Can understanding reward help illuminate anhedonia?

Purpose of review: The goal of this paper is to examine how reward processing might help us understand the symptom of anhedonia. Recent findings: There are extensive reviews exploring the relationship between responses to rewarding stimuli and depression. These often include a discussion on anhedonia and how this might be underpinned in particular by dysfunctional reward processing. However, there is no specific consensus on whether studies to date have adequately examined the various sub-components of reward processing or how these might relate in turn to various aspects of anhedonia symptoms. Summary: The approach to understanding the symptom of anhedonia should be to examine all the sub-components of reward processing at the subjective and objective behavioural and neural level, with well validated tasks that can be replicated. Investigating real life experiences of anhedonia and how theses might be predicted by objective lab measures is also needed in future research

Expanding the diversity of mycobacteriophages: Insights into genome architecture and evolution

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists. © 2011 Hatfull et al

Immune mechanisms in malaria: new insights in vaccine development.

Early data emerging from the first phase 3 trial of a malaria vaccine are raising hopes that a licensed vaccine will soon be available for use in endemic countries, but given the relatively low efficacy of the vaccine, this needs to be seen as a major step forward on the road to a malaria vaccine rather than as arrival at the final destination. The focus for vaccine developers now moves to the next generation of malaria vaccines, but it is not yet clear what characteristics these new vaccines should have or how they can be evaluated. Here we briefly review the epidemiological and immunological requirements for malaria vaccines and the recent history of malaria vaccine development and then put forward a manifesto for future research in this area. We argue that rational design of more effective malaria vaccines will be accelerated by a better understanding of the immune effector mechanisms involved in parasite regulation, control and elimination

RASOnD - A comprehensive resource and search tool for RAS superfamily oncogenes from various species

<p>Abstract</p> <p>Background</p> <p>The Ras superfamily plays an important role in the control of cell signalling and division. Mutations in the Ras genes convert them into active oncogenes. The Ras oncogenes form a major thrust of global cancer research as they are involved in the development and progression of tumors. This has resulted in the exponential growth of data on Ras superfamily across different public databases and in literature. However, no dedicated public resource is currently available for data mining and analysis on this family. The present database was developed to facilitate straightforward accession, retrieval and analysis of information available on Ras oncogenes from one particular site.</p> <p>Description</p> <p>We have developed the RAS Oncogene Database (RASOnD) as a comprehensive knowledgebase that provides integrated and curated information on a single platform for oncogenes of Ras superfamily. RASOnD encompasses exhaustive genomics and proteomics data existing across diverse publicly accessible databases. This resource presently includes overall 199,046 entries from 101 different species. It provides a search tool to generate information about their nucleotide and amino acid sequences, single nucleotide polymorphisms, chromosome positions, orthologies, motifs, structures, related pathways and associated diseases. We have implemented a number of user-friendly search interfaces and sequence analysis tools. At present the user can (i) browse the data (ii) search any field through a simple or advance search interface and (iii) perform a BLAST search and subsequently CLUSTALW multiple sequence alignment by selecting sequences of Ras oncogenes. The Generic gene browser, GBrowse, JMOL for structural visualization and TREEVIEW for phylograms have been integrated for clear perception of retrieved data. External links to related databases have been included in RASOnD.</p> <p>Conclusions</p> <p>This database is a resource and search tool dedicated to Ras oncogenes. It has utility to cancer biologists and cell molecular biologists as it is a ready source for research, identification and elucidation of the role of these oncogenes. The data generated can be used for understanding the relationship between the Ras oncogenes and their association with cancer. The database updated monthly is freely accessible online at <url>http://202.141.47.181/rasond/</url> and <url>http://www.aiims.edu/RAS.html</url>.</p

Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growth-phase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene

Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

Unchanged muscle fiber conduction velocity relates to mild acidosis during exhaustive bicycling

Muscle fiber conduction velocity (MFCV) has often been shown to decrease during standardized fatiguing isometric contractions. However, several studies have indicated that the MFCV may remain constant during fatiguing dynamic exercise. It was investigated if these observations can be related to the absence of a large decrease in pH and if MFCV can be considered as a good indicator of acidosis, also during dynamic bicycle exercise. High-density surface electromyography (HDsEMG) was combined with read-outs of muscle energetics recorded by in vivo 31P magnetic resonance spectroscopy (MRS). Measurements were performed during serial exhausting bouts of bicycle exercise at three different workloads. The HDsEMG recordings revealed a small and incoherent variation of MFCV during all high-intensity exercise bouts. 31P MRS spectra revealed a moderate decrease in pH at the end of exercise (~0.3 units down to 6.8) and a rapid ancillary drop to pH 6.5 during recovery 30 s post-exercise. This additional degree of acidification caused a significant decrease in MFCV during cycling immediately after the rest period. From the data a significant correlation between MFCV and [H+] ([H+] = 10−pH) was calculated (p < 0.001, Pearson’s R = −0.87). Our results confirmed the previous observations of MFCV remaining constant during fatiguing dynamic exercise. A constant MFCV is in line with a low degree of acidification, considering the presence of a correlation between pH and MFCV after further increasing acidification

Characterizing the Intramolecular H-bond and Secondary Structure in Methylated GlyGlyH+ with H2 Predissociation Spectroscopy

Click on the DOI link below to access the article (may not be free).We report vibrational predissociation spectra of the four protonated dipeptides derived from glycine and sarcosine, GlyGlyH(+)center dot(H-2)(1,2), GlySarH(+)center dot(D-2)(2), SarGlyH(+)center dot(H-2)(2), and SarSarH(+)center dot(D-2)(2), generated in a cryogenic ion trap. Sharp bands were recovered by monitoring photoevaporation of the weakly bound H-2 (D-2) molecules in a linear action regime throughout the 700-4200 cm(-1) range using a table-top laser system. The spectral patterns were analyzed in the context of the low energy structures obtained from electronic structure calculations. These results indicate that all four species are protonated on the N-terminus, and feature an intramolecular H-bond involving the amino group. The large blue-shift in the H-bonded N-H fundamental upon incorporation of a methyl group at the N-terminus indicates that this modification significantly lowers the strength of the intramolecular H-bond. Methylation at the amide nitrogen, on the other hand, induces a significant rotation (similar to 110 degrees) about the peptide backbone.Peer reviewe