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AbstractWe present the mitochondrial genome of the deep-sea, epibenthic, irregular echinoid Echinocrepis rostrata, representing the first sequenced mitogenome of the order Holasteroida. The length of the complete E. rostrata mitochondrial genome is 15,716 base pairs, and its GC content is 34.87%. It contains 13 protein-coding genes, two rRNA genes, and 22 tRNA genes, whose order is identical to that of all other available echinoid mitogenomes. Phylogenetic analysis of available mitochondrial genomes, based on all coding loci, places E. rostrata as the sister group to spatangoids (heart urchins).

Abstract Background Central Michigan University (CMU) participated in a state-wide SARS-CoV-2 wastewater monitoring program since 2021. Wastewater samples were collected from on-campus sites and nine off-campus wastewater treatment plants servicing small metropolitan and rural communities. SARS-CoV-2 genome copies were quantified using droplet digital PCR and results were reported to the health department. Results One rural, off-campus site consistently produced higher concentrations of SARS-CoV-2 genome copies. Samples from this site were sequenced and contained predominately a derivative of Alpha variant lineage B.1.1.7, detected from fall 2021 through summer 2023. Mutational analysis of reconstructed genes revealed divergence from the Alpha variant lineage sequence over time, including numerous mutations in the Spike RBD and NTD. Conclusions We discuss the possibility that a chronic SARS-CoV-2 infection accumulated adaptive mutations that promoted long-term infection. This study reveals that small wastewater treatment plants can enhance resolution of rare events and facilitate reconstruction of viral genomes due to the relative lack of contaminating sequences.

Summary: Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are dysregulated in many pervasive diseases. Recently, we discovered that ERK1/2 is oxidized by signal-generated hydrogen peroxide in various cell types. Since the putative sites of oxidation lie within or near ERK1/2’s ligand-binding surfaces, we investigated how oxidation of ERK2 regulates interactions with the model substrates Sub-D and Sub-F. These studies revealed that ERK2 undergoes sulfenylation at C159 on its D-recruitment site surface and that this modification modulates ERK2 activity differentially between substrates. Integrated biochemical, computational, and mutational analyses suggest a plausible mechanism for peroxide-dependent changes in ERK2-substrate interactions. Interestingly, oxidation decreased ERK2’s affinity for some D-site ligands while increasing its affinity for others. Finally, oxidation by signal-generated peroxide enhanced ERK1/2’s ability to phosphorylate ribosomal S6 kinase A1 (RSK1) in HeLa cells. Together, these studies lay the foundation for examining crosstalk between redox- and phosphorylation-dependent signaling at the level of kinase-substrate selection.

Abstract Background Preclinical models like cancer cell lines and patient‐derived xenografts (PDXs) are vital for studying disease mechanisms and evaluating treatment options. It is essential that they accurately recapitulate the disease state of interest to generate results that will translate in the clinic. Prior studies have demonstrated that preclinical models do not recapitulate all biological aspects of human tissues, particularly with respect to the tissue of origin gene expression signatures. Therefore, it is critical to assess how well preclinical model gene expression profiles correlate with human cancer tissues to inform preclinical model selection and data analysis decisions. Aims Here we evaluated how well preclinical models recapitulate human cancer and non‐diseased tissue gene expression patterns in silico with respect to the full gene expression profile as well as subsetting by the most variable genes, genes significantly correlated with tumor purity, and tissue‐specific genes. Methods By using publicly available gene expression profiles across multiple sources, we evaluated cancer cell line and patient‐derived xenograft recapitulation of tumor and non‐diseased tissue gene expression profiles in silico. Results We found that using the full gene set improves correlations between preclinical model and tissue global gene expression profiles, confirmed that glioblastoma (GBM) PDX global gene expression correlation to GBM tumor global gene expression outperforms GBM cell line to GBM tumor global gene expression correlations, and demonstrated that preclinical models in our study often failed to reproduce tissue‐specific expression. While including additional genes for global gene expression comparison between cell lines and tissues decreases the overall correlation, it improves the relative rank between a cell line and its tissue of origin compared to other tissues. Our findings underscore the importance of using the full gene expression set measured when comparing preclinical models and tissues and confirm that tissue‐specific patterns are better preserved in GBM PDX models than in GBM cell lines. Conclusion Future studies can build on these findings to determine the specific pathways and gene sets recapitulated by particular preclinical models to facilitate model selection for a given study design or goal.

Pilargidae is a family of free-living and burrowing marine annelids. A lack of available molecular data for most of these species has precluded a molecular assessment of their phylogenetic relationships and has left uncertain the placement of Antonbruunia, which is hypothesized to be either a member of Pilargidae or its sister clade, the monotypic family Antonbruunidae. In this study, we describe the new species Antonbruunia milenae sp. nov., found at 845 m of depth off the coast of San Diego, California, USA, and we address the phylogeny of these organisms using 15 novel mitogenomes and multiple Sanger-sequenced loci. Our results show that Antonbruunia falls within Pilargidae, making Antonbruunidae a junior synonym of Pilargidae. Glyphohesione was transferred from Pilarginae to Synelminae, the previously unassigned genera Otopsis and Antonbruunia were shown to belong within Synelminae, and Hermundura was assigned to Phyllodocida incertae sedis. Sigambra was found to be non-monophyletic. Four different mitogenome gene orders were found among Pilargidae. Changes between the gene orders and the ancestral state gene order of the family were inferred. Two species have introns within the COI gene. These efforts represent a significant expansion of the available molecular resources for pilargids, as well as the basis for a more stable taxonomy.

Xyloplax is a genus of three species of sea stars previously found only on sunken wood in the deep ocean. Their circular and petaloid bodies, which lend them their common name “sea daisy”, and their presumed exclusive diet of wood make them an unusual and rare element of deep-sea ecosystems. We describe here the fourth species of Xyloplax from the eastern Pacific Ocean, Xyloplax princealberti n. sp., which ranges from offshore Canada to the Gulf of California (Mexico) and Costa Rica. Though sampled geographically close to another described species of Xyloplax from the northeastern Pacific, X. janetae, this new species is unique morphologically and according to available DNA data. The short abactinal spines are the most obvious feature that distinguishes X. princealberti n. sp. from other Xyloplax. The minimum distance for mitochondrial cytochrome c oxidase subunit I from Xyloplax princealberti n. sp. to the only other available Xyloplax, X. janetae, was 13.5%. We also describe Ridgeia vestimentiferan tubeworm bushes from active hydrothermal vents as a new Xyloplax habitat, the first record of a non-wood substrate, and a new reproductive strategy, simultaneous hermaphroditism, for this genus. We generated the first mitochondrial genome for a member of Xyloplax and analyzed it with other available asteroid data using nucleotide-coding or amino acid (for protein-coding genes) plus nucleotide coding (for rRNA genes). The nucleotide-coding results place Xylopax as part of the clade Velatida, consistent with a previous phylogenomic analysis that included Xyloplax princealberti n. sp. (as Xyloplax sp.), though the placement of Velatida within Asteroidea differed. The amino acid plus nucleotide coding recovered Velatida to be a grade with X. princealberti n. sp. as sister group to all other Asteroidea.

Dorvilleids belonging to Ophryotrocha Claparède & Mecznikow, 1869 are known from deep-sea hydrothermal vents in the Pacific, Atlantic, Indian and Southern Oceans. However, how they colonized and diversified in these ecosystems has not been assessed in detail. Here, a collection of Pacific hydrothermal vent Ophryotrocha was examined using morphology and DNA markers (COI, 16S and H3). Five new species were revealed, largely expanding the diversity of the group at this habitat type. They are Ophryotrocha charlottae sp. nov., O. kailae sp. nov., O. marinae sp. nov., O. pruittae sp. nov. from eastern Pacific, and O. bohnorum sp. nov. from the western Pacific. Phylogenetic analyses based on the concatenated alignments of all three genes suggest vent habitants have been colonized several times independently within Ophryotrocha. One clade of six vent species was recovered, indicative of diversification following a colonization of hydrothermal vents, likely in the eastern Pacific. An Indian Ocean species, O. jiaolongi, was nested inside this clade and was closely related to one of the new species from the Gulf of California, diverging from it by less than 4% on COI.

Highlights Genetic, epigenetic, hormonal, immunological, metabolic, and environmental factors affect sex-biased drug responses. Drug repurposing approaches provide a significant advantage over novel drug development by reducing lengthy and costly clinical trials. Advances in compute processing power and optimized algorithms for computational systems have increased the efficiency and feasibility of computational drug repurposing. Multiple challenges still need to be addressed for sex-aware drug repurposing, including the insufficient understanding of the cause of variation of drug responses due to sex differences, better performing sex-aware repurposing methods, and the lack of large and balanced datasets to develop improved methods. Future low-dimensional representations of molecular association and network approaches could significantly impact the field of sex-aware drug repurposing.

Here, we present the first mitochondrial genome of Eiconaxius baja. The mitogenome contains 13 protein-coding genes (PCGs), two rRNA genes, and 22 tRNA genes. The total length of the complete E. baja mitochondrial genome is 16,212 base pairs, and the GC content is 26.82%. The gene order is consistent with that of Eiconaxius serratus, and most other members of Axiidea. Phylogenetic analysis based on 13 PCGs places E. baja sister to E. serratus within Axiidae.

Alzheimer's disease (AD) is the most common neurodegenerative disease and affects persons of all races, ethnic groups, and sexes. The disease is characterized by neuronal loss leading to cognitive decline and memory loss. There is no cure and the effectiveness of existing treatments is limited and depends on the time of diagnosis. The long prodromal period, during which patients' ability to live a normal life is not affected despite neuronal loss, often leads to a delayed diagnosis because it can be mistaken for normal aging of the brain. In order to make a substantial impact on AD patient survival, early diagnosis may provide a greater therapeutic window for future therapies to slow AD-associated neurodegeneration. Current gold standards for disease detection include magnetic resonance imaging and positron emission tomography scans, which visualize amyloid β and phosphorylated tau depositions and aggregates. Liquid biopsies, already an active field of research in precision oncology, are hypothesized to provide early disease detection through minimally or non-invasive sample collection techniques. Liquid biopsies in AD have been studied in cerebrospinal fluid, blood, ocular, oral, and olfactory fluids. However, most of the focus has been on blood and cerebrospinal fluid due to biomarker specificity and sensitivity attributed to the effects of the blood-brain barrier and inter-laboratory variation during sample collection. Many studies have identified amyloid β and phosphorylated tau levels as putative biomarkers, however, advances in next-generation sequencing-based liquid biopsy methods have led to significant interest in identifying nucleic acid species associated with AD from liquid tissues. Differences in cell-free RNAs and DNAs have been described as potential biomarkers for AD and hold the potential to affect disease diagnosis, treatment, and future research avenues.

Echinoids are key components of modern marine ecosystems. Despite a remarkable fossil record, the emergence of their crown group is documented by few specimens of unclear affinities, rendering their early history uncertain. The origin of sand dollars, one of its most distinctive clades, is also unclear due to an unstable phylogenetic context. We employ 18 novel genomes and transcriptomes to build a phylogenomic dataset with a near-complete sampling of major lineages. With it, we revise the phylogeny and divergence times of echinoids, and place their history within the broader context of echinoderm evolution. We also introduce the concept of a chronospace – a multidimensional representation of node ages – and use it to explore methodological decisions involved in time calibrating phylogenies. We find the choice of clock model to have the strongest impact on divergence times, while the use of site-heterogeneous models and alternative node prior distributions show minimal effects. The choice of loci has an intermediate impact, affecting mostly deep Paleozoic nodes, for which clock-like genes recover dates more congruent with fossil evidence. Our results reveal that crown group echinoids originated in the Permian and diversified rapidly in the Triassic, despite the relative lack of fossil evidence for this early diversification. We also clarify the relationships between sand dollars and their close relatives and confidently date their origins to the Cretaceous, implying ghost ranges spanning approximately 50 million years, a remarkable discrepancy with their rich fossil record.

Polynoidae Kinberg, 1856 has five branchiate genera: Branchipolynoe Pettibone, 1984, Branchinotogluma Pettibone, 1985, Branchiplicatus Pettibone, 1985, Peinaleopolynoe Desbruyères & Laubier, 1988, and Thermopolynoe Miura, 1994, all native to deep-sea, chemosynthetic-based habitats. Of these, Peinaleopolynoe has two accepted species; Peinaleopolynoe sillardi Desbruyères & Laubier, 1988 (Atlantic Ocean) and Peinaleopolynoe santacatalina Pettibone, 1993 (East Pacific Ocean). The goal of this study was to assess the phylogenetic position of Peinaleopolynoe, utilizing DNA sequences from a broad sampling of deep-sea polynoids. Representatives from all five branchiate genera were included, several species of which were sampled from near the type localities; Branchinotogluma sandersi Pettibone, 1985 from the Galápagos Rift (E/V “Nautilus”); Peinaleopolynoe sillardi from organic remains in the Atlantic Ocean; Peinaleopolynoe santacatalina from a whalefall off southern California (R/V “Western Flyer”) and Thermopolynoe branchiata Miura, 1994 from Lau Back-Arc Basin in the western Pacific (R/V “Melville”). Phylogenetic analyses were conducted using mitochondrial (COI, 16S rRNA, and CytB) and nuclear (18S rRNA, 28S rRNA, and H3) genes. The analyses revealed four new Peinaleopolynoe species from the Pacific Ocean that are formally described here: Peinaleopolynoe orphanae Hatch & Rouse, sp. nov., type locality Pescadero Basin in the Gulf of California, Mexico (R/V “Western Flyer”); Peinaleopolynoe elvisi Hatch & Rouse, sp. nov. and Peinaleopolynoe goffrediae Hatch & Rouse, sp. nov., both with a type locality in Monterey Canyon off California (R/V “Western Flyer”) and Peinaleopolynoe mineoi Hatch & Rouse, sp. nov. from Costa Rica methane seeps (R/V “Falkor”). In addition to DNA sequence data, the monophyly of Peinaleopolynoe is supported by the presence of ventral papillae on segments 12–15. The results also demonstrated the paraphyly of Branchinotogluma and Lepidonotopodium Pettibone, 1983 and taxonomic revision of these genera is required. We apply the subfamily name Lepidonotopodinae Pettibone 1983, for the clade comprised of Branchipolynoe, Branchinotogluma, Bathykurila, Branchiplicatus, Lepidonotopodium, Levensteiniella Pettibone, 1985, Thermopolynoe, and Peinaleopolynoe.

The four named species of Branchipolynoe all live symbiotically in mytilid mussels (Bathymodiolus) that occur at hydrothermal vents or methane seeps. Analyses using mitochondrial (COI and 16S) and nuclear (ITS) genes, as well as morphology, were conducted on a collection of Branchipolynoe from Pacific Costa Rican methane seeps and West Pacific hydrothermal vents. This revealed five new species of Branchipolynoe, and these are formally described. The new species from Costa Rica live in three species of Bathymodiolus mussels (also new) at depths ranging from 1000 to 1800 m. Branchipolynoe kajsae n. sp. and Branchipolynoe halliseyae n. sp. were found in all three undescribed Bathymodiolus species, while Branchipolynoe eliseae n. sp. was found in Bathymodiolus spp. 1 and 2, and Branchipolynoe meridae n. sp. was found in Bathymodiolus spp. 1 and 3. Hence, Bathymodiolus sp. 1 hosted all four of the new species, while the other two Bathymodiolus hosted three each. Most mussels contained only one specimen of Branchipolynoe; where there was more than one, these were often a female and smaller male of the same species. The newly discovered species from the West Pacific, Branchipolynoe tjiasmantoi n. sp., lives in unidentified Bathymodiolus at depths ranging from 674 to 2657 m from hydrothermal vents in the North Fiji (Fiji) and Lau Basins (Tonga) and also from New Zealand, Vanuatu, and the Manus Basin (Papua New Guinea). The phylogenetic and biogeographical implications of this diversity of Branchipolynoe are discussed.

Forest cover loss in the tropics is well known to cause warming at deforested sites, with maximum temperatures being particularly sensitive. Forest loss causes warming by altering local energy balance and surface roughness, local changes that can propagate across a wide range of spatial scales. Consequently, temperature increases result from not only changes in forest cover at a site, but also by the aggregate effects of non-local forest loss. We explored such non-local warming within Brazil’s Amazon and Cerrado biomes, the region with the world’s single largest amount of forest loss since 2000. Two datasets, one consisting of in-situ air temperature observations and a second, larger dataset consisting of ATs derived from remotely-sensed observations of land surface temperature, were used to quantify changes in maximum temperature due to forest cover loss at varying length-scales. We considered undisturbed forest locations (1 km ^2 in extent), and forest loss trends in annuli (‘halos’), located 1–2 km, 2–4 km, 4–10 km and 10–50 km from these undisturbed sites. Our research finds significant and substantial non-local warming, suggesting that historical estimates of warming due to forest cover loss under-estimate warming or mis-attribute warming to local change, where non-local changes also influence the pattern of temperature warming.

Abstract Our recent article, “Are Brazil's Deforesters Avoiding Detection?” demonstrated that focusing illegal deforestation enforcement on the subset of forest monitored by the flagship PRODES system has caused PRODES to capture a declining share of deforestation in the Brazilian Amazon. Deforesters may be purposively seeking out forests not monitored for enforcement. Addressing the problem would help Brazil maintain a cutting‐edge forest governance model worthy of transfer to other nations. Two commentaries questioned our decision to investigate solely PRODES and not additional government monitoring systems. We focused on PRODES because it is the most salient deforestation monitoring system. Other key deforestation monitoring systems are all either limited to the same monitoring footprint as PRODES, not used for enforcement, or are rarely used for measuring forest loss in the Brazilian Amazon. We do agree with the commentaries that Brazil's new satellite monitoring protocol for greenhouse gas emissions estimation is critical progress of the type we were advocating in our original article.

Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10-15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity.

Embryonic neuroepithelia and adult subventricular zone (SVZ) stem and progenitor cells express nestin. We characterized a transgenic line that expresses enhanced green fluorescent protein (eGFP) specified to neural tissue by the second intronic enhancer of the nestin promoter that had several novel features. During embryogenesis, the dorsal telencephalon contained many and the ventral telencephalon few eGFP+ cells. eGFP+ cells were found in postnatal and adult neurogenic regions. eGFP+ cells in the SVZ expressed multiple phenotype markers, glial fibrillary acidic protein, Dlx, and neuroblast-specific molecules suggesting the transgene is expressed through the lineage. eGFP+ cell numbers increased in the SVZ after cortical injury, suggesting this line will be useful in probing postinjury neurogenesis. In non-neurogenic regions, eGFP was strongly expressed in oligodendrocyte progenitors, but not in astrocytes, even when they were reactive. This eGFP+ mouse will facilitate studies of proliferative neuroepithelia and adult neurogenesis, as well as of parenchymal oligodendrocytes.

This letter uses satellite remote sensing to examine patterns of cropland expansion, cropland abandonment, and changing cropping frequency in Mato Grosso, Brazil from 2001 to 2011. During this period, Mato Grosso emerged as a globally important center of agricultural production. In 2001, 3.3 million hectares of mechanized agriculture were cultivated in Mato Grosso, of which 500 000 hectares had two commercial crops per growing season (double cropping). By 2011, Mato Grosso had 5.8 million hectares of mechanized agriculture, of which 2.9 million hectares were double cropped. We found these agricultural changes to be selective with respect to land attributes—significant differences ( p

Abstract Background The suicide risk in patients with atrial fibrillation receiving novel oral anticoagulants or warfarin has not been evaluated in real-world practice. Moreover, reducing vitamin K levels may increase the suicide risk, underscoring the importance of selecting appropriate oral anticoagulants to prevent unintended outcomes. Therefore, we aimed to evaluate the association between different types of oral anticoagulants and the risk of attempted and completed suicide among patients with atrial fibrillation. Methods This nationwide study retrieved data from Taiwan's National Health Insurance Research Database from 2012 to 2020. This study included patients with atrial fibrillation aged 20 years and older who newly received oral anticoagulant treatment, and who had no contraindications for NOACs and no history of suicide-related events. The main outcomes were suicide-related outcomes, including attempted suicide and completed suicide. This study employed the target trial emulation framework to improve the causal inference for the observed association. Results A total of 103,768 (71.74%) patients taking NOACs and 40,877 (28.26%) patients taking warfarin were included in this study. Compared to those receiving warfarin, patients receiving NOACs were associated with a lower risk of suicide-related outcomes (HR, 0.82; 95% CIs, 0.69–0.96). Conclusions The findings of this cohort study suggested that patients receiving NOACs were associated with a lower risk of suicidal attempts but similar risk of complete suicide, compared to those receiving warfarin. Considering the risk of suicide, NOACs could be the preferred anticoagulants for patients with atrial fibrillation.

Rad And Gem-Like GTP-Binding Protein 2 (Rem2), a member of the RGK family of Ras-like GTPases, is implicated in Huntington’s disease and Long QT Syndrome and is highly expressed in the brain and endocrine cells. We examine the evolutionary history of Rem2 identified in various mammalian species, focusing on the role of purifying selection and coevolution in shaping its sequence and protein structural constraints. Our analysis of Rem2 sequences across 175 mammalian species found evidence for strong purifying selection in 70% of non-invariant codon sites which is characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2’s role in the regulation of neuronal development and function. We inferred epistatic effects in 50 pairs of codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences which revealed the dynamics of how substitutions that change the gene sequence of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and gene - interactions that have shaped the sequence and structure of the Rem2 protein, we gain a stronger understanding of its biological and functional constraints.

Fatty acid esters being biodegradable and environment friendly has been a sought-after class of molecule for various food grade applications. This work involves the incorporation of fatty acid esters namely cetyl-caprylate and cetyl-caprate in edible Carboxymethyl cellulose -based films. The esters were enzymatically synthesized by esterification of caprylic acid and capric acid respectively with cetyl alcohol at a molar ratio of 1:1, using Candida antarctica lipase B which was immobilized (10 % w/w) at 65 °C. Carboxymethyl cellulose films were prepared. To it, glycerol and by emulsification, cetyl-caprylate or cetyl-caprate esters were amalgamated. Film characterizations involved analysis of surface morphology, mechanical properties, and thermal properties. It was further characterized by X-Ray diffraction analysis, water vapor permeability, and moisture uptake. Barrier property carboxymethyl cellulose films showed significant improvement due to the incorporation of cetyl-caprylate or cetyl-caprate esters. However, when the film's melting point was measured, it was seen that glycerol influenced the thermal properties more prominently than cetyl-caprylate and cetyl-caprate esters. Thus, the addition of an optimized amount of glycerol and cetyl-caprylate or cetyl-caprate esters to the carboxymethyl cellulose films is required for improved mechanical strength and better thermal properties. Further, an antimicrobial well diffusion assay of both the esters established the antimicrobial property of the same, which thereby recommends the addition of the wax esters even more.

Abstract Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.

The dynamic fluctuations in autumn temperatures, particularly the marked diurnal variations and the subsequent precipitous drops are key and a pivotal role in viticulture, as they critically influence the acclimation process of grapevines to cold, thereby directly impacting their survival and productivity in cold-climate regions. In this comprehensive study, we investigated the cold hardiness of four grapevine cultivars: ‘Itasca’, ‘Frontenac’, ‘La Crescent’, and ‘Marquette’, focusing on how these cultivars and their individual buds (1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, and 9th) respond to fluctuating weather and low temperatures typical of autumn [-1.1°C (30°F) -9.4°C (15°F) and -17.8°C (0°F)]. Our results illuminated the striking variability in cold hardiness that was manifest not only among the different cultivars but also within individual buds on the same vine, underscoring the critical influence of bud position on a vine for cold hardiness. ‘Frontenac’ showed greater cold hardiness at critical temperatures at which 10%, and 50% of the dormant buds were lethally affected by cold (LT10 and LT50) compared to ‘Itasca’ and ‘La Crescent’, with ‘Marquette’ exhibiting intermediate values. However, in cultivars such as ‘Itasca’ and ‘Marquette’, certain buds demonstrated a pronounced hardiness when faced with colder temperatures, while others exhibited a heightened sensitivity, thereby revealing a nuanced interplay between bud position and a vine’s ability to withstand cold stress. Our study revealed a notable divergence from traditional viticulture understanding; apical buds demonstrated greater cold hardiness than basal buds and opened new paths for research into grapevine physiology. Our results also indicated a significant trend wherein older vines across all studied cultivars displayed enhanced cold hardiness, particularly pronounced at the critical LT50 and the critical temperature at which 90% of the dormant buds were lethally affected by cold (LT90) thresholds, in comparison to younger vines. Moreover, our findings shed light on the impact of autumn’s diurnal temperature variations and the subsequent drop in temperatures on vine cold hardiness, thus highlighted the complex interplay between environmental temperature dynamics and dormant bud hardiness. In conclusion, our study showed that the cold damage observed in grapevines in North Dakota was not a result of extreme temperature fluctuations in the fall. This was confirmed by testing the vines after they had reached various threshold temperatures through differential thermal analysis (DTA) and optical differential nucleation and expansion analysis (ODNEAL) methodologies, particularly before the onset of severe pre-winter cold conditions. These comprehensive findings highlighted the complexity of the vine’s response to climatic conditions and viticultural management, pointing to the need for specific strategies in vineyard management and cultivar selection to optimize bud hardiness and productivity in the face of various environmental challenges, especially in cold climate viticulture.

Abstract Background The harsh conditions of high-altitude environments are known to drive the evolution of physiological and morphological traits in endothermic animals. These conditions are expected to result in the adaptive evolution of protein coding genes encoded in mitochondrial genomes that are vital for the oxidative phosphorylation pathway. In this study, we formally tested for signatures of adaptive evolution on mitochondrial protein coding genes in Tapirus pinchaque and other odd-toed ungulates inhabiting high-elevation environments. Results The AT-rich mitochondrial genome of T. pinchaque is 16,750 bp long. A phylomitogenomic analysis supports the monophyly of the genus Tapirus and families in the Perissodactyla. The ratio of non-synonymous to synonymous substitutions demonstrated that all mitochondrial genes undergo purifying selection in T. pinchaque and other odd ungulates living at high elevations. Over this negative background selection, Branch Models suggested that cox3 and nad6 might be undergoing stronger purifying selection than other mitochondrial protein coding genes. Furthermore, Site Models suggested that one and four sites in nad2 and nad5, respectively, could be experiencing positive selection. However, these results were supported by Likelihood Ratio Tests but not Bayesian Empirical Bayes posterior probabilities. Additional analyses (in DataMonkey) indicated a relaxation of selection strength in nad6, evidence of episodic diversifying selection in cob, and revealed episodic positive/diversifying selection signatures for two sites in nad1, and one site each in nad2 and nad4. Conclusion The mitochondrial genome of T. pinchaque is an important genomic resource for conservation of this species and this study contributes to the understanding of adaptive evolution of mitochondrial protein coding genes in odd-toed ungulates inhabiting high-altitude environments.

Recent trends in aeroelastic analysis have shown a great interest in understanding the role of shock boundary layer interaction in predicting the dynamic instability of aircraft structural components at supersonic and hypersonic flows. The analysis of such complex dynamics requires a time-accurate fluid-structure interaction solver. This study focuses on the development of such a solver by coupling a finite-volume Navier-Stokes solver for fluid flow with a finite-element solver for structural dynamics. The coupled solver is then verified for the prediction of several panel instability cases in 2D and 3D uniform flows and in the presence of an impinging shock for a range of subsonic and supersonic Mach numbers, dynamic pressures, and shock strengths. The panel deflections and limit cycle oscillation amplitudes, frequencies, and bifurcation point predictions were compared within 10% of the benchmark results; thus, the solver was deemed verified. Future studies will focus on extending the solver to 3D turbulent flows and applying the solver to study the effect of turbulent load fluctuations and shock boundary layer interactions on the fluid-structure coupling and structural dynamics of 2D panels.

The Columbia River Basin faces a threat from the potential invasion of zebra mussels (Dreissena polymorpha), notorious for their ability to attach to various substrates, including concrete, which is common in fishway construction. Extensive mussel colonization within fishways may affect fish passage by altering flow patterns or creating physical barriers, leading to increased travel times, or potentially preventing passage altogether. Many factors affect mussel habitat suitability including vectors of dispersal, water parameters, and various hydrodynamic quantities, such as water depth, velocity, and turbulence. The objective of this study is to assess the potential for zebra mussels to attach to fishway surfaces and form colonies in the McNary Lock and Dam Oregon-shore fishway and evaluate the potential impact of this infestation on the fishway’s efficiency. A computational fluid dynamics (CFD) model of the McNary Oregon-shore fishway was developed using the open-source code OpenFOAM, with the two-phase solver interFoam. Mesh quality is critical to obtain a reliable solution, so the numerical mesh was refined near the free surface and all solid surfaces to properly capture the complex flow patterns and free surface location. The simulation results for the 6-year average flow rate showed good agreement with the measured water column depth over each weir. Regions susceptible to mussel infestation were identified, and an analysis was performed to determine the mussel’s preference to colonize as a function of the depth-averaged velocity, water depth, and wall shear stress. Habitat suitability criteria were applied to the output of the hydraulic variables from the CFD solution and provided insight into the potential impact on the fishway efficiency. Details on the mesh construction, model setup, and numerical results are presented and discussed.

OBJECTIVES/GOALS: Weaimed to compare subjective and objective sleep in individuals with chronic post-concussive symptoms. We hypothesized an association between self-reported sleep quality and objective sleep parameters, which is different for concussed and control cohorts. METHODS/STUDY POPULATION: 28 individuals with chronic post-concussive symptoms and 13 age-matched controls (no concussion history) completed the ISI, PSQI, PROMIS Depression, Anxiety, Stress and Cognitive questionnaires at enrollment. Objective sleep parameters were obtained for a minimum of 7 days and up to 30 days with a validated sleep monitoring device placed under the subject’s bed (Emfit). For each night, raw activity data per minute were analyzed to determinein-bed, sleep, wake, andout-of-bedtimes. These measures were used to calculate total sleep time (TST), sleep onset latency (SOL), and wake after sleep onset (WASO) for each night. RESULTS/ANTICIPATED RESULTS: Concussed individuals reported worse sleep with PSQI and ISI scores significantly higher than controls. They also showedsignificant associations between PSQI and Dep ression, ISI and Depression, and ISI and Anxiety scores. There was no difference between objective sleep parameters in the concussed and control cohorts (in-bed/sleep/wake/out-of-bed times, TST, SOL, and WASO). Instead, higher PSQI, ISI, Depression, Anxiety, and Stress scores (greater symptom burden) were all associated with later sleep times, where as higher Cognitive scores (greater cognitive function) were associated with earlier sleep times, regardless of group status. DISCUSSION/SIGNIFICANCE: Concussed individuals report worse subjective sleep but no differences to controls when objectively assessing sleep. Depression/anxiety, and not concussion status, determine objective sleep parameters. Psychiatric comorbidities should inform the treatment of post-concussive sleep disturbances.

The global cost-benefit analysis of pesticide use during the last 30 years has been characterized by a significant increase during the period from 1990 to 2007 followed by a decline. This observation can be attributed to several factors including, but not limited to, pest resistance, lack of novelty with respect to modes of action or classes of chemistry, and regulatory action. Due to current and projected increases of the global population, it is evident that the demand for food, and consequently, the usage of pesticides to improve yields will increase. Addressing these challenges and needs while promoting new crop protection agents through an increasingly stringent regulatory landscape requires the development and integration of infrastructures for innovative, cost- and time-effective discovery and development of novel and sustainable molecules. Significant advances in artificial intelligence (AI) and cheminformatics over the last two decades have improved the decision-making power of research scientists in the discovery of bioactive molecules. AI- and cheminformatics-driven molecule discovery offers the opportunity of moving experiments from the greenhouse to a virtual environment where thousands to billions of molecules can be investigated at a rapid pace, providing unbiased hypothesis for lead generation, optimization, and effective suggestions for compound synthesis and testing. To date, this is illustrated to a far lesser extent in the publicly available agrochemical research literature compared to drug discovery. In this review, we provide an overview of the crop protection discovery pipeline and how traditional, cheminformatics, and AI technologies can help to address the needs and challenges of agrochemical discovery towards rapidly developing novel and more sustainable products.

Background: We previously developed a non-invasive approach to localize the site of early left ventricular activation origin in real time using 12-lead ECG, and to project the predicted site onto a generic LV endocardial surface using the smallest angle between two vectors algorithm (SA).Objectives: To improve the localization accuracy of the non-invasive approach by utilizing the K-nearest neighbors algorithm (KNN) to reduce projection errors.Methods: Two datasets were used. Dataset #1 had 1012 LV endocardial pacing sites with known coordinates on the generic LV surface and corresponding ECGs, while dataset #2 included 25 clinically-identified VT exit sites and corresponding ECGs. The non-invasive approach used “population” regression coefficients to predict the target coordinates of a pacing site or VT exit site from the initial 120-m QRS integrals of the pacing site/VT ECG. The predicted site coordinates were then projected onto the generic LV surface using either the KNN or SA projection algorithm.Results: The non-invasive approach using the KNN had a significantly lower mean localization error than the SA in both dataset #1 (9.4 vs. 12.5 mm, p < 0.05) and dataset #2 (7.2 vs. 9.5 mm, p < 0.05). The bootstrap method with 1,000 trials confirmed that using KNN had significantly higher predictive accuracy than using the SA in the bootstrap assessment with the left-out sample (p < 0.05).Conclusion: The KNN significantly reduces the projection error and improves the localization accuracy of the non-invasive approach, which shows promise as a tool to identify the site of origin of ventricular arrhythmia in non-invasive clinical modalities.

Inflammation is associated with the pathogenesis of myelodysplastic syndromes (MDS) and emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPC) exhibit an altered response to inflammation. Deletion of chromosome 5 (del(5q)) is the most common chromosomal abnormality in MDS. Although this MDS subtype contains several haploinsufficient genes that impact innate immune signaling, the effects of inflammation on del(5q) MDS HSPC remains undefined. Utilizing a model of del(5q)-like MDS, inhibiting the IRAK1/4-TRAF6 axis improved cytopenias, suggesting that activation of innate immune pathways contributes to certain clinical features underlying the pathogenesis of low-risk MDS. However, low-grade inflammation in the del(5q)-like MDS model did not contribute to more severe disease but instead impaired the del(5q)-like HSPC as indicated by their diminished numbers, premature attrition and increased p53 expression. Del(5q)-like HSPC exposed to inflammation became less quiescent, but without affecting cell viability. Unexpectedly, the reduced cellular quiescence of del(5q) HSPC exposed to inflammation was restored by p53 deletion. These findings uncovered that inflammation confers a competitive advantage of functionally defective del(5q) HSPC upon loss of p53. Since TP53 mutations are enriched in del(5q) AML following an MDS diagnosis, increased p53 activation in del(5q) MDS HSPC due to inflammation may create a selective pressure for genetic inactivation of p53 or expansion of a pre-existing TP53-mutant clone.

The impacts of weed interference on hemp (Cannabis sativa) yield are largely unstudied despite causing serious economic losses in most cropping systems. For high-cannabidiol (CBD) hemp, understanding the role of weed competition on CBD and tetrahydrocannabinol (THC) content may help promote profitability and regulatory compliance. Therefore, we tested the effects of varying waterhemp [Amaranthus tuberculatus (zero, one, three, and five waterhemp plants per planting hole)] and hemp (zero or one hemp plants per planting hole) planting densities on total hemp yield, chemical composition, and aboveground waterhemp biomass in plasticulture. There was no significant total biomass or stripped floral biomass yield loss resulting from waterhemp competition, although unexpectedly high variation in hemp phenotypes likely limited the ability to detect subtle differences between treatments. Furthermore, there was no significant effect of competition treatment on total CBD, total THC, or measured terpene composition. However, waterhemp biomass was reduced significantly by competition from hemp in comparison with hemp-free treatments. Suppression of waterhemp by hemp and lack of significant yield loss suggest that hemp can be highly competitive and grown successfully without herbicides in certain circumstances.

Social behavior is complex and fundamental, and its deficits are common pathological features for several psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Acute stress may have a negative impact on social behavior, and these effects can vary based on sex. The aim of this study was to explore the effect of acute footshock stress, using analogous parameters to those commonly used in fear conditioning assays, on the sociability of male and female C57BL/6J mice in a standard social approach test. Animals were divided into two main groups of footshock stress (22 male, 24 female) and context exposed control (23 male and 22 female). Each group had mice that were treated intraperitoneally with either the benzodiazepine-alprazolam (control: 10 male, 10 female; stress: 11 male, 11 female), or vehicle (control: 13 male, 12 female; stress: 11 male, 13 female). In all groups, neuronal activation during social approach was assessed using immunohistochemistry against the immediate early gene product cFos. Although footshock stress did not significantly alter sociability or latency to approach a social stimulus, it did increase defensive tail-rattling behavior specifically in males (p = 0.0022). This stress-induced increase in tail-rattling was alleviated by alprazolam (p = 0.03), yet alprazolam had no effect on female tail-rattling behavior in the stress group. Alprazolam lowered cFos expression in the medial prefrontal cortex (p = 0.001 infralimbic area, p = 0.02 prelimbic area), and social approach induced sex-dependent differences in cFos activation in the ventromedial intercalated cell clusters (p = 0.04). Social approach following stress-induced cFos expression was positively correlated with latency to approach and negatively correlated with sociability in the prelimbic area and multiple amygdala subregions (all p < 0.05). Collectively, our results suggest that acute footshock stress induces sex-dependent alterations in defensiveness and differential patterns of cFos activation during social approach.

Social behavior is complex and fundamental, and its deficits are common pathological features for several psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Acute stress may have a negative impact on social behavior, and these effects can vary based on sex. The aim of this study was to explore the effect of acute footshock stress, using analogous parameters to those commonly used in fear conditioning assays, on the sociability of male and female C57BL/6J mice in a standard social approach test. Animals were divided into two main groups of footshock stress (22 male, 24 female) and context exposed control (23 male and 22 female). Each group had mice that were treated intraperitoneally with either the benzodiazepine—alprazolam (control: 10 male, 10 female; stress: 11 male, 11 female), or vehicle (control: 13 male, 12 female; stress: 11 male, 13 female). In all groups, neuronal activation during social approach was assessed using immunohistochemistry against the immediate early gene product cFos. Although footshock stress did not significantly alter sociability or latency to approach a social stimulus, it did increase defensive tail-rattling behavior specifically in males (p = 0.0022). This stress-induced increase in tail-rattling was alleviated by alprazolam (p = 0.03), yet alprazolam had no effect on female tail-rattling behavior in the stress group. Alprazolam lowered cFos expression in the medial prefrontal cortex (p = 0.001 infralimbic area, p = 0.02 prelimbic area), and social approach induced sex-dependent differences in cFos activation in the ventromedial intercalated cell clusters (p = 0.04). Social approach following stress-induced cFos expression was positively correlated with latency to approach and negatively correlated with sociability in the prelimbic area and multiple amygdala subregions (all p < 0.05). Collectively, our results suggest that acute footshock stress induces sex-dependent alterations in defensiveness and differential patterns of cFos activation during social approach.

Scholars in the community engagement field have long discussed measures to sustain community engagement on campus. When COVID-19 emerged, however, university operations, including community-engaged teaching and research, had to pivot. The conversation was no longer about sustaining community engagement but about enduring the pandemic for the sake of students, faculty, and community. In order to inform a more durable community engagement strategy for the postpandemic world, we apply a sensemaking approach for the purpose of organizational learning. We collected quantitative data about 40 planned courses and surveyed 22 community-engaged faculty from April to August 2020 (spring–summer academic quarters). In the same period, we gathered qualitative data from 41 respondents comprising 28 faculty and 13 community partners. The quantitative analysis suggested that, overall, faculty maintained a positive outlook regarding the strategies they used to address the needs of students and community partners and regarding their own expectations and innovations. The qualitative data revealed seven themes—loss and challenge, future uncertainty, action strategies, communication strategies, technology, collaborative resilience, and student considerations—that can help us consider community engagement through the lenses of experience, adaptation, and sustainability. The insights provided here offer ways to improve durability within sustainable community engagement practices.

Evolved resistance to herbicides necessitates alternative weed control strategies. Allelopathic crops show promise as an alternative to exogenous herbicides and could be used to reduce establishment, growth, and reproduction of weeds. Individual cannabinoids and terpenes found in hemp (Cannabis sativa L.) show allelopathic potential, but allelopathic effects of plant residue have not been characterized. A laboratory assay found that crude, acetone-soluble hemp extracts diluted to 2.5 mg mL−1 reduced the germination of a bioindicator species. However, tested concentrations below 2.5 mg mL−1 were not more effective than the no-extract control treatment at reducing germination. A greenhouse study found that soil-incorporated hemp residue was not more effective than a maize (Zea mays L.) residue treatment comparison in reducing plant growth. However, a simulated chaff line experiment in the greenhouse showed that the equivalent of 378 g m−2 hemp residue on the soil surface can effectively reduce and delay the germination of waterhemp [Amaranthus tuberculatus (Moq.) Sauer] in comparison to bare-soil, or a maize residue treatment comparison. Together, these results show that incorporated hemp residue will likely not be an effective weed control practice. However, chaff lining hemp residue may be an effective practice for the control of certain weeds and warrants further research in a field setting.

There is a chronic underrepresentation of Māori and Pacific academics in our university sector in Aotearoa New Zealand. Sitting behind the disparity are a range of practices that support some groups in Aotearoa New Zealand to succeed and move more freely through higher education institutions than others. In response to scholarship highlighting this issue, a collective of students and staff at Te Herenga Waka | Victoria University of Wellington came together to organise an action-oriented workshop to draw attention to ways that universities are governed through power relations. Attention was also paid to mitigating power imbalances in the organisation, format, and delivery of the event, and between attendees, presenters, and event facilitators from dominant and non-dominant ethnic and cultural groups. This reflection piece is not so much a recounting of the event itself but rather an opportunity to share with the wider academic world ways in which the collective attempted to hold our university accountable for failing in their responsibilities to the people on whose ancestral lands they exist.

Aim: The aim of this study was to understand traditional knowledge of tick ecology and remedies for tick-borne diseases (TBDs) among the Maasai people in northern Tanzania. Materials and Methods: Semi-structured interviews were conducted among specific groups likely to be knowledgeable about tick ecology and TBDs in livestock among the Maasai people. Results: A total of 25 plant species belonging to 18 families were used to treat 8 different TBDs of livestock. Most of the plant species used were of Fabaceae and Burseraceae families. Aloe volkensii, Cissus grandifolia, and Terminalia brownii were the most commonly used plant species. The major plant growth form used was trees, while stems and bark were the main plant parts used. Most treatments were taken orally. Conclusion: Maasai people have substantial knowledge on tick ecology exemplified by their ability to differentiate between different tick species and the range of remedies for each of the TBDs. Because traditional ethnoveterinary remedies are frequently utilized, their effectiveness should be further investigated.

The expansion of crop agriculture onto low productivity cattle pastures in the agricultural frontier of Brazil is a form of agricultural intensification that can help to contribute to global food and climate goals. However, the amount of pasture to crop conversion in the region lags both agronomic and economic potential. We administered a survey in combination with a lab-in-the-field experiment to 559 farmers in Mato Grosso, Brazil. We used the results to explore behavioral determinants of pasture to crop conversion. We compared farmers choices across two rounds of a risk game meant to mimic the economic risk of decisions to convert pasture to crops. We found framing the risk game to concern agriculture profoundly altered subjects’ experimental choices. These discrepancies involved the majority of experimental subjects, and were highly heterogenous in nature. They were also somewhat predictive of subjects’ behavior converting pasture to cropland. Our findings indicate that farmers may make economic decisions involving agriculture and/or agricultural land differently from other economic decisions. Our finding is of relevance for research into the propensity of farmers to intensify and for policies seeking to influence rates of agricultural intensification.

Ocular albinism type 1 (OA), caused by mutations in the OA1 gene, encodes a G-protein coupled receptor, OA1, localized in melanosomal membranes of the retinal pigment epithelium (RPE). This disorder is characterized by both RPE macro-melanosomes and abnormal decussation of ganglion cell axons at the brain's optic chiasm. We demonstrated previously that Oa1 specifically activates Gαi3, which also signals in the Oa1 transduction pathway that regulates melanosomal biogenesis. In this study, we screened the human Gαi3 gene, GNAI3, in DNA samples from 26 patients who had all clinical characteristics of OA but in whom a specific mutation in the OA1 gene had not been found, and in 6 normal control individuals. Using the Agilent HaloPlex Target Enrichment System and next-generation sequencing (NGS) on the Illumina MiSeq platform, we identified 518 variants after rigorous filtering. Many of these variants were corroborated by Sanger sequencing. Overall, 98.8% coverage of the GNAI3 gene was obtained by the HaloPlex amplicons. Of all variants, 6 non-synonymous and 3 synonymous were in exons, 41 in a non-coding exon embedded in the 3' untranslated region (UTR), 6 in the 5' UTR, and 462 in introns. These variants included novel SNVs, insertions, deletions, and a frameshift mutation. All were found in at least one patient but none in control samples. Using computational methods, we modeled the GNAI3 protein and its non-synonymous exonic mutations and determined that several of these may be the cause of disease in the patients studied. Thus, we have identified GNAI3 as a second gene possibly responsible for X-linked ocular albinism.

BACKGROUND: Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS). Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human tissue factor knock-in (hTF-KI) transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859) were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v.) attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. CONCLUSIONS: This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies.

Abstract Background Williams syndrome (WS) is a rare genetic disorder caused by the deletion of approximately 25 genes at 7q11.23 that involves mild to moderate intellectual disability (ID). When using functional magnetic resonance imaging (fMRI) to compare individuals with ID to typically developing individuals, there is a possibility that differences in IQ contribute to between-group differences in BOLD signal. If IQ is correlated with BOLD signal, then group-level analyses should adjust for IQ, or else IQ should be matched between groups. If, however, IQ is not correlated with BOLD signal, no such adjustment or criteria for matching (and exclusion) based on IQ is necessary. Methods In this study, we aimed to test this hypothesis systematically using four extant fMRI datasets in WS. Participants included 29 adult subjects with WS (17 men) demonstrating a wide range of standardized IQ scores (composite IQ mean = 67, SD = 17.2). We extracted average BOLD activation for both cognitive and task-specific anatomically defined regions of interest (ROIs) in each individual and correlated BOLD with composite IQ scores, verbal IQ scores and non-verbal IQ scores in Spearman rank correlation tests. Results Of the 312 correlations performed, only six correlations (2%) in four ROIs reached statistical significance at a P value < 0.01, but none survived correction for multiple testing. All six correlations were positive. Therefore, none supports the hypothesis that IQ is negatively correlated with BOLD response. Conclusions These data suggest that the inclusion of subjects with below normal IQ does not introduce a confounding factor, at least for some types of fMRI studies with low cognitive load. By including subjects who are representative of IQ range for the targeted disorder, findings are more likely to generalize to that population.

Abstract Background The default network is a set of brain regions that exhibit a reduction in BOLD response during attention-demanding cognitive tasks, and distinctive patterns of functional connectivity that typically include anti-correlations with a fronto-parietal network involved in attention, working memory, and executive control. The function of the default network regions has been attributed to introspection, self-awareness, and theory of mind judgments, and some of its regions are involved in episodic memory processes. Results Using the method of psycho-physiological interactions, we studied the functional connectivity of several regions in a fronto-parietal network involved in a paired image discrimination task involving transitive inference. Some image pairs were derived from an implicit underlying sequence A>B>C>D>E, and some were independent (F>G, H>J, etc). Functional connectivity between the fronto-parietal regions and the default network regions depended on the presence of the underlying sequence relating the images. When subjects viewed learned and novel pairs from the sequence, connectivity between these two networks was higher than when subjects viewed learned and novel pairs from the independent sets. Conclusions These results suggest that default network regions were involved in maintaining the internal model that subserved discrimination of image pairs derived from the implicit sequence, and contributed to introspective access of an internal sequence model built during training. The default network may not be a unified entity with a specific function, but rather may interact with other functional networks in task-dependent ways.

Abstract Background Inhibited temperament - the predisposition to respond to new people, places or things with wariness or avoidance behaviors - is associated with increased risk for social anxiety disorder and major depression. Although the magnitude of the amygdala's response to novelty has been identified as a neural substrate of inhibited temperament, there may also be differences in temporal dynamics (latency, duration, and peak). We hypothesized that persons with inhibited temperament would have faster responses to novel relative to familiar neutral faces compared to persons with uninhibited temperament. We used event-related functional magnetic resonance imaging to measure the temporal dynamics of the blood oxygen level dependent (BOLD) response to both novel and familiar neutral faces in participants with inhibited or uninhibited temperament. Results Inhibited participants had faster amygdala responses to novel compared with familiar faces, and both longer and greater amygdala response to all faces. There were no differences in peak response. Conclusion Faster amygdala response to novelty may reflect a computational bias that leads to greater neophobic responses and represents a mechanism for the development of social anxiety.