Rethinking the Composition of a Rational Antibiotic Arsenal for the 21st Century

The importance of the human microbiome in health may be the single most valuable development in our conception of the microbial world since Pasteur\u27s germ theory of the 1860s. Its implications for our understanding of health and pathogenesis are profound. Coupled with the revolution in diagnostics that we are now witnessing - a revolution that changes medicine from a science of symptoms to a science of causes - we cannot continue to develop antibiotics as we have for the past 80 years. Instead, we need to usher in a new conception of the role of antibiotics in treatment: away from single molecules that target broad phylogenetic spectra and towards targeted molecules that cripple the pathogen while leaving the rest of the microbiome largely intact

HEY LARRY! INVESTIGATING INTERRUPTIONS IN FUTURE VERTICAL LIFT PLATFORMS

Using technology to improve human performance is critical to maximizing the benefits of future combat systems. This study explores the effects of interruptions during high and low cognitive load states when completing dynamic tasks. Furthermore, it provides insight into how to integrate artificial intelligence and virtual assistants into future aircraft effectively. This research and the following analysis provided the Holistic Situation Awareness and Decision Making (HSA-DM) program office with meaningful data and recommendations that will enable them to reduce the impact of interruptions while improving the performance of future pilots. Specifically, this study collected and examined heart rate variability, subjective cognitive load, flight metrics, interruption lag, and task resumption lag while participants piloted an aircraft and performed dynamic tasks in a flight simulator. There were three different modalities used to assist participants with completing interrupted tasks while performing their primary task. The research team determined that the tactile activated artificial intelligence was the most effective at reducing total interruption time while having the smallest effects on flight performance and cognitive load.Major, United States ArmyMajor, United States ArmyCaptain, United States ArmyCaptain, United States ArmyCaptain, United States ArmyApproved for public release. Distribution is unlimited

Prototype Cryospheric Experimental Synthetic Aperture Radiometer (CESAR)

Present satellite microwave radiometers typically have a coarse spatial resolution of several kilometers or more. This is only adequate only over homogenous areas. Significantly enhanced spatial resolution is critically important to reduce the uncertainty of estimated cryospheric parameters in heterogeneous and climatically-sensitive areas. Examples include: (1) dynamic sea ice areas with frequent lead and polynya developments and variable ice thicknesses, (2) mountainous areas that require improved retrieval of snow water equivalent, and (3) melting outlet glacier or ice shelf areas along the coast of Greenland and Antarctica. For these situations and many others, an Earth surface spot size of no more than 100 m is necessary to retrieve the information needed for significant new scientific progress, including the synthesis of field observations with satellite observations with high confidence

Relationships between Irritable Bowel Syndrome Pain, Skin Temperature Indices of Autonomic Dysregulation, and Sensitivity to Thermal Cutaneous Stimulation

This study evaluated relationships between irritable bowel syndrome (IBS) pain, sympathetic dysregulation, and thermal pain sensitivity. Eight female patients with diarrhea-predominant IBS and ten healthy female controls were tested for sensitivity to thermal stimulation of the left palm. A new method of response-dependent thermal stimulation was used to maintain pain intensity at a predetermined level (35%) by adjusting thermal stimulus intensity as a function of pain ratings. Clinical pain levels were assessed prior to each testing session. Skin temperatures were recorded before and after pain sensitivity testing. The temperature of palmar skin dropped (1.5°C) when the corresponding location on the opposite hand of control subjects was subjected to prolonged thermal stimulation, but this response was absent for IBS pain patients. The patients also required significantly lower stimulus temperatures than controls to maintain a 35% pain rating. Baseline skin temperatures of patients were significantly correlated with thermode temperatures required to maintain 35% pain ratings. IBS pain intensity was not significantly correlated with skin temperature or pain sensitivity. The method of response-dependent stimulation revealed thermal hyperalgesia and increased sympathetic tone for chronic pain patients, relative to controls. Similarly, a significant correlation between resting skin temperatures and thermal pain sensitivity for IBS but not control subjects indicates that tonic sympathetic activation and a thermal hyperalgesia were generated by the chronic presence of visceral pain. However, lack of a significant relationship between sympathetic tone and ratings of IBS pain casts doubt on propositions that the magnitude of IBS pain is determined by psychological stress

In vivo UTE-MRI reveals positive effects of raloxifene on skeletal bound water in skeletally mature beagle dogs

Raloxifene positively affects mechanical properties of the bone matrix in part through modification of skeletal bound water. The goal of this study was to determine if raloxifene induced alterations in skeletal hydration could be measured in vivo using ultra-short echotime magnetic resonance imaging (UTE-MRI). Twelve skeletally mature female beagle dogs (n=6/group) were treated for 6 months with oral doses of saline vehicle (VEH, 1 ml/kg/day) or raloxifene (RAL, 0.5 mg/kg/day). Following six months of treatment, all animals underwent in vivo UTE-MRI of the proximal tibial cortical bone. UTE-MRI signal intensity versus echotime curves were analyzed by fitting a double exponential to determine the short and long relaxation times of water with the bone (dependent estimations of bound and free water, respectively). Raloxifene-treated animals had significantly higher bound water (+14%; p = 0.05) and lower free water (-20%) compared to vehicle-treated animals. These data provide the first evidence that drug-induced changes in skeletal hydration can be non-invasively assessed using UTE-MRI.Funding for this study was provided by NIH (AR 62002 and a BIRT supplement). Raloxifene was provided by through an MTA with Eli Lilly

Effect of Aquaculture-Related Diets on the Long-Term Performance and Condition of the Rock Crab, Cancer irroratus

Shellfish and salmonid aquaculture operations in Eastern Canada attract several mobile epibenthic species as a result of added structural complexity and increased food availability (bivalve fall-off and waste salmonid feed). It is not clear whether the aggregation of predators and scavengers below coastal farms contributes positively or negatively to their population dynamics, due to concerns about the quality of food items found under farms. We conducted an 18-month laboratory study to investigate the effect of diets composed of 1) mixed items, 2) mussels (Mytilus edulis), and 3) salmonid feed on the performance and condition of the rock crab, Cancer irroratus. Diet had no impact on crab survival but several negative consequences were observed in crabs fed the salmonid feed diet when compared to the mixed diet: reduced 1) moulting rates during the second growing season, 2) inter-molt growth, 3) gonad and hepatopancreas indices, 4) hemolymph dissolved compounds, 5) hepatopancreatic glycogen, and 6) shell hardness. Crabs fed the mussel diet had similar performance and condition when compared to the mixed diet. Fatty acid composition of muscle, gonad, and hepatopancreas tissues revealed that a salmonid feed diet decreased n3/n6 ratio when compared to a mixed or a mussel diet; those differences were mostly due to increases in the proportions of terrestrial (18:1n9 and 18:2n6) and decreases in proportions of marine essential (20:5n3 and 22:6n3) fatty acids. Together, these results point to a minimal impact of a mussel-only diet on crabs, whereas the salmonid feed diet resulted in negative impacts on condition. Our experimental results explored the consequences of a ‘worst-case scenario’ in which crabs were forced to feed on a single item for a long period of time; the realized impact in field settings will depend on other factors such as consumption of alternate food items underneath a farm, proportion of time spent in farms, and level of overlap between crab habitat and aquaculture facilities

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

Acknowledgments We thank Craig Irving for his assistance with NMR spectroscopy and Pat Keating, Dr. Jessica Bame, and Dr. Graeme Anderson for their assistance with HRMS.Peer reviewe

The paradox of verbal autopsy in cause of death assignment: symptom question unreliability but predictive accuracy

Background: We believe that it is important that governments understand the reliability of the mortality data which they have at their disposable to guide policy debates. In many instances, verbal autopsy (VA) will be the only source of mortality data for populations, yet little is known about how the accuracy of VA diagnoses is affected by the reliability of the symptom responses. We previously described the effect of the duration of time between death and VA administration on VA validity. In this paper, using the same dataset, we assess the relationship between the reliability and completeness of symptom responses and the reliability and accuracy of cause of death (COD) prediction. Methods: The study was based on VAs in the Population Health Metrics Research Consortium (PHMRC) VA Validation Dataset from study sites in Bohol and Manila, Philippines and Andhra Pradesh, India. The initial interview was repeated within 3-52 months of death. Question responses were assessed for reliability and completeness between the two survey rounds. COD was predicted by Tariff Method. Results: A sample of 4226 VAs was collected for 2113 decedents, including 1394 adults, 349 children, and 370 neonates. Mean question reliability was unexpectedly low (kappa = 0.447): 42.5 % of responses positive at the first interview were negative at the second, and 47.9 % of responses positive at the second had been negative at the first. Question reliability was greater for the short form of the PHMRC instrument (kappa = 0.497) and when analyzed at the level of the individual decedent (kappa = 0.610). Reliability at the level of the individual decedent was associated with COD predictive reliability and predictive accuracy. Conclusions: Families give coherent accounts of events leading to death but the details vary from interview to interview for the same case. Accounts are accurate but inconsistent; different subsets of symptoms are identified on each occasion. However, there are sufficient accurate and consistent subsets of symptoms to enable the Tariff Method to assign a COD. Questions which contributed most to COD prediction were also the most reliable and consistent across repeat interviews; these have been included in the short form VA questionnaire. Accuracy and reliability of diagnosis for an individual death depend on the quality of interview. This has considerable implications for the progressive roll out of VAs into civil registration and vital statistics (CRVS) systems

Structural Features Underlying Raloxifene’s Biophysical Interaction with Bone Matrix

Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure–activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen

Tracking CMEs using data from the Solar Stormwatch project; observing deflections and other properties

With increasing technological dependence, society is becoming ever more affected by changes in the near-Earth space environment caused by space weather. The primary driver of these hazards are coronal mass ejections (CMEs). Solar Stormwatch is a citizen science project in which volunteers participated in several activities which characterised CMEs in the remote sensing images from the SECCHI instrument package on the twin STEREO spacecraft. Here, we analyse the results of the 'Track-it-back' activity, in which CMEs were tracked back through the COR2, COR1 and EUVI images. Analysis of the COR1, COR2 and EUVI data together allows CMEs to be studied consistently throughout the whole field-of-view spanned by these instruments (out to 15 solar radii). 4783 volunteers took part in this activity, creating a dataset containing 23,801 estimates of CME timing, location and size. We used this data to produce a catalogue of 41 CMEs, which is the first to consistently track CMEs through each of these instruments. We assess how the CME speeds, propagation directions and widths vary as the CMEs propagate through the fields of view of the different imagers. In particular, we compare the observed CME deflections between the COR1 and COR2 fields of view to the separation between the CME source region and the heliospheric current sheet (HCS), demonstrating that, in general, these CMEs appear to deflect towards the HCS, consistent with other modelling studies of CME propagation