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Whole-Organism Developmental Expression Profiling Identifies RAB-28 as a Novel Ciliary GTPase Associated with the BBSome and Intraflagellar Transport
Primary cilia are specialised sensory and developmental signalling devices extending from the surface of most eukaryotic cells. Defects in these organelles cause inherited human disorders (ciliopathies) such as retinitis pigmentosa and Bardet-Biedl syndrome (BBS), frequently affecting many physiological and developmental processes across multiple organs. Cilium formation, maintenance and function depend on intracellular transport systems such as intraflagellar transport (IFT), which is driven by kinesin-2 and IFT-dynein motors and regulated by the Bardet-Biedl syndrome (BBS) cargo-adaptor protein complex, or BBSome. To identify new cilium-associated genes, we employed the nematode C. elegans, where ciliogenesis occurs within a short timespan during late embryogenesis when most sensory neurons differentiate. Using whole-organism RNA-Seq libraries, we discovered a signature expression profile highly enriched for transcripts of known ciliary proteins, including FAM-161 (FAM161A orthologue), CCDC-104 (CCDC104), and RPI-1 (RP1/RP1L1), which we confirm are cilium-localised in worms. From a list of 185 candidate ciliary genes, we uncover orthologues of human MAP9, YAP, CCDC149, and RAB28 as conserved cilium-associated components. Further analyses of C. elegans RAB-28, recently associated with autosomal-recessive cone-rod dystrophy, reveal that this small GTPase is exclusively expressed in ciliated neurons where it dynamically associates with IFT trains. Whereas inactive GDP-bound RAB-28 displays no IFT movement and diffuse localisation, GTP-bound (activated) RAB-28 concentrates at the periciliary membrane in a BBSome-dependent manner and undergoes bidirectional IFT. Functional analyses reveal that whilst cilium structure, sensory function and IFT are seemingly normal in a rab-28 null allele, overexpression of predicted GDP or GTP locked variants of RAB-28 perturbs cilium and sensory pore morphogenesis and function. Collectively, our findings present a new approach for identifying ciliary proteins, and unveil RAB28, a GTPase most closely related to the BBS protein RABL4/IFT27, as an IFT-associated cargo with BBSome-dependent cell autonomous and non-autonomous functions at the ciliary base.
Journal Article
عندما كانت بغداد تحكم العالم الإسلامي
كتاب \"عندما كانت بغداد تحكم العالم الإسلامي\" للمؤرخ البريطاني هيو كينيدي يتناول تاريخ بغداد خلال فترة الخلافة العباسية، حيث كانت مركزا للحضارة الإسلامية والعلمية والفنية. يروي الكتاب قصة صعود وسقوط بغداد كعاصمة للعالم الإسلامي، مسلطا الضوء على الإنجازات الثقافية والعلمية التي حققتها المدينة خلال القرنين الأولين من حكم العباسيين، في هذا الكتاب، يوضح كينيدي كيف أصبحت بغداد مركزا للعلوم والفنون والفلسفة بفضل جهود الخلفاء العباسيين مثل هارون الرشيد وابنه المأمون، الذين أسسوا بيت الحكمة وشجعوا على ترجمة الأعمال الفلسفية والعلمية من اليونانية والفارسية والهندية إلى العربية، كما يصف الكتاب كيف ازدهرت التجارة والفنون والأدب في بغداد، مما جعلها واحدة من أعظم المدن في التاريخ الإسلامي.
BOOK
Assessment of ferroptosis as a promising candidate for metastatic uveal melanoma treatment and prognostication
Uveal melanoma (UM) is the most common primary intraocular tumour in adults. Local resection, radiation therapy, and enucleation are the current first-line, primary UM treatments. However, regardless of the treatment received, around 50% of UM patients will develop metastatic disease within five to 7 years. In the largest published series of unselected patients with metastatic UM (mUM), the median survival time after diagnosis of metastasis was 3.6 months, with less than 1% of patients surviving beyond 5 years. Approved drugs for treatment of mUM include systemic treatment with tebentafusp-tebn or isolated hepatic perfusion (IHP) with melphalan. However, these drugs are only available to a subset of patients and improve survival by only a few months, highlighting the urgent need for new mUM treatments. Accurately predicting which patients are at high risk for metastases is also crucial. Researchers are developing gene expression signatures in primary UM to create reliable prognostic models aimed at improving patient follow-up and treatment strategies. In this review we discuss the evidence supporting ferroptosis, a non-apoptotic form of cell death, as a potential novel treatment target and prognosticator for UM.
Journal Article
الفتوح الإسلامية : كيف غير انتشار الإسلام العالم الذي نعيش فية
يطرح هذا الكتاب السؤال ويجيب عنه، والسؤال الذى يطرحه الكتاب هو لماذا كان نجاح المسلمين سريعا وواسع النطاق بحيث فتحوا معظم أنحاء العالم خلال القرنين السابع والثامن الميلاديين، فى غضون قرن من الزمان تقريبا ؟ وكيف تمكنوا من تحويل الفتح إلى تغيير دائم فى مصائر المناطق والشعوب ؟ حول هذين السؤالين الجوهريين، وما يتفرع عنهما بالضرورة من أسئلة، تدور فصول هذا الكتاب.
Book
Meaningful associations in the adolescent brain cognitive development study
•Describes the ABCD study aims and design.•Covers issues surrounding estimation of meaningful associations, including population inferences, effect sizes, and control of covariates.•Outlines best practices for reproducible research and reporting of results.•Provides worked examples that illustrate the main points of the paper.
The Adolescent Brain Cognitive Development (ABCD) Study is the largest single-cohort prospective longitudinal study of neurodevelopment and children's health in the United States. A cohort of n = 11,880 children aged 9–10 years (and their parents/guardians) were recruited across 22 sites and are being followed with in-person visits on an annual basis for at least 10 years. The study approximates the US population on several key sociodemographic variables, including sex, race, ethnicity, household income, and parental education. Data collected include assessments of health, mental health, substance use, culture and environment and neurocognition, as well as geocoded exposures, structural and functional magnetic resonance imaging (MRI), and whole-genome genotyping. Here, we describe the ABCD Study aims and design, as well as issues surrounding estimation of meaningful associations using its data, including population inferences, hypothesis testing, power and precision, control of covariates, interpretation of associations, and recommended best practices for reproducible research, analytical procedures and reporting of results.
Journal Article
الفتوح العربية الكبرى : كيف غير انتشار الإسلام العالم الذي نعيش فيه
يطرح هذا الكتاب السؤال ويجيب عنه، والسؤال الذي يطرحه الكتاب : لماذا ؟ وكيف ؟ لماذا كان نجاح المسلمین سريعا وواسع النطاق بحيث فتحوا معظم أنحاء عالم القرنين السابع والثامن الميلاديين في غضون قرن من الزمان تقريبا ؟ وكيف تمكنوا من تحويل الفتح إلى تغيير دائم في مصائر المناطق والشعوب ؟ هذان السؤالان الجوهريان، وما يتفرع عنهما بالضرورة من أسئلة، هما اللذان تدور فصول الكتاب حولهما، والكتاب مناقشة علمية مدهشة لجميع جوانب هذين السؤالين ؛ ويطرح المؤلف أفكارا جديدة مدهشة حول قيمة المصادر التاريخية العربية، وما تحمله من سرديات ومعلومات تعبر عن رؤية النخبة الإسلامية لنفسها زمن تدوين هذه الروايات.
Book
Family income, parental education and brain structure in children and adolescents
Socioeconomic status is associated with cognitive development, but the extent to which this reflects neuroanatomical differences is unclear. In 1,099 children and adolescents, family income was nonlinearly associated with brain surface area, and this association was greatest among disadvantaged children. Further, surface area mediated links between income and executive functioning.
Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children.
Journal Article
Hypophosphatemia attenuates improvements in vitality after intravenous iron treatment in patients with inflammatory bowel disease
PurposeIron deficiency anemia is common in people with inflammatory bowel disease (IBD), causing deterioration in quality of life, which can be reversed by treatment that increases iron stores and hemoglobin levels. The present post hoc analyses estimate health state utility values for patients with IBD after treatment with ferric derisomaltose or ferric carboxymaltose and evaluate the health domains driving the changes.MethodsSF-36v2 responses were recorded at baseline and day 14, 35, 49, and 70 from 97 patients enrolled in the randomized, double-blind, PHOSPHARE-IBD trial (ClinicalTrials.gov ID: NCT03466983), in which patients with IBD across five European countries were randomly allocated to either ferric derisomaltose or ferric carboxymaltose. Changes in SF-36v2 scale scores and SF-6Dv2 health utility values were analyzed by mixed models.ResultsIn both treatment arms, SF-6Dv2 utility values and all SF-36v2 scale scores, except Bodily Pain, improved significantly (p = < 0.0001). The improvement in SF-6Dv2 utility values showed no significant treatment group difference. The improvement in utility values was completely explained by improvement in Vitality scores. Vitality scores showed significantly larger improvement with ferric derisomaltose versus ferric carboxymaltose (p = 0.026). Patients with the smallest decrease in phosphate had significantly larger improvements in Vitality scores at each time point (p = < 0.05 for all comparisons) and overall (p = 0.0006).ConclusionsUtility values improved significantly with intravenous iron treatment. Improvement in utility values was primarily driven by Vitality scores, which showed significantly greater improvement in the ferric derisomaltose arm. Smaller decreases in phosphate were associated with significantly higher Vitality scores, suggesting that quality of life improvement is attenuated by hypophosphatemia. The utility values can inform future cost-utility analysis.
Journal Article