Radiologic patterns of distant organ metastasis in advanced breast cancer patients: Prospective review of computed tomography images.

BACKGROUND: Breast cancer (BC) metastases to the abdomen and pelvis affect the liver, mesentery, retroperitoneum, peritoneum, bladder, kidney, ovary, and uterus. The study documented the radiological pattern and features of the chest, bone, abdominal and pelvic (AP) metastases among advanced BC patients. AIM: The aim is to document the radiological pattern and features of breast cancer metastasis in the chest, abdomen, pelvis and bones. MATERIALS AND RESULTS: Chest, abdominal, and pelvic computed tomography scan images of 36 patients with advanced BC were collated from Cape Coast Teaching Hospital and RAAJ Diagnostics. The images were prospectively assessed for metastasis to the organs of the chest, AP soft tissues, and bones. Radiologic features of metastasis of the lungs, liver, lymph nodes (LNs), and bones were documented. Patients' demographics, clinical data, and histopathology reports were also collected. The data were captured using UVOSYO and exported to Microsoft Excel templates. The data obtained were descriptively analyzed. Only 2.8% of BCs exhibited metaplastic BC, whereas 97.2% had invasive ductal BC. Triple-negative cases were 55.6%. Of 36 patients, 31 (86.1%), 21 (58.3%), and 14(38.8%) were diagnosed of chest, AP, and bone tissues metastasis, respectively. LN involvement was reported in 26 (72.2%) patients. Majority, 21 (58.3%) were diagnosed of multiple sites metastasis with 15 (41.7%) showing single site. Lungs (77.4%, 24/31) and liver (47.6%, 10/21) were the most affected distant organs. Most bone metastases were lytic lesions (92.9%, 13/14) with the vertebrae (85.7%, 12/14) been the most affected. CONCLUSION: According to the study, advanced BC patients have a higher-than-average radiologic incidence of lung, liver, bone, and LN metastases.

Upper Airway Epithelial Tissue Transcriptome Analysis Reveals Immune Signatures Associated with COVID-19 Severity in Ghanaians.

The immunological signatures driving the severity of coronavirus disease 19 (COVID-19) in Ghanaians remain poorly understood. We performed bulk transcriptome sequencing of nasopharyngeal samples from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected Ghanaians with mild and severe COVID-19, as well as healthy controls to characterize immune signatures at the primary SARS-CoV-2 infection site and identify drivers of disease severity. Generally, a heightened antiviral response was observed in SARS-CoV-2-infected Ghanaians compared with uninfected controls. COVID-19 severity was associated with immune suppression, overexpression of proinflammatory cytokines, including CRNN, IL1A, S100A7, and IL23A, and activation of pathways involved in keratinocyte proliferation. SAMD9L was among the differentially regulated interferon-stimulated genes in our mild and severe disease cohorts, suggesting that it may play a critical role in SARS-CoV-2 pathogenesis. By comparing our data with a publicly available dataset from a non-African (Indians) (GSE166530), an elevated expression of antiviral response-related genes was noted in COVID-19-infected Ghanaians. Overall, the study describes immune signatures driving COVID-19 severity in Ghanaians and identifies immune drivers that could serve as potential prognostic markers for future outbreaks or pandemics. It further provides important preliminary evidence suggesting differences in antiviral response at the upper respiratory interface in sub-Saharan Africans (Ghanaians) and non-Africans, which could be contributing to the differences in disease outcomes. Further studies using larger datasets from different populations will expand on these findings.

Knowledge, attitude and perception towards COVID-19 among representative educated sub-Saharan Africans: A cross-sectional study during the exponential phase of the pandemic.

Coronavirus disease 2019 (COVID-19) pandemic, caused by the Severe Acute Coronavirus 2 (SARS-CoV-2), is a global health threat with extensive misinformation and conspiracy theories. Therefore, this study investigated the knowledge, attitude and perception of sub-Saharan Africans (SSA) on COVID-19 during the exponential phase of the pandemic. In this cross-sectional survey, self-administered web-based questionnaires were distributed through several online platforms. A total of 1046 respondents from 35 SSA countries completed the survey. The median age was 33 years (18-76 years) and about half (50.5%) of them were males. More than 40% across all socio-demographic categories except the Central African region (21.2%), vocational/secondary education (28.6%), student/unemployed (35.5%), had high COVID-19 knowledge score. Socio-demographic factors and access to information were associated with COVID-19 knowledge. Bivariate analysis revealed that independent variables, including the region of origin, age, gender, education and occupation, were significantly (p < 0.05) associated with COVID-19 knowledge. Multivariate analysis showed that residing in East (odds ratio [OR]: 7.9, 95% confidence interval (CI): 4.7-14, p<0.001), Southern (OR: 3.7, 95% CI: 2.1-6.5, p<0.001) and West (OR: 3.9, 95% CI: 2.9-5.2, p<0.001) Africa was associated with high COVID-19 knowledge level. Apart from East Africa (54.7%), willingness for vaccine acceptance across the other SSA regions was <40%. About 52%, across all socio-demographic categories, were undecided. Knowledge level, region of origin, age, gender, marital status and religion were significantly (p < 0.05) associated with COVID-19 vaccine acceptance. About 67.4% were worried about contracting SARS-CoV-2, while 65.9% indicated they would consult a health professional if exposed. More than one-third of the respondents reported that their governments had taken prompt measures to tackle the pandemic. Despite high COVID-19 knowledge in our study population, most participants were still undecided regarding vaccination, which is critical in eliminating the pandemic. Therefore, extensive, accurate, dynamic and timely education in this aspect is of ultimate priority.

The COVID-19, tuberculosis and HIV/AIDS: Ménage à Trois.

In December 2019, a novel pneumonic condition, Coronavirus disease 2019 (COVID- 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), broke out in China and spread globally. The presentation of COVID-19 is more severe in persons with underlying medical conditions such as Tuberculosis (TB), Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) and other pneumonic conditions. All three diseases are of global concern and can significantly affect the lungs with characteristic cytokine storm, immunosuppression, and respiratory failure. Co-infections of SARS-CoV-2 with HIV and Mycobacterium tuberculosis (Mtb) have been reported, which may influence their pathogenesis and disease progression. Pulmonary TB and HIV/AIDS patients could be more susceptible to SARS-CoV-2 infection leading to lethal synergy and disease severity. Therefore, the biological and epidemiological interactions of COVID-19, HIV/AIDS, and TB need to be understood holistically. While data is needed to predict the impact of the COVID-19 pandemic on these existing diseases, it is necessary to review the implications of the evolving COVID-19 management on HIV/AIDS and TB control, including therapy and funding. Also, the impact of long COVID on patients, who may have this co-infection. Thus, this review highlights the implications of COVID-19, HIV/AIDS, and TB co-infection compares disease mechanisms, addresses growing concerns, and suggests a direction for improved diagnosis and general management.

Curcumin loaded Ag-TiO2-halloysite nanotubes platform for combined chemo-photodynamic therapy treatment of cancer cells.

The use of naturally occurring anticancer materials in combination with doped metal oxide has emerged as one of the most promising ways for improving anticancer treatment efficacy. In this study, the anticancer potential of curcumin-loaded Ag-TiO2-halloysite nanotubes (curcumin-loaded Ag-TiO2-HNTs) was examined. Ag-TiO2-HNTs with different wt% of Ag-TiO2 were synthesized and characterized using XRD, TGA, FT-IR, UV-Vis spectroscopy, and SEM-EDX. The XRD results revealed the presence of crystalline TiO2. However, the presence of Ag was detected through the SEM-EDX analysis. Cyclic voltammetry measurements suggested the enhancement of the release of ROS from TiO2 upon deposition with Ag. FT-IR and TGA analysis confirmed the successful loading of curcumin inside the nanotubes of the halloysite. In vitro drug released studies revealed the release of approximately 80-99% curcumin within 48 hours. Kinetic model studies revealed that the release of curcumin from HNT and Ag-TiO2-HNT followed the first-order and Higuchi models, respectively. The light irradiated curcumin-loaded Ag-TiO2-HNTs samples exhibited considerable anticancer potential as compared to the free curcumin, irradiated Ag-TiO2 NPs samples, and unirradiated curcumin loaded Ag-TiO2-HNTs samples. The obtained results revealed that combined chemo- and photodynamic therapy using curcumin-loaded Ag-TiO2-HNTs nanomaterial has the potential as an effective anticancer treatment method.

Probing SARS-CoV-2-positive plasma to identify potential factors correlating with mild COVID-19 in Ghana, West Africa.

BACKGROUND: West Africa has recorded a relatively higher proportion of asymptomatic coronavirus disease 2019 (COVID-19) cases than the rest of the world, and West Africa-specific host factors could play a role in this discrepancy. Here, we assessed the association between COVID-19 severity among Ghanaians with their immune profiles and ABO blood groups. METHODS: Plasma samples were obtained from Ghanaians PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive individuals. The participants were categorized into symptomatic and asymptomatic cases. Cytokine profiling and antibody quantification were performed using Luminex™ multiplex assay whereas antigen-driven agglutination assay was used to assess the ABO blood groups. Immune profile levels between symptomatic and asymptomatic groups were compared using the two-tailed Mann-Whitney U test. Multiple comparisons of cytokine levels among and between days were tested using Kruskal-Wallis with Dunn's post hoc test. Correlations within ABO blood grouping (O's and non-O's) and between cytokines were determined using Spearman correlations. Logistic regression analysis was performed to assess the association of various cytokines with asymptomatic phenotype. RESULTS: There was a trend linking blood group O to reduced disease severity, but this association was not statistically significant. Generally, symptomatic patients displayed significantly (p < 0.05) higher cytokine levels compared to asymptomatic cases with exception of Eotaxin, which was positively associated with asymptomatic cases. There were also significant (p < 0.05) associations between other immune markers (IL-6, IL-8 and IL-1Ra) and disease severity. Cytokines' clustering patterns differ between symptomatic and asymptomatic cases. We observed a steady decrease in the concentration of most cytokines over time, while anti-SARS-CoV-2 antibody levels were stable for at least a month, regardless of the COVID-19 status. CONCLUSIONS: The findings suggest that genetic background and pre-existing immune response patterns may in part shape the nature of the symptomatic response against COVID-19 in a West African population. This study offers clear directions to be explored further in larger studies.

Knowledge, attitude and perception of West Africans towards COVID-19: a survey to inform public health intervention.

BACKGROUND: The first case of the novel coronavirus disease-2019 (COVID-19) in West Africa was first confirmed in Nigeria in February 2020. Since then, several public health interventions and preventive measures have been implemented to curtail transmission of the causative agent, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Therefore, this study was performed to assess the knowledge, attitudes, and perceptions of West Africans towards COVID-19. METHODS: An online survey was conducted between 29 September to 29 October 2020 among West Africans. Thirty-three survey questions were designed to collect sociodemographic data and participants' knowledge, attitude and perception towards COVID-19. The study targeted all West African nationals who were 18 years and above, and willing to participate in the study. Participants were either in-country or abroad. RESULTS: Overall, 1106 respondents (≥18 years) from 16 West African countries, with about 12.1% of them residing outside the West African subregion, participated in the survey. The respondents had an average COVID-19 knowledge score of 67.82 ± 8.31, with knowledge of the disease significantly associated with the country of residence (p = 0.00) and marginally (p = 0.05) so with settlement types (i.e., urban, suburban and rural areas). Most respondents (93.4%) could identify the main COVID-19 symptoms, and 73.20% would consult a healthcare professional if infected with SARS-CoV-2. Also, 75.2% of the respondents are willing to receive the COVID-19 vaccine, whereas 10.40% and 14.40% are unwilling and undecided, respectively. Perceptions of what constitute COVID-19 preventive measures were highly variable. Approximately, 8% of the respondents felt that their government responded excellently in managing the pandemic while a third felt that the response was just good. Also, more than half (54%) opined that isolation and treatment of COVID-19 patients is a way of curbing SARS-CoV-2 spread. CONCLUSIONS: Most West Africans have basic knowledge of COVID-19 and showed a positive attitude, with likely proactive practice towards the disease. However, results showed that these varied across countries and are influenced by the types of settlements. Therefore, the health and education authorities in various countries should develop focused measures capturing people in different settlements to improve their preventative measures when designing public health interventions for COVID-19 and any future epidemics or pandemics.

Pathogen-Induced Epigenetic Modifications in Cancers: Implications for Prevention, Detection and Treatment of Cancers in Africa.

Cancer is a major public health burden worldwide. Tumor formation is caused by multiple intrinsic and extrinsic factors. Many reports have demonstrated a positive correlation between the burden of infectious pathogens and the occurrence of cancers. However, the mechanistic link between pathogens and cancer development remains largely unclear and is subject to active investigations. Apart from somatic mutations that have been widely linked with various cancers, an appreciable body of knowledge points to alterations of host epigenetic patterns as key triggers for cancer development. Several studies have associated various infectious pathogens with epigenetic modifications. It is therefore plausible to assume that pathogens induce carcinogenesis via alteration of normal host epigenetic patterns. Thus, Africa with its disproportionate burden of infectious pathogens is threatened by a dramatic increase in pathogen-mediated cancers. To curb the potential upsurge of such cancers, a better understanding of the role of tropical pathogens in cancer epigenetics could substantially provide resources to improve cancer management among Africans. Therefore, this review discusses cancer epigenetic studies in Africa and the link between tropical pathogens and cancer burden. In addition, we discuss the potential mechanisms by which pathogens induce cancers and the opportunities and challenges of tropical pathogen-induced epigenetic changes for cancer prevention, detection and management.

Chitosan-Coated Halloysite Nanotubes As Vehicle for Controlled Drug Delivery to MCF-7 Cancer Cells In Vitro.

The aim of the work is to improve the release properties of curcumin onto human breast cancer cell lines using coated halloysite nanotubes (HNTs) with chitosan as a polycation. A loading efficiency of 70.2% (w/w) was attained for loading 4.9 mg of the drug into 0.204 g bed volume of HNTs using the vacuum suction method. Results acquired from Brunauer-Emmett-Teller (BET), Fourier-transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), scanning electron spectroscopy (SEM), zeta potential, and thermogravimetric analysis (TGA) indicated the presence of the drug and the biopolymer in and around the nanotubes. The release properties of drug-loaded HNTs (DLHNTs) and chitosan-coated drug-loaded HNTs (DLHNTs-CH) were evaluated. The release percentages of DLHNTs and DLHNTs-CH after 6 h were 50.7 and 37%, respectively. Based on the correlation coefficients obtained by fitting the release nature of curcumin from the two samples, the Korsmeyer-Peppas model was found to be the best-fitted model. In vitro cell viability studies were carried out on the human breast cancer cell line MCF-7, using the MTT and trypan blue exclusion assays. Prior to the Trypan blue assay, the IC50 of curcumin was determined to be ~30 µM. After 24 h of incubation, the recorded cell viability values were 94, 68, 57, and 51% for HNTs, DLHNTs-CH, DLHNTs, and curcumin, respectively. In comparison to the release studies, it could be deducted that sustained lethal doses of curcumin were released from the DLHNTs-CH within the same time. It is concluded from this work that the "burst release" of naked drugs could be slowly administered using chitosan-coated HNTs as potential drug carriers.

Breast cancer in sub-Saharan Africa: The current state and uncertain future.

Breast cancer is the commonest cause of global cancer-related deaths in women and a public health burden in sub-Saharan Africa (SSA). Although the disease incidence in SSA seems lower, mortality rates are disproportionately high in comparison to high-income countries. The global disease burden is growing, with SSA reporting the majority of cases; however, the dearth of information results in insufficient data which is barely representative of the actual disease burden in this population. Future incidence predictions assign the subregion with a majority of the cases and associated deaths. Breast cancer presents with racial and ethnic variations, and available evidence suggests geographical diversity and persistent risk factors that have barely been explored in SSA. Breast cancer is a complex genetic disease, but the genetic risk factors in the extant African population, which is the most genetically diverse population, is scant and of low quality. This review focuses on the burden, prevalence, detection, treatment, survival, biology, as well as risk factors, and reinforces the need for breast cancer-associated risk factor investigation and population-specific studies in SSA.

AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer.

Activating protein 2 alpha (AP-2α; encoded by TFAP2A) functions as a tumor suppressor and influences response to therapy in several cancer types. We aimed to characterize regulation of the transcriptome by AP-2α in colon cancer. CRISPR-Cas9 and short hairpin RNA were used to eliminate TFAP2A expression in HCT116 and a panel of colon cancer cell lines. AP-2α target genes were identified with RNA sequencing and chromatin immunoprecipitation sequencing. Effects on cell cycle were characterized in cells synchronized with aphidicolin and analyzed by FACS and Premo FUCCI. Effects on invasion and tumorigenesis were determined by invasion assay, growth of xenografts, and phosphorylated histone H3 (PHH3). Knockout of TFAP2A induced significant alterations in the transcriptome including repression of TGM2, identified as a primary gene target of AP-2α. Loss of AP-2α delayed progression through S-phase into G2-M and decreased phosphorylation of AKT, effects that were mediated through regulation of TGM2. Buparlisib (BKM120) repressed in vitro invasiveness of HCT116 and a panel of colon cancer cell lines; however, loss of AP-2α induced resistance to buparlisib. Similarly, buparlisib repressed PHH3 and growth of tumor xenografts and increased overall survival of tumor-bearing mice, whereas, loss of AP-2α induced resistance to the effect of PI3K inhibition. Loss of AP-2α in colon cancer leads to prolonged S-phase through altered activation of AKT leading to resistance to the PI3K inhibitor, Buparlisib. The findings demonstrate an important role for AP-2α in regulating progression through the cell cycle and indicates that AP-2α is a marker for response to PI3K inhibitors. IMPLICATIONS: AP-2α regulated cell cycle through the PI3K cascade and activation of AKT mediated through TGM2. AP-2α induced sensitivity to Buparlisib/BKM120, indicating that AP-2α is a biomarker predictive of response to PI3K inhibitors.

Towards understanding antimicrobial activity, cytotoxicity and the mode of action of dichapetalins A and M using in silico and in vitro studies.

Dichapetalum madagascariense Poir (Dichapetalaceae) is traditionally used to treat bacterial infections, jaundice, urethritis and viral hepatitis in Africa. Its root contains a broad spectrum of biologically active dichapetalins. To evaluate the plant's effect on human MCF-7 cells and its' antibacterial and antiparasitic potentials, we isolated and identified the known dichapetalins A and M from the roots. Both dichapetalins were tested on six bacterial strains (Shigella flexneri, Bacillus cereus, Salmonella paratyphi B, Listeria monocytogenes, Escherichia coli, Staphylococcus aureus) and two parasite strains; Trypanosoma brucei brucei, and Leishmania donovani using the Alamar Blue assay system. Dichapetalins A and M were more potent against B. cereus with IC50 values of 11.15 and 3.15 µg/ml, respectively, compared to the positive control ampicillin (IC50 = 19.50 µg/ml). Dichapetalins A (IC50 = 74.22 µg/ml) and M (IC50 = 72.34 µg/ml) were less active against T. b. brucei, compared to the standard Suramin (IC50 = 4.96 µg/ml). Dichapetalin M showed moderate activity against L. donovani (Amphotericin B: IC50 = 0.21 µg/ml) with an IC50 of 16.80 µg/ml. In human MCF-7 cells expressing the NR1I2 receptor, the activity of dichapetalin M was higher (IC50 = 4.71 µM and 3.95 µM) for 48 and 72 h of treatment, respectively compared to Curcumin with IC50 of 17.49 µM and 12.53 µM for 48 and 72 h of treatment, respectively. Results from in vitro expression studies with qPCR confirmed an antagonistic effect of dichapetalin M on PXR (NR1I2) signaling; supporting the PXR signaling pathway as a possible mode of action of dichapetalin M as predicted by in silico results. These findings confirm previous studies that D. madagascariense can be a source of potential lead compounds for development of novel antibiotic, antiparasitic and anticancer medicines, and provide further insights into the mechanism of action of the dichapetalins.

Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation. METHODS: Blood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR. RESULTS: CF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF. CONCLUSIONS: CF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.

Monocyte derived macrophages from CF pigs exhibit increased inflammatory responses at birth.

BACKGROUND: We sought to address whether CF macrophages have a primary functional defect as a consequence of CFTR loss and thus contribute to the onset of infection and inflammation observed in CF lung disease. METHODS: Monocyte derived macrophages (MDMs) were prepared from newborn CF and non-CF pigs. CFTR mRNA expression was quantified by rtPCR and anion channel function was determined using whole cell patch clamp analysis. IL8 and TNFα release from MDMs in response to lipopolysaccharide stimulation was measured by ELISA. RESULTS: CFTR was expressed in MDMs by Q-rtPCR at a lower level than in epithelial cells. MDMs exhibited functional CFTR current at the cell membrane and this current was absent in CF MDMs. CF MDMs demonstrated an exaggerated response to lipopolysaccharide stimulation. CONCLUSIONS: In the absence of CFTR function, macrophages from newborn CF pigs exhibit an increased inflammatory response to a lipopolysaccharide challenge. This may contribute to the onset and progression of CF lung disease.

Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase.

Epilepsy is a common disabling disease with complex, multifactorial genetic and environmental etiology. The small fraction of epilepsies subject to Mendelian inheritance offers key insight into epilepsy disease mechanisms; and pathologies brought on by mutations in a single gene can point the way to generalizable therapeutic strategies. Mutations in the PRICKLE genes can cause seizures in humans, zebrafish, mice, and flies, suggesting the seizure-suppression pathway is evolutionarily conserved. This pathway has never been targeted for novel anti-seizure treatments. Here, the mammalian PRICKLE-interactome was defined, identifying prickle-interacting proteins that localize to synapses and a novel interacting partner, USP9X, a substrate-specific de-ubiquitinase. PRICKLE and USP9X interact through their carboxy-termini; and USP9X de-ubiquitinates PRICKLE, protecting it from proteasomal degradation. In forebrain neurons of mice, USP9X deficiency reduced levels of Prickle2 protein. Genetic analysis suggests the same pathway regulates Prickle-mediated seizures. The seizure phenotype was suppressed in prickle mutant flies by the small-molecule USP9X inhibitor, Degrasyn/WP1130, or by reducing the dose of fat facets a USP9X orthologue. USP9X mutations were identified by resequencing a cohort of patients with epileptic encephalopathy, one patient harbored a de novo missense mutation and another a novel coding mutation. Both USP9X variants were outside the PRICKLE-interacting domain. These findings demonstrate that USP9X inhibition can suppress prickle-mediated seizure activity, and that USP9X variants may predispose to seizures. These studies point to a new target for anti-seizure therapy and illustrate the translational power of studying diseases in species across the evolutionary spectrum.

PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders.

The frequent comorbidity of Autism Spectrum Disorders (ASDs) with epilepsy suggests a shared underlying genetic susceptibility; several genes, when mutated, can contribute to both disorders. Recently, PRICKLE1 missense mutations were found to segregate with ASD. However, the mechanism by which mutations in this gene might contribute to ASD is unknown. To elucidate the role of PRICKLE1 in ASDs, we carried out studies in Prickle1(+/-) mice and Drosophila, yeast, and neuronal cell lines. We show that mice with Prickle1 mutations exhibit ASD-like behaviors. To find proteins that interact with PRICKLE1 in the central nervous system, we performed a yeast two-hybrid screen with a human brain cDNA library and isolated a peptide with homology to SYNAPSIN I (SYN1), a protein involved in synaptogenesis, synaptic vesicle formation, and regulation of neurotransmitter release. Endogenous Prickle1 and Syn1 co-localize in neurons and physically interact via the SYN1 region mutated in ASD and epilepsy. Finally, a mutation in PRICKLE1 disrupts its ability to increase the size of dense-core vesicles in PC12 cells. Taken together, these findings suggest PRICKLE1 mutations contribute to ASD by disrupting the interaction with SYN1 and regulation of synaptic vesicles.