WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers.

Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor α (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Furthermore, ovarian cancer cell lines with rs3820282 variant genotype are WNT4 dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulates the distinct metabolic phenotypes of ILC and gynecologic cancers. SIGNIFICANCE: WNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT4 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment.

Unravelling the role of [Ru(bpy)2(OH2)2]2+ complexes in photo-activated chemotherapy.

Photoactivated chemotherapy (PACT) has emerged as a promising strategy to selectively target cancer cells by using light irradiation to generate cytotoxic complexes in situ through a mechanism involving ligand-loss. Due to their rich optical properties and excited state chemistry, Ru polypyridyl complexes have attracted significant attention for PACT. However, studying PACT is complicated by the fact that many of these Ru complexes can also undergo excited-state electron transfer to generate 1O2 species. In order to deconvolute the biological roles of possible photo-decomposition products without the added complication of excited-state electron transfer chemistry, we have developed a methodology to systematically investigate each product individually, and assess the structure-function relationship. Here, we synthesized a series of eight distinct Ru polypyridyl complexes: Ru-Xa ([Ru(NN)3]2+), Ru-Xb ([Ru(NN)2py2]2+), and Ru-Xc ([Ru(NN)(OH2)2]2+) where NN = 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, or dimethyl 2,2'-bipyridine-4,4'-dicarboxylate and py = pyridine. The cytotoxicity of these complexes was investigated in two cell lines amenable to PACT: H23 (breast cancer) and T47D (lung cancer). We confirmed that light irradiation of Ru-Xa and Ru-Xb complexes generate Ru-Xc complexes through UV-visible spectroscopy, and observed that the Ru-Xc complexes are the most toxic against the cancer cell lines. In addition, we have shown that ligand release and biological activity including bovine serum albumin (BSA) binding, lipophilicity, and DNA interaction are altered when different groups are appended to the bipyridine ligands. We believe that the methodology presented here will enhance the development of more potent and selective PACT agents moving forward.

Neuroplasticity associated with changes in conversational turn-taking following a family-based intervention.

Children's early language environments are associated with linguistic, cognitive, and academic development, as well as concurrent brain structure and function. This study investigated neurodevelopmental mechanisms linking language input to development by measuring neuroplasticity associated with an intervention designed to enhance language environments of families primarily from lower socioeconomic backgrounds. Families of 52 4-to-6 year-old children were randomly assigned to a 9-week, interactive, family-based intervention or no-contact control group. Children completed pre- and post-assessments of verbal and nonverbal cognition (n = 52), structural magnetic resonance imaging (n = 45), and home auditory recordings of language exposure (n = 39). Families who completed the intervention exhibited greater increases in adult-child conversational turns, and changes in turn-taking mediated intervention effects on language and executive functioning measures. Collapsing across groups, turn-taking changes were also positively correlated with cortical thickening in left inferior frontal and supramarginal gyri, the latter of which mediated relationships between changes in turn-taking and children's language development. This is the first study of longitudinal neuroplasticity in response to changes in children's language environments, and findings suggest that conversational turns support language development through cortical growth in language and social processing regions. This has implications for early interventions to enhance children's language environments to support neurocognitive development.

Evaluation of Four-Dimensional Computed Tomography as a Technique for Quantifying Carpal Motion.

Delayed diagnosis of dynamic carpal instability often occurs because early changes in bone alignment and movement are difficult to detect and manifest mainly during a dynamic/functional task. Current diagnostic tools are only able to examine the carpal bones under static or sequential-static conditions. Four-dimensional (three dimensions + time) computed tomography (4DCT) enables quantification of carpal mechanics through 3D volume sequences of the wrist in motion. A comprehensive understanding of carpal mechanics is needed to define normal function and structure and provide targets for treatment of carpal injuries. In this study, measurements of scaphoid translation and joint congruency were taken by creating models from the CT scans of the carpals in extreme frames of motion, registering those models to the neutral position, transforming the models into a local coordinate system, and using software to calculate the joint surface areas (JSA). Results indicated that the centroid of the scaphoid translated 6.4 ± 1.3 mm and extended from extreme radial to extreme ulnar deviation. Results are consistent with the literature. An additional study was performed to measure the responsiveness of the 4DCT technique presented. Bone models from each frame of motion for radio ulnar deviation (RUD) and flexion extension (FE) were created and distinct differences between their JSA were measured qualitatively and quantitatively. The results show that there was statistically significantly different JSA within carpal joints between RUD and FE. These studies provide the first step in developing the methodology when using 4DCT scanning to measure subtle abnormalities in the wrist.

Replication and extension of a family-based training program to improve cognitive abilities in young children.

Childhood socioeconomic status (SES) is associated with persistent academic achievement gaps, which necessitates evidence-based, scalable interventions to improve children's outcomes. The present study reports results from a replication and extension of a family-based training program previously found to improve cognitive development in lower-SES preschoolers (Neville et al., 2013). One hundred and one primarily low-SES families with 107 children aged 4-7 years were randomly assigned to the intervention or passive control group. Intent-to-treat regression models revealed that children whose families were assigned to the intervention group did not exhibit significant benefit on composite measures of nonverbal IQ, executive functioning, or language skills, though post-hoc analyses suggested marginal improvement on the fluid reasoning subcomponent of nonverbal IQ. Treatment-on-treated models revealed a significant positive effect of intervention attendance on fluid reasoning and a negative effect on vocabulary. We discuss potential causes for the non-replication, including differences in the sample composition, size, and assessment choices. Results suggest the need to more broadly assess scalable interventions with varying populations and ensure appropriate cultural and geographical adaptations to achieve maximum benefits for children from diverse backgrounds.

Evaluation of individual finger forces during activities of daily living in healthy individuals and those with hand arthritis.

INTRODUCTION: Measuring finger forces during activities of daily living and how these forces change for individuals with pathologies such as arthritis is valuable to our understanding of hand function. PURPOSE OF THE STUDY: The purpose of this study was to determine the forces of individual fingers during the performance of daily activities in healthy participants and determine the envelope of these applied forces. METHODS: This is a cross-sectional study investigating twenty-five healthy participants (12 female: 22-65 years old and 13 male: 20-53 years old) and participants with osteoarthritis (12 female: 52-79 years old and 9 male: 64-79 years old) examined at one time point. The force sensors were calibrated for each individual using a load cell to provide force output in Newtons. Each participant performed 19 activities of daily living two times. Force was plotted over time for each task, and the maximum force in each finger during that task was evaluated. RESULTS: The range of applied forces was 1.4 ± 0.6 N to 34.8 ± 1.6 N for healthy participants and 2.3 ± 1.0 N to 30.7 ± 3.7 N for those with osteoarthritis. DISCUSSION: Sensors allowed for real-time monitoring of finger forces during tasks of daily life. This provides the opportunity to isolate hand grips based on finger recruitment and provide information about the magnitude of forces during the activity. CONCLUSION: Measurement of individual finger forces can provide more accurate biomechanical models of the hand and determine the effect of disease on hand functions.

Associations between cortical thickness and reasoning differ by socioeconomic status in development.

Although lower socioeconomic status (SES) is generally negatively associated with performance on cognitive assessments, some children from lower-SES backgrounds perform as well as their peers from higher-SES backgrounds. Yet little research has examined whether the neural correlates of individual differences in cognition vary by SES. The current study explored whether relationships between cortical structure and fluid reasoning differ by SES in development. Fluid reasoning, a non-verbal component of IQ, is supported by a distributed frontoparietal network, with evidence for a specific role of rostrolateral prefrontal cortex (RLPFC). In a sample of 115 4-7-year old children, bilateral thickness of RLPFC differentially related to reasoning by SES: thicker bilateral RLPFC positively correlated with reasoning ability in children from lower-SES backgrounds, but not in children from higher-SES backgrounds. Similar results were found in an independent sample of 59 12-16-year old adolescents. Furthermore, young children from lower-SES backgrounds with strong reasoning skills were the only group to show a positive relationship between RLPFC thickness and age. In sum, we found that relationships between cortical thickness and cognition differ by SES during development.

Language Exposure Relates to Structural Neural Connectivity in Childhood.

Neuroscience research has elucidated broad relationships between socioeconomic status (SES) and young children's brain structure, but there is little mechanistic knowledge about specific environmental factors that are associated with specific variation in brain structure. One environmental factor, early language exposure, predicts children's linguistic and cognitive skills and later academic achievement, but how language exposure relates to neuroanatomy is unknown. By measuring the real-world language exposure of young children (ages 4-6 years, 27 male/13 female), we confirmed the preregistered hypothesis that greater adult-child conversational experience, independent of SES and the sheer amount of adult speech, is related to stronger, more coherent white matter connectivity in the left arcuate and superior longitudinal fasciculi on average, and specifically near their anterior termination at Broca's area in left inferior frontal cortex. Fractional anisotropy of significant tract subregions mediated the relationship between conversational turns and children's language skills and indicated a neuroanatomical mechanism underlying the SES "language gap." Post hoc whole-brain analyses revealed that language exposure was not related to any other white matter tracts, indicating the specificity of this relationship. Results suggest that the development of dorsal language tracts is environmentally influenced, specifically by early, dialogic interaction. Furthermore, these findings raise the possibility that early intervention programs aiming to ameliorate disadvantages in development due to family SES may focus on increasing children's conversational exposure to capitalize on the early neural plasticity underlying cognitive development.SIGNIFICANCE STATEMENT Over the last decade, cognitive neuroscience has highlighted the detrimental impact of disadvantaged backgrounds on young children's brain structure. However, to intervene effectively, we must know which proximal aspects of the environmental aspects are most strongly related to neural development. The present study finds that young children's real-world language exposure, and specifically the amount of adult-child conversation, correlates with the strength of connectivity in the left hemisphere white matter pathway connecting two canonical language regions, independent of socioeconomic status and the sheer volume of adult speech. These findings suggest that early intervention programs aiming to close the achievement gap may focus on increasing children's conversational exposure to capitalize on the early neural plasticity underlying cognitive development.

Beyond the 30-Million-Word Gap: Children's Conversational Exposure Is Associated With Language-Related Brain Function.

Children's early language exposure impacts their later linguistic skills, cognitive abilities, and academic achievement, and large disparities in language exposure are associated with family socioeconomic status (SES). However, there is little evidence about the neural mechanisms underlying the relation between language experience and linguistic and cognitive development. Here, language experience was measured from home audio recordings of 36 SES-diverse 4- to 6-year-old children. During a story-listening functional MRI task, children who had experienced more conversational turns with adults-independently of SES, IQ, and adult-child utterances alone-exhibited greater left inferior frontal (Broca's area) activation, which significantly explained the relation between children's language exposure and verbal skill. This is the first evidence directly relating children's language environments with neural language processing, specifying both an environmental and a neural mechanism underlying SES disparities in children's language skills. Furthermore, results suggest that conversational experience impacts neural language processing over and above SES or the sheer quantity of words heard.