Recent Serendipitous Articles

Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor.

Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013 May;69(Pt 5):472-6

Authors: Guevara T, Ksiazek M, Skottrup PD, Cerdà-Costa N, Trillo-Muyo S, de Diego I, Riise E, Potempa J, Gomis-Rüth FX

Abstract
Karilysin is the only metallopeptidase identified as a virulence factor in the odontopathogen Tannerella forsythia owing to its deleterious effect on the host immune response during bacterial infection. The very close structural and sequence-based similarity of its catalytic domain (Kly18) to matrix metalloproteinases suggests that karilysin was acquired by horizontal gene transfer from an animal host. Previous studies by phage display identified peptides with the consensus sequence XWFPXXXGGG (single-letter amino-acid codes; X represents any residue) as karilysin inhibitors with low-micromolar binding affinities. Subsequent refinement revealed that inhibition comparable to that of longer peptides could be achieved using the tetrapeptide SWFP. To analyze its binding, the high-resolution crystal structure of the complex between Kly18 and SWFP was determined and it was found that the peptide binds to the primed side of the active-site cleft in a substrate-like manner. The catalytic zinc ion is clamped by the α-amino group and the carbonyl O atom of the serine, thus distantly mimicking the general manner of binding of hydroxamate inhibitors to metallopeptidases and contributing, together with three zinc-binding histidines from the protein scaffold, to an octahedral-minus-one metal-coordination sphere. The tryptophan side chain penetrates the deep partially water-filled specificity pocket of Kly18. Together with previous serendipitous product complexes of Kly18, the present results provide the structural determinants of inhibition of karilysin and open the field for the design of novel inhibitory strategies aimed at the treatment of human periodontal disease based on a peptidic hit molecule.

PMID: 23695557 [PubMed - in process]

Amyand's Hernia: A Serendipitous Diagnosis.

Case Rep Surg. 2013;2013:125095

Authors: Mewa Kinoo S, Aboobakar MR, Singh B

Abstract
An Amyand's hernia refers to the presence of an appendix within an inguinal hernia sac. This uncommon finding occurs in less than 1% of all right side inguinal hernias; to date, this finding has been reported in only 14 patients with left side inguinal hernias. The preoperative diagnosis of this condition is uncommon. We report the 15th case of a left side Amyand's hernia that was diagnosed preoperatively on a contrast enema study as well as the relatively more common right-sided Amyand's hernia diagnosed serendipitously at surgery.

PMID: 23691419 [PubMed - as supplied by publisher]

Serendipity and targeted hope.

Lab Anim (NY). 2013 May 21;42(6):227

Authors: McKellips P

PMID: 23689463 [PubMed - as supplied by publisher]

Cavitating pulmonary nodules growing in a favourable medium.

Thorax. 2013 May 18;

Authors: Carbonelli C, Prati F, Carretto E, Cavazza A, Spaggiari L, Magnani G

Abstract
Pulmonary involvement due to Nocardia is generally associated with cell-mediated immunosuppressive conditions and risk factors like HIV infection, lymphoproliferative diseases, diabetes and steroid therapy. Pulmonary alveolar proteinosis (PAP) is a well-known risk factor for Nocardia infection and is usually easily detectable on a high-resolution CT scan as ground-glass opacities with geographical distribution, crazy paving pattern and varying amounts of pulmonary consolidation. Pulmonary nocardiosis should be considered in apparently immunocompetent patients who present with PAP and a suspected opportunistic infection. We report a case of pulmonary nocardiosis occurring in a patient with radiologically inapparent PAP. The serendipitous finding of PAP on transbronchial biopsy further increased the likelihood of a Nocardia infection, subsequently confirmed by a surgical biopsy.

PMID: 23687074 [PubMed - as supplied by publisher]

Serendipitous Discovery of a Prodrug of a PARP-1 Inhibitor.

Chem Biol Drug Des. 2013 May 17;

Authors: Dunn D, Husten J, Aimone LD, Ator MA, Chatterjee S

Abstract
During SAR development of previously reported pyrrolocarbazole 1, a potent PARP-1 inhibitor, compound 14 was discovered serendipitously to be a prodrug of compound 1. This article is protected by copyright. All rights reserved.

PMID: 23679830 [PubMed - as supplied by publisher]

Correction to Serendipitous Assemblies of Two Large Phosphonate Cages: A Co15 Distorted Molecular Cube and a Co12 Butterfly Type Core Structure.

Inorg Chem. 2013 May 14;

Authors: Sheikh JA, Goswami S, Adhikary A, Konar S

PMID: 23672396 [PubMed - as supplied by publisher]

International women physicians' perspectives on choosing an academic medicine career.

Perspect Med Educ. 2013 Apr 12;

Authors: Borges NJ, Grover AC, Navarro AM, Raque-Bogdan TL, Elton C

Abstract
Concerns about recruiting physicians into academic careers is an international issue. A qualitative study with United States (US) women physicians revealed insights into how, when, and why physicians choose an academic career in medicine. The current study explored international women physicians' perspectives on their career choice of academic medicine and determined if different themes emerged. We expanded the 2012 study of US women physicians by interviewing women physicians in Canada, Pakistan, Mexico, and Sweden to gain an international perspective on choosing an academic career. Interviews were thematically analyzed against themes identified in the previous study. Based on themes identified in the study of US physicians, qualitative analysis of 7 international women physicians revealed parallel themes for the following areas: Why academic medicine? Fit; People; Aspects of academic health centre environment. How the decision to enter academic medicine was made? Decision-making style; Emotionality When the decision to enter academic medicine was made? Practising physician; Fellowship; Medical student. Work-life balance, choosing academic medicine by default, serendipity, intellectual stimulation, mentors, research and teaching were among the areas specifically highlighted. Conclusion: Parallel themes exist regarding how, why, and when US and international women physicians choose academic medicine as a career path.

PMID: 23670692 [PubMed - as supplied by publisher]

Treatment of bipolar disorder.

Lancet. 2013 May 11;381(9878):1672-82

Authors: Geddes JR, Miklowitz DJ

Abstract
We review recent developments in the acute and long-term treatment of bipolar disorder and identify promising future routes to therapeutic innovation. Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics. Substantial progress has been made in the development and assessment of adjunctive psychosocial interventions. Long-term maintenance and possibly acute stabilisation of depression can be enhanced by the combination of psychosocial treatments with drugs. The development of future treatments should consider both the neurobiological and psychosocial mechanisms underlying the disorder. We should continue to repurpose treatments and to recognise the role of serendipity. We should also investigate optimum combinations of pharmacological and psychotherapeutic treatments at different stages of the illness. Clarification of the mechanisms by which different treatments affect sleep and circadian rhythms and their relation with daily mood fluctuations is likely to help with the treatment selection for individual patients. To be economically viable, existing psychotherapy protocols need to be made briefer and more efficient for improved scalability and sustainability in widespread implementation.

PMID: 23663953 [PubMed - in process]

The myelodysplastic syndrome as a prototypical epigenetic disease.

Blood. 2013 May 9;121(19):3811-7

Authors: Issa JP

Abstract
The myelodysplastic syndrome (MDS) is a clonal disorder characterized by increased stem cell proliferation coupled with aberrant differentiation resulting in a high rate of apoptosis and eventual symptoms related to bone marrow failure. Cellular differentiation is an epigenetic process that requires specific and highly ordered DNA methylation and histone modification programs. Aberrant differentiation in MDS can often be traced to abnormal DNA methylation (both gains and losses of DNA methylation genome wide and at specific loci) as well as mutations in genes that regulate epigenetic programs (TET2 and DNMT3a, both involved in DNA methylation control; EZH2 and ASXL1, both involved in histone methylation control). The epigenetic nature of MDS may explain in part the serendipitous observation that it is the disease most responsive to DNA methylation inhibitors; other epigenetic-acting drugs are being explored in MDS as well. Progression in MDS is characterized by further acquisition of epigenetic defects as well as mutations in growth-controlling genes that seem to tip the proliferation/apoptosis balance and result in the development of acute myelogenous leukemia. Although MDS is clinically and physiologically heterogeneous, a case can be made that subsets of the disease can be largely explained by disordered stem cell epigenetics.

PMID: 23660859 [PubMed - in process]

Transient astronomy with the Gaia satellite.

Philos Trans A Math Phys Eng Sci. 2013 Jun 13;371(1992):20120239

Authors: Hodgkin ST, Wyrzykowski L, Blagorodnova N, Koposov S

Abstract
Gaia is a cornerstone European Space Agency astrometry space mission and a successor to the Hipparcos mission. Gaia will observe the whole sky for 5 years, providing a serendipitous opportunity for the discovery of large numbers of transient and anomalous events, e.g. supernovae, novae and microlensing events, gamma-ray burst afterglows, fallback supernovae, as well as theoretical or unexpected phenomena. In this paper, we discuss our preparations to use Gaia to search for transients at optical wavelengths, and briefly describe the early detection, classification and prompt publication of anomalous sources.

PMID: 23630374 [PubMed - in process]

[What's new about infantile hemangiomas?]

Arch Pediatr. 2013 Apr 27;

Authors: Dreyfus I, Maza A, Mazereeuw-Hautier J

Abstract
Infantile hemangioma is the most common vascular tumor of childhood. This benign tumor appears during the first weeks of life, grows during the first months (endothelial proliferation) and then involutes slowly and spontaneously until resolution (possibly with sequelae) which is observed after several years. Although they are always benign tumors, infantile hemangiomas can cause complications. Regarding their location or size, infantile hemangiomas can be life or function-threatening. They are also painful when ulcerated and can cause permanent disfigurement or long-term adverse psychological consequences. Since 2008 and the serendipitous discovery of the efficacy of propranolol in the treatment of infantile hemangiomas, systemic propranolol therapy has been widely used, with a very interesting benefits/risks balance. It has progressively superseded general corticosteroid therapy. A Compassionate Use Program (CUP) for systemic propranolol therapy has been developed in France and represents nowadays the first-line use for the vast majority of French prescribers.

PMID: 23628116 [PubMed - as supplied by publisher]

Small Molecules CK-666 and CK-869 Inhibit Actin-Related Protein 2/3 Complex by Blocking an Activating Conformational Change.

Chem Biol. 2013 Apr 23;

Authors: Hetrick B, Han MS, Helgeson LA, Nolen BJ

Abstract
Actin-related protein 2/3 (Arp2/3) complex is a seven-subunit assembly that nucleates branched actin filaments. Small molecule inhibitors CK-666 and CK-869 bind to Arp2/3 complex and inhibit nucleation, but their modes of action are unknown. Here, we use biochemical and structural methods to determine the mechanism of each inhibitor. Our data indicate that CK-666 stabilizes the inactive state of the complex, blocking movement of the Arp2 and Arp3 subunits into the activated filament-like (short pitch) conformation, while CK-869 binds to a serendipitous pocket on Arp3 and allosterically destabilizes the short pitch Arp3-Arp2 interface. These results provide key insights into the relationship between conformation and activity in Arp2/3 complex and will be critical for interpreting the influence of the inhibitors on actin filament networks in vivo.

PMID: 23623350 [PubMed - as supplied by publisher]

Chronic diarrhea as the presenting feature of primary systemic AL amyloidosis: serendipity or delayed diagnosis?

BMC Gastroenterol. 2013 Apr 24;13(1):71

Authors: Wang C, Li Y, Jin Y, Zhou W, Zhu Y, Yao F, Qian J

Abstract
BACKGROUND: Chronic diarrhea in adults is a common symptom with a wide range of underlying etiologies. Although various strategies have been proposed for evaluation, there are still cases with undetermined origins even after extensive workup. Amyloidosis with gastrointestinal (GI) involvement is one of the causes that should be considered in adult patients with chronic diarrhea. We report a case of primary systemic amyloid light-chain (AL) amyloidosis, presenting initially as chronic diarrhea and weight loss. CASE PRESENTATION: A 43-year-old man with chronic diarrhea and weight loss was referred to our hospital. Prior to his presentation, extensive evaluation including an exploratory laparotomy was carried out and did not yield any valuable findings. An echocardiography performed after repeated episodes of orthostatic hypotension revealed infiltrative cardiomyopathy. Moreover, biopsies of the terminal ileum revealed amyloid deposition confirmed by Congo Red staining. Finally, a diagnosis of systemic AL amyloidosis was made after hematological workup. Anti-plasma cell therapy did ameliorate his GI symptoms. CONCLUSION: Although amyloidosis with GI involvement is a rare cause of chronic diarrhea, it should be considered especially in patients with intestinal malabsorption and extra-GI manifestations, such as orthostatic hypotension. The delayed diagnosis in the present case highlights the importance of recognizing clinical "red flags" not seemingly related to one another, and underscores the need to get intestinal biopsies even with normal endoscopic appearance of the mucosa.

PMID: 23617890 [PubMed - as supplied by publisher]

Identifying novel Plasmodium falciparum erythrocyte invasion receptors using systematic extracellular protein interaction screens.

Cell Microbiol. 2013 Apr 25;

Authors: Bartholdson SJ, Crosnier C, Bustamante LY, Rayner JC, Wright GJ

Abstract
The invasion of host erythrocytes by the parasite Plasmodium falciparum initiates the blood stage of infection responsible for the symptoms of malaria. Invasion involves extracellular protein interactions between host erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. Despite significant research effort, many merozoite surface ligands have no known erythrocyte binding partner, most likely due to the intractable biochemical nature of membrane-tethered receptor proteins and their interactions. The few receptor-ligand pairs that have been described have largely relied on sourcing erythrocytes from patients with rare blood groups, a serendipitous approach that is unsatisfactory for systematically identifying novel receptors. We have recently developed a scalable assay called AVEXIS (for AVidity-based EXtracellular Interaction Screen), designed to circumvent the technical difficulties associated with the identification of extracellular protein interactions, and applied it to identify erythrocyte receptors for orphan Plasmodium falciparum merozoite ligands. Using this approach, we have recently identified Basigin (CD147) and Semaphorin-7A (CD108) as receptors for RH5 and MTRAP, respectively. In this essay, we review techniques used to identify Plasmodium receptors and discuss how they could be applied in the future to identify novel receptors both for Plasmodium parasites but also other pathogens.

PMID: 23617720 [PubMed - as supplied by publisher]

Nanobatteries in redox-based resistive switches require extension of memristor theory.

Nat Commun. 2013 Apr 23;4:1771

Authors: Valov I, Linn E, Tappertzhofen S, Schmelzer S, van den Hurk J, Lentz F, Waser R

Abstract
Redox-based nanoionic resistive memory cells are one of the most promising emerging nanodevices for future information technology with applications for memory, logic and neuromorphic computing. Recently, the serendipitous discovery of the link between redox-based nanoionic-resistive memory cells and memristors and memristive devices has further intensified the research in this field. Here we show on both a theoretical and an experimental level that nanoionic-type memristive elements are inherently controlled by non-equilibrium states resulting in a nanobattery. As a result, the memristor theory must be extended to fit the observed non-zero-crossing I-V characteristics. The initial electromotive force of the nanobattery depends on the chemistry and the transport properties of the materials system but can also be introduced during redox-based nanoionic-resistive memory cell operations. The emf has a strong impact on the dynamic behaviour of nanoscale memories, and thus, its control is one of the key factors for future device development and accurate modelling.

PMID: 23612312 [PubMed - in process]