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The salience of a visual stimulus is often reduced by nearby stimuli, an effect known as surround suppression of perceived contrast, which may help in locating the borders of an object. Weaker surround suppression has been observed in schizophrenia but it is unclear whether this abnormality is present in other mental disorders with similar symptomatology, or is evident in people with genetic liability for schizophrenia. By examining surround suppression among subjects with schizophrenia or bipolar affective disorder, their unaffected biological relatives and healthy controls we sought to determine whether diminished surround suppression was specific to schizophrenia, and if subjects with a genetic risk for either disorder would show similar deficits. Measuring perceived contrast in different surround conditions also allowed us to investigate how this suppression depends on the similarity of target and surrounding stimuli. Surround suppression was weaker among schizophrenia patients regardless of surround configuration. Subjects with bipolar affective disorder showed an intermediate deficit, with stronger suppression than in schizophrenia but weaker than control subjects. Surround suppression was normal in relatives of both patient groups. Findings support a deficit in broadly tuned (rather than sharply orientation- or direction-selective) suppression mechanisms. Weak broadly tuned suppression during visual perception is evident in schizophrenia and bipolar affective disorder, consistent with impaired gain control related to the clinical expression of these conditions.

Variations in the Crumbs homolog-1 (CRB1) gene are associated with a wide variety of autosomal recessive retinal dystrophies, including early onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). CRB1 belongs to the Crumbs family, which in mammals includes CRB2 and CRB3. Here, we studied the specific roles of CRB2 in rod photoreceptor cells and whether ablation of CRB2 in rods exacerbates the Crb1-disease. Therefore, we assessed the morphological, retinal, and visual functional consequences of specific ablation of CRB2 from rods with or without concomitant loss of CRB1. Our data demonstrated that loss of CRB2 in mature rods resulted in RP. The retina showed gliosis and disruption of the subapical region and adherens junctions at the outer limiting membrane. Rods were lost at the peripheral and central superior retina, while gross retinal lamination was preserved. Rod function as measured by electroretinography was impaired in adult mice. Additional loss of CRB1 exacerbated the retinal phenotype leading to an early reduction of the dark-adapted rod photoreceptor a-wave and reduced contrast sensitivity from 3-months-of-age, as measured by optokinetic tracking reflex (OKT) behavior testing. The data suggest that CRB2 present in rods is required to prevent photoreceptor degeneration and vision loss.

Despite the large amount of variation found in the night (scotopic) vision capabilities of healthy volunteers, little effort has been made to characterize this variation and factors, genetic and non-genetic, that influence it. In the largest population of healthy observers measured for scotopic visual acuity (VA) and contrast sensitivity (CS) to date, we quantified the effect of a range of variables on visual performance. We found that young volunteers with excellent photopic vision exhibit great variation in their scotopic VA and CS, and this variation is reliable from one testing session to the next. We additionally identified that factors such as Circadian preference, iris color, astigmatism, depression, sex and education have no significant impact on scotopic visual function. We confirmed previous work showing that the amount of time spent on the vision test influences performance and that laser eye surgery results in worse scotopic vision. We also showed a significant effect of intelligence and photopic visual performance on scotopic VA and CS, but all of these variables collectively explain <30% of the variation in scotopic vision. The wide variation seen in young healthy volunteers with excellent photopic vision, the high test-retest agreement, and the vast majority of the variation in scotopic vision remaining unexplained by obvious non-genetic factors suggests a strong genetic component. Our preliminary genome-wide association study (GWAS) of 106 participants ruled out any common genetic variants of very large effect and paves the way for future, larger genetic studies of scotopic vision.

Wolfram syndrome is an early onset genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1-/- mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs) were performed in Wfs1-/- and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC) abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP), protein disulfide isomerase (PDI) and inositol-requiring enzyme 1 alpha (Ire1α) markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1-/- mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1-/- mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1-/- optic pathways.

As an epigenetic modulator of gene expression, Methyl-CpG binding protein 2 (MeCP2) is essential for normal neurological function. Dysfunction of MeCP2 is associated with a variety of neurological disorders. MECP2 gene duplication in human causes neuropsychiatric symptoms such as mental retardation and autism. MeCP2 overexpression in mice results in neurobehavioural disorders, dendritic abnormalities, and synaptic defects. However, how gain of MeCP2 function influences cortical processing of sensory information remains unclear. In this study, we examined visual processing in a mouse model of MECP2 duplication syndrome (MECP2 Tg1 mouse) at 8 and 14 weeks, which were before and after the onset of behavioural symptoms, respectively. In vivo extracellular recordings from primary visual cortex (V1) showed that neurons in Tg1 mice at both adult ages preferred higher spatial frequencies (SFs) than those in wild-type (WT) littermate controls, and the semi-saturation contrasts of neurons were lower in Tg1 mice at 8 weeks but not at 14 weeks. Behavioural experiments showed that the performance for visual detection at high SFs and low contrasts was higher in MECP2 Tg1 mice. Thus, MeCP2 gain-of-function in mice leads to higher visual acuity and contrast sensitivity, both at the levels of cortical response and behavioural performance.

Regulation of ion and pH homeostasis is essential for normal neuronal function. The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. Here we show that NCBE is strongly expressed in the retina. As GABA(A) receptors conduct both chloride and bicarbonate, we hypothesized that NCBE may be relevant for GABAergic transmission in the retina. Importantly, we found a differential expression of NCBE in bipolar cells: whereas NCBE was expressed on ON and OFF bipolar cell axon terminals, it only localized to dendrites of OFF bipolar cells. On these compartments, NCBE colocalized with the main neuronal chloride extruder KCC2, which renders GABA hyperpolarizing. NCBE was also expressed in starburst amacrine cells, but was absent from neurons known to depolarize in response to GABA, like horizontal cells. Mice lacking NCBE showed decreased visual acuity and contrast sensitivity in behavioral experiments and smaller b-wave amplitudes and longer latencies in electroretinograms. Ganglion cells from NCBE-deficient mice also showed altered temporal response properties. In summary, our data suggest that NCBE may serve to maintain intracellular chloride and bicarbonate concentration in retinal neurons. Consequently, lack of NCBE in the retina may result in changes in pH(i) regulation and chloride-dependent inhibition, leading to altered signal transmission and impaired visual function.

We describe here the morphological and functional alterations of the retina of mutant zebrafish, night blindness c ( nbc ). The nbc mutant was isolated from the F1 generation of N -ethyl- N -nitrosourea mutagenized founders. Visual sensitivity of wildtype and heterozygous ( nbc (+/-)) mutant fish was determined using a behavioral assay based on visually mediated escape responses. Histology, immunocytochemistry, and electroretinography were used to study structural and functional changes of the outer retina. The behavioral visual response of nbc (+/-) mutants started to deteriorate at 12 months of age. Considerable variations existed between the extents of retinal degeneration of individual fish. In the most severe cases, both rod and cone outer segments were degenerated. In moderate cases, only rod outer segments were affected. Yet in other cases, no degeneration was detected. The retina of homozygous ( nbc (-/-)) larvae had a normal appearance. However, they develop abnormally and died before 9 days post fertilization. In conclusion, nbc causes late-onset and progressive dominant retinal degeneration of both rod and cone photoreceptor cells. However, nbc is not a retina-specific gene, as the homozygous fish displayed extra-retinal defects.

ObjectivesTo investigate whether CT-based radiomics signature can predict KRAS/NRAS/BRAF mutations in colorectal cancer (CRC).MethodsThis retrospective study consisted of a primary cohort (n = 61) and a validation cohort (n = 56) with pathologically confirmed CRC. Patients underwent KRAS/NRAS/BRAF mutation tests and contrast-enhanced CT before treatment. A total of 346 radiomics features were extracted from portal venous-phase CT images of the entire primary tumour. Associations between the genetic mutations and clinical background, tumour staging, and histological differentiation were assessed using univariate analysis. RELIEFF and support vector machine methods were performed to select key features and build a radiomics signature.ResultsThe radiomics signature was significantly associated with KRAS/NRAS/BRAF mutations (P < 0.001). The area under the curve, sensitivity, and specificity for predicting KRAS/NRAS/BRAF mutations were 0.869, 0.757, and 0.833 in the primary cohort, respectively, while they were 0.829, 0.686, and 0.857 in the validation cohort, respectively. Clinical background, tumour staging, and histological differentiation were not associated with KRAS/NRAS/BRAF mutations in both cohorts (P>0.05).ConclusionsThe proposed CT-based radiomics signature is associated with KRAS/NRAS/BRAF mutations. CT may be useful for analysis of tumour genotype in CRC and thus helpful to determine therapeutic strategies.Key Points• Key features were extracted from CT images of the primary colorectal tumour.• The proposed radiomics signature was significantly associated with KRAS/NRAS/BRAF mutations.• In the primary cohort, the proposed radiomics signature predicted mutations.• Clinical background, tumour staging, and histological differentiation were unable to predict mutations.

Purpose With the updated World Health Organization (WHO) 2016 neuropathological diagnostic criteria, radiographic prognostic associations in lower-grade gliomas (LGG, WHO grade II and III) are undergoing re-evaluation. Methods We identified 316 LGG patients (151 grade II and 165 grade III) for a combined cohort from three independent databases. We analyzed the preoperative axial FLAIR, axial T2-weighted and post-gadolinium volumetric T1-weighted MR images. The molecular data collected included the status of IDH1 / 2, TP53, TERT promoter and ATRX mutations, in addition to 1p/19q co-deletions. In a subset of cases (n = 133), we assessed the “T2-FLAIR mismatch” sign. Results Gliomas were assigned to one of the three molecular groups: Group O ( IDH -mutant, 1p/19q co-deleted oligodendrogliomas, n = 95), Group A ( IDH -mutant, ATRX inactivated astrocytomas, n = 175) and Group G ( IDH wild-type, GBM-like, n = 46). A contrast-enhancing tumor was seen in 98 patients (31%), most frequently in Group G (n = 28/45, 57%), when compared to Group A (n = 49/175, 28%) and Group O (n = 24/95, 25.3%) tumors (p = 0.008 and p = 0.0011, respectively). Consistent with previous reports, T2-FLAIR mismatch was preferentially found in Group A tumors (73.1%, 60 of 82), although its presence was not associated with survival, after controlling for molecular group. False positive mismatch sign was noted in 28.5% (12/42) Group O tumors, but none of the tumors in Group G. A combination of all three factors: age under 40 years at first diagnosis, a tumor size larger than 6 cm and T2-FLAIR mismatch was highly specific for IDH mutant astrocytoma (Group A). Conclusion We identify radiographic correlates of molecular groups in lower-grade gliomas, which join clinical demographic features in defining the characteristic presentation of these tumors. Radiographic correlates of prognosis in LGG require re-evaluation within molecular group.

Desiccation tolerance is an ancient and complex trait that spans all major lineages of life on earth. Although important in the evolution of land plants, the mechanisms that underlay this complex trait are poorly understood, especially for vegetative desiccation tolerance (VDT). The lack of suitable closely related plant models that offer a direct contrast between desiccation tolerance and sensitivity has hampered progress. We have assembled high-quality genomes for two closely related grasses, the desiccation-tolerant Sporobolus stapfianus and the desiccation-sensitive Sporobolus pyramidalis. Both species are complex polyploids; S. stapfianus is primarily tetraploid, and S. pyramidalis is primarily hexaploid. S. pyramidalis undergoes a major transcriptome remodeling event during initial exposure to dehydration, while S. stapfianus has a muted early response, with peak remodeling during the transition between 1.5 and 1.0 grams of water (gH₂O) g−1 dry weight (dw). Functionally, the dehydration transcriptome of S. stapfianus is unrelated to that for S. pyramidalis. A comparative analysis of the transcriptomes of the hydrated controls for each species indicated that S. stapfianus is transcriptionally primed for desiccation. Cross-species comparative analyses indicated that VDT likely evolved from reprogramming of desiccation tolerance mechanisms that evolved in seeds and that the tolerance mechanism of S. stapfianus represents a recent evolution for VDT within the Chloridoideae. Orthogroup analyses of the significantly differentially abundant transcripts reconfirmed our present understanding of the response to dehydration, including the lack of an induction of senescence in resurrection angiosperms. The data also suggest that failure to maintain protein structure during dehydration is likely critical in rendering a plant desiccation sensitive.