1,941 research outputs found
Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds
Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets
Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies.
This is the final version of the article. It first appeared from Frontiers via https://doi.org/10.3389/fphys.2016.00467Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na+ channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na+, K+, Ca2+, and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge. Three hypotheses based on abnormal depolarization, abnormal repolarization, and current-load-mismatch have been put forward to explain the electrophysiological mechanisms responsible for BrS. Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening VT/VF. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction and based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers.GT received a BBSRC Doctoral CASE Studentship at the University of Cambridge and thanks the Croucher Foundation of Hong Kong for the support of his Clinical Assistant Professorship. YC is supported by the ESRC for her Ph.D. studies at the University of Cambridge. BY received funding from the Research Grant Council of Hong Kong for his research
Women's preference for cesarean delivery and differences between Taiwanese women undergoing different modes of delivery
<p>Abstract</p> <p>Background</p> <p>The rate of cesarean delivery was 35% in 2007 in Taiwan. It is unclear how many of the cesarean deliveries were without medical indications. Women's preference for cesarean delivery during their course of pregnancy has rarely been studied and therefore our objectives were to examine rate of cesarean deliveries without medical indications, to explore women's preference for cesarean delivery as their gestation advances, and to compare background and perinatal factors among women who underwent different modes of delivery in Taiwan.</p> <p>Methods</p> <p>This prospective study applied a longitudinal design. The study participants were 473 women who received prenatal care at four hospitals in Taipei and answered structured questionnaires at 20 to 24 weeks of pregnancy, 34 to 36 weeks of pregnancy, and 5 to 7 weeks after delivery.</p> <p>Results</p> <p>Of the 151 women (31.9%) who had cesarean deliveries, 19.9% were without medical indication. Three indications: malpresentation, prior cesarean section, and dysfunctional labor together accounted for 82.6% of cesarean section with medical indications. The prevalence of maternal preference for cesarean delivery was found to be 12.5% and 17.5% during the second and third trimester, respectively. Of the women who preferred cesarean delivery during the second trimester, 93.2% eventually had a cesarean delivery. Women who were older, with older spouses, and who had health problems before or during pregnancy were more likely to have cesarean deliveries.</p> <p>Conclusions</p> <p>About 20% of cesarean deliveries were without medical indications. Women's preference for cesarean delivery during the second trimester predicts subsequent cesarean delivery. Counseling regarding mode of delivery should be offered early in pregnancy, especially for women who are older or with older spouses, have health problems, or had a prior cesarean section.</p
Imaging Electronic Correlations in Twisted Bilayer Graphene near the Magic Angle
Twisted bilayer graphene with a twist angle of around 1.1{\deg} features a
pair of isolated flat electronic bands and forms a strongly correlated
electronic platform. Here, we use scanning tunneling microscopy to probe local
properties of highly tunable twisted bilayer graphene devices and show that the
flat bands strongly deform when aligned with the Fermi level. At half filling
of the bands, we observe the development of gaps originating from correlated
insulating states. Near charge neutrality, we find a previously unidentified
correlated regime featuring a substantially enhanced flat band splitting that
we describe within a microscopic model predicting a strong tendency towards
nematic ordering. Our results provide insights into symmetry breaking
correlation effects and highlight the importance of electronic interactions for
all filling factors in twisted bilayer graphene.Comment: Main text 9 pages, 4 figures; Supplementary Information 25 page
Using malware for software-defined networking–based smart home security management through a taint checking approach
The ‘new normality’ in research? What message are we conveying our medical students?
The impact of COVID-19
on medical education has been
mainly viewed from the perspective of the imposed transition
from face-to-
face
to online delivery of information and
the inforced stopping of practical teaching in hospitals.1-5
However, unfortunately, the deleterious effects of COVID-19
on how research findings are obtained, communicated and
valued needs also careful consideration. Whilst teaching students
that it is a genuinely exciting and unique time to be
in medicine, as teachers of a subject entitled ‘Introduction
to Research’ to second-year
medical students, we feel particularly
worried about what the handling of the pandemia
is transmitting our future physicians. Now, more than ever
before, scholars need to reaffirm the importance on how research
findings are obtained and communicated
Automating the Communication of Cybersecurity Knowledge: Multi-Case Study
Cybersecurity is essential for the protection of companies against cyber
threats. Traditionally, cybersecurity experts assess and improve a company's
capabilities. However, many small and medium-sized businesses (SMBs) consider
such services not to be affordable. We explore an alternative do-it-yourself
(DIY) approach to bringing cybersecurity to SMBs. Our method and tool, CYSEC,
implements the Self-Determination Theory (SDT) to guide and motivate SMBs to
adopt good cybersecurity practices. CYSEC uses assessment questions and
recommendations to communicate cybersecurity knowledge to the end-user SMBs and
encourage self-motivated change. In this paper, the operationalisation of SDT
in CYSEC is presented and the results of a multi-case study shown that offer
insight into how SMBs adopted cybersecurity practices with CYSEC. Effective
automated cybersecurity communication depended on the SMB's hands-on skills,
tools adaptedness, and the users' willingness to documenting confidential
information. The SMBs wanted to learn in simple, incremental steps, allowing
them to understand what they do. An SMB's motivation to improve security
depended on the fitness of assessment questions and recommendations with the
SMB's business model and IT infrastructure. The results of this study indicate
that automated counselling can help many SMBs in security adoption. The final
publication is available at Springer via
https://link.springer.com/chapter/10.1007%2F978-3-030-59291-2_8Comment: 14 pages, 1 figure, 13th World Conference on Information Security
Educatio
Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma
Longitudinal seroepidemiologic study of the 2009 pandemic influenza A (H1N1) infection among health care workers in a children's hospital
<p>Abstract</p> <p>Background</p> <p>To probe seroepidemiology of the 2009 pandemic influenza A (H1N1) among health care workers (HCWs) in a children's hospital.</p> <p>Methods</p> <p>From August 2009 to March 2010, serum samples were drawn from 150 HCWs in a children's hospital in Taipei before the 2009 influenza A (H1N1) pandemic, before H1N1 vaccination, and after the pandemic. HCWs who had come into direct contact with 2009 influenza A (H1N1) patients or their clinical respiratory samples during their daily work were designated as a high-risk group. Antibody levels were determined by hemagglutination inhibition (HAI) assay. A four-fold or greater increase in HAI titers between any successive paired sera was defined as seroconversion, and factors associated with seroconversion were analyzed.</p> <p>Results</p> <p>Among the 150 HCWs, 18 (12.0%) showed either virological or serological evidence of 2009 pandemic influenza A (H1N1) infection. Of the 90 unvaccinated HCWs, baseline and post-pandemic seroprotective rates were 5.6% and 20.0%. Seroconversion rates among unvaccinated HCWs were 14.4% (13/90), 22.5% (9/40), and 8.0% (4/50) for total, high-risk group, and low-risk group, respectively. Multivariate analysis revealed being in the high-risk group is an independent risk factor associated with seroconversion.</p> <p>Conclusion</p> <p>The infection rate of 2009 pandemic influenza A (H1N1) in HCWs was moderate and not higher than that for the general population. The majority of unvaccinated HCWs remained susceptible. Direct contact of influenza patients and their respiratory samples increased the risk of infection.</p
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