Development of PDT/PET theranostics: synthesis and biological evaluation of an ¹⁸F-radiolabeled water soluble porphyrin

Synthesis of the first water-soluble porphyrin radiolabeled with fluorine-18 is described: a new molecular theranostic agent which integrates the therapeutic selectivity of photodynamic therapy (PDT) with the imaging efficacy of positron emission tomography (PET). Generation of the theranostic was carried out through the conjugation of a cationic water-soluble porphyrin bearing an azide functionality to a fluorine-18 radiolabeled prosthetic bearing an alkyne functionality through click conjugation, with excellent yields obtained in both cold and hot synthesis. Biological evaluation of the synthesized structures shows the first example of an 18 F-radiolabeled porphyrin retaining photocytotoxicity following radiolabeling and demonstrable conjugate uptake and potential application as a radiotracer in vivo. The promising results gained from biological evaluation demonstrate the potential of this structure as a clinically relevant theranostic agent, offering exciting possibilities for the simultaneous imaging and photodynamic treatment of tumors

Seasonal heat content changes in the western Mediterranean Sea as a means for evaluating surface heat flux formulations

The semienclosed western Mediterranean Sea has proven to be a useful location to evaluate surface heat flux estimates. In the past the directly measured average oceanic heat transport from the Atlantic into the Mediterranean Sea through the Strait of Gibraltar of similar to 5.2 +/- 1.3 W m(-2) has been compared to estimates of the average heat flux across the surface of the Mediterranean Sea. On long timescales both should closely balance each other. By using a monthly temperature climatology of the western Mediterranean Sea we offer the possibility to extend the comparison to the seasonal timescale. This gives additional information with which different surface heat flux data sets can be evaluated. The seasonal heat content changes of the western Mediterranean and the advective exchange of heat through the Straits of Gibraltar and Sicily are estimated on the basis of a new extensive hydrographic data set and of published values for the volume transports. To demonstrate the method, a limited number of surface heat flux data sets are compared with the oceanographically calculated counterpart. The comparison reveals that some heat fluxes do not only agree well for the long-term averages but also for the seasonal timescale, whereas others show larger deviations. The remaining rms discrepancies of +/-10.2 W m(-2) for the best heat flux data set are smaller than the uncertainty of the oceanographic estimate and of a reasonable magnitude compared to the uncertainty of the long-term average of similar to 5 W m(-2)

Dynamics of Planetary Systems in Star Clusters

At least 10-15% of nearby sun-like stars have known Jupiter-mass planets. In contrast, very few planets are found in mature open and globular clusters such as the Hyades and 47 Tuc. We explore here the possibility that this dichotomy is due to the post-formation disruption of planetary systems associated with the stellar encounters in long-lived clusters. One supporting piece of evidence for this scenario is the discovery of freely floating low-mass objects in star forming regions. We use two independent numerical approaches, a hybrid Monte Carlo and a direct $N$-body method, to simulate the impact of the encounters. We show that the results of numerical simulations are in reasonable agreement with analytical determinations in the adiabatic and impulsive limits. They indicate that distant stellar encounters generally do not significantly modify the compact and nearly circular orbits. However, moderately close stellar encounters, which are likely to occur in dense clusters, can excite planets' orbital eccentricity and induce dynamical instability in systems which are closely packed with multiple planets. We compute effective cross sections for the dissolution of planetary systems and show that, for all initial eccentricities, dissolution occurs on time scales which are longer than the dispersion of small stellar associations, but shorter than the age of typical open and globular clusters. Although it is much more difficult to disrupt short-period planets, close encounters can excite modest eccentricity among them, such that subsequent tidal dissipation leads to orbital decay, tidal inflation, and even disruption of the close-in planets.Comment: 57 pages, 14 figures, 4 tables, major revision by authors, accepted for publication at the Astrophysical Journal (ApJ

Livestock-associated Methicillin-Resistant Staphylococcus aureus Sequence Type 398 in Humans, Canada

Recent emergence of infections resulting from this strain is of public health concern

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Mutation in 23S rRNA Associated with Macrolide Resistance in Neisseria gonorrhoeae

Fifty-six azithromycin-resistant (MICs, 2.0 to 4.0 μg/ml) Neisseria gonorrhoeae strains with cross-resistance to erythromycin (MICs, 2.0 to 64.0 μg/ml), isolated in Canada between 1997 and 1999, were characterized, and their mechanisms of azithromycin resistance were determined. Most (58.9%) of them belonged to auxotype-serotype class NR/IB-03, with a 2.6-mDa plasmid. Based on resistance to crystal violet (MICs ≥ 1 μg/ml), 96.4% of these macrolide-resistant strains appeared to have increased efflux. Nine of the eleven strains selected for further characterization were found to have a promoter region mtrR mutation, a single-base-pair (A) deletion in the 13-bp inverted repeat, which is believed to cause overexpression of the mtrCDE-encoded efflux pump. The two remaining macrolide-resistant strains (erythromycin MIC, 64.0 μg/ml; azithromycin MIC, 4.0 μg/ml), which did not have the mutation in the mtrR promoter region, were found to have a C2611T mutation (Escherichia coli numbering) in the peptidyltransferase loop in domain V of the 23S rRNA alleles. Although mutations in domain V of 23S rRNA alleles had been reported in other bacteria, including E. coli, Streptococcus pneumoniae, and Helicobacter pylori, this is the first observation of these mutations associated with macrolide resistance in N. gonorrhoeae

Short interspersed repetitive elements (SINEs) from the cichlid fish, Oreochromis niloticus, and their chromosomal localization by fluorescent in situ hybridization

In the present study, we describe the cloning and characterization of a new SINE-like element from O. niloticus (ROn-2) and show the distribution of this SINE and a previously isolated SINE, ROn-1, in the chromosomes of O. niloticus. The ROn-2 element is 359 base pairs (bp) in length, contains short direct terminal repeats, a tRNA-related region similar to tRNA Val and tRNA Arg, a tRNA-unrelated region, and a poly-A tail. Analysis of the chromosomal distribution of ROn-1 and ROn-2 by fluorescent in situ hybridization showed that both SINE sequences are present in all chromosomes of tilapia, and organized in small clusters. The only exception was a large cluster of ROn-1 repeats found in the middle of the long arm of chromosome 1. In view of our data we discuss the hypothesis that the absence of large clusters of SINE sequences and the structural composition of these sequences may explain the absence of base-specific fluorochrome bands in the chromosomes of tilapia

Single-Nucleotide Repeat Analysis for Subtyping Bacillus anthracis Isolates

Single-nucleotide repeats (SNRs) are variable-number tandem repeats that display very high mutation rates. In an outbreak situation, the use of a marker system that exploits regions with very high mutation rates, such as SNRs, allows the differentiation of isolates with extremely low levels of genetic diversity. This report describes the identification and analysis of SNR loci of Bacillus anthracis. SNR loci were selected in silico, and the loci with the highest diversity were used to design and test locus-specific primers against a number of B. anthracis strains with the same multilocus variable-number tandem repeat analysis (MLVA) genotype. SNR markers that allowed strains with the same MLVA genotype to be differentiated from each other were identified. The resulting SNR marker system can be used as a molecular epidemiological tool in a natural outbreak or bioterrorism event, offering the best chance of distinguishing very closely related isolates

Coherence of western boundary pressure at the RAPID WAVE array: boundary wave adjustments or deep western boundary current advection?

We investigate the coherence between ocean bottom pressure signals at the the RAPID WAVE array on the western North Atlantic continental slope, including the Woods Hole Oceanographic Institution Line W. Highly coherent pressure signals propagate southwestward along the slope, at speeds in excess of 128 m/s, consistent with expectations of barotropic Kelvin-like waves. We also see coherent signals in the smaller pressure differences relative to 1000 m depth, which are expected to be associated with depth-dependent basin-wide meridional transport variations, or an overturning circulation. These signals are coherent and almost in phase for all time scales from 3.6 years down to 3 months. Coherence is still seen at shorter time scales for which group delay estimates are consistent with a propagation speed of about 1 m/s over 990 km of continental slope, but with large error bounds on the speed. This is roughly consistent with expectations for propagation of coastally-trapped waves, though somewhat slower than expected. A comparison with both Eulerian currents and Lagrangian float measurements shows that the coherence is inconsistent with a propagation of signals by advection, except possibly on time scales longer than 6 months