Search

Adaptive gain theory proposes that the dynamic shifts between exploration and exploitation control states are modulated by the locus coeruleus-norepinephrine system and reflected in tonic and phasic pupil diameter. This study tested predictions of this theory in the context of a societally important visual search task: the review and interpretation of digital whole slide images of breast biopsies by physicians (pathologists). As these medical images are searched, pathologists encounter difficult visual features and intermittently zoom in to examine features of interest. We propose that tonic and phasic pupil diameter changes during image review may correspond to perceived difficulty and dynamic shifts between exploration and exploitation control states. To examine this possibility, we monitored visual search behavior and tonic and phasic pupil diameter while pathologists (N = 89) interpreted 14 digital images of breast biopsy tissue (1,246 total images reviewed). After viewing the images, pathologists provided a diagnosis and rated the level of difficulty of the image. Analyses of tonic pupil diameter examined whether pupil dilation was associated with pathologists difficulty ratings, diagnostic accuracy, and experience level. To examine phasic pupil diameter, we parsed continuous visual search data into discrete zoom-in and zoom-out events, including shifts from low to high magnification (e.g., 1× to 10×) and the reverse. Analyses examined whether zoom-in and zoom-out events were associated with phasic pupil diameter change. Results demonstrated that tonic pupil diameter was associated with image difficulty ratings and zoom level, and phasic pupil diameter showed constriction upon zoom-in events, and dilation immediately preceding a zoom-out event. Results are interpreted in the context of adaptive gain theory, information gain theory, and the monitoring and assessment of physicians diagnostic interpretive processes.

ObjectiveAutosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality.MethodsLinkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.ResultsWe defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied.InterpretationSSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.

The basis of immune evasion, a hallmark of cancer, can differ even when cancers arise from one cell type such as in the human skin keratinocyte carcinomas: basal and squamous cell carcinoma. Here we showed that the basal cell carcinoma tumorinitiating cell surface protein CD200, through ectodomain shedding, was responsible for the near absence of NK cells within the basal cell carcinoma tumor microenvironment. In situ, CD200 underwent ectodomain shedding by metalloproteinases MMP3 and MMP11, which released biologically active soluble CD200 into the basal cell carcinoma microenvironment. CD200 bound its cognate receptor on NK cells to suppress MAPK pathway signaling that in turn blocked indirect (IFN-[gamma] release) and direct cell killing. In addition, reduced ERK phosphorylation relinquished negative regulation of PPAR[gamma]- regulated gene transcription and led to membrane accumulation of the Fas/FADD death receptor and its ligand, FasL, which resulted in activation-induced apoptosis. Blocking CD200 inhibition of MAPK or PPAR[gamma] signaling restored NK cell survival and tumor cell killing, with relevance to many cancer types. Our results thus uncover a paradigm for CD200 as a potentially novel and targetable NK cell-specific immune checkpoint, which is responsible for NK cell-associated poor outcomes in many cancers., Introduction Epithelia are constantly exposed to environmental carcinogens and as such epithelial cancers, carcinomas, are the commonest adult malignancies and cancer-associated mortality. The transformation of epithelial tissues, carcinogenesis, is often [...]

In nerve terminals, neurotransmitters are packaged in synaptic vesicles, and released by exocytosis. Empty synaptic vesicles are rapidly recycled for reuse by endocytosis. Much progress has been made in identifying the proteins involved in synaptic-vesicle trafficking, but the mechanism and regulation of endocytosis have largely remained an enigma. One approach to defining regulatory proteins that might be involved is to study stimulus-dependent phosphorylation events in nerve terminals. This has led to the identification of dephosphin, which is quantitatively dephosphorylated by nerve-terminal depolarization. Sequencing reveals that dephosphin is identical with dynamin I, a GTP-binding protein that functions in endocytosis. Phosphorylation and dephosphorylation of nerve-terminal dynamin I/dephosphin regulates its intrinsic GTPase activity in parallel with the regulation of synaptic-vesicle recycling. Therefore, phosphorylation and dephosphorylation of dynamin I might provide a [Ca.sup.2+]-dependent switch for endocytosis in the synaptic-vesicle pathway.