Legionella Subvert the Functions of Rab1 and Sec22b to Create a Replicative Organelle

Legionella pneumophila is a bacterial pathogen that infects eukaryotic host cells and replicates inside a specialized organelle that is morphologically similar to the endoplasmic reticulum (ER). To better understand the molecular mechanisms governing transport of the Legionella-containing vacuole (LCV), we have identified host proteins that participate in the conversion of the LCV into a replicative organelle. Our data show that Rab1 is recruited to the LCV within minutes of uptake. Rab1 recruitment to the LCV precedes remodeling of this compartment by ER-derived vesicles. Genetic inhibition studies demonstrate that Rab1 is important for the recruitment of ER-derived vesicles to the LCV and that inhibiting Rab1 function abrogates intracellular growth of Legionella. Morphological studies indicate that the Sec22b protein is located on ER-derived vesicles recruited to the LCV and that Sec22b is delivered to the LCV membrane. Sec22b function was found to be important for biogenesis of the specialized organelle that supports Legionella replication. These studies demonstrate that Legionella has the ability to subvert Rab1 and Sec22b function to facilitate the transport and fusion of ER-derived vesicles with the LCV, resulting in the formation of a specialized organelle that can support bacterial replication

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Rab proteins and endocytic trafficking: potential targets for therapeutic intervention. Advanced Drug Delivery Reviews 55

Abstract Rab GTPases serve as master regulators of vesicular membrane transport on both the exo-and endocytic pathways. In their active forms, rab proteins serve in cargo selection and as scaffolds for the sequential assembly of effectors requisite for vesicle budding, cytoskeletal transport, and target membrane fusion. Rab protein function is in turn tightly regulated at the level of protein expression, localization, membrane association, and activation. Alterations in the rab GTPases and associated regulatory proteins or effectors have increasingly been implicated in causing human disease. Some diseases such as those resulting in bleeding and pigmentation disorders (Griscelli syndrome), mental retardation, neuropathy (Charcot -Marie -Tooth), kidney disease (tuberous sclerosis), and blindness (choroideremia) arise from direct loss of function mutations of rab GTPases or associated regulatory molecules. In contrast, in a number of cancers (prostate, liver, breast) as well as vascular, lung, and thyroid diseases, the overexpression of select rab GTPases have been tightly correlated with disease pathogenesis. Unique therapeutic opportunities lie ahead in developing strategies that target rab proteins and modulate the endocytic pathway.

Splicing UNIX into a Genome Mapping Laboratory

The Whitehead Institute/MIT Center for Genome Research is responsible for a number of large genome mapping efforts, the scale of which create problems of data and workflow management that dictate reliance on computer support. Two years ago, when we started to design the informatics support for the laboratory, we realized that the fluid and everchanging nature of the experimental protocols precluded any effort to create a single monolithic piece of software. Instead we designed a system that relied on multiple distributed data analysis and processing tools knit together by a centralized database. The obvious choice of operating systems was UNIX. In order to make this choice palatable to the laboratory biologists---who rightly consider it their job to do experiments rather than to interact with computers, and who have come to expect all software to be as intuitive and responsive as the Apple Macintoshes on their desks---we designed a system that runs automatically and essentially invisibly. Whenever it is necessary for the informatics system to interact with a member of the laboratory we have carefully chosen a user interface paradigm that best balances the user's expectations against the system's capabilities. When possible we have chosen to adapt familiar software to our user interface needs rather than to write user interfaces from scratch. We've managed to hide the power of UNIX behind the innocuous personal computer-based front ends our users know and love, using techniques that should be applicable in other environments as well. 1

Abstract Splicing UNIX into a Genome Mapping Laboratory

Research is responsible for a number of large genome mapping efforts, the scale of which create problems of data and workflow management that dictate reliance on computer support. Two years ago, when we started to design the informatics support for the laboratory, we realized that the fluid and everchanging nature of the experimental protocols precluded any effort to create a single monolithic piece of software. Instead we designed a system that relied on multiple distributed data analysis and processing tools knit together by a centralized database. The obvious choice of operating systems was UNIX. In order to make this choice palatable to the laboratory biologists—who rightly consider it their job to do experiments rather than to interact with computers, and who have come to expect all software to be as intuitive and responsive as the Apple Macintoshes on their desks—we designed a system that runs automatically and essentially invisibly. Whenever it is necessary for the informatics system to interact with a member of the laboratory we have carefully chosen a user interface paradigm that best balances the user’s expectations against the system’s capabilities. When possible we have chosen to adapt familiar software to our user interface needs rather than to write user interfaces from scratch. We’ve managed to hide the power of UNIX behind the innocuous personal computer-based front ends our users know and love, using techniques that should be applicable in other environments as well