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Melioidosis is an endemic disease in numerous tropical regions. Additionally, the bacterium that causes melioidosis, Burkholderia pseudomallei , has potential to be used as a biological weapon. Therefore, development of effective and affordable medical countermeasures to serve regions affected by the disease and to have medical countermeasures available in the event of a bioterrorism attack remains critical. The current study evaluated the efficacy of eight distinct acute phase ceftazidime treatment regimens administered therapeutically in the murine model. At the conclusion of the treatment period, survival rates were significantly greater in several of the treated groups when compared to the control group. Pharmacokinetics of a single dose of ceftazidime were examined at 150 mg/kg, 300 mg/kg, and 600 mg/kg and were compared to an intravenous clinical dose administered at 2000 mg every eight hours. The clinical dose has an estimated 100% f T > 4*MIC which exceeded the highest murine dose of 300 mg/kg every six hours at 87.2% f T > 4*MIC. Based upon survival at the end of the treatment regimen and supplemented by pharmacokinetic modeling, a daily dose of 1200 mg/kg of ceftazidime, administered every 6 h at 300 mg/kg, provides protection in the acute phase of inhalation melioidosis in the murine model.

Patient outcome in anthrax is critically dependent on early diagnosis followed by effective treatment. We describe a rapid lateral flow immunoassay that detects capsular antigen of Bacillus anthracis that is shed into blood during infection. Inhalational anthrax is a fatal infectious disease. Rapid and effective treatment is critically dependent on early and accurate diagnosis. Blood culture followed by identification and confirmation may take days to provide clinically relevant information. In contrast, immunoassay for a shed antigen, the capsular polypeptide gamma- d -polyglutamate (γDPGA), can provide rapid results at the point of care. In this study, a lateral flow immunoassay for γDPGA was evaluated in a robust nonhuman primate model of inhalational anthrax. The results showed that the time to a positive result with the rapid test using either serum or blood as a clinical specimen was similar to the time after infection when a blood culture became positive. In vitro testing showed that the test was equally sensitive with cultures of the three major clades of Bacillus anthracis . Cultures from other Bacillus spp. that are known to produce γDPGA also produced positive results. The test was negative with human sera from 200 normal subjects and 45 subjects with culture-confirmed nonanthrax bacterial or fungal sepsis. Taken together, the results showed that immunoassay for γDPGA is an effective surrogate for blood culture in a relevant cynomolgus monkey model of inhalational anthrax. The test would be a valuable aid in early diagnosis of anthrax, which is critical for rapid intervention and a positive outcome. Use of the test could facilitate triage of patients with signs and symptoms of anthrax in a mass-exposure incident and in low-resource settings where laboratory resources are not readily available. IMPORTANCE Patient outcome in anthrax is critically dependent on early diagnosis followed by effective treatment. We describe a rapid lateral flow immunoassay that detects capsular antigen of Bacillus anthracis that is shed into blood during infection. The test was evaluated in a robust cynomolgus monkey model of inhalational anthrax. Rapid detection of capsular antigen is an effective surrogate for the time-consuming and laboratory-intensive diagnosis by blood culture, direct fluorescent antibody staining, or other molecular testing. The test can be performed at the point of patient contact, is rapid and inexpensive, and can be used by individuals with minimal training.

Background Chikungunya virus (CHIKV) is transmitted via mosquito bite and potentially by aerosol, causing chikungunya fever and arthritic disease in humans. There are currently no licensed vaccines or antiviral therapeutics to protect against CHIKV infection in humans. Animal models recapitulating human disease, especially for transmission by aerosol, are needed for licensure of such medical countermeasures. Methods Cynomolgus macaques (CMs) were challenged by intradermal (ID) inoculation or exposure to an aerosol containing CHIKV Ross strain at different target infectious doses (10 3 –10 7 plaque forming units (PFU)). The clinical and virologic courses of disease were monitored up to 14 days post-exposure. Results ID infection of CMs led to overt clinical disease, detectable viremia, and increased blood markers of liver damage. Animals challenged by aerosol exhibited viremia and increased liver damage biomarkers with minimal observed clinical disease. All animals survived CHIKV challenge. Conclusions We have described CHIKV infection in CMs following ID inoculation and, for the first time, infection by aerosol. Based on limited reported cases in the published literature, the aerosol model recapitulates the virologic findings of human infection via this route. The results of this study provide additional evidence for the potential use of CMs as a model for evaluating medical countermeasures against CHIKV.

Leflunomide is an experimental immunosuppressive agent that has shown efficacy as an antiviral agent against human cytomegalovirus (HCMV) and polyomavirus strain BK (BKV). An antiviral regimen has been approved for immunosuppressed patients suffering complications from HCMV infection, whereas a good treatment option for patients infected with BKV does not exist. Unfortunately, the antiviral treatment options for patients infected with HCMV have helped promote the propagation of multidrug resistant HCMV strains. New antiviral treatment options must be developed to ensure the health of immunosuppressed patients suffering from HCMV and BKV infection. This body of work illustrates the possible antiviral mechanisms associated with Leflunomide using an in vitro model system. We have tested the hypothesis that the antiviral activity of A77 1726, the active metabolite of Leflunomide, is a result of its inhibition of phosphorylation of one or more viral structural proteins. Western blot, Southern (Dot Blot) blot, and CMV gene array analysis demonstrated that Leflunomide does not inhibit HCMV DNA synthesis, the translation of essential viral proteins, or the transcription of viral mRNA. 32P-orthophosphate labeling experiments confirm a reduction in the phosphorylation of more than one of the HCMV tegument proteins. In addition, immunohistochemical staining showed discrete changes in localization of these tegument proteins in Leflunomide-treated cells. Co-immunoprecipitation experiments confirm that Leflunomide disrupts the interaction of viral tegument proteins suggesting that Leflunomide may inhibit complete infectious virion assembly by altering the phosphorylation states of one or more viral structural proteins. The second aspect of this work was to determine if Leflunomide would inhibit the replication of BKV, a polyoma virus unrelated to HCMV. We tested the hypothesis that A77 1726 would inhibit the production of infectious BKV particles without inhibiting DNA synthesis or large T antigen translation. Plaque assay data demonstrated a log decrease in viral titers when infected cells were treated with A77 1726. Western blot and Southern blot data confirmed the inhibition was not due to a block in protein translation of the large T antigen or a viral DNA synthesis. Immunohistochemistry confirmed there was no reduction of the large T antigen protein when infected cells were treated with A77 1726. When the phosphorylation of the large T antigen was assessed, no reductions in phosphorylation could be detected. Further studies must be completed to determine a definitive antiviral mechanism in respect to BKV, but our data supports the hypothesis that Leflunomide inhibits the replication of BKV in vitro.

To meet the requirements of the Animal Rule, the efficacy of monotherapy with ANTHRASIL ® (Anthrax Immune Globulin Intravenous (Human)) for inhalational anthrax was evaluated in blinded studies using rabbit and nonhuman primate models. Animals in both studies were randomized to treatment groups exposed to ~ 200 LD 50 Bacillus anthracis (Ames strain) spores by the aerosol route to induce inhalational anthrax. Rabbits (N = 50/group) were treated with either 15 U/kg ANTHRASIL or a volume-matching dose of IGIV after disease onset as determined by the detection of bacterial toxin in the blood. At the end of the study, survival rates were 2% (1 of 48) in the IGIV control group, and 26% (13 of 50) in the ANTHRASIL-treated group (p = 0.0009). Similarly, ANTHRASIL was effective in cynomolgus monkeys (N = 16/group) when administered therapeutically after the onset of toxemia, with 6% survival in the IGIV control and a dose-related increase in survival of 36%, 43%, and 70% with 7.5, 15 or 30 U/kg doses of ANTHRASIL, respectively. These studies formed the basis for approval of ANTHRASIL by FDA under the Animal Rule.

Deployment of ultracold atom interferometers (AI) into space will capitalize on quantum advantages and the extended freefall of persistent microgravity to provide high-precision measurement capabilities for gravitational, Earth, and planetary sciences, and to enable searches for subtle forces signifying physics beyond General Relativity and the Standard Model. NASA’s Cold Atom Lab (CAL) operates onboard the International Space Station as a multi-user facility for fundamental studies of ultracold atoms and to mature space-based quantum technologies. We report on pathfinding experiments utilizing ultracold 87 Rb atoms in the CAL AI. A three-pulse Mach–Zehnder interferometer was studied to understand the influence of ISS vibrations. Additionally, Ramsey shear-wave interferometry was used to manifest interference patterns in a single run that were observable for over 150 ms free-expansion time. Finally, the CAL AI was used to remotely measure the Bragg laser photon recoil as a demonstration of the first quantum sensor using matter-wave interferometry in space. NASA’s Cold Atom Lab has operated on the International Space Station since 2018 to study quantum gases and mature quantum technologies in Earth’s orbit. Here, Williams et al., report on a series of pathfinding experiments exploring the first quantum sensor using atom interferometry in space.

BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery. BAG3 is a Hsp70 co-chaperone that is highly expressed in muscles. Here the authors show that several myofibrillar myopathy causing BAG3 mutations are not impaired in Hsp70 binding, but rather impair the ADP-ATP exchange step of the Hsp70 cycle, causing the aggregation of BAG3, Hsp70 and Hsp70 clients and leading to a collapse of protein homeostasis.

Demonstration of a new, effective therapy for human anthrax disease is quite challenging, given the rarity of clinical illness. In this study, a monoclonal antibody against the protective antigen of anthrax toxin was shown to be beneficial in two animal models of anthrax infection; the dose required to achieve similar benefit in humans was determined. A monoclonal antibody against the protective antigen of anthrax toxin was shown to be beneficial in two animal models of anthrax infection; the dose required to achieve similar benefit in humans was determined. Bacillus anthracis causes anthrax, a zoonotic infection affecting a wide range of mammalian species, and it can be transmitted from animals to humans. 1 The innate hardiness of B. anthracis endospores has allowed anthrax spores to be developed as “weapons-grade” material for biologic weapons. 2 The largest outbreak of inhalational anthrax occurred in 1979 in Sverdlovsk (in the former Soviet Union), 3 and the 2001 anthrax attacks were the first confirmed outbreak associated with intentional anthrax release in the United States. 4 , 5 Inhalational anthrax exposure rapidly progresses to bacteremia and toxemia, with mortality ranging from 45 to 80%. 1 , 2 , 5 Although several antibiotics . . .

Atom interferometers deployed in space are excellent tools for high precision measurements, navigation, or Earth observation. In particular, differential interferometric setups feature common-mode noise suppression and enable reliable measurements in the presence of ambient platform noise. Here we report on orbital magnetometry campaigns performed with differential single- and double-loop interferometers in NASA’s Cold Atom Lab aboard the International Space Station. By comparing measurements with atoms in magnetically sensitive and insensitive states, we have realized atomic magnetometers mapping magnetic field curvatures. Our results pave the way towards precision quantum sensing missions in space. Atom-interferometers-based quantum sensors in space promise high-precision fundamental physics tests and geophysical applications. Here, the authors demonstrate the measurement of magnetic field curvatures via differential Bose-Einstein condensate interferometers at the NASA Cold Atom Laboratory aboard the International Space Station, by suppressing the effect of vibrational noise and improving atom source control.

The capability to reach ultracold atomic temperatures in compact instruments has recently been extended into space 1 , 2 . Ultracold temperatures amplify quantum effects, whereas free fall allows further cooling and longer interactions time with gravity—the final force without a quantum description. On Earth, these devices have produced macroscopic quantum phenomena such as Bose–Einstein condensates (BECs), superfluidity, and strongly interacting quantum gases 3 . Terrestrial quantum sensors interfering the superposition of two ultracold atomic isotopes have tested the universality of free fall (UFF), a core tenet of Einstein’s classical gravitational theory, at the 10 −12 level 4 . In space, cooling the elements needed to explore the rich physics of strong interactions or perform quantum tests of the UFF has remained elusive. Here, using upgraded hardware of the multiuser Cold Atom Lab (CAL) instrument aboard the International Space Station (ISS), we report, to our knowledge, the first simultaneous production of a dual-species BEC in space (formed from 87 Rb and 41 K), observation of interspecies interactions, as well as the production of 39 K ultracold gases. Operating a single laser at a ‘magic wavelength’ at which Rabi rates of simultaneously applied Bragg pulses are equal, we have further achieved the first spaceborne demonstration of simultaneous atom interferometry with two atomic species ( 87 Rb and 41 K). These results are an important step towards quantum tests of UFF in space and will allow scientists to investigate aspects of few-body physics, quantum chemistry and fundamental physics in new regimes without the perturbing asymmetry of gravity. Using upgraded hardware of the multiuser Cold Atom Lab (CAL) aboard the International Space Station (ISS), Bose–Einstein condensates (BECs) of two atomic isotopes are simultaneously created and used to demonstrate interspecies interactions and dual species atom interferometry in space.