Antivirals in medical biodefense

The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha- and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development

Photophysics of phycoerythrocyanins from the cyanobacterium Westiellopsis prolifica studied by time-resolved fluorescence and coherent anti-Stokes Raman scattering spectroscopy

Three building blocks of the antenna complexes of the cyanobacterium Westiellopsis prolifica were studied: PEC(X), which is similar to the α-subunit of phycoerythrocyanin (PEC), trimers of PEC and monomers derived from these by deaggregation with KSCN. The fit of the fluorescence decay curve of PEC(X) requires at least four exponentials, although it supposedly contains only one chromophore. The coherent anti-Stokes Raman scattering (CARS) spectra indicate that the heterogeneity observed is due to geometrical isomers, which are in part generated by photoinduced processes. A similar heterogeneity in chromophore structure and properties is also found in the monomers, where four exponentials are needed to fit the fluorescence decay curve. As in trimers, there is a long-lived, low-amplitude component, which can be assigned to impurities and/or oxidation products. The energy transfer time between the two phyocyanobilin chromophores in the β-subunit is about 500 ps; the lifetime of the fluorescing β-chromophore is 1.5 ns. The phycoviolobilin chromophore in the α-subunit adopts different geometries characterized by fluorescence lifetimes of about 240 and 800 ps. No evidence was found for energy transfer between the α-chromophore and the β-chromophores. This energy transfer occurs in trimers on a time scale of less than 20 ps; the energy transfer time between the two different types of β-chromophore is about 250 ps and the lifetime of the terminal emitter is about 1.5 ns. The excited state kinetics are therefore similar to those of PEC trimers from Mastigocladus laminosus, as are the CARS spectra, indicating a similar chromophore—protein arrangement. In comparison with phycocyanin, the ordering of the excited states of chromophores β84 and β155 may be changed. Although PEC trimers of Westiellopsis prolifica show almost as good a photostability as trimers of Mastigocladus laminosus, monomers are so photolabile that no CARS spectra could be recorded

Computer calculations of heterogeneous equilibria in the system C-O-H-N-Si-Ar

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44678/1/10853_2004_Article_BF00549333.pd

Inter-annual decrease in pulse rate and peak frequency of Southeast Pacific blue whale song types

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Malige, F., Patris, J., Buchan, S. J., Stafford, K. M., Shabangu, F., Findlay, K., Hucke-Gaete, R., Neira, S., Clark, C. W., & Glotin, H. Inter-annual decrease in pulse rate and peak frequency of Southeast Pacific blue whale song types. Scientific Reports, 10(1), (2020): 8121, doi:10.1038/s41598-020-64613-0.A decrease in the frequency of two southeast Pacific blue whale song types was examined over decades, using acoustic data from several different sources in the eastern Pacific Ocean ranging between the Equator and Chilean Patagonia. The pulse rate of the song units as well as their peak frequency were measured using two different methods (summed auto-correlation and Fourier transform). The sources of error associated with each measurement were assessed. There was a linear decline in both parameters for the more common song type (southeast Pacific song type n.2) between 1997 to 2017. An abbreviated analysis, also showed a frequency decline in the scarcer southeast Pacific song type n.1 between 1970 to 2014, revealing that both song types are declining at similar rates. We discussed the use of measuring both pulse rate and peak frequency to examine the frequency decline. Finally, a comparison of the rates of frequency decline with other song types reported in the literature and a discussion on the reasons of the frequency shift are presented.The authors thank the help of Explorasub diving center (Chile), Agrupación turística Chañaral de Aceituno (Chile), ONG Eutropia (Chile), Valparaiso university (Chile), the international institutions and research programs CTBTO, IWC, BRILAM STIC AmSud 17-STIC-01. S.J.B. thanks support from the Center for Oceanographic Research COPAS Sur-Austral, CONICYT PIA PFB31, Biology Department of Woods Hole Oceanographic Institution, the Office of Naval Research Global (awards N62909-16-2214 and N00014-17-2606), and a grant to the Centro de Estudios Avanzados en Zonas Ãridas (CEAZA) “Programa Regional CONICYT R16A10003”. We thank SABIOD MI CNRS, EADM MaDICS CNRS and ANR-18-CE40-0014 SMILES supporting this research. We are grateful to colleagues at DCLDE 2018 and SOLAMAC 2018 conferences for useful comments on the preliminary version of this work. In this work we used only the free and open-source softwares Latex, Audacity and OCTAVE

Visual and passive acoustic observations of blue whale trios from two distinct populations

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Schall, E., Di Iorio, L., Berchok, C., Filun, D., Bedrinana-Romano, L., Buchan, S. J., Van Opzeeland, I., Sears, R., & Hucke-Gaete, R. Visual and passive acoustic observations of blue whale trios from two distinct populations. Marine Mammal Science, (2019): 1-10, doi:10.1111/mms.12643.Blue whale populations from both hemispheres are thought to undertake annual migrations between high latitude feeding grounds and low latitude breeding grounds (Mackintosh, 1966). For individuals of some populations these predetermined movements to and from wintering areas where calving occurs have been confirmed through photo‐identification, satellite‐tracking, and passive acoustic monitoring (Burtenshaw et al., 2004; Mate, Lagerquist, & Calambokidis, 1999; Sears & Perrin, 2002; Stafford, Nieukirk, & Fox, 1999a). However, for many blue whale populations no clear migratory behavior has been reported and locations of respective breeding grounds remain unclear (e.g., Hucke‐Gaete, Osman, Moreno, Findlay, & Ljungblad, 2004; Samaran et al., 2013; Stafford, Chapp, Bohnenstiel, & Tolstoy, 2011; Thomisch et al., 2016). On feeding grounds in the Gulf of St. Lawrence and along the coast of California, blue whales have been observed to form female–male pairs during summer, which can remain stable up to over several weeks, with the number of pairs increasing towards the end of summer (Sears & Perrin, 2002; Calambokidis, unpublished data;1 RS, unpublished data). These pairs are sometimes joined by a second male, forming a blue whale trio, which often is observed to engage in surface active behaviors lasting several minutes (Sears & Perrin, 2002; RS, unpublished data). The formation of blue whale trios is probably related to reproductive competition between male escorts and female choice (RS, unpublished data). Blue whale males produce population‐specific songs likely functioning as reproductive advertisement (Edds‐Walton, 1997; Oleson et al. 2007a; Stafford, Fox, & Clark, 1998). Several studies have reported song year‐round in low‐, mid‐, and high‐latitude waters, frequently with high song production rates during summer on the feeding grounds (e.g., Barlow et al., 2018; Buchan, Stafford, & Hucke‐Gaete, 2015; Samaran, Adam, & Guinett, 2010; Širović et al., 2004; Stafford, Nieukirk, & Fox, 1999b; Thomisch et al., 2016). Therefore, breeding activities in blue whales may be more opportunistic, i.e., not restricted to the breeding season or to a specific habitat.ES thanks Prof. Dr. Per J. Palsbøll for the supervision of the initial Master research project, the Marco Polo fund, and the University Groningen for covering travel expenses. We thank the Melimoyu Ecosystem Research Institute, SNP Patagonia Sur, and the company Teledyne Reson for partially funding the acoustic data collection in southern Chile. RHG is thankful to WWF‐Germany/Chile for partially funding fieldwork through grants to Centro Ballena Azul. CLB thanks the team of the Mingan Island Cetacean Study for their logistical support of boats and lodging, access to the North Atlantic blue whale database, and field assistance; Yvon Bélanger for opening his home to her and RS's field crews; for financial support from the National Science Foundation (Graduate Fellowship), National Defense Industrial Association, American Museum of Natural History (Lerner Gray Fund for Marine Research Grant), Penn State Applied Research Laboratory, and private donors Jeff and Lynn Kraus; and graduate advisors at Penn State University David L. Bradley, Thomas B. Gabrielson, and Diana McCammon. LDI thanks the Croisières du Grand Héron and Center Mériscope for allowing and supporting fieldwork, the Animal Behavior Department of the University of Zurich (Switzerland), the Bioacoustics Research Program at Cornell University (USA) and Prof. M. Manser and C. W. Clark for supervising LDI's Ph.D. The work was supported by grants to LDI for her PhD from the Forschungskommission der Universität Zürich, Züricher Tierschutz, Basler Stiftung für Biologische Forschung, SCNAT, Zangger‐Weber‐Stiftung, SSVA. SJB thanks the Center for Oceanographic Research COPAS Sur‐Austral, CONICYT PIA PFB31, the Office of Naval Research Global (awards N62909‐16‐2214 and N00014‐17‐2606), and a grant to the Centro de Estudios Avanzados en Zonas Áridas from Programa Regional CONICYT R16A10003 for support during manuscript writing. We would like to thank the field crews (F. Viddi, J. Ruiz, A. Carpentier, M. Lessard, A. Liebschner, C. Ramp, S. Angel, K. Aucrenaz, T. Doniol‐Valcroze, J. LeBreus, B. Kot, and J. Puschock) for their immense commitment to blue whale research

Vision, mission, and values: From concept to execution at Mayo Clinic

Mayo Clinic displays steadfast commitment to patient care, referral relations, and health care quality through institutional examples of unique, value-add endeavors that are under way with the Mayo Clinic Patient Experience Subcommittee and the Referring Physician Office. In this article, we share the Mayo Model of Care and patient stories that embody the 8 Mayo Clinic values of respect, compassion, integrity, healing, teamwork, excellence, innovation, and stewardship. The Mayo founders imparted to their staff the passion for patient care by encouraging a fair and just culture for its employees. This culture allows the creation, maintenance, and improvement of clinical care, research studies, and educational curricula, which in turn propagate the mission–“To inspire hope and contribute to health and well-being by providing the best care to every patient through integrated clinical practice, education, and research.

Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum

The post-translational farnesylation of proteins serves to anchor a subset of intracellular proteins to membranes in eukaryotic organisms and also promotes protein-protein interactions. Inhibition of protein farnesyltransferase (PFT) is lethal to the pathogenic protozoa Plasmodium falciparum. Parasites were isolated that were resistant to BMS-388891, a tetrahydroquinoline (THQ) PFT inhibitor. Resistance was associated with a 12-fold decrease in drug susceptibility. Genotypic analysis revealed a single point mutation in the beta subunit in resistant parasites. The resultant tyrosine 837 to cysteine alteration in the beta subunit corresponded to the binding site for the THQ and peptide substrate. Biochemical analysis of Y837C-PFT demonstrated a 13-fold increase in BMS-388891 concentration necessary for inhibiting 50% of the enzyme activity. These data are consistent with PFT as the target of BMS-388891 in P. falciparum and suggest that PFT inhibitors should be combined with other antimalarial agents for effective therapy

The impact of predation by marine mammals on Patagonian toothfish longline fisheries

Predatory interaction of marine mammals with longline fisheries is observed globally, leading to partial or complete loss of the catch and in some parts of the world to considerable financial loss. Depredation can also create additional unrecorded fishing mortality of a stock and has the potential to introduce bias to stock assessments. Here we aim to characterise depredation in the Patagonian toothfish (Dissostichus eleginoides) fishery around South Georgia focusing on the spatio-temporal component of these interactions. Antarctic fur seals (Arctocephalus gazella), sperm whales (Physeter macrocephalus), and orcas (Orcinus orca) frequently feed on fish hooked on longlines around South Georgia. A third of longlines encounter sperm whales, but loss of catch due to sperm whales is insignificant when compared to that due to orcas, which interact with only 5% of longlines but can take more than half of the catch in some cases. Orca depredation around South Georgia is spatially limited and focused in areas of putative migration routes, and the impact is compounded as a result of the fishery also concentrating in those areas at those times. Understanding the seasonal behaviour of orcas and the spatial and temporal distribution of “depredation hot spots” can reduce marine mammal interactions, will improve assessment and management of the stock and contribute to increased operational efficiency of the fishery. Such information is valuable in the effort to resolve the human-mammal conflict for resources

A new efficient trial design for assessing reliability of ankle-brachial index measures by three different observer groups

BACKGROUND: The usual method of assessing the variability of a measure such as the ankle brachial index (ABI) as a function of different observer groups is to obtain repeated measurements. Because the number of possible observer-subject combinations is impractically large, only a few small studies on inter- and intraobserver variability of ABI measures have been carried out to date. The present study proposes a new and efficient study design. This paper describes the study methodology. METHODS: Using a partially balanced incomplete block design, six angiologists, six primary-care physicians and six trained medical office assistants performed two ABI measurements each on six individuals from a group of 36 unselected subjects aged 65–70 years. Each test subject is measured by one observer from each of the three observer groups, and each observer measures exactly six of the 36 subjects in the group. Each possible combination of two observers occurs exactly once per patient and is not repeated on a second subject. The study involved four groups of 36 subjects (144), plus standbys. RESULTS: The 192 volunteers present at the study day were similar in terms of demographic characteristics and vascular risk factors: mean age 68.6 ± 1.7; mean BMI 29.1 ± 4.6; mean waist-hip ratio 0.92 ± 0.09; active smokers 12%; hypertension 60.9%; hypercholesterolemia 53.4%; diabetic 17.2%. A complete set of ABI measurements (three observers performing two Doppler measurements each) was obtained from 108 subjects. From all other subjects at least one ABI measurement was obtained. The mean ABI was 1.08 (± 0.13), 15 (7.9%) volunteers had an ABI <0.9, and none had an ABI >1.4, i.e. a ratio that may be associated with increased stiffening of the arterial walls. CONCLUSION: This is the first large-scale study investigating the components of variability and thus reliability in ABI measurements. The advantage of the new study design introduced here is that only one sixth of the number of theoretically possible measurements is required to obtain information about measurement errors. Bland-Altman plots show that there are only small differences and no systematic bias between the observers from three occupational groups with different training backgrounds

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy