Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (Berenil®), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (MPXR) is the result of loss of a separate High Affinity Pentamidine Transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the “selectivity region” of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this remarkable ability

Best Effort and Practice Activation Codes

Activation Codes are used in many different digital services and known by many different names including voucher, e-coupon and discount code. In this paper we focus on a specific class of ACs that are short, human-readable, fixed-length and represent value. Even though this class of codes is extensively used there are no general guidelines for the design of Activation Code schemes. We discuss different methods that are used in practice and propose BEPAC, a new Activation Code scheme that provides both authenticity and confidentiality. The small message space of activation codes introduces some problems that are illustrated by an adaptive chosen-plaintext attack (CPA-2) on a general 3-round Feis- tel network of size 2^(2n) . This attack recovers the complete permutation from at most 2^(n+2) plaintext-ciphertext pairs. For this reason, BEPAC is designed in such a way that authenticity and confidentiality are in- dependent properties, i.e. loss of confidentiality does not imply loss of authenticity.Comment: 15 pages, 3 figures, TrustBus 201

These are not the k-mers you are looking for: efficient online k-mer counting using a probabilistic data structure

K-mer abundance analysis is widely used for many purposes in nucleotide sequence analysis, including data preprocessing for de novo assembly, repeat detection, and sequencing coverage estimation. We present the khmer software package for fast and memory efficient online counting of k-mers in sequencing data sets. Unlike previous methods based on data structures such as hash tables, suffix arrays, and trie structures, khmer relies entirely on a simple probabilistic data structure, a Count-Min Sketch. The Count-Min Sketch permits online updating and retrieval of k-mer counts in memory which is necessary to support online k-mer analysis algorithms. On sparse data sets this data structure is considerably more memory efficient than any exact data structure. In exchange, the use of a Count-Min Sketch introduces a systematic overcount for k-mers; moreover, only the counts, and not the k-mers, are stored. Here we analyze the speed, the memory usage, and the miscount rate of khmer for generating k-mer frequency distributions and retrieving k-mer counts for individual k-mers. We also compare the performance of khmer to several other k-mer counting packages, including Tallymer, Jellyfish, BFCounter, DSK, KMC, Turtle and KAnalyze. Finally, we examine the effectiveness of profiling sequencing error, k-mer abundance trimming, and digital normalization of reads in the context of high khmer false positive rates. khmer is implemented in C++ wrapped in a Python interface, offers a tested and robust API, and is freely available under the BSD license at github.com/ged-lab/khmer

Problems in Treating Experimentally Induced Acute Hepatic Failure by Hemoperfusion or Cross Circulation

Acute hepatic failure was induced in rats by galactosamine injection intraperitoneally (1 gm per kg). Twenty-four hours later rats were treated by hemoperfusion (HP) over encapsulated sorbents: cellulose acetate-coated charcoal, polyelectrolyte-coated XAD4, a combination of both, or cross circulation with a healthy donor. Compared with control treatment (prevention of hypoglycemia by glucose infusion), the survival rate was not improved by HP or cross circulation: controls 19% vs. treated animals 0 to 17%. Extension of duration or increased frequency of HP gave the same survival rates. Computer simulation based on zero-order introduction of a possible toxin into a two-compartment model shows that HP up to 5 hr per day is not able to clear the body effectively from the assumed toxin if its partition coefficient exceeds a value of 50

40 Gigabit ethernet: prototyping transparent end-to-end connectivity

The ever increasing demands of data intensive eScience applications have pushed the limits of computer networks. With the launch of the new 40 Gigabit Ethernet (40GE) standard, 802.3ba, applications can go beyond the common 10 Gigabit/s per data stream barrier for both local area, and as demonstrated in the GLIF 2010 and Supercomputing 2010 demos [3], wide area setups. In this article we profile the performance of state-of-the-art server hardware combined with 40GE technology. We give an insight on the issues involved with ultra high performance network adapters and suggest optimization approaches

Discussion of the results of the boundary-layer tests of an airfoil fitted with a rotary cylinder

The results of the velocity measurements in the boundary layer described in NACA-TM 411 are here discussed in greater detail. The measurements made were of the velocity distribution in the vicinity of an airfoil model fitted with a rotary cylinder and were undertaken for the purpose of obtaining a closer insight into the phenomena observed in experimenting with this model