A Freeze Frame View of Vesicular Stomatitis Virus Transcription Defines a Minimal Length of RNA for 5′ Processing

The RNA synthesis machinery of vesicular stomatitis virus (VSV) comprises the genomic RNA encapsidated by the viral nucleocapsid protein (N) and associated with the RNA dependent RNA polymerase, the viral components of which are a large protein (L) and an accessory phosphoprotein (P). The 241 kDa L protein contains all the enzymatic activities necessary for synthesis of the viral mRNAs, including capping, cap methylation and polyadenylation. Those RNA processing reactions are intimately coordinated with nucleotide polymerization such that failure to cap results in termination of transcription and failure to methylate can result in hyper polyadenylation. The mRNA processing reactions thus serve as a critical check point in viral RNA synthesis which may control the synthesis of incorrectly modified RNAs. Here, we report the length at which viral transcripts first gain access to the capping machinery during synthesis. By reconstitution of transcription in vitro with highly purified recombinant polymerase and engineered templates in which we omitted sites for incorporation of UTP, we found that transcripts that were 30-nucleotides in length were uncapped, whereas those that were 31-nucleotides in length contained a cap structure. The minimal RNA length required for mRNA cap addition was also sufficient for methylation since the 31-nucleotide long transcripts were methylated at both ribose-2′-O and guanine-N-7 positions. This work provides insights into the spatial relationship between the active sites for the RNA dependent RNA polymerase and polyribonucleotidyltransferase responsible for capping of the viral RNA. We combine the present findings with our recently described electron microscopic structure of the VSV polymerase and propose a model of how the spatial arrangement of the capping activities of L may influence nucleotide polymerization

Post-graduation migration intentions of students of Lebanese medical schools: a survey study

<p>Abstract</p> <p>Background</p> <p>The international migration of physicians is a global public health problem. Lebanon is a source country with the highest emigration factor in the Middle East and North Africa and the 7th highest in the World. Given that residency training abroad is a critical step in the migration of physicians, the objective of this study was to survey students of Lebanese medical schools about their intentions to train abroad and their post training plans.</p> <p>Methods</p> <p>Our target population consisted of all students of Lebanese medical schools in the pre-final and final years of medical school. We developed the survey questionnaire based on the results of a qualitative study assessing the intentions and motives for students of Lebanese medical schools to train abroad. The questionnaire inquired about student's demographic and educational characteristics, intention to train abroad, the chosen country of abroad training, and post-training intention of returning to Lebanon.</p> <p>Results</p> <p>Of 576 eligible students, 425 participated (73.8% response rate). 406 (95.5%) respondents intended to travel abroad either for specialty training (330 (77.6%)) or subspecialty training (76 (17.9%)). Intention to train abroad was associated with being single compared with being married. The top 4 destination countries were the US (301(74.1%)), France (49 (12.1%)), the United Kingdom (31 (7.6%)) and Canada (17 (4.2%)). One hundred and two (25.1%) respondents intended to return to Lebanon directly after finishing training abroad; 259 (63.8%) intended to return to Lebanon after working abroad temporarily for a varying number or years; 43 (10.6%) intended to never return to Lebanon. The intention to stay indefinitely abroad was associated male sex and having a 2^ndcitizenship. It was inversely associated with being a student of one of the French affiliated medical schools and a plan to train in a surgical specialty.</p> <p>Conclusion</p> <p>An alarming percentage of students of Lebanese medical schools intend to migrate for post graduate training, mainly to the US. A minority intends to return directly to Lebanon after finishing training abroad.</p

Stochastic Gravity: Theory and Applications

Whereas semiclassical gravity is based on the semiclassical Einstein equation with sources given by the expectation value of the stress-energy tensor of quantum fields, stochastic semiclassical gravity is based on the Einstein-Langevin equation, which has in addition sources due to the noise kernel. In the first part, we describe the fundamentals of this new theory via two approaches: the axiomatic and the functional. In the second part, we describe three applications of stochastic gravity theory. First, we consider metric perturbations in a Minkowski spacetime, compute the two-point correlation functions of these perturbations and prove that Minkowski spacetime is a stable solution of semiclassical gravity. Second, we discuss structure formation from the stochastic gravity viewpoint. Third, we discuss the backreaction of Hawking radiation in the gravitational background of a black hole and describe the metric fluctuations near the event horizon of an evaporating black holeComment: 100 pages, no figures; an update of the 2003 review in Living Reviews in Relativity gr-qc/0307032 ; it includes new sections on the Validity of Semiclassical Gravity, the Stability of Minkowski Spacetime, and the Metric Fluctuations of an Evaporating Black Hol

Graduates of Lebanese medical schools in the United States: an observational study of international migration of physicians

BACKGROUND: As healthcare systems around the world are facing increasing physician shortages, more physicians are migrating from low to high income countries. As an illustrative case of international migration of physicians, we evaluated the current number and historical trends of Lebanese medical graduates (LMG) in the US, and compared their characteristics to those of US medical graduates (USMG) and other international medical graduates (IMG). METHODS: We evaluated the number of LMG using the 2004 the American Medical Association Physicians' Professional Data (AMA-PPD) and then compared it to the number of graduates of other countries. We evaluated the historical trends using the 1978–2004 historical files of the AMA-PPD. We analyzed the characteristics of all LMG and compared them to a random sample of 1000 USMG and a random sample of 1000 IMG using the 2004 AMA-PPD. RESULTS: In 2004, there were 2,796 LMG in the US, constituting 1.3% of all IMG. Compared to other foreign countries contributing to the US physician workforce, Lebanon ranked 2nd after adjusting for country population size (about 4 million) and 21st overall. About 40% of those who graduated from Lebanese medical schools in the last 25 years are currently active physicians in the US. Since 1978, the number of LMG in the US showed a consistent upward trend at a rate of approximately 71 additional graduates per year. Compared with USMG and IMG, LMG were more likely to work in medical research (OR = 2.31; 95% Confidence Interval (CI) = 1.21; 4.43 and OR = 2.63; 95% CI = 1.34; 5.01, respectively) and to be board certified (OR = 1.43; 95% CI = 1.14; 1.78 and OR = 2.04; 95% CI = 1.65;2.53, respectively) and less likely to be in family practice (OR = 0.14; 95% CI = 0.10; 0.19 and OR = 0.18; 95% CI = 0.12; 0.26, respectively). CONCLUSION: Given the magnitude and historical trends of migration of LMG to the US, further exploration of its causes and impact is warranted. High income countries should consider the consequences of their human resources policies on both low income countries' and their own healthcare systems

Association between respiratory tract diseases and secondhand smoke exposure among never smoking flight attendants: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Little is known about long-term adverse health consequences experienced by flight attendants exposed to secondhand smoke (SHS) during the time smoking was allowed on airplanes. We undertook this study to evaluate the association between accumulated flight time in smoky airplane cabins and respiratory tract diseases in a cohort of never smoking flight attendants.</p> <p>Methods</p> <p>We conducted a mailed survey in a cohort of flight attendants. Of 15,000 mailed questionnaires, 2053 (14%) were completed and returned. We excluded respondents with a personal history of smoking (n = 748) and non smokers with a history of respiratory tract diseases before the age of 18 years (n = 298). The remaining 1007 respondents form the study sample.</p> <p>Results</p> <p>The overall study sample was predominantly white (86%) and female (89%), with a mean age of 54 years. Overall, 69.7% of the respondents were diagnosed with at least one respiratory tract disease. Among these respondents, 43.4% reported a diagnosis of sinusitis, 40.3% allergies, 30.8% bronchitis, 23.2% middle ear infections, 13.6% asthma, 13.4% hay fever, 12.5% pneumonia, and 2.0% chronic obstructive pulmonary disease. More hours in a smoky cabin were observed to be significantly associated with sinusitis (OR = 1.21; p = 0.024), middle ear infections (OR = 1.30; p = 0.006), and asthma (OR = 1.26; p = 0.042).</p> <p>Conclusion</p> <p>We observed a significant association between hours of smoky cabin exposure and self-reported reported sinusitis, middle ear infections, and asthma. Our findings suggest a dose-response between duration of SHS exposure and diseases of the respiratory tract. Our findings add additional evidence to the growing body of knowledge supporting the need for widespread implementation of clean indoor air policies to decrease the risk of adverse health consequences experienced by never smokers exposed to SHS.</p

Identification of dimethylamine monooxygenase in marine bacteria reveals a metabolic bottleneck in the methylated amine degradation pathway

Methylated amines (MAs) are ubiquitous in the marine environment and their subsequent flux into the atmosphere can result in the formation of aerosols and ultimately cloud condensation nuclei. Therefore, these compounds have a potentially important role in climate regulation. Using Ruegeria pomeroyi as a model, we identified the genes encoding dimethylamine (DMA) monooxygenase (dmmABC) and demonstrate that this enzyme degrades DMA to monomethylamine (MMA). Although only dmmABC are required for enzyme activity in recombinant Escherichia coli, we found that an additional gene, dmmD, was required for the growth of R. pomeroyi on MAs. The dmmDABC genes are absent from the genomes of multiple marine bacteria, including all representatives of the cosmopolitan SAR11 clade. Consequently, the abundance of dmmDABC in marine metagenomes was substantially lower than the genes required for other metabolic steps of the MA degradation pathway. Thus, there is a genetic and potential metabolic bottleneck in the marine MA degradation pathway. Our data provide an explanation for the observation that DMA-derived secondary organic aerosols (SOAs) are among the most abundant SOAs detected in fine marine particles over the North and Tropical Atlantic Ocean

Pulse pressure and age at menopause

BACKGROUND: The objective of this study was to study the association of early age at menopause with pulse pressure (PP), a marker of arterial stiffness, and PP change. METHODS: The effect of natural menopause was studied in 2484 women from the Atherosclerosis Risk in Communities (ARIC) Study who had not used hormone replacement therapy and who had not had a hysterectomy. The cross-sectional association of age with PP was evaluated in the entire cohort. The cross-sectional association of recalled age at menopause was evaluated in the 1688 women who were postmenopausal at baseline. PP change over 6 years was assessed in relation to menopausal age separately in women who were postmenopausal at baseline and in those whose menopause occurred during the 6-year interval. RESULTS: Chronological age was strongly and positively associated with PP in cross-sectional analyses, but not independently associated with PP change. While menopausal age was not associated cross-sectionally with PP, early age at menopause (age<45) was significantly and independently associated with a slightly larger increase in PP (8.4, 95% CI 7.0–9.8) than later menopause (6.5, 95% CI 5.8;7.2). However, among normotensive women the difference was not statistically significant (p = 0.07, 6.1 vs 4.7). CONCLUSIONS: Early age at menopause may be related to a greater increase in arterial stiffness, but the effect appears to be small and further evidence is needed

The patient experience

The impact of improved treatments for the management of hormone-sensitive breast cancer extends beyond clinical responses. Thanks to appropriate literature and access to the internet, patient awareness of treatment options has grown and patients are now, in many cases, able to engage their oncologists in informed conversations regarding treatment and what to expect in terms of efficacy and safety. Indeed, patients realize that although there is no cure for metastatic disease, treatment can greatly reduce the risk of progression and in the adjuvant setting, where treatment is administered with a curative intent, current treatment options reduce the risk of relapse. The approval of letrozole throughout the breast cancer continuum has provided patients with many reassuring options. The improvement in outcome with letrozole is achieved without a detrimental effect on overall quality of life. Adverse events such as hot flushes, arthralgia, vaginal dryness, and potential osteoporosis are most significant from the patient’s perspective, and it is important that caregivers pay attention to patients experiencing these events, as they can impact compliance unless effectively explained and managed. The major benefits of letrozole are to improve prospects for long-term survivorship in the adjuvant setting and to delay progression and the need for chemotherapy in the metastatic setting

Stochastic Gravity: Theory and Applications

Whereas semiclassical gravity is based on the semiclassical Einstein equation with sources given by the expectation value of the stress-energy tensor of quantum fields, stochastic semiclassical gravity is based on the Einstein-Langevin equation, which has in addition sources due to the noise kernel.In the first part, we describe the fundamentals of this new theory via two approaches: the axiomatic and the functional. In the second part, we describe three applications of stochastic gravity theory. First, we consider metric perturbations in a Minkowski spacetime: we compute the two-point correlation functions for the linearized Einstein tensor and for the metric perturbations. Second, we discuss structure formation from the stochastic gravity viewpoint. Third, we discuss the backreaction of Hawking radiation in the gravitational background of a quasi-static black hole.Comment: 75 pages, no figures, submitted to Living Reviews in Relativit