Rationale
The behavioral effects of the nicotine metabolites nornicotine and cotinine have not been investigated extensively.
Objectives
To evaluate the effects of nicotine, cotinine, and ...nornicotine, given alone or in combination, on locomotor activity and emission of ultrasonic vocalizations in male adult rats.
Methods
Rats were first given home cage nicotine injections to make them tolerant to the drug’s locomotor depressant effects. On subsequent days, locomotor activity (LMA) and ultrasonic vocalizations were recorded in an open field, for 60 min after challenge injection, using repeated measures designs. In single-drug experiments, subjects were tested with nicotine 0.05–0.4 mg/kg, cotinine 0.03–3 mg/kg, or nornicotine 0.1–10 mg/kg. In drug-combination experiments, saline or nicotine 0.2 mg/kg challenge was preceded by cotinine (0, 0.3, 3 mg/kg) or nornicotine (0, 0.1, 0.3, 1, 3 mg/kg) injection.
Results
High doses of nornicotine increased LMA and blunted the locomotor stimulant effect of nicotine. Less consistently, nicotine and high doses of nornicotine decreased the 50-kHz call rate, with no clear evidence of a nornicotine × nicotine interaction. Cotinine, given alone or before nicotine injection, altered neither LMA nor the call rate. No drug altered the relative prevalence of flat vs. trill 50-kHz call subtypes, except that the highest dose of nornicotine promoted flat calls over trills. No drug evoked 22-kHz calls.
Conclusion
Nornicotine can exert an acute anti-nicotine effect in vivo
,
as previously reported in vitro. The finding that nicotine did not detectably alter the 50-kHz call profile appears consistent with this drug’s mild subjective effects in human subjects.
Aims
Clinical features and outcomes in the novel phenotype heart failure with mid‐range ejection fraction HFmrEF, ejection fraction (EF) 40–49% were compared with heart failure with reduced EF ...(HFrEF, EF <40%) and preserved EF (HFpEF, EF ≥50%).
Methods and results
In the Swedish Heart Failure Registry, we assessed the association between baseline characteristics and EF group using multivariable logistic regressions, and the association between EF group and all‐cause mortality using multivariable Cox regressions. Of 42 061 patients, 56% had HFrEF, 21% had HFmrEF, and 23% had HFpEF. Characteristics were continuous for age (72 ± 12 vs. 74 ± 12 vs. 77 ± 11 years), proportion of women (29% vs. 39% vs. 55%), and 13 other characteristics. Coronary artery disease (CAD) was distinctly more common in HFrEF (54%) and HFmrEF (53%) vs. HFpEF (42%); adjusted odds ratio for CAD in HFmrEF vs. HFpEF was 1.52 95% confidence interval (CI) 1.41–1.63. For six additional characteristics HFmrEF resembled HFrEF, for seven characteristics HFmrEF resembled HFpEF, and for 10 characteristics there was no pattern. The adjusted hazard ratio (HR) for mortality in HFrEF vs. HFpEF was 1.35 (95% CI 1.14–1.60) at 30 days, 1.26 (95% CI 1.17–1.35) at 1 year, and 1.20 (95% CI 1.14–1.26) at 3 years. In contrast, HFmrEF and HFpEF had a similar prognosis (HR 1.06, 95% CI 0.86–1.30 at 30 days; HR 1.08, 95% CI 1.00–1.18 at 1 year; and HR 1.06, 95% CI 1.00–1.12 at 3 years). Three‐year mortality was higher in HFmrEF than in HFpEF in the presence of CAD (HR 1.11, 95% CI 1.02–1.21), but not in the absence of CAD (HR 1.02, 95% CI 0.94–1.12; P for interaction <0.001).
Conclusions
HFmrEF was an intermediate phenotype, except that CAD was more common in HFmrEF and HFrEF vs. HFpEF, crude all‐cause mortality was lower in HFmrEF and HFrEF, adjusted all‐cause mortality was lower in HFmrEF and HFpEF, and CAD portended a higher adjusted risk of death in HFmrEF and HFrEF.
Flaviviruses comprise major emerging pathogens such as dengue virus (DENV) or Zika virus (ZIKV). The flavivirus RNA genome is replicated by the RNA-dependent-RNA polymerase (RdRp) domain of ...non-structural protein 5 (NS5). This essential enzymatic activity renders the RdRp attractive for antiviral therapy. NS5 synthesizes viral RNA via a "de novo" initiation mechanism. Crystal structures of the flavivirus RdRp revealed a "closed" conformation reminiscent of a pre-initiation state, with a well ordered priming loop that extrudes from the thumb subdomain into the dsRNA exit tunnel, close to the "GDD" active site. To-date, no allosteric pockets have been identified for the RdRp, and compound screening campaigns did not yield suitable drug candidates. Using fragment-based screening via X-ray crystallography, we found a fragment that bound to a pocket of the apo-DENV RdRp close to its active site (termed "N pocket"). Structure-guided improvements yielded DENV pan-serotype inhibitors of the RdRp de novo initiation activity with nano-molar potency that also impeded elongation activity at micro-molar concentrations. Inhibitors exhibited mixed inhibition kinetics with respect to competition with the RNA or GTP substrate. The best compounds have EC50 values of 1-2 μM against all four DENV serotypes in cell culture assays. Genome-sequencing of compound-resistant DENV replicons, identified amino acid changes that mapped to the N pocket. Since inhibitors bind at the thumb/palm interface of the RdRp, this class of compounds is proposed to hinder RdRp conformational changes during its transition from initiation to elongation. This is the first report of a class of pan-serotype and cell-active DENV RdRp inhibitors. Given the evolutionary conservation of residues lining the N pocket, these molecules offer insights to treat other serious conditions caused by flaviviruses.
Looks can be deceiving Rutherford, Susan; Wan, Justin S.H.; Cohen, Joel M. ...
Evolution,
02/2021, Letnik:
75, Številka:
2
Journal Article
Recenzirano
Understanding the mechanisms underlying species divergence remains a central goal in evolutionary biology. Landscape genetics can be a powerful tool for examining evolutionary processes. We used ...genome-wide scans to genotype samples from populations of eight Angophora species. Angophora is a small genus within the eucalypts comprising common and rare species in a heterogeneous landscape, making it an appropriate group to study speciation. We found A. hispida was highly differentiated from the other species. Two subspecies of A. costata (subsp. costata and subsp. euryphylla) formed a group, while the third (subsp. leiocarpa, which is only distinguished by its smooth fruits and provenance) was supported as a distinct pseudocryptic species. Other species that are morphologically distinct could not be genetically differentiated (e. g., A. floribunda and A. subvelutina). Distribution and genetic differentiation within Angophora were strongly influenced by temperature and humidity, as well as biogeographic barriers, particularly rivers and higher elevation regions. While extensive introgression was found between many populations of some species (e. g., A. bakeri and A. floribunda), others only hybridized at certain locations. Overall, our findings suggest multiple mechanisms drove evolutionary diversification in Angophora and highlight how genome-wide analyses of related species in a diverse landscape can provide insights into speciation.
This study investigates the textural characteristics of sediments collected at eroded and deposited areas of highly severed eroded coastline of Batu Pahat, Malaysia. Samples were taken from ...systematically selected 23 locations along the 67km stretch of coastline and are extended to the fluvial sediments of the main river of Batu Pahat. Grain size distribution analysis was conducted to identify its textural characteristics and associated sedimentary transport behaviours. Sediments obtained along the coastline were fine-grained material with averaged mean size of 7.25 ϕ, poorly sorted, positively skewed and has wide distributions. Samples from eroded and deposition regions displayed no distinctive characteristics and exhibited similar profiles. The high energy condition transported the sediments as suspension, mostly as pelagic and the sediments were deposited as shallow marine and agitated deposits. The fluvial sediments of up to 3km into the river have particularly similar profile of textural characteristics with the neighbouring marine sediments from the river mouth. Profiles were similar with marine sediments about 3km opposite the main current and can go up to 10km along the current of Malacca Straits.
Display omitted
•An investigation on the detailed sediment characteristics and sediment transport pattern at severely eroded coastline.•A field work study, covering litospheres and hydrospheres.•Identification of erosion and deposition areas along the coastline.•There was no distinctive sediment transport pattern along the coastline.•The influence of incoming rivers in sediment distribution is evident.
The pathogenic role of ischemic heart disease (IHD) in heart failure (HF) with reduced ejection fraction (HFrEF; EF <40%) is well established, but its pathogenic and prognostic significance in HF ...with midrange (HFmrEF; EF 40%-50%) and preserved EF (HFpEF; EF ≥50%) has been much less explored.
We evaluated 42 987 patients from the Swedish Heart Failure Registry with respect to baseline IHD, outcomes (IHD, HF, cardiovascular events, and all-cause death), and EF change during a median follow-up of 2.2 years. Overall, 23% had HFpEF (52% IHD), 21% had HFmrEF (61% IHD), and 55% had HFrEF (60% IHD). After multivariable adjustment, associations with baseline IHD were similar for HFmrEF and HFrEF and lower in HFpEF (risk ratio, 0.91 0.89-0.93 versus HFmrEF and risk ratio, 0.90 0.88-0.92 versus HFrEF). The adjusted risk of IHD events was similar for HFmrEF versus HFrEF and lower in HFpEF (hazard ratio, 0.89 0.84-0.95 versus HFmrEF and hazard ratio, 0.84 0.80-0.90 versus HFrEF). After adjustment, prevalent IHD was associated with increased risk of IHD events and all other outcomes in all EF categories except all-cause mortality in HFpEF. Those with IHD, particularly new IHD events, were also more likely to change to a lower EF category and less likely to change to a higher EF category over time.
HFmrEF resembled HFrEF rather than HFpEF with regard to both a higher prevalence of IHD and a greater risk of new IHD events. Established IHD was an important prognostic factor across all HF types.
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