Prediction of cytochrome P450 isoform responsible for metabolizing a drug molecule

Background

ATP-binding cassette (ABC) transporters protect cells against unrelated (toxic) substances by pumping them across cell membranes. Earlier we showed that many ABC transporters are highly expressed in hematopoietic stem cells (HSCs) compared to more committed progenitor cells. The ABC transporter expression signature may guarantee lifelong protection of HSCs but may also preserve stem cell integrity by extrusion of agents that trigger their differentiation. Here we have studied whether non-hematopoietic stem cells (non-HSCs) exhibit a similar ABC transporter expression signature as HSCs.

Results

ABC transporter expression profiles were determined in non-hematopoietic stem cells (non-HSCs) from embryonic, neonatal and adult origin as well as in various mature blood cell types. Over 11,000 individual ABC transporter expression values were generated by Taqman Low Density Arrays (TLDA) to obtain a sensitivity comparable with quantitative real-time polymerase chain reactions. We found that the vast majority of transporters are significantly higher expressed in HSCs compared to non-HSCs. Furthermore, regardless their origin, non-HSCs exhibited strikingly similar ABC transporter expression profiles that were distinct from those in HSCs. Yet, sets of transporters characteristic for different stem cell types could be identified, suggesting restricted functions in stem cell physiology. Remarkably, in HSCs we could not pinpoint any single transporter expressed at an evidently elevated level when compared to all the mature blood cell types studied.

Conclusions

These findings challenge the concept that individual ABC transporters are implicated in maintaining stem cell integrity. Instead, a distinct ABC transporter expression signature may be essential for stem cell function. The high expression of specific transporters in non-HSCs and mature blood cells suggests a specialized, cell type dependent function and warrants further functional experiments to determine their exact roles in cellular (patho)physiology.     

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63

Waanders E, Venselaar H, te Morsche RHM, de Koning DB, Kamath PS, Torres VE, Somlo S, Drenth JPH. Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation‐sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, Poly Phen , and p Mut and sift . We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non‐sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.     

Excimer laser surface ablation: a review of recent literature

The aim was to review the recently published literature on excimer laser surface ablation procedures, including photorefractive keratectomy (PRK), laser sub‐epithelial keratomileusis (LASEK), microkeratome‐assisted PRK (epi‐LASIK) and trans‐epithelial (laser‐assisted) PRK, to help elucidate where and how surface ablation may best fit into current refractive surgical practice. The emphasis was on publications within the last three years and included systemic reviews, meta‐analyses and randomised controlled trials. Where such evidence did not exist, selective large series cohort studies, case‐controlled studies and case series with follow‐up preferably greater than six months were examined and included. Refractive and visual outcomes are excellent and comparable to those after LASIK even in complex cases after previous corneal surgery. Indeed, surface ablation combined with corneal collagen cross‐linking may be used in selected eyes with biomechanical instability, where LASIK is contraindicated. In addition, there is evidence to suggest that there may be less induction of higher order aberrations with surface techniques. Long‐term stability and safety appear to be extremely satisfactory. The literature supports the use of modern excimer laser surface treatments, with outcomes comparable to those after LASIK and evidence of less induction of higher‐order aberrations. Follow‐up studies at 10 to 20 years indicate excellent stability and safety.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Lexical shifts,substantive changes,and continuity in State of the Union discourse, 1790–2014

This study reveals that the entry into World War I in 1917 indexed the decisive transition to the modern period in American political consciousness, ushering in new objects of political discourse, a more rapid pace of change of those objects, and a fundamental reframing of the main tasks of governance. We develop a strategy for identifying meaningful categories in textual corpora that span long historic durées, where terms, concepts, and language use changes. Our approach is able to account for the fluidity of discursive categories over time, and to analyze their continuity by identifying the discursive stream as the object of interest.When did modern political discourse emerge in the United States? What is distinctive of basic understandings of the tasks of governance today, in contrast to those that organized the politics of an earlier period? Can the origins of contemporary political understandings be located in the discourse of the past? The annual State of the Union address (hereafter, SoU), in which the US president reports broadly on the progress and challenges of his administration, provides a singular standpoint from which to address the evolution of the tasks of governance. It can thus be used to investigate old questions like those above using network-based text analysis strategies.This study reveals that the entry into World War I (WWI) in 1917 indexed the decisive transition to the modern period in American political consciousness, ushering in new objects of political discourse, a more rapid pace of change of those objects, and a fundamental reframing of the main tasks of governance. At the same time, this study demonstrates that discourse distinctive to modern politics, although it later crystalized around the liberal welfare state, in fact emerged before the transition to the modern period.We offer a unique view of American political history, which tracks the articulation of the major tasks of governance in American political and social discourse. To do so, we develop a strategy for identifying meaningful categories in textual corpora that span long historic durées. We are able to account for the fluidity of discursive categories over time, and to analyze their continuity by identifying the discursive stream as the object of interest. The methodological approach developed in this article can be used to meaningfully analyze texts produced over very long historical periods, where terms, concepts, and language use changes—to our knowledge, a problem not satisfactorily solved.     

EARLY CARCINOMA TONGUE – SURGICAL OPTIONS

A retrospective analysis of 127 surgically treated cases of T-1, T-2 carcinoma of oral tongue during the period 1987-1990 was undertaken. 68.5 per cent (87) underwent hemiglossectomy and 31.5 per cent (40) underwent wide excision. There were loco-regional recurrences in 22 per cent (27). In the hemiglossectomy group 9 per cent (8 of 87) had local recurrences compared to 25 per cent (10 of 40) of wide excision group, (P = 0.01). Mean disease free survival was 40 months and 33 months for hemiglossectomy group and wide excision group respectively, (P = 0.006). It is seen that local recurrences are significantly less for the hemiglossectomy group compared to the wide excision group.KEY WORDS: Disease free survival, Early cancer, Recurrence, Surgery, Tongue