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Missing visual information, such as a gap between an object or an occluded view, has been shown to disrupt visual search and make amodal completion inefficient. Previous research, using simple black bars as stimuli, failed to show a pop-out effect (flat search slope across increasing visual set sizes) during a feature search when the target was partially occluded, but not in cases where it was fully visible. We wanted to see if this lack of a pop-out effect during feature (orientation) search extended to complex objects (Experiment 1) and identity search (Experiment 2). Participants completed orientation and identity visual search tasks by deciding whether the target was present or not present. Bayesian analyses was conducted to find evidence for observed data to be under the null (pop-out effects) or alternative hypotheses (differences in search slopes). When no occluders or gaps were present, a pop-out effect occurred when searching for a simple objects' orientation or identity. In addition, object complexity affected identity search, with anecdotal evidence suggesting that some complex object may not show a pop-out effect. Furthermore, white occluding bars were more disruptive than having a gap of visual information for feature search but not for identity search. Overall, pop-out effects do occur for simple objects, but when the task is more difficult, search for real-world objects is greatly affected by any type of visual disruption.

The Kv11.1 voltage-gated potassium channel, encoded by the KCNH2 gene, conducts the rapidly activating delayed rectifier current in the heart. KCNH2 pre-mRNA undergoes alternative polyadenylation to generate two C-terminal Kv11.1 isoforms in the heart. Utilization of a poly(A) signal in exon 15 produces the full-length, functional Kv11.1a isoform, while intron 9 polyadenylation generates the C-terminally truncated, nonfunctional Kv11.1a-USO isoform. The relative expression of Kv11.1a and Kv11.1a-USO isoforms plays an important role in the regulation of Kv11.1 channel function. In this study, we tested the hypothesis that the RNA polyadenylate binding protein nuclear 1 (PABPN1) interacts with a unique 22 nt adenosine stretch adjacent to the intron 9 poly(A) signal and regulates KCNH2 pre-mRNA alternative polyadenylation and the relative expression of Kv11.1a C-terminal isoforms. We showed that PABPN1 inhibited intron 9 poly(A) activity using luciferase reporter assays, tandem poly(A) reporter assays, and RNA pulldown assays. We also showed that PABPN1 increased the relative expression level of the functional Kv11.1a isoform using RNase protection assays, immunoblot analyses, and patch clamp recordings. Our present findings suggest a novel role for the RNA-binding protein PABPN1 in the regulation of functional and nonfunctional Kv11.1 isoform expression.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca 2+ signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP 3 )-mediated Ca 2+ release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism – fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca 2+ signals in human primary skin fibroblasts. Our results indicate that IP 3 -mediated Ca 2+ release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP 3 -mediated Ca 2+ signaling represent a convergent hub function shared across the spectrum of autistic disorders – whether caused by rare highly penetrant mutations or sporadic forms – and holds promise as a biomarker for diagnosis and novel drug discovery.

A major challenge for clustering algorithms is to balance the trade-off between homogeneity, i.e. , the degree to which an individual cluster includes only related sequences, and completeness, the degree to which related sequences are broken up into multiple clusters. Most algorithms are conservative in grouping sequences with other sequences. Remote homologs may fail to be clustered together and instead form unnecessarily distinct clusters. The resulting clusters have high homogeneity but completeness that is too low. We propose Complet+, a computationally scalable post-processing method to increase the completeness of clusters without an undue cost in homogeneity. Complet+ proves to effectively merge closely-related clusters of protein that have verified structural relationships in the SCOPe classification scheme, improving the completeness of clustering results at little cost to homogeneity. Applying Complet+ to clusters obtained using MMseqs2’s clusterupdate achieves an increased V-measure of 0.09 and 0.05 at the SCOPe superfamily and family levels, respectively. Complet+ also creates more biologically representative clusters, as shown by a substantial increase in Adjusted Mutual Information (AMI) and Adjusted Rand Index (ARI) metrics when comparing predicted clusters to biological classifications. Complet+ similarly improves clustering metrics when applied to other methods, such as CD-HIT and linclust. Finally, we show that Complet+ runtime scales linearly with respect to the number of clusters being post-processed on a COG dataset of over 3 million sequences. Code and supplementary information is available on Github: https://github.com/EESI/Complet-Plus .

Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence‐based guidelines. This systematic review aims to understand enablers and barriers to pharmacogenomics implementation in pediatric oncology by assessing the knowledge, attitudes, and practice of healthcare professionals and consumers. Medline, Embase, Emcare, and PsycINFO database searches identified 146 relevant studies of which only three met the inclusion criteria. These studies reveal that consumers were concerned with pharmacogenomic test costs, insurance discrimination, data sharing, and privacy. Healthcare professionals possessed mostly positive attitudes toward pharmacogenomic testing yet identified lack of experience and training as barriers to implementation. Education emerged as the key enabler, reported in all three studies and both healthcare professionals and consumer groups. However, despite the need for education, no studies utilizing a pediatric oncology consumer or healthcare professional group have reported on the implementation or analysis of a pharmacogenomic education program in pediatric oncology. Increased access to guidelines, expert collaborations and additional guidance interpreting results were further enablers established by healthcare professionals. The themes identified mirror those reported in broader pediatric genetic testing literature. As only a small number of studies met inclusion criteria for this review, further research is warranted to elicit implementation determinants and advance pediatric pharmacogenomics.

The ezrin-radixin-moesin (ERM) family of proteins have emerged as key regulatory molecules in linking F-actin to specific membrane proteins, especially in cell surface structures. Merlin, the product of the NF2 tumor suppressor gene, has sequence similarity to ERM proteins and binds to some of the same membrane proteins, but lacks a C-terminal F-actin binding site. In this review we discuss how ERM proteins and merlin are negatively regulated by an intramolecular association between their N- and C-terminal domains. Activation of at least ERM proteins can be accomplished by C-terminal phosphorylation in the presence of PIP2. We also discuss membrane proteins to which ERM and merlin bind, including those making an indirect linkage through the PDZ-containing adaptor molecules EBP50 and E3KARP. Finally, the function of these proteins in cortical structure, endocytic traffic, signal transduction, and growth control is discussed.

Flagellar length is tightly regulated in the biflagellate alga Chlamydomonas reinhardtii. Several genes required for control of flagellar length have been identified, including LF1, a gene required to assemble normal-length flagella. The lf1 mutation causes cells to assemble extra-long flagella and to regenerate flagella very slowly after amputation. Here we describe the positional cloning and molecular characterization of the LF1 gene using a bacterial artificial chromosome (BAC) library. LF1 encodes a protein of 804 amino acids with no obvious sequence homologs in other organisms. The single LF1 mutant allele is caused by a transversion that produces an amber stop at codon 87. Rescue of the lf1 phenotype upon transformation was obtained with clones containing the complete LF1 gene as well as clones that lack the last two exons of the gene, indicating that only the amino-terminal portion of the LF1 gene product (LF1p) is required for function. Although LF1 helps regulate flagellar length, the LF1p localizes almost exclusively in the cell body, with <1% of total cellular LF1p localizing to the flagella.

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) ( n  = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk. Analysis of rare protein-truncating, damaging missense and copy number variants from exome sequencing of 63,237 individuals identifies 72 genes associated with autism spectrum disorder.

Thyroid hormones (thyroxine, T4, and triiodothyronine, T3) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5–10% of the world’s population. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), a large iodoglycoprotein consisting of upstream regions I-II-III (responsible for synthesis of most T4) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T3, which can also be generated extrathyroidally by T4 deiodination). Using CRISPR/Cas9-mediated mutagenesis, we engineered a knock-in of secretory ChEL into the endogenous TG locus. Secretory ChEL acquires Golgi-type glycans and is properly delivered to the thyroid follicle lumen, where T3 is first formed. Homozygous knock-in mice are capable of thyroidal T3 synthesis but largely incompetent for T4 synthesis such that T4-to-T3 conversion contributes little. Instead, T3 production is regulated thyroidally by thyrotropin (TSH). Compared to cog/cog mice with conventional hypothyroidism (low serum T4 and T3), the body size of ChEL-knock-in mice is larger; although, these animals with profound T4 deficiency did exhibit a marked elevation of serum TSH and a large goiter, despite normal circulating T3 levels. ChEL knock-in mice exhibited a normal expression of hepatic markers of thyroid hormone action but impaired locomotor activities and increased anxiety-like behavior, highlighting tissue-specific differences in T3 versus T4 action, reflecting key considerations in patients receiving thyroid hormone replacement therapy.

Abstract Disclosure: C.E. Citterio: None. B. Morales-Rodriguez: None. X. Liao: None. C. Vu: None. R. Nguyen: None. J. Tsai: None. J. Le: None. I. Metawea: None. M. Liu: None. D.P. Olson: None. S. Refetoff: None. P. Arvan: None. Thyroid hormones (T4 and T3) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5-10% of the world’s population. T3 and T4 may make distinct contributions to the physiology of different organ systems, and a subset of hypothyroid patients treated with T4 do not fully normalize their symptoms despite achieving normal TSH levels. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), consisting of upstream regions I-II-III (responsible for synthesis of most T4) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T3, which can also be generated extrathyroidally by T4 deiodination). Genetically-engineered mice with a thyroid gland designed for disproportionate T3 generation from the T3-forming ChEL domain of Tg, named ChEL-KI, are capable of thyroidal T3 synthesis but largely incompetent for T4 synthesis such that T4-to-T3 conversion contributes little. We have examined the physiology of a thyroidally-derived T3-centric hormonal environment. Compared to cog/cog mice with conventional hypothyroidism (low serum T4and T3), body size was greater in ChEL-KI mice; although these animals with profound T4 deficiency, despite normal circulating T3 levels, did exhibit a marked elevation of serum TSH and developed a large goiter. ChEL-KI mice exhibited normal expression of the hepatic markers of thyroid hormone action ME1 and D1, indicating that these markers do not require normal circulating levels of T4 but are supported by circulating levels of T3. In contrast with the liver, the CNS is thought to rely substantially on local T3 production from T4 via D2-mediated 5’-deiodination. We examined additional CNS functions that have been reported to be linked to phenotypes in hypothyroid rodents and humans. Both ChEL-KI and cog/cog mice exhibited similar behavioral abnormalities such as impaired motor activity and locomotion, as well as increased anxiety-like behavior compared to euthyroid controls. Thus, we conclude that normal circulating T3 cannot efficiently replace the role of T4 in supporting these behaviors that require local generation of T3 in the CNS. This work highlights tissue-specific differences in T3 versus T4 action, reflecting key considerations in hypothyroid patients receiving thyroid hormone replacement therapy. Presentation: Saturday, July 12, 2025