Mutations in KPTN Cause Macrocephaly, Neurodevelopmental Delay, and Seizures

The proper development of neuronal circuits during neuromorphogenesis and neuronal-network formation is critically dependent on a coordinated and intricate series of molecular and cellular cues and responses. Although the cortical actin cytoskeleton is known to play a key role in neuromorphogenesis, relatively little is known about the specific molecules important for this process. Using linkage analysis and whole-exome sequencing on samples from families from the Amish community of Ohio, we have demonstrated that mutations in KPTN, encoding kaptin, cause a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures. Our immunofluorescence analyses in primary neuronal cell cultures showed that endogenous and GFP-tagged kaptin associates with dynamic actin cytoskeletal structures and that this association is lost upon introduction of the identified mutations. Taken together, our studies have identified kaptin alterations responsible for macrocephaly and neurodevelopmental delay and define kaptin as a molecule crucial for normal human neuromorphogenesis

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Tectonic Evolution of the Zagros Suture-and Imbricate Zones in Iraq

Orogenic belts are expressions of tectonic activity, often host various natural resources (e.g. petroleum and minerals reserves), and influence the society and environment through hazards (e.g. landslides, earthquakes), climate and cultural divides. The Alpine-Himalayan system is one of the most important orogenic belts in the world with regards to all these aspects. The Zagros Fold-and-Thrust Belt is a part of the central Alpine-Himalayan system, where a wealth of natural resources have been found, including one of the largest petroleum reserves in the world, and many mineral deposits. This thesis focuses on the Imbricate- and Suture zones of the Zagros Fold- and Thrust Belt in Iraq. Research activities here have been limited, mainly due to the apparent relative depletion in natural resources and because of geopolitical security issues. The study area consists of rock masses that have formed as the result of convergence between the Arabian and Eurasian plates from the Late Cretaceous to the present day. Bedrock comprise alternating sequences of Mesozoic siliciclastic and carbonaceous rocks. It is a key area to study ongoing continental collision. The objective of this thesis is to improve the knowledge of the crustal architecture of this relatively unknown part of the Zagros Fold- and Thrust Belt. The results form a basis for future natural resources exploration. The thesis work consists of a local desk study of alluvial fans using remote sensing data (Landsat 8, Operation Land Imager satellite data and Digital Elevation Model), and two seasons of structural geological field work along regional traverses. The study area of field work is 1800 km2 large. The results were subsequently incorporated into a 3D structural framework model in the software Move of Petroleum Experts, Edinburgh, UK (version 2019.1). Remote sensing and GIS techniques were used to analyze neotectonic activity of alluvial fans.  Their formation and morphology are influenced by subsurface faulting. Results indicate the location of active faults, and allowed their extrapolation along strike. The aim of field work is to constrain the tectonic history of the area. Structural data were collected from six traverses, varying in length from 4.4 to 25.0 km, using a combination of digital and traditional methods. Based on the style and geometry of the mesoscale folds, buckling is suggested as the dominant mechanism for folding, where flexural slip folding has been followed by shear folding. I have estimated the amount of internal crustal shortening using Ramsey’s equation: Most intense shortening observed close to the Suture zone (~60%). The amount of shortening is about 10% less in the Imbricate zone (~50%). Based on the results above, 3D geological models have constructed. They reveal the structural styles and role of pre-existing faults, and their influence on the crustal architecture of the area. These models act as a base for potential natural resource explorations activities. The structural evolution of thrust sheets within the study area occur as a piggyback sequence. The structural style of the Suture zone is characterized by three main thrust sheets, that are subparallel with the NW-SE striking and NE dipping Main Zagros Fault. The structural framework of the 3D geological models presented in this thesis are derived purely from surface data (field work, remote sensing), and represents the state of art. At this stage, there are no clear candidates for future natural resources exploration. In order to advance the 3D geological models, subsurface data are required, such as seismic and borehole data. These type of data will provide better constraints at depth, which may be key for finding prospects for exploration within the Imbricate and Suture zones

Geometric Analysis of the Minor Structures in Iraqi Part of the Zagros Belt, NE Iraq

Geometric analysis was carried out on part of the Zagros Belt, along the border between Iraq andIran, within rocks of Cretaceous age, which are composed of alternative sequences of competentand incompetent layers, and it contains a number of minor structures. The minor folds identifiedwithin the study area have different shapes, orientations and sizes, and exhibit high intensityfolding. Their wave length and amplitude range from few centimeters up to tens of meters. They areranged from gentle to tight according to the Fleuty, 1964 classification. Class 1B is dominated andfollowed by class 1C according to the Ramsay, 1967. The orientation of the minor folds, theirrelation with the major structures, variance in their shapes and sizes and difference interlimb angle,all indicate that they were developed progressively and in harmony with the major structuredevelopment. It can be concluded that the congruous and subcongruous minor folds weredeveloped successively during a single phase of deformation with simulation of variouscompressive stress directions (generally, at NE-SW and E-W), and the reorientation of the stressfield from one direction to another is attributed to the oblique collision between the Arabian andEurasian plates and to the anticlockwise rotation of the Arabian plate relative to Eurasian plate

Geometric Analysis of the Minor Structures in Iraqi Part of the Zagros Belt, NE Iraq

Geometric analysis was carried out on part of the Zagros Belt, along the border between Iraq andIran, within rocks of Cretaceous age, which are composed of alternative sequences of competentand incompetent layers, and it contains a number of minor structures. The minor folds identifiedwithin the study area have different shapes, orientations and sizes, and exhibit high intensityfolding. Their wave length and amplitude range from few centimeters up to tens of meters. They areranged from gentle to tight according to the Fleuty, 1964 classification. Class 1B is dominated andfollowed by class 1C according to the Ramsay, 1967. The orientation of the minor folds, theirrelation with the major structures, variance in their shapes and sizes and difference interlimb angle,all indicate that they were developed progressively and in harmony with the major structuredevelopment. It can be concluded that the congruous and subcongruous minor folds weredeveloped successively during a single phase of deformation with simulation of variouscompressive stress directions (generally, at NE-SW and E-W), and the reorientation of the stressfield from one direction to another is attributed to the oblique collision between the Arabian andEurasian plates and to the anticlockwise rotation of the Arabian plate relative to Eurasian plate

Tectonics and Neotectonics of the Mesopotamian Plain : A Critical Review

The Mesopotamian Plain is a part of the Mesopotamia Foredeep of the Zagros Foreland Basin and is a part of the Zagros Fold – Thrust Belt. The plain covers the central part of Iraq and extends south eastwards. It is a large continuously subsiding basin since the Upper Miocene (11.62 Ma). The plain is covered by thick Quaternary sediments of the Tigris and Euphrates rivers with their tributaries and distributaries. Therefore, the plain shows no structural features on the surface, except a main fault escarpment that extends from south of Al-Najaf city to south of Nasiriya city representing part of Abu Jir Active Fault Zone. However, the rolling topography, in the northern parts of the plain indicates subsurface anticlines that are still growing up, such as Balad, Samarra, Tikrit and Baiji anticlines. Moreover, many buried subsurface anticlines are present in different parts of the plain. All are growing anticlines and have caused continuous shift to the Tigris and Euphrates River and their distributaries indicating Neotectonic activities. The minimum and maximum subsidence amounts in the plain are zero and – 2500 m, respectively.Validerad;2020;Nivå 1;2020-04-24 (marisr)</p

Pengenalan Media Pembelajaran Pemrograman Membuat Website Pada Html Smk Swasta Harapan Padangsidimpuan

Pelaksanaan kegiatan ini dilatarbelakangi sistem pembelajaran yang masih menggunakan metode yang lama seperti ceramah, diskusi, tanya jawab dan lainnya. Dari keadaan ini maka perlu dilakukan suatu terobosan baru dengan mengajarkan siswa tentang pembelajaran pemrograman membuat website di SMK Swasta Harapan padangsidimpuan. Pada prosses pembelajaran peserta didik diharapkan mampu mendapat pengalaman baru melalui media pembelajaran interaktif yaitu menggunakan aplikasi pemrograman. Media pembelajaran ini diperlukan agar peserta didik mengerti dan memahami cara mengoperasikan program dengan menggunakan aplikasi Visual Studio Code. Metode yang digunakan dalam kegiatan ini adalah metode pendekatan agar peserta didik dapat mendalami dan termotivasi dalam pembelajaran. Hasil yang didapatkan dalam kegiatan ini adalah tingginya partisifasi peserta didik dalam melakukan pembelajaran pembuatan website menggunakan Visual Studio Code dengan Fasilitas yang sudah disediakan sekolah. The implementation of this activity is based on a learning system that still uses the old methods such as lectures, discussions, questions and answers and others. From this situation, it is necessary to make a new breakthrough by teaching students about learning programming to create a website at the Harapan Padangsidimpuan Private Vocational School. In the learning process, students are expected to be able to get new experiences through interactive learning media, namely using programming applications. This learning media is needed so that students understand and understand how to operate the program using the Visual Studio Code application. The method used in this activity is an approach method so that students can explore and be motivated in learning. The results obtained in this activity are the high participation of students in learning to make websites using Visual Studio Code with facilities that have been provided by the schoo