-lengths in the interior, and younger fission-track ages clustering at 38–26 Ma with long mean track-lengths in the coastal region. Differently from other regions of Victoria Land, the younger ages are found as far as 50–70 km inland. Single grain apatite (U-Th-Sm)/He ages cluster at 50–30 Ma with younger ages in the coastal domain. Topography analysis reveals that the Admiralty Mountains has high local relief, with an area close to the coast, 180 km long and 70 km large, having the highest local relief of >2500 m. This coincides with the location of the youngest fission-track ages. The shape of the area with highest local relief matches the shape of a recently detected low velocity zone beneath the northern TAM, indicating that high topography of the Admiralty Mountains region is likely sustained by a mantle thermal anomaly. We used the obtained constraints on the amount of removed crustal section to reconstruct back-eroded profiles and calculate the erosional load in order to test flexural uplift models. We found that our back-eroded profiles are better reproduced by a constant elastic thickness of intermediate values (Te = 20–30 km). This suggests that, beneath the Admiralty Mountains, the elastic properties of the lithosphere are different with respect to other TAM sectors, likely due to a stationary Cenozoic upper mantle thermal anomaly in the region

Pathogenic variants in CRX have distinct cis-regulatory effects on enhancers and silencers in photoreceptors

Dozens of variants in the gene for the homeodomain transcription factor (TF) cone-rod homeobox