Infectious diseases are common in marine environments, but the effects of a changing climate on marine pathogens are not well understood. Here we review current knowledge about how the climate drives ...host-pathogen interactions and infectious disease outbreaks. Climate-related impacts on marine diseases are being documented in corals, shellfish, finfish, and humans; these impacts are less clearly linked for other organisms. Oceans and people are inextricably linked, and marine diseases can both directly and indirectly affect human health, livelihoods, and well-being. We recommend an adaptive management approach to better increase the resilience of ocean systems vulnerable to marine diseases in a changing climate. Land-based management methods of quarantining, culling, and vaccinating are not successful in the ocean; therefore, forecasting conditions that lead to outbreaks and designing tools/approaches to influence these conditions may be the best way to manage marine disease.
Twenty-four percent of all U.S. opioid overdose deaths involve a prescription opioid. Changing prescribing practices is considered a key step in reducing opioid overdoses. Primary care providers ...(PCPs) commonly lack the patient engagement skills needed to address patient resistance to taper or end opioid prescriptions. We developed and evaluated a protocol aimed at improving PCP opioid-prescribing patterns and modeled on the evidence-based Screening, Brief Intervention, and Referral to Treatment (SBIRT) approach. We conducted a time series trial comparing provider opioid prescribing 8 months before and 8 months after training with the PRomoting Engagement for Safe Tapering of Opioids (PRESTO) protocol. The 148 Ohio PCPs who completed PRESTO training gained confidence in their ability to engage their patients on the topics of opioid overdose risk and potential opioid tapering. Promoting Engagement for Safe Tapering of Opioids participants had decreased opioid-prescribing over time, but this was not significantly different from Ohio PCPs who had not received PRESTO training. Participants completing PRESTO training had small, but significant increased buprenorphine prescribing over time compared with Ohio PCPs who had not received PRESTO training. The PRESTO approach and opioid risk pyramid warrant further study and validation.
The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological ...properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.
When estimating mortality from disease with fish population models, common disease surveillance data such as infection prevalence are not always informative, especially for fast-acting diseases that ...may go unobserved in infrequently sampled populations. In these cases, seroprevalence — the proportion of fish with measurable antibody levels in their blood — may be more informative. In cases of life-long immunity, seroprevalence data require less frequent sampling intervals than infection prevalence data and can reflect the cumulative exposure history of fish. We simulation tested the usefulness of seroprevalence data in an age-structured fish stock assessment model using viral hemorrhagic septicemia virus (VHSV) in Pacific herring (Clupea pallasii) as a case study. We developed a novel epidemiological model to simulate population dynamics and seroprevalence data and fitted to these data in an integrated catch-at-age model with equations that estimate age- and time-varying mortality from disease. We found that simulated seroprevalence data can provide accurate estimates of infection history and disease-associated mortality. Importantly, even models that misspecified nonstationary processes in background or disease-associated mortality, but included seroprevalence data, accurately estimated annual infection and population abundance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sterol regulatory element-binding proteins (SREBPs) are master transcriptional regulators of the mevalonate pathway and lipid metabolism and represent an attractive therapeutic target for lipid ...metabolic disorders. SREBPs are maintained in the endoplasmic reticulum (ER) in a tripartite complex with SREBP cleavage-activating protein (SCAP) and insulin-induced gene protein (INSIG). When new lipid synthesis is required, the SCAP-SREBP complex dissociates from INSIG and undergoes ER-to-Golgi transport where the N-terminal transcription factor domain is released by proteolysis. The mature transcription factor translocates to the nucleus and stimulates expression of the SREBP gene program. Previous studies showed that dipyridamole, a clinically prescribed phosphodiesterase (PDE) inhibitor, potentiated statin-induced tumor growth inhibition. Dipyridamole limited nuclear accumulation of SREBP, but the mechanism was not well resolved. In this study, we show that dipyridamole selectively blocks ER-to-Golgi movement of the SCAP-SREBP complex and that this is independent of its PDE inhibitory activity.
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•Dipyridamole, a PDE inhibitor, decreases lipogenesis by inhibiting SREBP maturation•Dipyridamole blocks SREBP independent of its PDE inhibitory action•A clickable photoprobe dipyridamole derivative binds to INSIG and SCAP•Dipyridamole derivatives are potentially therapeutic for lipid disorders
Esquejo et al. report that dipyridamole, an FDA-approved anti-thrombotic phosphodiesterase (PDE) inhibitor, impedes endoplasmic reticulum to Golgi trafficking of sterol regulatory element-binding proteins (SREBPs) preventing their activation. A chemically modified version of dipyridamole that has no effect on PDE remains effective at SREBP blockage.
Echinoderms, positioned taxonomically at the base of deuterostomes, provide an important system for the study of the evolution of the immune system. However, there is little known about the cellular ...components and genes associated with echinoderm immunity. The 2013-2014 sea star wasting disease outbreak is an emergent, rapidly spreading disease, which has led to large population declines of asteroids in the North American Pacific. While evidence suggests that the signs of this disease, twisting arms and lesions, may be attributed to a viral infection, the host response to infection is still poorly understood. In order to examine transcriptional responses of the sea star Pycnopodia helianthoides to sea star wasting disease, we injected a viral sized fraction (0.2 μm) homogenate prepared from symptomatic P. helianthoides into apparently healthy stars. Nine days following injection, when all stars were displaying signs of the disease, specimens were sacrificed and coelomocytes were extracted for RNA-seq analyses. A number of immune genes, including those involved in Toll signaling pathways, complement cascade, melanization response, and arachidonic acid metabolism, were differentially expressed. Furthermore, genes involved in nervous system processes and tissue remodeling were also differentially expressed, pointing to transcriptional changes underlying the signs of sea star wasting disease. The genomic resources presented here not only increase understanding of host response to sea star wasting disease, but also provide greater insight into the mechanisms underlying immune function in echinoderms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We characterized a natural sea louse epizootic of Caligus clemensi and the effects of parasitism on Pacific herring Clupea pallasii in Port Angeles Harbor, WA, USA. Infestation prevalence on newly ...metamorphosed age 0 Pacific herring reached 100% prevalence by mid-August. At this time, the mean louse intensity was 4.6 lice/fish, and a positive correlation occurred between louse intensity and herring body length. The epizootic then waned, with infestation prevalence decreasing to less than 25% and the mean parasite intensity falling below 1 louse. While skin injuries were not detected, motile lice preferentially aggregated around head and anterior dorsal areas. However, louse tropism became evenly distributed over the body as the parasite intensity increased. Louse-induced mortality in herring was negligible in controlled experiments. These results indicate that Caligus clemensi epizootics reach high prevalence, but also fade from mid-summer to early fall. Due to the predominant presence of motile copepod stages, we suggest that the epizootic fades because lice complete their life cycle and dislodge from the host; however, multiple explanations for epidemic fading are possible.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Finding time in the medical curriculum to focus on motivational interviewing (MI) training is a challenge in many medical schools. We developed a software-based training tool, "Real-time Assessment ...of Dialogue in Motivational Interviewing" (ReadMI), that aims to advance the skill acquisition of medical students as they learn the MI approach. This human-artificial intelligence teaming may help reduce the cognitive load on a training facilitator.
During their Family Medicine clerkship, 125 third-year medical students were scheduled in pairs to participate in a 90-minute MI training session, with each student doing two role-plays as the physician. Intervention group students received both facilitator feedback and ReadMI metrics after their first role-play, while control group students received only facilitator feedback.
While students in both conditions improved their MI approach from the first to the second role-play, those in the intervention condition used significantly more open-ended questions, fewer closed-ended questions, and had a higher ratio of open to closed questions.
MI skills practice can be gained with a relatively small investment of student time, and artificial intelligence can be utilized both for the measurement of MI skill acquisition and as an instructional aid.
Pacific herring (
), a cornerstone of marine food webs, generally spawn on marine macroalgae in shallow nearshore areas that are disproportionately at risk from oil spills. Herring embryos are also ...highly susceptible to toxicity from chemicals leaching from oil stranded in intertidal and subtidal zones. The water-soluble components of crude oil trigger an adverse outcome pathway that involves disruption of the physiological functions of cardiomyocytes in the embryonic herring heart. In previous studies, impaired ionoregulation (calcium and potassium cycling) in response to specific polycyclic aromatic hydrocarbons (PAHs) corresponds to lethal embryolarval heart failure or subtle chamber malformations at the high and low ends of the PAH exposure range, respectively. Sublethal cardiotoxicity, which involves an abnormal outgrowth (ballooning) of the cardiac ventricular chamber soon after hatching, subsequently compromises juvenile heart structure and function, leading to pathological hypertrophy of the ventricle and reduced individual fitness, measured as cardiorespiratory performance. Previous studies have not established a threshold for these sublethal and delayed-in-time effects, even with total (∑)PAH exposures as low as 29 ng/g of wet weight (tissue dose). Here, we extend these earlier findings showing that (1)
gene expression provides an oil exposure metric that is more sensitive than typical quantitation of PAHs via GC-MS and (2) heart morphometrics in herring embryos provide a similarly sensitive measure of toxic response. Early life stage injury to herring (impaired heart development) thus occurs below the quantitation limits for PAHs in both water and embryonic tissues as a conventional basis for assessing oil-induced losses to coastal marine ecosystems.
Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, ...difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1–FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.
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