👤 Laura E Jackson

Exposure to a Western diet during gestation and lactation adversely impacts offspring mood, learning, and memory. We determined if high dose maternal methyl donor nutrient (MDN) supplementation ameliorated the effects of a high fat/high sucrose (HFS) diet during gestation and lactation on the behavior of young, adult offspring. Rat dams consumed the following diets through gestation and lactation: [1] AIN93G control (CON) diet, [2] 45% fat diet with sucrose (HFS), [3] CON diet supplemented with folic acid, B MDN supplementation increased depression-related behavior regardless of maternal base diet (P = 0.003). Learning under stress was reduced in offspring of MDN supplemented dams evidenced by fewer SBET escapes (P = 0.042) and increased escape latency in FR1 trials (P = 0.037). MDNs did not alter novelty reactivity, anxiety-related behavior, or working memory but improved reference memory (P = 0.023). MDNs did not affect corticosterone, reduced BDNF when dams consumed the HFS diet (P = 0.025), and tended to increase DNA methylation (P = 0.065). Maternal MDN supplementation increased depression-related behavior and decreased learning under stress, indicating high dose MDN supplementation may not be warranted. Show less

We investigate whether common circle of Willis (CoW) variants relate to cerebral blood flow (CBF) characteristics among aging adults. Vanderbilt Memory and Aging Project participants free of clinical stroke ( Show less

The genetic basis of sporadic early-onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late-onset Alzheimer's disease (LOAD) polygenic risk in EOAD. A LOAD polygenic score (PGS) was calculated in the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset (p = 0.106) or with cognitive performance (p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal-associated protein 25 (SNAP-25) (p = 2.3 × 10 While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal-associated protein 25 (SNAP-25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD. Show less

Single-cell RNA-sequencing has identified that Alzheimer's disease (AD) pathology in humans is associated with activation of disease-associated microglia (DAM). Microglial signatures of human AD have not been consistently identified in AD mouse models. Since the inflammatory response of rats is more like humans, we profiled microglial transcriptomes in aging TgF344-AD rats, which overexpress two human AD risk genes. Classic DAM gene activation ( Show less

Apolipoprotein E (ApoE) mediates the bidirectional transport of lipids between cells. In the brain, this includes the transfer of lipids from neurons to glia. ApoE4, a major risk factor for Alzheimer's disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) confer resistance to disease, yet little is known regarding how these variants affect lipid trafficking. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by extracting oxidized unsaturated lipids through the ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids, leading to endolysosomal dysfunction. By reducing the oxidized lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity caused by excitotoxicity. Our findings reveal how ApoE2 and ApoE3Ch help protect neurons from neurodegeneration. Show less

Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10-8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10-3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10-8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10-9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci. Show less

Periventricular nodular heterotopia (PVNH) is a common malformation of cortical development. We describe a distinctive imaging phenotype characterized by bilateral small heterotopic nodules of grey matter in the frontal periventricular regions, with an overview of the clinical, imaging, and genetic features. Investigators reviewed available brain MRI studies, clinical records and genetic findings of 32 individuals with bilateral frontal PVNH, ascertained from multiple centres between 1996 and 2021. The imaging phenotype consists of multiple, small, bilateral nodules of PVNH maximal along the frontal horns of the lateral ventricles. Frontal PVNH was associated with heterogeneous, often subtle, additional brain malformations in 72 % (23/32) individuals. The clinical phenotype was variable and included mild focal epilepsy in 7/32 and mild-moderate cognitive impairment or developmental delay in 13/32. Microarray was normal in 13/16 and exome or genome sequencing normal in 8/13 where testing was performed. A genetic diagnosis was achieved in seven patients; pathogenic chromosome deletions of 7q11.23 and 7p22.1, pathogenic intragenic variants in KANSL1, STXBP1 and MAP1B (mother-daughter pair), and a combined 13q12.12 deletion (containing SACS) and an intragenic SACS variant. Bilateral frontal PVNH has a variable clinical phenotype, but generally milder sequelae than other forms of bilateral PVNH. A genetic diagnosis was made by chromosome microarray alone in 13 % or by exome or genome sequencing in 38 % where access to testing was available, with no recurrent genetic cause being found. Our PVNH cohort data suggest that PVNH could be classified in three main groups: FLNA-associated "classic" bilateral frontocentral PVNH, posterior/infrasylvian PVNH and this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH. Show less

Chronic intakes of functional foods (probiotics, apples and oats) have been reported to have beneficial effects on hepatic lipid regulation and glycaemic control, but mechanistic human studies humans are limited. An ex-vivo study was performed to determine the chronic effects of probiotics, oats, and apples on the expression of genes related to markers of cardiometabolic health in peripheral blood monocular cells (PBMC). In this CABALA sub-study (n = 59/61, age: 52 ± 12y), blood PBMC were also isolated before and 8 weeks after the daily consumption of either a probiotic with bile salt hydrolase activity (Lactobacillus reuteri), porridge oats, Renetta Canada apples or a control. Relative PBMC mRNA gene expression was determined and correlations performed between the fold change in response to the functional interventions and change in cardiometabolic disease risk markers. Relative to baseline, there was an upregulation in the PBMC TLR4 mRNA expression in the control compared with the probiotics and apples groups (p[Formula: see text]0.024). Moderate inverse correlations were found between the fold change in GPBAR1 mRNA expression and change in plasma total and secondary BAs, HMGCR and SREBF1 mRNA gene expressions and high-density lipoprotein-cholesterol, and SREBF1 and GIPR mRNA gene expressions and glucose. TLR4 and TNFSF14 mRNA gene expressions were associated with pro-inflammatory cytokines (p=0.05). Probiotic and apples interventions attenuated the upregulation in PBMC TLR4 mRNA expression observed with the control. Correlations between fold change in mRNA gene expression and changes in cardiometabolic disease risk markers in response to the functional interventions were in agreement with previous studies. The study was registered at clinical trials.gov (ref. NCT03369548). Show less

Protein-protein interactions (PPIs) mediate many fundamental cellular processes. Control of PPIs through optically or chemically responsive protein domains has had a profound impact on basic research and some clinical applications. Most chemogenetic methods induce the association, i.e., dimerization or oligomerization, of target proteins, whilst the few available dissociation approaches either break large oligomeric protein clusters or heteromeric complexes. Here, we have exploited the controlled dissociation of a homodimeric oxidoreductase from mycobacteria (MSMEG₂₀₂₇₎ by its native cofactor, F Show less

ObjectiveTo describe characteristic CLEFT-Q response profiles and patterns in patients with cleft palate and/or lip (CP ± L).DesignRetrospective analysis using latent profile analysis (LPA) to categorize patient-reported outcome responses into distinct profiles.SettingTertiary care pediatric hospital with multidisciplinary cleft team.Patients, ParticipantsPatients aged 8-29 years with CP ± L completing CLEFT-Q questionnaires from September 2021 to June 2025 ( Show less

Adhering to 24-h movement guidelines protects children's health and wellbeing. We investigated adherence among a sample of children in regional and rural Victoria, Australia. Analysis was conducted using baseline data from RESPOND, a large community-based obesity prevention intervention conducted in regional and rural Victoria, Australia. Children (aged approx. 9-12 years) self-reported screen time and wore a wrist-worn accelerometer for seven days to determine the mean daily time spent on moderate to vigorous physical activity (MVPA), light physical activity (LPA), sedentary and sleeping. Multi-level linear and logistic regressions were used to estimate associations between accelerometry outcomes and individual and school level demographics overall and by gender, accounting for school level clustering. Valid accelerometry data were obtained for 1,264 students. Twenty-two percent (22%) of boys and 16% of girls met all three movement guidelines and 11% boys and 9% of girls met none of the guidelines. Boys engaged in more MVPA, and less LPA than girls. Compared to those in grade 4 (aged approx. 9-10 years), students in grade 6 (aged approx. 11-12 years) had significantly reduced MVPA minutes (- 7.8; 95%CI -12.3, - 3.4); increased sedentary minutes (31.0; 95%CI 22.7, 39.3), and reduced odds of meeting screen time guidelines (odds ratio, 0.65; 95%CI 0.50, 0.84). Stratification by gender found these results to be consistent for boys and girls. Living in a medium or large rural town was associated with having 6.4 (95%CI 0.0, 12, 8) more minutes in MVPA (boys) and greater odds of adhering to screen time guidelines (OR, 1.96 (95%CI 1.02, 3.79) (girls) compared to living in regional centers. Sleep minutes were lower for students who spoke a language other than English at home (- 21.0 95%CI - 32.5, - 9.5). Only screen-time adherence for girls was associated with socioeconomic status. This study highlights low adherence to three Australian movement behavior guidelines among this large sample of regional and rural Victorian children. Large gender-differences in duration and adherence to MVPA and screen-time guidelines and declines with increasing age (all guidelines), highlight the need for population-wide interventions. • Time spent in movement behaviors (moderate-to-vigorous physical activity, light-intensity physical activity, sedentary behavior and sleep are important for children's health. • Few studies have examined device-measured movement behaviors and adherence to 24-h movement guidelines among regional children and whether this varies by gender, rurality and socioeconomic background. • This study found 22% of boys and 16% of girls met the 24-h movement recommendations, with 11% of boys and 9% of girls meeting no guideline. • Living in a medium or large rural town was associated with more moderate to vigorous physical activity in boys, and less screen-time among girls compared to those living in regional centers. Higher socioeconomic status was associated with less screen-time among girls. Show less

Protists are polyphyletic single-celled eukaryotes that underpin global ecosystem functioning, particularly in the oceans. Most remain uncultured, limiting the investigation of their physiology and cell biology. MArine STramenopiles (MASTs) are heterotrophic protists that, although related to well-characterized photosynthetic diatoms and parasitic oomycetes, are poorly studied. The Nanomonadea (MAST-3) species Show less

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10 Show less

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands. Show less

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an Show less

Serum low density lipoprotein (LDL) cholesterol shows marked interindividual variation in response to the replacement of saturated fatty acids (SFAs) with unsaturated fatty acids (UFAs). To demonstrate the efficacy of United Kingdom guidelines for exchanging dietary SFAs for UFAs, to reduce serum LDL cholesterol and other cardiovascular disease (CVD) risk factors, and to identify determinants of the variability in LDL cholesterol response. Healthy males (n = 109, mean ± SD age 48 ± 11 y; BMI 25.1 ± 3.3 kg/m Transition from a higher-SFA/lower-UFA to a lower-SFA/higher-UFA diet significantly reduced fasting blood lipids: LDL cholesterol (-0.50 mmol/L; 95% confidence interval [CI]: -0.58, -0.42), high-density lipoprotein (HDL) cholesterol (-0.11 mmol/L; 95% CI: -0.14, -0.08), and total cholesterol (TC) (-0.65 mmol/L; 95% CI:-0.75, -0.55). The dietary exchange also reduced apolipoprotein (apo)B, TC:HDL cholesterol ratio, non-HDL cholesterol, E-selectin (P < 0.0001), and LDL subfraction composition (cholesterol [LDL-I and LDL-II], apoB100 [LDL-I and LDL-II], and TAG [LDL-II]) (P < 0.01). There was also an increase in plasma biomarkers of cholesterol intestinal absorption (β-sitosterol, campesterol, cholestanol), and synthesis (desmosterol) (P < 0.0001) and fold change in PBMC LDL-receptor mRNA expression relative to the higher-SFA/lower-UFA diet (P = 0.035). Marked interindividual variation in the change in serum LDL cholesterol response (-1.39 to +0.77 mmol/L) to this dietary exchange was observed, with 33.7% of this variation explained by serum LDL cholesterol before the lower-SFA/higher-UFA diet and reduction in dietary SFA intake (adjusted R These findings support the efficacy of United Kingdom SFA dietary guidelines for the overall lowering of serum LDL cholesterol but showed marked variation in LDL cholesterol response. Further identification of the determinants of this variation will facilitate targeting and increasing the efficacy of these guidelines. The RISSCI-1 study was registered with ClinicalTrials.Gov (No. NCT03270527). Show less

Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms. Show less

The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here, we report that G-quadruplex DNA (G4-DNA) accumulates in neurons, in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory in male C57/BL6 mice. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation. Show less

Only a limited number of genetic diseases are diagnosable in archaeological individuals and none have had causal mutations identified in genome-wide screens. Two individuals from the Gaelic Irish Medieval burial ground of Ballyhanna, Co. Donegal, showed evidence of bone tumours consistent with the autosomal dominant condition multiple osteochondromas. Genome sequencing of the earlier individual uncovered a missense mutation in the second exon of EXT1, a specific lesion that has been identified in several modern patients. The later individual lacked this but displayed a novel frameshift mutation leading to a premature stop codon and loss of function in the same gene. These molecular confirmations of a paleopathological diagnosis within a single rural ancient context are surprisingly disjunct, given the observation of clusters of this disease in modern isolated populations and a de novo mutation rate of only 10%. Show less

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( Show less

Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in poor outcomes. The tumor microenvironment cytokine Oncostatin-M (OSM) initiates PDAC plasticity, inducing the reprogramming to a stem-like/mesenchymal state, which enhances metastasis and therapy resistance. Using a panel of PDAC cells driven through epithelial-mesenchymal transition (EMT) by OSM or the transcription factors ZEB1 or SNAI1, we find that OSM uniquely induces tumor initiation and gemcitabine resistance independently of its ability to induce a CD44HI/mesenchymal phenotype. In contrast, while ZEB1 and SNAI1 induce a CD44HI/mesenchymal phenotype and migration comparable with OSM, they are unable to promote tumor initiation or robust gemcitabine resistance. Transcriptomic analysis identified that OSM-mediated stemness requires MAPK activation and sustained, feed-forward transcription of OSMR. MEK and ERK inhibitors prevented OSM-driven transcription of select target genes and stem-like/mesenchymal reprogramming, resulting in reduced tumor growth and resensitization to gemcitabine. We propose that the unique properties of OSMR, which hyperactivates MAPK signaling when compared with other IL6 family receptors, make it an attractive therapeutic target, and that disrupting the OSM-OSMR-MAPK feed-forward loop may be a novel way to therapeutically target the stem-like behaviors common to aggressive PDAC. Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC. Show less

Selenium is an important micronutrient for foetal development. MicroRNAs play an important role in the function of the placenta, in communication between the placenta and maternal systems, and their expression can be altered through environmental and nutritional cues. To investigate the associations between placental selenium concentration and microRNA expression in the placenta, our observational study included 393 mother-child pairs from the New Hampshire Birth Cohort Study (NHBCS) and the Rhode Island Child Health Study (RICHS). Placental selenium concentrations were quantified using inductively coupled plasma mass spectrometry, and microRNA transcripts were measured using RNA-seq. We fit negative binomial additive models for assessing the association between selenium and microRNAs. We used the microRNA Data Integration Portal (mirDIP) to predict the target mRNAs of the differentially expressed microRNAs and verified the relationships between miRNA and mRNA targets in a subset of samples using existing whole transcriptome data (N = 199). We identified a non-monotonic association between selenium concentration and the expression of miR-216a-5p/miR-217-5p cluster (effective degrees of freedom, EDF = 2.44 and 2.08; FDR = 3.08 × 10 Show less

Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. GLP-1 and PYY levels were assessed in body mass index-matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders. Show less

The Wnt/β-catenin signaling pathway is aberrantly activated in the majority of colorectal cancer cases due to somatic mutations in the adenomatous polyposis coli (APC) gene. Prohibitin 1 (PHB1) serves pleiotropic cellular functions with dynamic subcellular trafficking, facilitating signaling crosstalk between organelles. Nuclear-localized PHB1 is an important regulator of gene transcription. Using mice with inducible intestinal epithelial cell (IEC)-specific deletion of Phb1 (Phb1 Show less

The deleterious effects of psychological stress on mainstream T lymphocytes are well documented. However, how stress impacts innate-like T cells is unclear. We report that long-term stress surprisingly abrogates both T helper 1 (T Show less

Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling. Many inhibitors of the Wnt/β-catenin pathway have been tested for Wnt-dependent cancers including colorectal cancer, but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or preclinical models of intestinal tumorigenesis. Show less

Studies have shown that the reduction in serum TAG concentrations with long-chain n-3 fatty acid supplementation is highly variable among individuals. The objectives of the present study were to compare the proportions of individuals whose TAG concentrations lowered after high-dose DHA and EPA, and to identify the predictors of response to both modalities. In a double-blind, controlled, crossover study, 154 men and women were randomised to three supplemented phases of 10 weeks each: (1) 2·7 g/d of DHA, (2) 2·7 g/d of EPA and (3) 3 g/d of maize oil, separated by 9-week washouts. As secondary analyses, the mean intra-individual variation in TAG was calculated using the standard deviation from the mean of four off-treatment samples. The response remained within the intra-individual variation (±0·25 mmol/l) in 47 and 57 % of participants after DHA and EPA, respectively. Although there was a greater proportion of participants with a reduction >0·25 mmol/l after DHA than after EPA (45 υ. 32 %; P 0·25 mmol/l after both DHA and EPA had higher non-HDL-cholesterol, TAG and insulin concentrations compared with other responders at baseline (all P < 0·05). In conclusion, supplementation with 2·7 g/d DHA or EPA had no meaningful effect on TAG concentrations in a large proportion of individuals with normal mean TAG concentrations at baseline. Although DHA lowered TAG in a greater proportion of individuals compared with EPA, the magnitude of TAG lowering among them was similar. Show less

Uterine leiomyomas, in contrast to sarcomas, tend to cease growth following menopause. In the setting of a rapidly enlarging uterine mass in a postmenopausal patient, clinical distinction of uterine leiomyoma from sarcoma is difficult and requires pathologic examination. A 74-year-old woman presented with postmenopausal bleeding and acute blood loss requiring transfusion. She was found to have a rapidly enlarging uterine mass clinically suspicious for sarcoma. An abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. A 15.5 cm partially necrotic intramural mass was identified in the uterine corpus. The tumor was classified as a cellular leiomyoma. RNA sequencing identified a KAT6B-KANSL1 fusion that was confirmed by RT-PCR and Sanger sequencing. After 6 months of follow-up, the patient remains asymptomatic without evidence of disease. Prior studies of uterine leiomyomas have identified KAT6B (previously MORF) rearrangements in uterine leiomyomas, but this case is the first to identify a KAT6B-KANSL1 gene fusion in a uterine leiomyoma. While alterations of MED12 and HMGA2 are most common in uterine leiomyomas, a range of other genetic pathways have been described. Our case contributes to the evolving molecular landscape of uterine leiomyomas. Show less