bluuebunny/crossref_metadata_2025_split huggingface dataset:
Riboswitches for Intracellular Study of Genes Involved in
Francisella
Pathogenesis
Authors: Reynoso Colleen M. K. , Miller Mark A. , Bina James E. , Gallivan Justin P. , Weiss David S. 
Published: November 2012

ABSTRACT

The study of many important intracellular bacterial pathogens requires an understanding of how specific virulence factors contribute to pathogenesis during the infection of host cells. This requires tools to dissect gene function, but unfortunately, there is a lack of such tools for research on many difficult-to-study, or understudied, intracellular pathogens. Riboswitches are RNA-based genetic control elements that directly modulate gene expression upon ligand binding. Here we report the application of theophylline-sensitive synthetic riboswitches to induce protein expression in the intracellular pathogen
Francisella
. We show that this system can be used to activate the bacterial expression of the reporter β-galactosidase during growth in rich medium. Furthermore, we applied this system to control the expression of green fluorescent protein during intracellular infection by the addition of theophylline directly to infected macrophages. Importantly, we could control the expression of a novel endogenous protein required for growth under nutrient-limiting conditions and replication in macrophages, FTN_0818. Riboswitch-mediated control of FTN_0818 rescued the growth of an
FTN_0818
mutant in minimal medium and during macrophage infection. This is the first demonstration of the use of a synthetic riboswitch to control an endogenous gene required for a virulence trait in an intracellular bacterium. Since this system can be adapted to diverse bacteria, the ability to use riboswitches to regulate intracellular bacterial gene expression will likely facilitate the in-depth study of the virulence mechanisms of numerous difficult-to-study intracellular pathogens such as
Ehrlichia chaffeensis
,
Anaplasma phagocytophilum
, and
Orientia tsutsugamushi
, as well as future emerging pathogens.

IMPORTANCE
Determining how specific bacterial genes contribute to virulence during the infection of host cells is critical to understanding how pathogens cause disease. This can be especially challenging with many difficult-to-study intracellular pathogens. Riboswitches are RNA-based genetic control elements that can be used to help dissect gene function, especially since they can be used in a broad range of bacteria. We demonstrate the utility of riboswitches, and for the first time show that riboswitches can be used to functionally control a bacterial gene that is critical to the ability of a pathogen to cause disease, during intracellular infection. Since this system can be adapted to diverse bacteria, riboswitches will likely facilitate the in-depth study of the virulence mechanisms of numerous difficult-to-study intracellular pathogens, as well as future emerging pathogens.
Unexpected Diversity of Signal Peptides in Prokaryotes
Authors: Payne Samuel H. , Bonissone Stefano , Wu Si , Brown Roslyn N. , Ivankov Dmitry N. , Frishman Dmitrij , Paša-Tolić Ljiljana , Smith Richard D. , Pevzner Pavel A. 
Published: November 2012

ABSTRACT

Signal peptides are a cornerstone mechanism for cellular protein localization, yet until now experimental determination of signal peptides has come from only a narrow taxonomic sampling. As a result, the dominant view is that Sec-cleaved signal peptides in prokaryotes are defined by a canonical AxA motif. Although other residues are permitted in the motif, alanine is by far the most common. Here we broadly examine proteomics data to reveal the signal peptide sequences for 32 bacterial and archaeal organisms from nine phyla and demonstrate that this alanine preference is not universal. Discoveries include fundamentally distinct signal peptide motifs from
Alphaproteobacteria
,
Spirochaetes
,
Thermotogae
and
Euryarchaeota
. In these novel motifs, alanine is no longer the dominant residue but has been replaced in a different way for each taxon. Surprisingly, divergent motifs correlate with a proteome-wide reduction in alanine. Computational analyses of ~1,500 genomes reveal numerous major evolutionary clades which have replaced the canonical signal peptide sequence with novel motifs.

IMPORTANCE
This article replaces a widely held general model with a more detailed model describing phylogenetically correlated variation in motifs for Sec secretion.
Genomic Characterization of a Newly Discovered Coronavirus Associated with Acute Respiratory Distress Syndrome in Humans
Authors: van Boheemen Sander , de Graaf Miranda , Lauber Chris , Bestebroer Theo M. , Raj V. Stalin , Zaki Ali Moh , Osterhaus Albert D. M. E. , Haagmans Bart L. , Gorbalenya Alexander E. , Snijder Eric J. , Fouchier Ron A. M. 
Published: November 2012

ABSTRACT

A novel human coronavirus (HCoV-EMC/2012) was isolated from a man with acute pneumonia and renal failure in June 2012. This report describes the complete genome sequence, genome organization, and expression strategy of HCoV-EMC/2012 and its relation with known coronaviruses. The genome contains 30,119 nucleotides and contains at least 10 predicted open reading frames, 9 of which are predicted to be expressed from a nested set of seven subgenomic mRNAs. Phylogenetic analysis of the replicase gene of coronaviruses with completely sequenced genomes showed that HCoV-EMC/2012 is most closely related to
Tylonycteris
bat coronavirus HKU4 (BtCoV-HKU4) and
Pipistrellus
bat coronavirus HKU5 (BtCoV-HKU5), which prototype two species in lineage C of the genus
Betacoronavirus
. In accordance with the guidelines of the International Committee on Taxonomy of Viruses, and in view of the 75% and 77% amino acid sequence identity in 7 conserved replicase domains with BtCoV-HKU4 and BtCoV-HKU5, respectively, we propose that HCoV-EMC/2012 prototypes a novel species in the genus
Betacoronavirus
. HCoV-EMC/2012 may be most closely related to a coronavirus detected in
Pipistrellus pipistrellus
in The Netherlands, but because only a short sequence from the most conserved part of the RNA-dependent RNA polymerase-encoding region of the genome was reported for this bat virus, its genetic distance from HCoV-EMC remains uncertain. HCoV-EMC/2012 is the sixth coronavirus known to infect humans and the first human virus within betacoronavirus lineage C.

IMPORTANCE
Coronaviruses are capable of infecting humans and many animal species. Most infections caused by human coronaviruses are relatively mild. However, the outbreak of severe acute respiratory syndrome (SARS) caused by SARS-CoV in 2002 to 2003 and the fatal infection of a human by HCoV-EMC/2012 in 2012 show that coronaviruses are able to cause severe, sometimes fatal disease in humans. We have determined the complete genome of HCoV-EMC/2012 using an unbiased virus discovery approach involving next-generation sequencing techniques, which enabled subsequent state-of-the-art bioinformatics, phylogenetics, and taxonomic analyses. By establishing its complete genome sequence, HCoV-EMC/2012 was characterized as a new genotype which is closely related to bat coronaviruses that are distant from SARS-CoV. We expect that this information will be vital to rapid advancement of both clinical and vital research on this emerging pathogen.
The Handover Toolbox: a knowledge exchange and training platform for improving patient care
Authors: Drachsler Hendrik , Kicken Wendy , van der Klink Marcel , Stoyanov Slavi , Boshuizen Henny P A , Barach Paul 
Published: November 2012

BackgroundSafe and effective patient handovers remain a global organisational and training challenge. Limited evidence supports available handover training programmes. Customisable training is a promising approach to improve the quality and sustainability of handover training and outcomes.ObjectiveWe present a Handover Toolbox designed in the context of the European HANDOVER Project. The Toolbox aims to support physicians, nurses, individuals in health professions training, medical educators and handover experts by providing customised handover training tools for different clinical needs and contexts.MethodsThe Handover Toolbox uses the Technology Enhanced Learning Design Process (TEL-DP), which encompasses user requirements analysis; writing personas; group concept mapping; analysis of suitable software; plus, minus, interesting rating; and usability testing. TEL-DP is aligned with participatory design approaches and ensures development occurs in close collaboration with, and engagement of, key stakeholders.ResultsApplication of TEL-DP confirmed that the ideal formats of handover training differs for practicing professionals versus individuals in health profession education programmes. Training experts from different countries differed in their views on the optimal content and delivery of training. Analysis of suitable software identified ready-to-use systems that provide required functionalities and can be further customised to users’ needs. Interest rating and usability testing resulted in improved usability, navigation and uptake of the Handover Toolbox.ConclusionsThe design of the Handover Toolbox was based on a carefully led stakeholder participatory design using the TEL-DP approach. The Toolbox supports a customisable learning approach that allows trainers to design training that addresses the specific information needs of the various target groups. We offer recommendations regarding the application of the Handover Toolbox to medical educators.
Technology support of the handover: promoting observability, flexibility and efficiency
Authors: Patterson Emily S 
Published: November 2012

BackgroundEfforts to standardise data elements and increase the comprehensiveness of information included in patient handovers have produced a growing interest in augmenting the verbal exchange of information with written communications conducted through health information technology (HIT).ObjectiveThe aim of this perspective is to offer recommendations to optimise technology support of handovers, based on a review of the relevant scientific literature.RecommendationsReview of the literature on human factors and the study of communication produced three recommendations. The first entails making available “shared knowledge” relevant to the handover and subsequent clinical management with intended and unintended recipients. The second is to create a flexible narrative structure (unstructured text fields) for human-human communications facilitated by technology. The third recommendation is to avoid reliance on real-time data entry during busy periods. Implementing these recommendations is anticipated to increase the observability (the ability to readily determine current status), flexibility, and efficiency of HIT-supported patient handovers.ConclusionsAnticipated benefits of technology-supported handovers include reducing reliance on human memory, increasing the efficiency and structure of the verbal exchange, avoiding readbacks of numeric data, and aiding clinical management following the handover. In cases when verbal handovers are delayed, do not occur, or involve members of the health care team without first-hand access to critical information, making ‘common ground’ observable for all recipients, creating a flexible narrative structure for communication and avoiding reliance on real-time data entry during the busiest times has implications for HIT design and day to day data entry and management operations. Benefits include increased observability, flexibility, and efficiency of HIT-supported patient handovers.
Context, culture and (non-verbal) communication affect handover quality
Authors: Frankel Richard M , Flanagan Mindy , Ebright Patricia , Bergman Alicia , O'Brien Colleen M , Franks Zamal , Allen Andrew , Harris Angela , Saleem Jason J 
Published: November 2012

BackgroundTransfers of care, also known as handovers, remain a substantial patient safety risk. Although research on handovers has been done since the 1980s, the science is incomplete. Surprisingly few interventions have been rigorously evaluated and, of those that have, few have resulted in long-term positive change. Researchers, both in medicine and other high reliability industries, agree that face-to-face handovers are the most reliable. It is not clear, however, what the term face-to-face means in actual practice.ObjectivesWe studied the use of non-verbal behaviours, including gesture, posture, bodily orientation, facial expression, eye contact and physical distance, in the delivery of information during face-to-face handovers.MethodsTo address this question and study the role of non-verbal behaviour on the quality and accuracy of handovers, we videotaped 52 nursing, medicine and surgery handovers covering 238 patients. Videotapes were analysed using immersion/crystallisation methods of qualitative data analysis. A team of six researchers met weekly for 18 months to view videos together using a consensus-building approach. Consensus was achieved on verbal, non-verbal, and physical themes and patterns observed in the data.ResultsWe observed four patterns of non-verbal behaviour (NVB) during handovers: (1) joint focus of attention; (2) ‘the poker hand’; (3) parallel play and (4) kerbside consultation. In terms of safety, joint focus of attention was deemed to have the best potential for high quality and reliability; however, it occurred infrequently, creating opportunities for education and improvement.ConclusionsAttention to patterns of NVB in face-to-face handovers coupled with education and practice can improve quality and reliability.
The bihemispheric posterior interior cerebellar artery: anatomic variations and clinical relevance in 11 cases
Authors: Carlson Andrew P , Alaraj Ali , Dashti Reza , Aletich Victor A 
Published: November 2012

PurposeAlthough the anatomic course of the posterior interior cerebellar artery (PICA) is variable, it is thought to be very rare for the artery to cross midline, with an estimated incidence of 0.1%. Bihemispheric PICA crosses midline and typically serves both PICA territories.MethodsWe present 11 cases of bihemispheric PICA discovered from retrospective angiogram review, the largest to date reported in the literature.ResultsFive cases were the typical bihemispheric PICA pattern, three were bihemispheric with distal vertebral hypoplasia, two cases were the vermian type, and one was atypical, with the PICA feeding a contralateral cerebellar arteriovenous malformation (AVM). The branching point to the contralateral hemisphere always occurred distal to the ascending tonsillar loop and all true bihemispheric variants had contralateral PICA aplasia.ConclusionsThe true incidence of this variant may be much higher than previously thought (3.6% in the current series), and has relevance for cerebrovascular disease, including aneurysm, AVM, and ischemic stroke. Neuroradiologists, neurologists, and neurosurgeons should be aware of this potential variant.
Dual Targeting of EGFR and HER3 with MEHD7945A Overcomes Acquired Resistance to EGFR Inhibitors and Radiation
Authors: Huang Shyhmin , Li Chunrong , Armstrong Eric A. , Peet Chimera R. , Saker Jarob , Amler Lukas C. , Sliwkowski Mark X. , Harari Paul M. 
Published: November 2012

Abstract
EGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A than cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Furthermore, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor–resistant cells by modulating cell-cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR inhibitors and offer preclinical proof-of-concept that MEHD7945A can effectively overcome EGFR inhibitor resistance. Cancer Res; 73(2); 824–33. ©2012 AACR.
1p36 Tumor Suppression—A Matter of Dosage?
Authors: Henrich Kai-Oliver , Schwab Manfred , Westermann Frank 
Published: November 2012

Abstract
A broad range of human malignancies is associated with nonrandom 1p36 deletions, suggesting the existence of tumor suppressors encoded in this region. Evidence for tumor-specific inactivation of 1p36 genes in the classic “two-hit” manner is scarce; however, many tumor suppressors do not require complete inactivation but contribute to tumorigenesis by partial impairment. We discuss recent data derived from both human tumors and functional cancer models indicating that the 1p36 genes CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a contribute to cancer development when reduced in dosage by genomic copy number loss or other mechanisms. We explore potential interactions among these candidates and propose a model where heterozygous 1p36 deletion impairs oncosuppressive pathways via simultaneous downregulation of several dosage-dependent tumor suppressor genes. Cancer Res; 72(23); 6079–88. ©2012 AACR.
Why Your New Cancer Biomarker May Never Work: Recurrent Patterns and Remarkable Diversity in Biomarker Failures
Authors: Kern Scott E. 
Published: November 2012

Abstract
Less than 1% of published cancer biomarkers actually enter clinical practice. Although best practices for biomarker development are published, optimistic investigators may not appreciate the statistical near-certainty and diverse modes by which the other 99% (likely including your favorite new marker) do indeed fail. Here, patterns of failure were abstracted for classification from publications and an online database detailing marker failures. Failure patterns formed a hierarchical logical structure, or outline, of an emerging, deeply complex, and arguably fascinating science of biomarker failure. A new cancer biomarker under development is likely to have already encountered one or more of the following fatal features encountered by prior markers: lack of clinical significance, hidden structure in the source data, a technically inadequate assay, inappropriate statistical methods, unmanageable domination of the data by normal variation, implausibility, deficiencies in the studied population or in the investigator system, and its disproof or abandonment for cause by others. A greater recognition of the science of biomarker failure and its near-complete ubiquity is constructive and celebrates a seemingly perpetual richness of biologic, technical, and philosophical complexity, the full appreciation of which could improve the management of scarce research resources. Cancer Res; 72(23); 6097–101. ©2012 AACR.
Vegetarian Diets and the Incidence of Cancer in a Low-risk Population
Authors: Tantamango-Bartley Yessenia , Jaceldo-Siegl Karen , Fan Jing , Fraser Gary 
Published: November 2012

Abstract
Background: Cancer is the second leading cause of death in the United States. Dietary factors account for at least 30% of all cancers in Western countries. As people do not consume individual foods but rather combinations of them, the assessment of dietary patterns may offer valuable information when determining associations between diet and cancer risk.
Methods: We examined the association between dietary patterns (non-vegetarians, lacto, pesco, vegan, and semi-vegetarian) and the overall cancer incidence among 69,120 participants of the Adventist Health Study-2. Cancer cases were identified by matching to cancer registries. Cox proportional hazard regression analysis was conducted to estimate hazard ratios, with “attained age” as the time variable.
Results: A total of 2,939 incident cancer cases were identified. The multivariate HR of overall cancer risk among vegetarians compared with non-vegetarians was statistically significant [HR, 0.92; 95% confidence interval (CI), 0.85–0.99] for both genders combined. Also, a statistically significant association was found between vegetarian diet and cancers of the gastrointestinal tract (HR, 0.76; 95% CI, 0.63–0.90). When analyzing the association of specific vegetarian dietary patterns, vegan diets showed statistically significant protection for overall cancer incidence (HR, 0.84; 95% CI, 0.72–0.99) in both genders combined and for female-specific cancers (HR, 0.66; 95% CI, 0.47–0.92). Lacto-ovo-vegetarians appeared to be associated with decreased risk of cancers of the gastrointestinal system (HR, 0.75; 95% CI, 0.60–0.92).
Conclusion: Vegetarian diets seem to confer protection against cancer.
Impact: Vegan diet seems to confer lower risk for overall and female-specific cancer than other dietary patterns. The lacto-ovo-vegetarian diets seem to confer protection from cancers of the gastrointestinal tract. Cancer Epidemiol Biomarkers Prev; 22(2); 286–94. ©2012 AACR.
A Feasibility Study of the Intraductal Administration of Chemotherapy
Authors: Love Susan M. , Zhang Wei , Gordon Eva J. , Rao Jianyu , Yang Hongying , Li Junyao , Zhang Bailin , Wang Xiang , Chen Guoji , Zhang Baoning 
Published: November 2012

Abstract
Preclinical data have shown the potential of the intraductal administration of chemotherapy for breast cancer prevention. Direct translation of this work has been stymied by the anatomical differences between rodents (one duct per teat) and women (5–9 ductal systems per breast). The objective of this phase I study was to show the safety and feasibility of intraductal administration of chemotherapy drugs into multiple ducts within one breast in women awaiting mastectomy for treatment of invasive cancer. Thirty subjects were enrolled in this dose escalation study conducted at a single center in Beijing, China. Under local anesthetic, one of two chemotherapy drugs, carboplatin or pegylated liposomal doxorubicin (PLD), was administered into five to eight ducts at three dose levels. Pharmacokinetic analysis has shown that carboplatin was rapidly absorbed into the bloodstream, whereas PLD, though more erratic, was absorbed after a delay. Pathologic analysis showed marked effects on breast duct epithelium in ducts treated with either drug compared with untreated ducts. The study investigators had no difficulty in identifying or cannulating ducts except in one case with a central cancer with subareolar involvement. This study shows the safety and feasibility of intraductal administration of chemotherapy into multiple ducts for the purpose of breast cancer prevention. This is an important step toward implementation of this strategy as a “chemical mastectomy”, where the potential for carcinogenesis in the ductal epithelium is eliminated pharmacologically, locally, and without the need for surgery. Cancer Prev Res; 6(1); 51–58;. ©2012 AACR.