Building integrated number sense in adults and children: Comparing fractions-only training with cross-notation number line training.

Mounting evidence points to the predictive power of cross-notation rational number understanding (e.g., 2/5 vs. 0.25) relative to within-notation understanding (e.g., 2/5 vs. 1/4) in predicting math outcomes. Although correlational in nature, these studies suggest that number sense training emphasizing integrating across notations may have more positive outcomes than a within-notation focus. However, this idea has not been empirically tested. Thus, across two studies with undergraduate students (N = 183 and N = 181), we investigated the effects of a number line training program using a cross-notation approach (one that focused on connections among fractions, decimals, and percentages) and a within-notation approach (one that focused on fraction magnitude representation only). Both number line approaches produced positive effects, but those of the cross-notation approach were larger for fraction magnitude estimation and cross-notation comparison accuracy. In a third study (N = 63), we adapted the cross-notation number line training for use in place of typical classroom warm-up activities for middle school students. Similar to the results with undergraduate students, the cross-notation training program yielded positive benefits for middle school students over a typical warm-up activity (fraction arithmetic practice). Together, these results suggest the importance of an integrated approach to teaching rational number notations, an approach that appears to be uncommon in current curricula.

Foundational Number Sense Training Gains Are Predicted by Hippocampal-Parietal Circuits.

The development of mathematical skills in early childhood relies on number sense, the foundational ability to discriminate among quantities. Number sense in early childhood is predictive of academic and professional success, and deficits in number sense are thought to underlie lifelong impairments in mathematical abilities. Despite its importance, the brain circuit mechanisms that support number sense learning remain poorly understood. Here, we designed a theoretically motivated training program to determine brain circuit mechanisms underlying foundational number sense learning in female and male elementary school-age children (7-10 years). Our 4 week integrative number sense training program gradually strengthened the understanding of the relations between symbolic (Arabic numerals) and nonsymbolic (sets of items) representations of quantity. We found that our number sense training program improved symbolic quantity discrimination ability in children across a wide range of math abilities including children with learning difficulties. Crucially, the strength of pretraining functional connectivity between the hippocampus and intraparietal sulcus, brain regions implicated in associative learning and quantity discrimination, respectively, predicted individual differences in number sense learning across typically developing children and children with learning difficulties. Reverse meta-analysis of interregional coactivations across 14,371 fMRI studies and 89 cognitive functions confirmed a reliable role for hippocampal-intraparietal sulcus circuits in learning. Our study identifies a canonical hippocampal-parietal circuit for learning that plays a foundational role in children's cognitive skill acquisition. Findings provide important insights into neurobiological circuit markers of individual differences in children's learning and delineate a robust target for effective cognitive interventions.SIGNIFICANCE STATEMENT Mathematical skill development relies on number sense, the ability to discriminate among quantities. Here, we develop a theoretically motivated training program and investigate brain circuits that predict number sense learning in children during a period important for acquisition of foundational cognitive skills. Our integrated number sense training program was effective in children across a wide a range of math abilities, including children with learning difficulties. We identify hippocampal-parietal circuits that predict individual differences in learning gains. Our study identifies a brain circuit critical for the acquisition of foundational cognitive skills, which will be useful for developing effective interventions to remediate learning disabilities.

Middle-schoolers' misconceptions in discretized nonsymbolic proportional reasoning explain fraction biases better than their continuous reasoning: Evidence from correlation and cluster analyses.

Early emerging nonsymbolic proportional skills have been posited as a foundational ability for later fraction learning. A positive relation between nonsymbolic and symbolic proportional reasoning has been reported, as well as successful nonsymbolic training and intervention programs enhancing fraction magnitude skills. However, little is known about the mechanisms underlying this relationship. Of particular interest are nonsymbolic representations, which can be in continuous formats that may emphasize proportional relations and in discretized formats that may prompt erroneous whole-number strategies and hamper access to fraction magnitudes. We assessed the proportional comparison skills of 159 middle-school students (mean age = 12.54 years, 43% females, 55% males, 2% other or prefer not to say) across three types of representations: (a) continuous, unsegmented bars, (b) discretized, segmented bars that allowed counting strategies, and (c) symbolic fractions. Using both correlational and cluster approaches, we also examined their relations to symbolic fraction comparison ability. Within each stimulus type, we varied proportional distance, and in the discretized and symbolic stimuli, we also manipulated whole-number congruency. We found that fraction distance across all formats modulated middle-schoolers' performance; however, whole-number information affected discretized and symbolic comparison performance. Further, continuous and discretized nonsymbolic performance was related to fraction comparison ability; however, discretized skills explained variance above and beyond the contributions of continuous skills. Finally, our cluster analyses revealed three nonsymbolic comparison profiles: students who chose the bars with the largest number of segments (whole-number bias), chance-level performers, and high performers. Crucially, students with a whole-number bias profile showed this bias in their fraction skills and failed to show any symbolic distance modulation. Together, our results indicate that the relation between nonsymbolic and symbolic proportional skills may be determined by the (mis)conceptions based on discretized representations, rather than understandings of proportional magnitudes, suggesting that interventions focusing on competence with discretized representations may show dividends for fraction understanding.

A Rab prenyl membrane-anchor allows effector recognition to be regulated by guanine nucleotide.

Membrane fusion is catalyzed by conserved proteins R, Qa, Qb, and Qc SNAREs, which form tetrameric RQaQbQc complexes between membranes; SNARE chaperones of the SM, Sec17/αSNAP, and Sec18/NSF families; Rab-GTPases (Rabs); and Rab effectors. Rabs are anchored to membranes by C-terminal prenyl groups, but can also function when anchored by an apolar polypeptide. Rabs are regulated by GTPase-activating proteins (GAPs), activating the hydrolysis of bound GTP. We have reconstituted fusion with pure components from yeast vacuoles including SNAREs, the HOPS (homotypic fusion and vacuole protein sorting) tethering and SNARE-assembly complex, and the Rab Ypt7, bound to membranes by either C-terminal prenyl groups (Ypt7-pr) or a recombinant transmembrane anchor (Ypt7-tm). We now report that HOPS-dependent fusion occurs with Ypt7 anchored by either means, but only Ypt7-pr requires GTP for activation and is inactive either with bound GDP or without bound guanine nucleotide. In contrast, Ypt7-tm is constitutively active for HOPS-dependent fusion, independent of bound guanine nucleotide. Fusion inhibition by the GAP Gyp1-46 is not limited to Ypt7-tm with bound GTP, indicating that this GAP has an additional mode of regulating fusion. Phosphorylation of HOPS by the vacuolar kinase Yck3 renders fusion strictly dependent on GTP-activated Ypt7, whether bound to membranes by prenyl or transmembrane anchor. The binding of GTP or GDP constitutes a selective switch for Ypt7, but with Ypt7-tm, this switch is only read by HOPS after phosphorylation to P-HOPS by its physiological kinase Yck3. The prenyl anchor of Ypt7 allows both HOPS and P-HOPS to be regulated by Ypt7-bound guanine nucleotide.

Exposure to violence is associated with decreased neural connectivity in emotion regulation and cognitive control, but not working memory, networks after accounting for socioeconomic status: a preliminary study.

Previous research has demonstrated behavioral and neural differences associated with experiencing adversity. However, adversity is unlikely to be a monolithic construct, and we expect that examining effects of more specific components such as exposure to violence in the home community will yield more concretely interpretable results. Here we account for effects of low socioeconomic status (SES) to examine the specific effects of exposure to violence on functional connectivity between brain areas known to be related to emotion regulation and working memory. Decreased resting state functional connectivity for individuals exposed to high compared to low levels of violence during childhood was predicted for two sets of areas: (1) bilateral amygdala with anterior medial regions involved in cognitive control of emotion, and (2) the right dorsolateral prefrontal cortex (dlPFC) with frontal and parietal regions implicated in working memory. Consistent with our predictions, increasing exposure to violence was related to decreased resting state functional connectivity between the right amygdala and anterior cingulate cortex, even after accounting for SES. Also after accounting for SES, exposure to violence was related to reductions in connectivity between the right dlPFC and frontal regions, but not with parietal regions typically associated with working memory. Overall, this pattern suggests increased exposure to violence in childhood is associated with reduced connectivity among key areas of the circuitry involved in emotion regulation and cognitive control, but not working memory. These results offer insight into the neural underpinnings of behavioral outcomes associated with exposure to violence, laying the foundation for ultimately designing interventions to address the effects of such exposure.

Parietal and hippocampal hyper-connectivity is associated with low math achievement in adolescence - A preliminary study.

Mathematical cognition requires coordinated activity across multiple brain regions, leading to the emergence of resting-state functional connectivity as a method for studying the neural basis of differences in mathematical achievement. Hyper-connectivity of the intraparietal sulcus (IPS), a key locus of mathematical and numerical processing, has been associated with poor mathematical skills in childhood, whereas greater connectivity has been related to better performance in adulthood. No studies to date have considered its role in adolescence. Further, hippocampal connectivity can predict mathematical learning, yet no studies have considered its contributions to contemporaneous measures of math achievement. Here, we used seed-based resting-state fMRI analyses to examine IPS and hippocampal intrinsic functional connectivity relations to math achievement in a group of 31 adolescents (mean age = 16.42 years, range 15-17), whose math performance spanned the 1% to 99% percentile. After controlling for IQ, IPS connectivity was negatively related to math achievement, akin to findings in children. However, the specific temporo-occipital regions were more akin to the posterior loci implicated in adults. Hippocampal connectivity with frontal regions was also negatively correlated with concurrent math measures, which contrasts with results from learning studies. Finally, hyper-connectivity was not a global feature of low math performance, as math performance did not modulate connectivity of Heschl's gyrus, a control seed not involved in math cognition. Our results provide preliminary evidence that adolescence is a transitional stage in which patterns found in childhood and adulthood can be observed; most notably, hyper-connectivity continues to be related to low math ability into this period.

Ergosterol interacts with Sey1p to promote atlastin-mediated endoplasmic reticulum membrane fusion in Saccharomyces cerevisiae.

Sterols play critical roles in various membrane fusion events, including soluble NSF attachment protein receptor-mediated membrane fusion, mainly by modulating the physical properties of biologic membranes; however, it remains unclear whether they also function in atlastin-mediated endoplasmic reticulum (ER) membrane fusion. Although ergosterol, the major sterol in yeast, is essential for fusion of Sey1p (yeast atlastin)-containing liposomes with an ER-mimicking lipid composition, fusion of phosphatidylcholine/phosphatidylserine liposomes does not require sterols. Here, we examined whether sterols are important for Sey1p-mediated ER fusion in Saccharomyces cerevisiae using an in vitro ER fusion assay with isolated yeast ER microsomes. Ergosterol-specific ligands inhibited microsome fusion, indicating that ergosterol is critical for ER fusion. However, microsomes isolated from yeast strains lacking genes that encode enzymes involved in synthesis of ergosterol from lanosterol still fused, suggesting that other sterols can replace ergosterol and support Sey1p-mediated ER fusion. Importantly, disruption of sterol-binding motifs in the transmembrane regions of Sey1p markedly reduced ER fusion. Sey1p physically interacted with Erg11p and Erg4p, which function in ergosterol biosynthesis, suggesting that Sey1p recruits ergosterol-synthesizing enzymes to fusion sites and thereby enriches ergosterol, which, in turn, may recruit more Sey1p. This positive feedback loop may facilitate ER membrane fusion by concentrating fusion factors at fusion sites.-Lee, M., Moon, Y., Lee, S., Lee, C., Jun, Y. Ergosterol interacts with Sey1p to promote atlastin-mediated endoplasmic reticulum membrane fusion in Saccharomyces cerevisiae.

Children's discrete proportional reasoning is related to inhibitory control and enhanced by priming continuous representations.

Children can successfully compare continuous proportions as early as 4 years of age, yet they struggle to compare discrete proportions at least to 10 years of age, especially when the discrete information is misleading. This study examined whether inhibitory control contributes to individual differences in discrete proportional reasoning and whether reasoning could be enhanced by priming continuous information. A total of 49 second-graders completed two tasks. In the Hearts and Flowers (H&F) task, a measure of inhibition, children pressed on either the corresponding or opposite side, depending on the identity of the displayed figure. In the Spinners task, a measure of proportional reasoning, children chose the spinner with the proportionally larger red area across continuous and two discrete formats. In the discrete adjacent format, the continuous stimuli were segmented into sections, which could be compatible with the proportional information or misleading; the discrete mixed format interspersed the colored sections from the discrete adjacent conditions. Finally, two priming groups were formed. Children who saw the continuous format immediately before the discrete adjacent format formed the continuous priming group (n = 26). Children who saw the discrete mixed format immediately before the discrete adjacent format formed the discrete priming group (n = 23). Our results showed that children who performed better on the H&F task also had better performance on the discrete counting misleading trials. Furthermore, children in the continuous priming group outperformed children in the discrete priming group, specifically in contexts where discrete information was misleading. These results suggest that children's proportional reasoning may be improved by fostering continuous representations of discrete stimuli and by enhancing inhibitory control skills.

Mechanistic insight into the nucleus-vacuole junction based on the Vac8p-Nvj1p crystal structure.

Formation of the nucleus-vacuole junction (NVJ) is mediated by direct interaction between the vacuolar protein Vac8p and the outer nuclear endoplasmic reticulum membrane protein Nvj1p. Herein we report the crystal structure of Vac8p bound to Nvj1p at 2.4-Å resolution. Vac8p comprises a flexibly connected N-terminal H1 helix followed by 12 armadillo repeats (ARMs) that form a right-handed superhelical structure. The extended 80-Å-long loop of Nvj1p specifically binds the highly conserved inner groove formed from ARM1-12 of Vac8p. Disruption of the Nvj1p-Vac8p interaction results in the loss of tight NVJs, which impairs piecemeal microautophagy of the nucleus in Saccharomyces cerevisiae Vac8p cationic triad (Arg276, Arg317, and Arg359) motifs interacting with Nvj1p are also critical to the recognition of Atg13p, a key component of the cytoplasm-to-vacuole targeting (CVT) pathway, indicating competitive binding to Vac8p. Indeed, mutation of the cationic triad abolishes CVT of Ape1p in vivo. Combined with biochemical data, the crystal structure reveals a Vac8p homodimer formed from ARM1, and this self-association, likely regulated by the flexible H1 helix and the C terminus of Nvj1p, is critical for Vac8p cellular functions.

Massive single visit cervical pre-cancer and cancer screening in eastern Democratic Republic of Congo.

BACKGROUND: In the Democratic Republic of Congo (DRC), practical and affordable strategies for cervical cancer screening are needed to detect and treat pre-cancerous and cancerous lesions in a timely fashion. This study presents the results of mass cervical cancer screenings in eastern DRC using a "screen and treat" approach. METHODS: In two mass cervical cancer screening campaigns, patients underwent a combination of visual inspection of the cervix with acetic acid, visual inspection of the cervix with Lugol iodine solution, and colposcopy with or without loop electrosurgical excision procedure. Cervical biopsy samples were taken for histology analysis. Marital status, age, history of abnormal bleeding, and number of pregnancies were recorded for each patient and association analyses were performed. RESULTS: Of the 644 women who received cervical pre-cancer and cancer screening, 48 had suspicious pre-cancer and cancer lesions that were biopsied (7.45%). On histology analysis cervical intraepithelial neoplasia (CIN) was identified in 15 (2.33%), squamous cell carcinoma (SCC) was identified in 6 (0.93%) and non-neoplastic cervicitis was identified in 11 (1.71%). Abnormal bleeding was significantly associated with CIN/SCC but no significant association was observed for prior pregnancy, patients' home region, or age. CONCLUSION: Forty-eight women with suspicious pre-cancerous or cancerous lesions were successfully identified using the "screen and treat" approach in eastern DRC, suggesting that this approach is feasible for reducing cervical cancer morbidity and mortality. However, community awareness would be necessary, providers would have to be properly trained, referral and follow up mechanisms would have to be put in place, and equipment / supplies would have to be secured if the "screen and treat" approach is to be successful on a wider scale. There is ongoing need for HPV vaccination in DRC as a primary prevention strategy against cervical cancer.

Bioengineered yeast-derived vacuoles with enhanced tissue-penetrating ability for targeted cancer therapy.

Despite the appreciable success of synthetic nanomaterials for targeted cancer therapy in preclinical studies, technical challenges involving their large-scale, cost-effective production and intrinsic toxicity associated with the materials, as well as their inability to penetrate tumor tissues deeply, limit their clinical translation. Here, we describe biologically derived nanocarriers developed from a bioengineered yeast strain that may overcome such impediments. The budding yeast Saccharomyces cerevisiae was genetically engineered to produce nanosized vacuoles displaying human epidermal growth factor receptor 2 (HER2)-specific affibody for active targeting. These nanosized vacuoles efficiently loaded the anticancer drug doxorubicin (Dox) and were effectively endocytosed by cultured cancer cells. Their cancer-targeting ability, along with their unique endomembrane compositions, significantly enhanced drug penetration in multicellular cultures and improved drug distribution in a tumor xenograft. Furthermore, Dox-loaded vacuoles successfully prevented tumor growth without eliciting any prolonged immune responses. The current study provides a platform technology for generating cancer-specific, tissue-penetrating, safe, and scalable biological nanoparticles for targeted cancer therapy.

Approximate Number Sense Shares Etiological Overlap with Mathematics and General Cognitive Ability.

Approximate number sense (ANS), the ability to rapidly and accurately compare quantities presented non-symbolically, has been proposed as a precursor to mathematics skills. Earlier work reported low heritability of approximate number sense, which was interpreted as evidence that approximate number sense acts as a fitness trait. However, viewing ANS as a fitness trait is discordant with findings suggesting that individual differences in approximate number sense acuity correlate with mathematical performance, a trait with moderate genetic effects. Importantly, the shared etiology of approximate number sense, mathematics, and general cognitive ability has remained unexamined. Thus, the etiology of approximate number sense and its overlap with math and general cognitive ability was assessed in the current study with two independent twin samples (N = 451 pairs). Results suggested that ANS acuity had moderate but significant additive genetic influences. ANS also had overlap with generalist genetic mechanisms accounting for variance and covariance in mathematics and general cognitive ability. Furthermore, ANS may have genetic factors unique to covariance with mathematics beyond overlap with general cognitive ability. Evidence across both samples was consistent with the proposal that the etiology of approximate number sense functions similar to that of mathematics and general cognitive skills.

In vitro assay using engineered yeast vacuoles for neuronal SNARE-mediated membrane fusion.

Intracellular membrane fusion requires not only SNARE proteins but also other regulatory proteins such as the Rab and Sec1/Munc18 (SM) family proteins. Although neuronal SNARE proteins alone can drive the fusion between synthetic liposomes, it remains unclear whether they are also sufficient to induce the fusion of biological membranes. Here, through the use of engineered yeast vacuoles bearing neuronal SNARE proteins, we show that neuronal SNAREs can induce membrane fusion between yeast vacuoles and that this fusion does not require the function of the Rab protein Ypt7p or the SM family protein Vps33p, both of which are essential for normal yeast vacuole fusion. Although excess vacuolar SNARE proteins were also shown to mediate Rab-bypass fusion, this fusion required homotypic fusion and vacuole protein sorting complex, which bears Vps33p and was accompanied by extensive membrane lysis. We also show that this neuronal SNARE-driven vacuole fusion can be stimulated by the neuronal SM protein Munc18 and blocked by botulinum neurotoxin serotype E, a well-known inhibitor of synaptic vesicle fusion. Taken together, our results suggest that neuronal SNARE proteins are sufficient to induce biological membrane fusion, and that this new assay can be used as a simple and complementary method for investigating synaptic vesicle fusion mechanisms.

Parietal hyper-connectivity, aberrant brain organization, and circuit-based biomarkers in children with mathematical disabilities.

Mathematical disabilities (MD) have a negative life-long impact on professional success, employment, and health outcomes. Yet little is known about the intrinsic functional brain organization that contributes to poor math skills in affected children. It is now increasingly recognized that math cognition requires coordinated interaction within a large-scale fronto-parietal network anchored in the intraparietal sulcus (IPS). Here we characterize intrinsic functional connectivity within this IPS-network in children with MD, relative to a group of typically developing (TD) children who were matched on age, gender, IQ, working memory, and reading abilities. Compared to TD children, children with MD showed hyper-connectivity of the IPS with a bilateral fronto-parietal network. Importantly, aberrant IPS connectivity patterns accurately discriminated children with MD and TD children, highlighting the possibility for using IPS connectivity as a brain-based biomarker of MD. To further investigate regional abnormalities contributing to network-level deficits in children with MD, we performed whole-brain analyses of intrinsic low-frequency fluctuations. Notably, children with MD showed higher low-frequency fluctuations in multiple fronto-parietal areas that overlapped with brain regions that exhibited hyper-connectivity with the IPS. Taken together, our findings suggest that MD in children is characterized by robust network-level aberrations, and is not an isolated dysfunction of the IPS. We hypothesize that intrinsic hyper-connectivity and enhanced low-frequency fluctuations may limit flexible resource allocation, and contribute to aberrant recruitment of task-related brain regions during numerical problem solving in children with MD.

Neural predictors of individual differences in response to math tutoring in primary-grade school children.

Now, more than ever, the ability to acquire mathematical skills efficiently is critical for academic and professional success, yet little is known about the behavioral and neural mechanisms that drive some children to acquire these skills faster than others. Here we investigate the behavioral and neural predictors of individual differences in arithmetic skill acquisition in response to 8-wk of one-to-one math tutoring. Twenty-four children in grade 3 (ages 8-9 y), a critical period for acquisition of basic mathematical skills, underwent structural and resting-state functional MRI scans pretutoring. A significant shift in arithmetic problem-solving strategies from counting to fact retrieval was observed with tutoring. Notably, the speed and accuracy of arithmetic problem solving increased with tutoring, with some children improving significantly more than others. Next, we examined whether pretutoring behavioral and brain measures could predict individual differences in arithmetic performance improvements with tutoring. No behavioral measures, including intelligence quotient, working memory, or mathematical abilities, predicted performance improvements. In contrast, pretutoring hippocampal volume predicted performance improvements. Furthermore, pretutoring intrinsic functional connectivity of the hippocampus with dorsolateral and ventrolateral prefrontal cortices and the basal ganglia also predicted performance improvements. Our findings provide evidence that individual differences in morphometry and connectivity of brain regions associated with learning and memory, and not regions typically involved in arithmetic processing, are strong predictors of responsiveness to math tutoring in children. More generally, our study suggests that quantitative measures of brain structure and intrinsic brain organization can provide a more sensitive marker of skill acquisition than behavioral measures.

Brain hyper-connectivity and operation-specific deficits during arithmetic problem solving in children with developmental dyscalculia.

Developmental dyscalculia (DD) is marked by specific deficits in processing numerical and mathematical information despite normal intelligence (IQ) and reading ability. We examined how brain circuits used by young children with DD to solve simple addition and subtraction problems differ from those used by typically developing (TD) children who were matched on age, IQ, reading ability, and working memory. Children with DD were slower and less accurate during problem solving than TD children, and were especially impaired on their ability to solve subtraction problems. Children with DD showed significantly greater activity in multiple parietal, occipito-temporal and prefrontal cortex regions while solving addition and subtraction problems. Despite poorer performance during subtraction, children with DD showed greater activity in multiple intra-parietal sulcus (IPS) and superior parietal lobule subdivisions in the dorsal posterior parietal cortex as well as fusiform gyrus in the ventral occipito-temporal cortex. Critically, effective connectivity analyses revealed hyper-connectivity, rather than reduced connectivity, between the IPS and multiple brain systems including the lateral fronto-parietal and default mode networks in children with DD during both addition and subtraction. These findings suggest the IPS and its functional circuits are a major locus of dysfunction during both addition and subtraction problem solving in DD, and that inappropriate task modulation and hyper-connectivity, rather than under-engagement and under-connectivity, are the neural mechanisms underlying problem solving difficulties in children with DD. We discuss our findings in the broader context of multiple levels of analysis and performance issues inherent in neuroimaging studies of typical and atypical development.

Missense Mutant Gain-of-Function Causes Inverted Formin 2 (INF2)-Related Focal Segmental Glomerulosclerosis (FSGS).

Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT) disease. Recent studies suggest that INF2, through its effects on actin and microtubule arrangement, can regulate processes including vesicle trafficking, cell adhesion, mitochondrial calcium uptake, mitochondrial fission, and T-cell polarization. Despite roles for INF2 in multiple cellular processes, neither the human pathogenic R218Q INF2 point mutation nor the INF2 knock-out allele is sufficient to cause disease in mice. This discrepancy challenges our efforts to explain the disease mechanism, as the link between INF2-related processes, podocyte structure, disease inheritance pattern, and their clinical presentation remains enigmatic. Here, we compared the kidney responses to puromycin aminonucleoside (PAN) induced injury between R218Q INF2 point mutant knock-in and INF2 knock-out mouse models and show that R218Q INF2 mice are susceptible to developing proteinuria and FSGS. This contrasts with INF2 knock-out mice, which show only a minimal kidney phenotype. Co-localization and co-immunoprecipitation analysis of wild-type and mutant INF2 coupled with measurements of cellular actin content revealed that the R218Q INF2 point mutation confers a gain-of-function effect by altering the actin cytoskeleton, facilitated in part by alterations in INF2 localization. Differential analysis of RNA expression in PAN-stressed heterozygous R218Q INF2 point-mutant and heterozygous INF2 knock-out mouse glomeruli showed that the adhesion and mitochondria-related pathways were significantly enriched in the disease condition. Mouse podocytes with R218Q INF2, and an INF2-mutant human patient's kidney organoid-derived podocytes with an S186P INF2 mutation, recapitulate the defective adhesion and mitochondria phenotypes. These results link INF2-regulated cellular processes to the onset and progression of glomerular disease. Thus, our data demonstrate that gain-of-function mechanisms drive INF2-related FSGS and explain the autosomal dominant inheritance pattern of this disease.

Adults systematically underestimate decimals and whole number exposure induces further magnitude-based underestimation.

Decimal numbers are generally assumed to be a straightforward extension of the base-ten system for whole numbers given their shared place value structure. However, in decimal notation, unlike whole numbers, the same magnitude can be expressed in multiple ways (e.g., 0.8, 0.80, 0.800, etc.). Here, we used a number line task with carefully selected stimuli to investigate how equivalent decimals (e.g., 0.8 and 0.80 on a 0-1 number line) and proportionally equivalent whole numbers (e.g., 80 on a 0-100 number line) are estimated. We find that young adults (n = 88, Mage = 20.22 years, SD = 1.65, 57 female) have a linear response pattern for both decimals and whole numbers, but those double-digit decimals (e.g., 0.08, 0.82, 0.80) are systematically underestimated relative to proportionally equivalent whole numbers (e.g., 8, 82, 80). Moreover, decimal string length worsens the underestimation, such that single-digit decimals (e.g., 0.8) are perceived as smaller than their equivalent double-digit decimals (e.g., 0.80). Finally, we find that exposing participants to whole number stimuli before decimal stimuli induces magnitude-based underestimation, that is, greater underestimation for larger decimals. Together, these results suggest a small but persistent underestimation bias for decimals less than one, and further that decimal magnitude estimation is fragile and subject to greater underestimation when exposed to whole numbers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Atypical pattern separation memory and its association with restricted interests and repetitive behaviors in autistic children.

LAY ABSTRACT: Memory challenges remain understudied in childhood autism. Our study investigates one specific aspect of memory function, known as pattern separation memory, in autistic children. Pattern separation memory refers to the critical ability to store unique memories of similar stimuli; however, its role in childhood autism remains largely uncharted. Our study first uncovered that the pattern separation memory was significantly reduced in autistic children, and then showed that reduced memory performance was linked to their symptoms of repetitive, restricted interest and behavior. We also identified distinct subgroups with profiles of reduced and increased generalization for pattern separation memory. More than 72% of autistic children showed a tendency to reduce memory generalization, focusing heavily on unique details of objects for memorization. This focus made it challenging for them to identify commonalities across similar entities. Interestingly, a smaller proportion of autistic children displayed an opposite pattern of increased generalization, marked by challenges in differentiating between similar yet distinct objects. Our findings advance the understanding of memory function in autism and have practical implications for devising personalized learning strategies that align with the unique memory patterns exhibited by autistic children. This study will be of broad interest to researchers in psychology, psychiatry, and brain development as well as teachers, parents, clinicians, and the wider public.

Forced interaction of cell surface proteins with Derlin-1 in the endoplasmic reticulum is sufficient to induce their dislocation into the cytosol for degradation.

Aberrantly folded proteins in the endoplasmic reticulum (ER) are rapidly removed into the cytosol for degradation by the proteasome via an evolutionarily conserved process termed ER-associated protein degradation (ERAD). ERAD of a subset of proteins requires Derlin-1 for dislocation into the cytosol; however, the molecular function of Derlin-1 remains unclear. Human cytomegalovirus US11 exploits Derlin-1-dependent ERAD to degrade major histocompatibility complex class I (MHC-I) molecules for immune evasion. Because US11 binds to both MHC-I molecules and Derlin-1 via its luminal and transmembrane domains (TMDs), respectively, the major role of US11 has been proposed to simply be delivery of MHC-I molecules to Derlin-1. Here, we directly tested this proposal by generating a hybrid MHC-I molecule, which contains the US11 TMD, and thus can associate with Derlin-1 in the absence of US11. Intriguingly, this MHC-I hybrid was rapidly degraded in a Derlin-1- and proteasome-dependent manner. Similarly, the vesicular stomatitis virus G protein, otherwise expressed at the cell surface, was degraded via Derlin-1-dependent ERAD when its TMD was replaced with that of US11. Thus, forced interaction of cell surface proteins with Derlin-1 is sufficient to induce their degradation via ERAD. Taken together, these results suggest that the main role of US11 is to recruit MHC-I molecules to Derlin-1, which then mediates the dislocation of MHC-I molecules into the cytosol for degradation.