A genome-wide spectrum of tandem repeat expansions in 338,963 humans.

The Genome Aggregation Database (gnomAD), widely recognized as the gold-standard reference map of human genetic variation, has largely overlooked tandem repeat (TR) expansions, despite the fact that TRs constitute ∼6% of our genome and are linked to over 50 human diseases. Here, we introduce the TR-gnomAD (https://wlcb.oit.uci.edu/TRgnomAD), a biobank-scale reference of 0.86 million TRs derived from 338,963 whole-genome sequencing (WGS) samples of diverse ancestries (39.5% non-European samples). TR-gnomAD offers critical insights into ancestry-specific disease prevalence using disparities in TR unit number frequencies among ancestries. Moreover, TR-gnomAD is able to differentiate between common, presumably benign TR expansions, which are prevalent in TR-gnomAD, from those potentially pathogenic TR expansions, which are found more frequently in disease groups than within TR-gnomAD. Together, TR-gnomAD is an invaluable resource for researchers and physicians to interpret TR expansions in individuals with genetic diseases.

Interaction of NF-κB and FOSL1 drives glioma stemness.

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor; GBM's inevitable recurrence suggests that glioblastoma stem cells (GSC) allow these tumors to persist. Our previous work showed that FOSL1, transactivated by the STAT3 gene, functions as a tumorigenic gene in glioma pathogenesis and acts as a diagnostic marker and potential drug target in glioma patients. Accumulating evidence shows that STAT3 and NF-κB cooperate to promote the development and progression of various cancers. The link between STAT3 and NF-κB suggests that NF-κB can also transcriptionally regulate FOSL1 and contribute to gliomagenesis. To investigate downstream molecules of FOSL1, we analyzed the transcriptome after overexpressing FOSL1 in a PDX-L14 line characterized by deficient FOSL1 expression. We then conducted immunohistochemical staining for FOSL1 and NF-κB p65 using rabbit polyclonal anti-FOSL1 and NF-κB p65 in glioma tissue microarrays (TMA) derived from 141 glioma patients and 15 healthy individuals. Next, mutants of the human FOSL1 promoter, featuring mutations in essential binding sites for NF-κB were generated using a Q5 site-directed mutagenesis kit. Subsequently, we examined luciferase activity in glioma cells and compared it to the wild-type FOSL1 promoter. Then, we explored the mutual regulation between NF-κB signaling and FOSL1 by modulating the expression of NF-κB or FOSL1. Subsequently, we assessed the activity of FOSL1 and NF-κB. To understand the role of FOSL1 in cell growth and stemness, we conducted a CCK-8 assay and cell cycle analysis, assessing apoptosis and GSC markers, ALDH1, and CD133 under varying FOSL1 expression conditions. Transcriptome analyses of downstream molecules of FOSL1 show that NF-κB signaling pathway is regulated by FOSL1. NF-κB p65 protein expression correlates to the expression of FOSL1 in glioma patients, and both are associated with glioma grades. NF-κB is a crucial transcription factor activating the FOSL1 promoter in glioma cells. Mutual regulation between NF-κB and FOSL1 contributes to glioma tumorigenesis and stemness through promoting G1/S transition and inhibiting apoptosis. Therefore, the FOSL1 molecular pathway is functionally connected to NF-κB activation, enhances stemness, and is indicative that FOSL1 may potentially be a novel GBM drug target.

TRPM7 transactivates the FOSL1 gene through STAT3 and enhances glioma stemness.

INTRODUCTION: We previously reported that TRPM7 regulates glioma cells' stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1 gene serves as an oncogene to promote glioma proliferation and invasion. METHODS: In the present study, we determined the effects of FOSL1 on glioma stem cell (GSC) markers CD133 and ALDH1 by flow cytometry, and the maintenance of stem cell activity by extreme limiting dilution assays (ELDA). To further gain insight into the mechanism by which TRPM7 activates transcription of the FOSL1 gene to contribute to glioma stemness, we constructed a FOSL1 promoter and its GAS mutants followed by luciferase reporter assays and ChIP-qPCR in a glioma cell line and glioma patient-derived xenoline. We further examined GSC markers ALDH1 and TRPM7 as well as FOSL1 by immunohistochemistry staining (IHC) in brain tissue microarray (TMA) of glioma patients. RESULTS: We revealed that FOSL1 knockdown reduces the expression of GSC markers CD133 and ALDH1, and FOSL1 is required to maintain stem cell activity in glioma cells. The experiments also showed that mutations of - 328 to - 336 and - 378 to - 386 GAS elements markedly reduced FOSL1 promoter activity. Constitutively active STAT3 increased while dominant-negative STAT3 decreased FOSL1 promoter activity. Furthermore, overexpression of TRPM7 enhanced while silencing of TRPM7 reduced FOSL1 promoter activity. ChIP-qPCR assays revealed that STAT3, present in nuclear lysates of glioma cells stimulated by constitutively activated STAT3, can bind to two GAS elements, respectively. We demonstrated that deacetylation of FOSL1 at the Lys-116 residue located within its DNA binding domain led to an increase in FOSL1 transcriptional activity. We found that the expression of TRPM7, ALDH1, and FOSL1 protein is associated with grades of malignant glioma, and TRPM7 protein expression correlates to the expression of ALDH1 and FOSL1 in glioma patients. CONCLUSIONS: These combined results demonstrated that TRPM7 induced FOSL1 transcriptional activation, which is mediated by the action of STAT3, a mechanism shown to be important in glioma stemness. These results indicated that FOSL1, similar to GSC markers ALDH1 and TRPM7, is a diagnostic marker and potential drug target for glioma patients.

3'aQTL-atlas: an atlas of 3'UTR alternative polyadenylation quantitative trait loci across human normal tissues.

Genome-wide association studies (GWAS) have identified thousands of non-coding single-nucleotide polymorphisms (SNPs) associated with human traits and diseases. However, functional interpretation of these SNPs remains a significant challenge. Our recent study established the concept of 3' untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs), which can be used to interpret ∼16.1% of GWAS SNPs and are distinct from gene expression QTLs and splicing QTLs. Despite the growing interest in 3'aQTLs, there is no comprehensive database for users to search and visualize them across human normal tissues. In the 3'aQTL-atlas (https://wlcb.oit.uci.edu/3aQTLatlas), we provide a comprehensive list of 3'aQTLs containing ∼1.49 million SNPs associated with APA of target genes, based on 15,201 RNA-seq samples across 49 human Genotype-Tissue Expression (GTEx v8) tissues isolated from 838 individuals. The 3'aQTL-atlas provides a ∼2-fold increase in sample size compared with our published study. It also includes 3'aQTL searches by Gene/SNP across tissues, a 3'aQTL genome browser, 3'aQTL boxplots, and GWAS-3'aQTL colocalization event visualization. The 3'aQTL-atlas aims to establish APA as an emerging molecular phenotype to explain a large fraction of GWAS risk SNPs, leading to significant novel insights into the genetic basis of APA and APA-linked susceptibility genes in human traits and diseases.

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research.

BACKGROUND: Metformin is among the most frequently prescribed antidiabetic drugs worldwide and remains the first-line therapy for type 2 diabetes due to its well-established glucose-lowering efficacy and favorable safety profile. SUMMARY: Studies over the past decades show that metformin also exerts many other beneficial effects independent of its glucose-lowering effect both in experimental models and human subjects. Among them, the most notable is its cardiovascular protective effect. In this review, we discuss the latest cutting-edge research findings on metformin's cardiovascular protection from both preclinical studies and randomized clinical trials. We focus on describing novel basic research discoveries reported in influential journals and discussing their implications in the context of latest clinical trial findings related to common cardiovascular and metabolic disorders, including atherosclerosis and dyslipidemia, myocardial injury, and heart failure. KEY MESSAGES: While substantial preclinical and clinical evidence suggests metformin as a potential cardiovascular protectant, large-scale randomized controlled trials are warranted to establish its clinical efficacy in treating patients with atherosclerotic cardiovascular disease and heart failure.

Binge drinking and sexual risk behavior among US sexual and gender minority college students.

BACKGROUND AND OBJECTIVES: Binge drinking and sexual risk behaviors have historically been associated with lesbian, gay, bisexual, and transgender (LGBT) adults; however, few studies have described this association among broader sexual and gender minority (SGM) students, who often identify outside of LGBT (e.g., asexual, queer). This study examined the relationship between binge drinking and sexual risk behaviors among SGM versus non-SGM college students. METHODS: A retrospective analysis was conducted with cross-sectional data from the Spring 2017 American College Health Association-National College Health Assessment (ACHA-NCHA) survey among US undergraduates (n = 47,821) across 92 institutions. Binge drinking was measured as more than five drinks consumed the last time the student socialized; sexual risk behavior was measured as the number of sexual partners in the past 12 months. RESULTS: Numerous undergraduates nationally identify as SGM (19.9%), with bisexual (32.7%), other SGM (26.1%), and asexual (25.4%) students comprising the largest subgroups. Prevalent among both SGM (28.1%) and non-SGM (29.6%) students, binge drinking had a significant main effect on the number of sexual partners. A significant interaction effect was observed between SGM identity and binge drinking on the number of sexual partners, such that this association was stronger in SGM versus non-SGM students. This effect remained significant across multiple SGM subgroups. DISCUSSION AND CONCLUSIONS: SGM students are more prevalent and diverse than previously reported. While prevalent overall, binge drinking may be uniquely sexualized among SGM students. SCIENTIFIC SIGNIFICANCE: In the first large-scale study assessing drinking among disaggregated SGM college students, data suggest tailoring alcohol interventions to SGM students, particularly those identifying outside of LGBT.

Preexisting Depression and Daytime Sleepiness in Women and Men.

BACKGROUND: Sleep problems can persist following the treatment of depression and remission of symptoms. The extent to which having a previous history of depression may be associated with current daytime sleepiness is largely unknown. METHODS: Data were obtained from the spring 2017 American College Health Association-National College Health Assessment (ACHA-NCHA) survey (92 institutions) which assessed self-reported health in U.S. college students (n = 41,670). Among the sample, 93.5% were 18-24 year of age, and 69.6% women. Logistic regression estimated the association between reported prior lifetime diagnosis of depression and daytime sleepiness from the past 7 days, while adjusting for depressive symptoms and antidepressant use from the past year. Unadjusted and adjusted logistic regression models stratified by gender were performed. RESULTS: Among those who reported problems with sleepiness, 31.6% women and 19.4% men had a preexisting depression diagnosis. Individuals with preexisting depression were more likely than those without this diagnosis to report sleepiness problems (women: OR = 1.4, CI = 1.3-1.6, p < .001; men: OR = 1.2, CI = 1.0-1.4, p < .01). However, this association differed significantly by gender, with women with a preexisting depression diagnosis having a 13.0% greater likelihood of sleepiness compared to men. CONCLUSIONS: Those with a preexisting depression diagnosis, and specifically women, may be at risk for daytime sleepiness even in the absence of current depressive mood-related symptoms. Given that many individuals are at risk for daytime sleepiness, mental health initiatives, including those on college campuses, should incorporate sleep hygiene within their programming.

In Vitro and In Vivo Characterization of 89Zirconium-Labeled Lintuzumab Molecule.

Objective: Positron emission tomography (PET) imaging is a powerful non-invasive method to determine the in vivo behavior of biomolecules. Determining biodistribution and pharmacokinetic (PK) properties of targeted therapeutics can enable a better understanding of in vivo drug mechanisms such as tumor uptake, off target accumulation and clearance. Zirconium-89 (89Zr) is a readily available tetravalent PET-enabling radiometal that has been used to evaluate the biodistribution and PK of monoclonal antibodies. In the current study, we performed in vitro and in vivo characterization of 89Zr-lintuzumab, a radiolabeled anti-CD33 antibody, as a model to evaluate the in vivo binding properties in preclinical models of AML. Methods: Lintuzumab was conjugated to p-SCN-Bn-deferoxamine (DFO) and labeled with 89Zr using a 5:1 µCi:µg specific activity at 37 °C for 1h. The biological activity of 89Zr-lintuzumab was evaluated in a panel of CD33 positive cells using flow cytometry. Fox Chase SCID mice were injected with 2 × 106 OCI-AML3 cells into the right flank. After 12 days, a cohort of mice (n = 4) were injected with 89Zr-lintuzumab via tail vein. PET/CT scans of mice were acquired on days 1, 2, 3 and 7 post 89Zr-lintuzumab injection. To demonstrate 89Zr-lintuzumab specific binding to CD33 expressing tumors in vivo, a blocking study was performed. This cohort of mice (n = 4) was injected with native lintuzumab and 24 h later 89Zr-lintuzumab was administered. This group was imaged 3 and 7 days after injection of 89Zr-lintuzumab. A full ex vivo biodistribution study on both cohorts was performed on day 7. The results from the PET image and ex vivo biodistribution studies were compared. Results: Lintuzumab was successfully radiolabeled with 89Zr resulting in a 99% radiochemical yield. The 89Zr-lintuzumab radioconjugate specifically binds CD33 positive cells in a similar manner to native lintuzumab as observed by flow cytometry. PET imaging revealed high accumulation of 89Zr-lintuzumab in OCI-AML3 tumors within 24h post-injection of the radioconjugate. The 89Zr-lintuzumab high tumor uptake remains for up to 7 days. Tumor analysis of the PET data using volume of interest (VOI) showed significant blocking of 89Zr-lintuzumab in the group pre-treated with native lintuzumab (pre-blocked group), thus indicating specific targeting of CD33 on OCI-AML3 cells in vivo. The tumor uptake findings from the PET imaging study are in agreement with those from the ex vivo biodistribution results. Conclusions: PET imaging of 89Zr-lintuzumab shows high specific uptake in CD33 positive human OCI-AML3 tumors. The results from the image study agree with the observations from the ex vivo biodistribution study. Our findings collectively suggest that PET imaging using 89Zr-lintuzumab could be a powerful drug development tool to evaluate binding properties of anti-CD33 monoclonal antibodies in preclinical cancer models.

A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset of NUTM1-rearranged tumors.

Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.

A natural impact-resistant bicontinuous composite nanoparticle coating.

Nature utilizes the available resources to construct lightweight, strong and tough materials under constrained environmental conditions. The impact surface of the fast-striking dactyl club from the mantis shrimp is an example of one such composite material; the shrimp has evolved the capability to localize damage and avoid catastrophic failure from high-speed collisions during its feeding activities. Here we report that the dactyl club of mantis shrimps contains an impact-resistant coating composed of densely packed (about 88 per cent by volume) ~65-nm bicontinuous nanoparticles of hydroxyapatite integrated within an organic matrix. These mesocrystalline hydroxyapatite nanoparticles are assembled from small, highly aligned nanocrystals. Under impacts of high strain rates (around 104 s-1), particles rotate and translate, whereas the nanocrystalline networks fracture at low-angle grain boundaries, form dislocations and undergo amorphization. The interpenetrating organic network provides additional toughening, as well as substantial damping, with a loss coefficient of around 0.02. An unusual combination of stiffness and damping is therefore achieved, outperforming many engineered materials.

Presenting age and features of females diagnosed with autism spectrum disorder.

AIM: Autism spectrum disorder (ASD) is reportedly more prevalent in males than in females. Hypotheses for this gender imbalance include differing presentations in females. The aim of this study was to identify gender-based ASD differences in age at presentation, clinical features, comorbidities and severity levels. METHODS: A cross-sectional study was conducted at a Child Development Unit. Children diagnosed with ASD during a 6-month period were analysed. RESULTS: A total of 195 children were analysed with a male-to-female ratio of 2.8:1. No difference was found between gender and age at diagnosis. Males were more likely to display deficits in imaginative play and use repeated or learned phrases. Females were more likely to present with proprioception and vestibular issues, fears reflecting sensory avoidance and ASD of lesser severity. CONCLUSION: Our study supports the hypothesis that gender-based differences exist within ASD presenting features. These differences should be considered when assessing for ASD in females to avoid under recognition.

Therapeutic options for mucinous ovarian carcinoma.

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma.

For the reference citation '[57]' in the second paragraph of the Results section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).

Serum microRNA is a biomarker for post-operative monitoring in glioma.

PURPOSE: A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients. METHODS: A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging. RESULTS: A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. CONCLUSIONS: We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

Maternal health behaviors during pregnancy in rural Northwestern China.

BACKGROUND: Maternal health during pregnancy is a key input in fetal health and child development. This study aims to systematically describe the health behaviors of pregnant women in rural China and identify which subgroups of women are more likely to engage in unhealthy behaviors during pregnancy. METHODS: We surveyed 1088 pregnant women in rural northwestern China on exposure to unhealthy substances, nutritional behaviors, the timing and frequency of antenatal care, and demographic characteristics. RESULTS: Pregnant women were active in seeking antenatal care and had low rates of alcohol consumption (5.1%), exposure to toxins (4.8%), and exposure to radiation (2.9%). However, tobacco exposure was widespread (40.3%), as was low dietary diversity (61.8%), unhealthy weight gain (59.7%), unhealthy pre-pregnancy BMI (29.7%), and no folic acid intake (17.1%). Maternal education is closely linked to better health behaviors, whereas experience with a previous pregnancy is not. CONCLUSIONS: Tobacco exposure and unhealthy nutritional behaviors are common among pregnant women in rural northwestern China. The findings indicate that in the absence of professional health information, relying on experience of previous pregnancies alone may not help rural women avoid unhealthy maternal behaviors. Maternal health education campaigns targeting nutrition and tobacco exposure during pregnancy may improve maternal, fetal, and child health in rural China.

Efficient penetration of Scp01-b and its DNA transfer abilities into cells.

The in vivo application potential of viral-based gene delivery approaches is hindered by a risk of insertional oncogenesis. Of the many delivery methods, cell-penetrating peptides (CPP)-based delivery has good biocompatibility and biodegradability. However, low efficiency is still the disadvantage of CPPs-based nucleic acid transfection, and delivery efficiency may vary from different CPPs. Here, we describe Scp01-b, as a new CPP, which can enter cultured cell lines and primary cultured cells examined by fluorescence microscopy and quantitative assay, the internalization process is a concentration, temperature, and incubation time-dependent manner. Scp01-b does not insert into the membrane directly and its uptake is mediated through endocytosis pathway. Moreover, Scp01-b could mediate the uptake of plasmid DNA into the Caski and HSC-T6 cells, and we noted that Scp01-b-mediated transfection efficiency was nearly the same with traditional liposome (TurboFectin)-mediated transfection. These findings suggest that Scp01-b can act as a useful tool for non-viral-based delivery in further application such as reprogramming and gene editing.

Evaluating the breast cancer predisposition role of rare variants in genes associated with low-penetrance breast cancer risk SNPs.

BACKGROUND: Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk. METHODS: The coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency ≤ 0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied. RESULTS: LoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n = 36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p = 0.077 and p = 0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants). CONCLUSIONS: Our data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.

Functional Control of Peptide Amphiphile Assemblies via Modulation of Internal Cohesion and Surface Chemistry Switch.

Understanding the impacts of the internal cohesion and surface chemistry of supramolecular systems on the collective behaviors in the contacts between the systems and biomolecules can greatly expand the functional diversity and adaptivity of supramolecular nanostructures. Here we show how the tuned molecular interactions modulate the morphologies and internal cohesion of peptide amphiphile (PA) self-assemblies and their resultant functions. Circular dichroism spectroscopy, fluorescence probing, atomic force and electron microscopy, along with molecular dynamics simulations, revealed that the PA self-assembly formed compact long fibers when surface charge repulsion was screened, but formed loose short fibers or micelle-like assemblies when hydrogen bonding was disrupted or hydrophobic core was enhanced. More importantly, depending on the strength of the phospholipid affinity for the cationic segment of the PA, the same internal cohesion of PA nanostructures can lead to either cell death or cell survival, providing unique insights into the design of supramolecular materials.