Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies.

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value <1x10-30). In cells over-expressing human or various mammalian orthologs of SLC22A24, we showed that steroid conjugates and bile acids were substrates of the transporter. Phylogenetic, genomic, and transcriptomic analyses suggested that SLC22A24 has a specialized role in the kidney and appears to function in the reabsorption of organic anions, and in particular, anionic steroids. Phenome-wide analysis showed that functional variants of SLC22A24 are associated with human disease such as cardiovascular diseases and acne, which have been linked to dysregulated steroid metabolism. Collectively, these functional genomic studies reveal a previously uncharacterized protein involved in steroid homeostasis, opening up new possibilities for SLC22A24 as a pharmacological target for regulating steroid levels

Has wild poliovirus been eliminated from Nigeria?

Wild poliovirus type 3 (WPV3) has not been seen anywhere since the last case of WPV3-associated paralysis in Nigeria in November 2012. At the time of writing, the most recent case of wild poliovirus type 1 (WPV1) in Nigeria occurred in July 2014, and WPV1 has not been seen in Africa since a case in Somalia in August 2014. No cases associated with circulating vaccine-derived type 2 poliovirus (cVDPV2) have been detected in Nigeria since November 2014. Has WPV1 been eliminated from Africa? Has WPV3 been eradicated globally? Has Nigeria interrupted cVDPV2 transmission? These questions are difficult because polio surveillance is based on paralysis and paralysis only occurs in a small fraction of infections. This report provides estimates for the probabilities of poliovirus elimination in Nigeria given available data as of March 31, 2015. It is based on a model of disease transmission that is built from historical polio incidence rates and is designed to represent the uncertainties in transmission dynamics and poliovirus detection that are fundamental to interpreting long time periods without cases. The model estimates that, as of March 31, 2015, the probability of WPV1 elimination in Nigeria is 84%, and that if WPV1 has not been eliminated, a new case will be detected with 99% probability by the end of 2015. The probability of WPV3 elimination (and thus global eradication) is >99%. However, it is unlikely that the ongoing transmission of cVDPV2 has been interrupted; the probability of cVDPV2 elimination rises to 83% if no new cases are detected by April 2016. Added July 10, 2015: On June 26, a cVDPV2 case was confirmed by the Global Polio Laboratory Network. The date of paralysis was May 16. The case provides new information about cVDPV2 prevalence that is useful for assessing the accuracy of previous predictions and informing an updated forecast for the time to cVDPV2 elimination.Comment: Added model validation section and updated cVDPV2 forecast in response to new case data; expanded material on surveillance sensitivity; additional minor edits; and references added. 24 pages, 4 figure

Ariel - Volume 11 Number 1

Executive Editors Ellen Feldman Leonardo S. Nasca, Jr. Business Managers Barbara L. Davies Martin B. Getzow News Editor Aaron D. Bleznak Features Editor Dave Van Wagoner CAHS Editor Joan M. Greco Editorial Page Editor Samuel Markind Photography Editor Leonardo S. Nasca, Jr. Sports Editor Paul F. Mansfiel

An Abort Mechanism for Nested Distributed Transactions

A transaction processing facility must have a mechanism for aborting transactions on request. This paper describes a mechanism for aborting transactions that can be arbitrarily nested and/or distributed. The mechanism consists of an "abort protocol" plus an adjustment to the commit protocol. The abort protocol locates and terminates as many of the transaction's operations as it can. If after the protocol has finished it is still possible that orphaned operations exist, then a simple check during the prepare phase of the commit protocol ensures that no orphan commits. The mechanism has many advantages: provided that the communication subsystem provides prompt failure detection, there will be no orphans: a site can abort unilaterally: there is little overhead on transaction-operation messages, and relatively few and relatively minor restrictions on the transaction facility: no information need be maintained in stable storage: and the abort protocol never blocks. The primary disadvantages of the mechanism are that the abort protocol must be synchronous, that it may over-abort in some cases, and that - if the communication subsystem does not provide prompt failure detection - there is no limit on the extent or lifetime of orphaned computations

Orphan proteins of unknown function in the mitochondrial intermembrane space proteome: new pathways and metabolic cross-talk

The mitochondrial intermembrane space (IMS) is involved in protein transport, lipid homeostasis and metal ion exchange, while further acting in signalling pathways such as apoptosis. Regulation of these processes involves protein modifications, as well as stress-induced import or release of proteins and other signalling molecules. Even though the IMS is the smallest sub-compartment of mitochondria, its redox state seems to be tightly regulated. However, the way in which this compartment participates in the cross-talk between the multiple organelles and the cytosol is far from understood. Here we focus on newly identified IMS proteins that may represent future challenges in mitochondrial research. We present an overview of the import pathways, the recently discovered new components of the IMS proteome and how these relate to key aspects of cell signalling and progress made in stem cell and cancer research