👤 Kainat Ahmed

Coronary angiography is the primary procedure for diagnosis and management decisions in coronary artery disease (CAD), but ad-hoc visual assessment of angiograms has high variability. Here we report a fully automated approach to interpret angiographic coronary artery stenosis from standard coronary angiograms. Using 13,843 angiographic studies from 11,972 adult patients at University of California, San Francisco (UCSF), between April 1, 2008 and December 31, 2019, we train neural networks to accomplish four sequential necessary tasks for automatic coronary artery stenosis localization and estimation. Algorithms are internally validated against criterion-standard labels for each task in hold-out test datasets. Algorithms are then externally validated in real-world angiograms from the University of Ottawa Heart Institute (UOHI) and also retrained using quantitative coronary angiography (QCA) data from the Montreal Heart Institute (MHI) core lab. The CathAI system achieves state-of-the-art performance across all tasks on unselected, real-world angiograms. Positive predictive value, sensitivity and F1 score are all ≥90% to identify projection angle and ≥93% for left/right coronary artery angiogram detection. To predict obstructive CAD stenosis (≥70%), CathAI exhibits an AUC of 0.862 (95% CI: 0.843-0.880). In UOHI external validation, CathAI achieves AUC 0.869 (95% CI: 0.830-0.907) to predict obstructive CAD. In the MHI QCA dataset, CathAI achieves an AUC of 0.775 (95%. CI: 0.594-0.955) after retraining. In conclusion, multiple purpose-built neural networks can function in sequence to accomplish automated analysis of real-world angiograms, which could increase standardization and reproducibility in angiographic coronary stenosis assessment. Show less

Surface water pollution caused by the discharge of effluents from industrial estates has become a major concern for Dhaka (Bangladesh). This study aims to have a concise look at the severe river water pollution, mainly from effluents discharged from the tannery village. Effluent samples were collected from five ejected points, including the central effluent treatment plant (CETP), twenty adjacent river water, and two pond water nearby Hemayetpur, Savar. Thirty-one parameters have been observed at these sampling points for three seasons, from April 2021 to January 2022. The results obtained from water quality indices, i.e., water quality index (WQI), entropy water quality index (EWQI), and irrigation water quality index (IWQI), show that most studied surface water samples ranked "unsuitable" for consumption, irrigation, and anthropogenic purposes. The highest health risk was observed downstream of Hemayetpur city at the Savar CETP discharge site, indicating higher levels of heavy metal in the river water following the tannery village. Carcinogenic and non-carcinogenic human health risks could be triggered mainly by water consumption as concentrations of arsenic (As), chromium (Cr), nickel (Ni), and lead (Pb) exceeded the upper benchmark of 1 × 10 Show less

The present study involves synthesis a new series of α-aminophosphonates 2a-f and 4a-d derivatives in good yield with a simple workup via Kabachnik-Fields reaction in the presence of lithium perchlorate as Lewis acid catalyst. All the newly synthesized compounds were confirmed using various physical, spectroscopic, and analytical data. The in vitro anticancer activities of each compound were evaluated against colorectal carcinoma Colon cancer (HCT-116) and Epdermoid carcinoma (HEP2) and also Human lung fibroblast normal cell line (WI38) compared with Doxorubicin. The results showed that Compounds 2a, 4b and 4d exhibited more potent inhibitory activity for Epdermoid Carcinoma (HEP2) compared with doxorubicin. For colon carcinoma cells (HCT-116) Compounds 2a, 2d and 4b gave the strongest activity among all compounds compared with doxorubicin. Moreover, all designed structures were docked into the active site of VEGFR2 and FGFR1 proteins. The result reveals that compound 2b and have the strongest inhibitory activity of the VEGFR2 and FGFR1 proteins indicating that these substances might conceivably operate as VEGFR2 and FGFR1 inhibitors and hence might take role in anticancer activities with various binding interactions. The 3D-QSAR models produced strong statistical results since they were defined by PLS factors 4 and confirmed by parameters as R2, R2 CV, Stability, F-value, P-value, RMSE, Q2, and Pearson-r. Show less

Diabetes mellitus is a burdensome disease that affects various cellular functions through altered glucose metabolism. Several reports have linked diabetes to cancer development; however, the exact molecular mechanism of how diabetes-related traits contribute to cancer progression is not fully understood. The current study aimed to explore the molecular mechanism underlying the potential effect of hyperglycemia combined with hyperinsulinemia on the progression of breast cancer cells. To this end, gene dysregulation induced by the exposure of MCF7 breast cancer cells to hyperglycemia (HG), or a combination of hyperglycemia and hyperinsulinemia (HGI), was analyzed using a microarray gene expression assay. Hyperglycemia combined with hyperinsulinemia induced differential expression of 45 genes (greater than or equal to two-fold), which were not shared by other treatments. On the other hand, in silico analysis performed using a publicly available dataset (GEO: GSE150586) revealed differential upregulation of 15 genes in the breast tumor tissues of diabetic patients with breast cancer when compared with breast cancer patients with no diabetes. Show less

Breast cancer is a common tumor type among women, with a high fatality due to metastasis. Metastasis suppressors encode proteins that inhibit the metastatic cascade independent of the primary tumor growth. Raf kinase inhibitory protein (RKIP) is one of the promising metastasis suppressor candidates. RKIP is reduced or lost in aggressive variants of different types of cancer. A few pre-clinical or clinical studies have capitalized on this protein as a possible therapeutic target. In this article, we employed two breast cancer cells to highlight the role of RKIP as an antimetastatic gene. One is the low metastatic MCF-7 with high RKIP expression, and the other is MDA-MB-231 highly metastatic cell with low RKIP expression. We used high-throughput data to explore how RKIP is lost in human tissues and its effect on cell mobility. Based on our previous work recapitulating the links between RKIP and SNAI, we experimentally manipulated RKIP in the cell models through its novel upstream NME1 and investigated the subsequent genotypic and phenotypic changes. We also demonstrated that RKIP explained the uneven migration abilities of the two cell types. Furthermore, we identified the regulatory circuit that might carry the effect of an existing drug, Epirubicin, on activating gene transcription. In conclusion, we propose and test a potential strategy to reverse the metastatic capability of breast cancer cells by chemically manipulating RKIP expression. Show less

The melanocortin-4 receptor (MC4R) has been critically investigated for the past two decades, and novel findings regarding MC4R signalling and its potential exploitation in weight loss therapy have lately been emphasized. An association between MC4R and obesity is well established, with disease-causing mutations affecting 1% to 6% of obese patients. More than 200 MC4R variants have been reported, although conflicting results as to their effects have been found in different cohorts. Most notably, some MC4R gain-of-function variants seem to rescue obesity and related complications via specific pathways such as beta-arrestin (ß-arrestin) recruitment. Broadly speaking, however, dysfunctional MC4R dysregulates satiety and induces hyperphagia. The picture at the mechanistic level is complicated as, in addition to the canonical G stimulatory pathway, the ß-arrestin signalling pathway and ions (particularly calcium) seem to interact with MC4R signalling to contribute to or alleviate obesity pathogenesis. Thus, the overall complexity of the MC4R signalling spectra has broadened considerably, indicating there is great potential for the development of new drugs to manage obesity and its related complications. Alpha-melanocyte-stimulating hormone is the major endogenous MC4R agonist, but structure-based ligand discovery studies have identified possible superior and selective agonists that can improve MC4R function. However, some of these agonists characterized in vitro and in vivo confer adverse effects in patients, as demonstrated in clinical trials. In this review, we provide a comprehensive insight into the genetics, function and regulation of MC4R and its contribution to obesity. We also outline new approaches in drug development and emerging drug candidates to treat obesity. Show less

Acute respiratory infection by influenza virus is a persistent and pervasive public health problem. Antiviral innate immunity initiated by type I interferon (IFN) is the first responder to pathogen invasion and provides the first line of defense. We discovered that Axin1, a scaffold protein, was reduced during influenza virus infection. We also found that overexpression of Axin1 and the chemical stabilizer of Axin1, XAV939, reduced influenza virus replication in lung epithelial cells. This effect was also observed with respiratory syncytial virus and vesicular stomatitis virus. Axin1 boosted type I IFN response to influenza virus infection and activated JNK/c-Jun and Smad3 signaling. XAV939 protected mice from influenza virus infection. Thus, our studies provide new mechanistic insights into the regulation of the type I IFN response and present a new potential therapeutic of targeting Axin1 against influenza virus infection. Show less

Saponins are triterpenoid or steroidal glycosides and are an important group of naturally occurring compounds of plant origin. They exhibit diverse pharmacological potentials including radical scavenging, as well as neuroprotective, anti-diabetic and anti-inflammatory activities, owing to their diverse chemical scaffolds. Saponins consist of an aglycone part (non-sugar) and a glycone part (sugar) and have at least one glycosidic (C-O sugar bond) linkage present between the glycone and aglycone mostly at C-3. On the basis of the aglycone part, saponins are classified into triterpenoid glycosides, steroid glycosides and alkaloid glycosides. Saponins exhibit neuroprotective activities against various disorders of the central nervous system (CNS) including stroke, Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). They mediate their therapeutic effects by modulation of various pathological targets. This study highlights various neuroprotective mechanisms of saponins including free radical scavenging, modulation of neuroprotective signaling pathways, activation of neurotrophic factors, modulation of neurotransmitters, inhibition of BACE1 enzyme and tau hyper-phosphorylation. The study concludes that saponins have considerable efficacy against various pathological targets of neurological disorders, especially AD, and might be an important source of leads against neurodegenerative disorders. Show less

Oxidative stress (OS) and c-Jun N-terminal kinase (JNK) are both key indicators implicated in neuro-inflammatory signalling pathways and their respective neurodegenerative diseases. Drugs targeting these factors can be considered as suitable candidates for treatment of neuronal dysfunction and memory impairment. The present study encompasses beneficial effects of a naturally occurring triterpenoid, friedelin, against scopolamine-induced oxidative stress and neurodegenerative pathologies in mice models. The treated animals were subjected to behavioural tests i.e., Y-maze and Morris water maze (MWM) for memory dysfunction. The underlying mechanism was determined via western blotting, antioxidant enzymes and lipid profile analyses. Molecular docking studies were carried out to predict the binding modes of friedelin in the binding pocket of p-JNK protein. The results reveal that scopolamine caused oxidative stress by (1) inhibiting catalase (CAT), peroxidase enzyme (POD), superoxide dismutase (SOD), and reduced glutathione enzyme (GSH); (2) the up-regulation of thiobarbituric acid reactive substances (TBARS) in mice brain; and (3) affecting the neuronal synapse (both pre- and post-synapse) followed by associated memory dysfunction. In contrast, friedelin administration not only abolished scopolamine-induced oxidative stress, glial cell activation, and neuro-inflammation but also inhibited p-JNK and NF-κB and their downstream signaling molecules. Moreover, friedelin administration improved neuronal synapse and reversed scopolamine-induced memory impairment accompanied by the inhibition of β-secretase enzyme (BACE-1) to halt amyloidogenic pathways of amyloid-β production. In summary, all of the results show that friedelin is a potent naturally isolated neuro-therapeutic agent to reverse scopolamine-induced neuropathology, which is characteristic of Alzheimer's disease. Show less

Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer's disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aβ). APPswe/PSdE1 (APP/PS1) mice display age-related Aβ accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APP/PS1/eNOS Show less

Cytokines are a group of immunomodulatory proteins leading to a variety of immune reactions in the human; these cytokines play a significant role in the development of appropriate immune responses against T. gondii. This study aims to reveal the association of toxoplasmosis with serum levels of IL-3, IL-17A, and IL-27 in aborted women. The blood samples of patients and controls were collected from Al-Alawiya Maternity Teaching Hospital/Baghdad/Iraq from 2019 to 2020 for detecting anti-T. gondii antibodies (IgG and IgM) and the level of interleukins by ELISA. The results of TORCH by rapid test for recurrent abortion recorded 25.3% seropositive for anti-Toxoplasma antibodies, and 31.5% seropositive for one or more cases of TORCH test (Cytomegalovirus, Rubella, and Herpes). Whereas the results for anti-T. gondii IgG and IgM antibodies were shown elevated positivity percentages by ELISA test; these percentages were 56.2% in recurrent abortion women with significant differences (P < 0.05). The results suggested that the IL-3 serum concentration of pregnant women, recurrent abortion, and recurrent abortion with toxoplasmosis was declined versus healthy women with significant differences (p < 0.05). However, the results revealed that the concentration of IL-17A in recurrent abortion, and recurrent abortion with toxoplasmosis elevated versus healthy women and pregnant women with significant difference (p < 0.05). Whereas the results indicated that the IL-27 serum concentration elevated with significant differences in recurrent abortion with toxoplasmosis group compared to healthy women, pregnant women, and recurrent abortion. Interestingly, the serum levels for IL-27 increased comparing to the levels of IL-3 and IL-17A in all groups with significant differences (P < 0.05). In conclusion, it appeared in this study that the role of IL-3, IL-17A, and IL-27 in the maternal immune response during infections can lead to abortion. Show less

Metastasis is associated with poor prognosis and is the major cause of death in cancer patients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire a highly migratory phenotype. Metabolic reprogramming is required to meet the energy demands during this process. Recent studies have indicated that autophagy is involved in EMT, during which cancer cells depend on autophagy activation for survival. However, accumulating evidence indicates that autophagy's involvement in cancer is context-dependent, acting as either promoter or inhibitor. In this study, we investigated the role of autophagy in supplying energy to support EMT. We induced EMT in Non-small cell lung cancer A549 cells using TGF-β1 with and without autophagy inhibition. Suppression of autophagy activity by knocking down of Show less

Autophagy controls levels of cellular components during normal and stress conditions; thus, it is a pivotal process for the maintenance of cell homeostasis. In cancer, autophagy protects cells from cancerous transformations that can result from genomic instability induced by reactive oxygen species or other damaged components, but it can also promote cancer survival by providing essential nutrients during the metabolic stress condition of cancer progression. However, the molecular mechanism underlying autophagy-dependent regulation of the epithelial to mesenchymal transition (EMT) and metastasis is still elusive. The intracellular level of NOTCH1 intracellular domain (NICD) in several cancer cells was studied under starvation, treatment with chloroquine or ATG7-knockdown. The autophagy activity in these cells was assessed by immunocytochemistry and molecular analyses. Cancer cell migration and invasion under modulation of autophagy were determined by in vitro scratch and Matrigel assays. In the study, autophagy activation stimulated degradation of NICD, a key transcriptional regulator of the EMT and cancer metastasis. We also found that NICD binds directly to LC3 and that the NICD/LC3 complex associates with SNAI1 and sequestosome 1 (SQSTM1)/p62 proteins. Furthermore, the ATG7 knockdown significantly inhibited degradation of NICD under starvation independent of SQSTM1-associated proteasomal degradation. In addition, NICD degradation by autophagy associated with the cellular level of SNAI1. Indeed, autophagy inhibited nuclear translocation of NICD protein and consequently decreased the transcriptional activity of its target genes. Autophagy activation substantially suppressed in vitro cancer cell migration and invasion. We also observed that NICD and SNAI1 levels in tissues from human cervical and lung cancer patients correlated inversely with expression of autophagy-related proteins. These findings suggest that the cellular level of NICD is regulated by autophagy during cancer progression and that targeting autophagy-dependent NICD/SNAI1 degradation could be a strategy for the development of cancer therapeutics. Show less

We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 Almost all Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for Show less

Pregnant women with gestational diabetes mellitus (GDM) are at risk of adverse outcomes, including gestational hypertension, pre-eclampsia, and preterm delivery. This study was undertaken to determine if apolipoprotein (apo) levels differed between pregnant women with and without GDM and if they were associated with adverse pregnancy outcome. Pregnant women (46 women with GDM and 26 women without diabetes (ND)) in their second trimester were enrolled in the study. Plasma apos were measured and correlated to demographic, biochemical, and pregnancy outcome data. apoA2, apoC1, apoC3 and apoE were lower in women with GDM compared with control women (p=0.0019, p=0.0031, p=0.0002 and p=0.015, respectively). apoA1, apoB, apoD, apoH, and apoJ levels did not differ between control women and women with GDM. Pearson bivariate analysis revealed significant correlations between gestational age at delivery and apoA2 for women with GDM and control women, and between apoA2 and apoC3 concentrations and C reactive protein (CRP) as a measure of inflammation for the whole group. Apoproteins apoA2, apoC1, apoC3 and apoE are decreased in women with GDM and may have a role in inflammation, as apoA2 and C3 correlated with CRP. The fact that apoA2 correlated with gestational age at delivery in both control women and women with GDM raises the hypothesis that apoA2 may be used as a biomarker of premature delivery, and this warrants further investigation. Show less

Juvenile-onset diabetes may occur in the context of a rare syndromic presentation, suggesting a monogenic etiology rather than a common multifactorial diabetes. In the present study, we report the case of a young diabetic Tunisian patient presenting learning problems, speech deficits, short stature, brachydactyly, and a normal weight. Whole exome sequencing analysis revealed five heterozygous genetic variants in Show less

Single nucleotide polymorphisms (SNPs) are predictive markers for diseases, also cytokines are undergoing genetic controls and their genetic polymorphisms have a functional role in regulating the levels of cytokine gene expression. This study aims to reveal the association of toxoplasmosis with serum levels and SNP of IL-27 in aborted women. Total, 200 blood samples of patients and controls were collected from Al-Alawiya Maternity Teaching Hospital/Baghdad/Iraq from 2019–2020 for detecting the level of IL-27 by ELISA while the allelic discrimination method was used for SNP IL-27 (rs153109). The results indicated the IL-27 serum concentration elevated with significant differences in recurrent abortion with toxoplasmosis group compared to healthy women, pregnant women, and recurrent abortion. Also, recurrent abortion had significant differences compared to healthy women and pregnant women (P<0.05). Moreover, SNP results of IL-27 showed no significant association between patients and controls. Considering the distribution of serum levels for IL-27 by SNP, it was observed that IL-27 serum levels for TT, TC, and CC genotypes elevated in the patient group versus the control group. In addition, it was observed elevation serum level of IL-27 for the genotypes TT, TC, and CC in recurrent abortion with toxoplasmosis in contrast to healthy women, pregnant women, and recurrent abortion (P<0.05). Also, in recurrent abortion, the level of IL-27 for TC, and CC genotype showed significant differences comparing to healthy and pregnant women (P<0.05). In conclusion, the level of IL-27 in recurrent abortion women with toxoplasmosis was higher than the recurrent abortion women, which may be due to the inflammatory response to toxoplasmosis. SNP of IL-27 has not represented as a risk factor in recurrent abortion women with toxoplasmosis. Show less

Drug screening strategies focus on quantifying the phenotypic effects of different compounds on biological systems. High-throughput technologies have the potential to understand further the mechanisms by which these drugs produce the desired outcome. Reverse causal reasoning integrates existing biological knowledge and measurements of gene and protein abundances to infer their function. This approach can be employed to appraise the existing biological knowledge and data to prioritize targets for cancer therapies. We applied text mining and a manual literature search to extract known interactions between several metastasis suppressors and their regulators. We then identified the relevant interactions in the breast cancer cell line MCF7 using a knockdown dataset. We finally adopted a reverse causal reasoning approach to evaluate and prioritize pathways that are most consistent and responsive to drugs that inhibit cell growth. We evaluated this model in terms of agreement with the observations under treatment of several drugs that produced growth inhibition of cancer cell lines. In particular, we suggested that the metastasis suppressor PEBP1/RKIP is on the receiving end of two significant regulatory mechanisms. One involves RELA (transcription factor p65) and SNAI1, which were previously reported to inhibit PEBP1. The other involves the estrogen receptor (ESR1), which induces PEBP1 through the kinase NME1. Our model was derived in the specific context of breast cancer, but the observed responses to drug treatments were consistent in other cell lines. We further validated some of the predicted regulatory links in the breast cancer cell line MCF7 experimentally and highlighted the points of uncertainty in our model. To summarize, our model was consistent with the observed changes in activity with drug perturbations. In particular, two pathways, including PEBP1, were highly responsive and would be likely targets for intervention. Show less

Autophagy is a highly conserved metabolic process involved in the degradation of intracellular components including proteins and organelles. Consequently, it plays a critical role in recycling metabolic energy for the maintenance of cellular homeostasis in response to various stressors. In cancer, autophagy either suppresses or promotes cancer progression depending on the stage and cancer type. Epithelial-mesenchymal transition (EMT) and cancer metastasis are directly mediated by oncogenic signal proteins including SNAI1, SLUG, ZEB1/2, and NOTCH1, which are functionally correlated with autophagy. In this report, we discuss the crosstalk between oncogenic signaling pathways and autophagy followed by possible strategies for cancer treatment via regulation of autophagy. Although autophagy affects EMT and cancer metastasis, the overall signaling pathways connecting cancer progression and autophagy are still illusive. In general, autophagy plays a critical role in cancer cell survival by providing a minimum level of energy via self-digestion. Thus, cancer cells face nutrient limitations and challenges under stress during EMT and metastasis. Conversely, autophagy acts as a potential cancer suppressor by degrading oncogenic proteins, which are essential for cancer progression, and by removing damaged components such as mitochondria to enhance genomic stability. Therefore, autophagy activators or inhibitors represent possible cancer therapeutics. We further discuss the regulation of autophagy-dependent degradation of oncogenic proteins and its functional correlation with oncogenic signaling pathways, with potential applications in cancer therapy. Show less

Pollution of industry-adjacent surface water bodies become a major environmental concern in Bangladesh recently. Therefore, this study aimed to elaborate assessment of physico-chemical characteristics of the Dhaleshwari River (the adjacent river of newly shifted tannery industrial park) and also the discharged effluent from the central effluent treatment plant (CETP) considering both seasonal and spatial variations. Among the examined 30 water quality parameters (including 11 heavy metals), only TDS, Cl Show less

Central leptin administration can ameliorate hyperglycemia in insulin-deficient rodent models independently of insulin; however, the underlying neuronal mechanism are unclear. Here, we investigate the contribution of key elements within the central melanocortin system by examining whether central leptin injection can ameliorate hyperglycemia in total insulin-deficient mice that either lacked melanocortin 4 receptors (MC4Rs) in the whole body [knockout (KO); MC4R KO] or selectively, in single-minded homolog 1 (SIM1)-expressing neurons (SIM1ΔMC4R). We further investigated the contribution of leptin receptors (LEPRs) in agouti-related protein (AgRP)-expressing neurons (AgRP∆LEPR). Leptin injections into the cerebral ventricle attenuated mortality and elevated blood glucose in total insulin-deficient MC4R KO mice. Total insulin-deficient SIM1ΔMC4R mice exhibited the same magnitude reduction of blood glucose in response to leptin injections as MC4R KO mice, suggesting SIM1 neurons are key to MC4R-mediated, insulin-independent, glucose-lowering effects of leptin. Central leptin injection also partially rescued glucose levels in total insulin-deficient AgRP∆LEPR mice. In brain slice studies, basal discharge of AgRP neurons from mice with total insulin deficiency was increased and leptin partially reduced their firing rate without membrane potential hyperpolarization. Collectively, our findings indicate that, contrary to glucose-lowering effects of leptin in the presence of insulin or partial insulin deficiency, MC4Rs in SIM1 neurons and LEPRs in AgRP neurons are not solely responsible for glucose-lowering effects of leptin in total insulin deficiency. This indicates that the central melanocortin system operates with other neuronal systems to fully mediate glucose-lowering effects of leptin in an insulin-independent manner. Show less

The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. To perform the largest PD genome-wide association study restricted to a single country. We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society. Show less

Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition. We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616). Maternal genotypes were imputed using IMPUTE. After running 33 separate FA fraction phenotypes, we found that SNPs known to be associated with serum FAs in the AA is the primary FA in breast milk influenced by genetic variation at the Show less

After injury to the mature central nervous system (CNS), myelin-derived inhibitory ligands bind to the Nogo-66 tripartite receptor complex expressed on axonal growth cones, comprised of LINGO-1 and p75 Show less

To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability. A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software. All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein. LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans. Show less

Raf kinase inhibitor protein (RKIP) plays a critical role in many signaling pathways as a multi-functional adapter protein. In particular, the loss of RKIP's function in certain types of cancer cells results in epithelial to mesenchymal transition (EMT) and the promotion of cancer metastasis. In addition, RKIP inhibits autophagy by modulating LC3-lipidation and mTORC1. How the RKIP-dependent inhibition of autophagy is linked to EMT and cancer progression is still under investigation. In this study, we investigated the ways by which RKIP interacts with key gene products in EMT and autophagy during the progression of prostate cancer. We first identified the gene products of interest using the corresponding gene ontology terms. The weighted-gene co-expression network analysis (WGCNA) was applied on a gene expression dataset from three groups of prostate tissues; benign prostate hyperplasia, primary and metastatic cancer. We found two modules of highly co-expressed genes, which were preserved in other independent datasets of prostate cancer tissues. RKIP showed potentially novel interactions with one EMT and seven autophagy gene products (TGFBR1; PIK3C3, PIK3CB, TBC1D25, TBC1D5, TOLLIP, WDR45 and WIPI1). In addition, we identified several upstream transcription modulators that could regulate the expression of these gene products. Finally, we verified some RKIP novel interactions by co-localization using the confocal microscopy analysis in a prostate cancer cell line. To summarize, RKIP interacts with EMT and autophagy as part of the same functional unit in developing prostate cancer. Show less

Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10 Show less