Molecular analysis of the association of HLA-B53 and resistance to severe malaria.

The protective association between the human leukocyte antigen HLA-B53 and severe malaria was investigated by sequencing of peptides eluted from this molecule followed by screening of candidate epitopes from pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical and cellular assays. Among malaria-immune Africans, HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no HLA-B53-restricted epitopes were identified in other antigens. These findings indicate a possible molecular basis for this HLA-disease association and support the candidacy of liver-stage-specific antigen-1 as a malaria vaccine component.     

Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation

Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.     

Zero outward flow velocity for plasma in a heliosheath transition layer

Voyager 1 has been in the reservoir of energetic ions and electrons that constitutes the heliosheath since it crossed the solar wind termination shock on 16 December 2004 at a distance from the Sun of 94 astronomical units (1?AU = 1.5?×?10(8)?km). It is now ～22?AU past the termination shock crossing. The bulk velocity of the plasma in the radial-transverse plane has been determined using measurements of the anisotropy of the convected energetic ion distribution. Here we report that the radial component of the velocity has been decreasing almost linearly over the past three years, from ～70?km?s(-1) to ～0?km?s(-1), where it has remained for the past eight months. It now seems that Voyager 1 has entered a finite transition layer of zero-radial-velocity plasma flow, indicating that the spacecraft may be close to the heliopause, the border between the heliosheath and the interstellar plasma. The existence of a flow transition layer in the heliosheath contradicts current predictions--generally assumed by conceptual models--of a sharp discontinuity at the heliopause.     

Stabilization of Discrete-Time Dynamical Systems Under Event-Triggered Impulsive Control with and Without Time-Delays

This paper investigates the issue of stabilization for discrete-time dynamical systems (DDS) by event-triggered impulsive control (ETIC). Based on some relatively simple threshold constants, three levels of event conditions are set and thus the ETIC scheme is designed. Three cases for ETIC with and without time-delays and data dropouts are studied respectively, and the criteria on exponential stability are derived for the controlled DDS. The stabilization in the form of exponential stability is achieved for DDS under the designed ETIC with or without time-delays. And in the case of the ETIC data dropouts, the conditions of exponential stabilization are derived for DDS and the maximal allowable dropout rates for ETIC are estimated. Finally, one example with numerical simulations is worked out for illustration.     

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.     

The accuracy of extrapolation methods; an automatic box–jenkins package sift

Hill and Woodworth (1980) proposed an algorithm suitable for identifying Box–Jenkins models automatically without reliance on the investigator. This paper first reviews the method. It is then used on the 111 series analysed by Anderson in the Makridakis forecasting competition. The results show that the automatic method of Hill and Woodworth is comparable in terms of accuracy to the full Box–Jenkins identification procedure.     

On the participation of the zona glomerulosa on the adrenal response to stress

Zusammenfassung Zwei Serien Ratten wurden durch Formalininjektion belastet. Die Zona glomerulosa der Nebennierenrinde reagierte durch Lipoidausscheidung nur in jener Serie, die durch hohe Lymphozytenzahl des Blutes, hohen Lipoidgehalt der Fasciculata, kleinere Aktivität der Lymphknötchen der Milz und auffallend intensive Stressreaktion der Fasciculata charakterisiert war. Bei Ratten, deren Glomerulosa ihre Lipoide ausgeschieden hatte, trat weder Schwellung noch Desintegration des lymphatischen Gewebes der Milz auf.     

A major susceptibility locus for leprosy in India maps to chromosome 10p13

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is prevalent in India, where about half of the world's estimated 800,000 cases occur. A role for the genetics of the host in variable susceptibility to leprosy has been indicated by familial clustering, twin studies, complex segregation analyses and human leukocyte antigen (HLA) association studies. We report here a genetic linkage scan of the genomes of 224 families from South India, containing 245 independent affected sibpairs with leprosy, mainly of the paucibacillary type. In a two-stage genome screen using 396 microsatellite markers, we found significant linkage (maximum lod score (MLS) = 4.09, P < 2x10-5) on chromosome 10p13 for a series of neighboring microsatellite markers, providing evidence for a major locus for this prevalent infectious disease. Thus, despite the polygenic nature of infectious disease susceptibility, some major, non-HLA-linked loci exist that may be mapped through obtainable numbers of affected sibling pairs.