Many shorebirds rely on small numbers of staging sites during long annual migrations. Numerous shorebird species are declining and understanding the importance of these staging sites is important for ...successful conservation. We surveyed endangered rufa red knots (Calidris canutus rufa) staging in James Bay, Ontario, Canada, during southbound migration in 2017 and 2018. We used mark-resight data and count data in an integrated Bayesian analysis to quantify migration phenology, estimate passage population size, and model the age structure of the stopover population. Many adult red knots arrived in James Bay in a single wave in early August in 2017, whereas adult red knots arrived in multiple smaller waves in July and mid-August in 2018. These waves may correspond with breeding phenology where more red knots bred successfully and arrived in one large event in 2017 and the higher number of earlier arrivals in July 2018 may have been failed breeders. We included a binomial generalized linear model in the integrated analysis to estimate that 20% and 10% of staging red knots were juveniles in 2017 and 2018, respectively. In future applications, this method could provide a metric to assess breeding performance and develop our understanding of its role in population declines. Overall, we estimated that up to 23% of the estimated rufa red knot population staged in southwestern James Bay for an average of 10–12 days. The region is a key staging site for endangered red knots and could be included in conservation planning.
Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and ...full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.
Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but ...may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard to inhibition of angiogenesis. N-methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.
Shorebirds are thought to be declining across North America but trend analyses for migrant shorebirds at interior sites in eastern North America have not been updated since the late 1990s. Data from ...a volunteer-based survey at stopover sites throughout Ontario were used to assess population trends of shorebirds over the period 1974–2009. Surveyors carried out 7,135 surveys of 258 sites and recorded 538,744 individuals of 43 shorebird species. Of 19 taxa for which trends were estimated, 17 appeared to be declining in abundance. Precision of the trend estimates was generally poor and only three declines were significant at α = 0.05. Total numbers of shorebirds recorded on surveys declined by four per cent per year, resulting in an estimated decrease in abundance of greater than 75% over the 35 years of observation. Rate of decline may be increasing for some species as declines for twelve species were larger for the period 1989–2009 vs. 1974–1989, and six species showed significant declines in the latter period whereas none did in the former period. Relating these declines in abundance at the surveyed sites to population declines is complicated by several potential sources of survey bias including changes in turnover rates and in migration timing and distributions of the species. However, given that these results are consistent with those of other migration surveys as well as those on the breeding and the wintering grounds, the most parsimonious explanation remains a widespread decline in shorebird populations.
Inhibition of the constitutively active casein kinase 2 (CK2) with 2-dimethyl-amino-4,5,6,7-tetrabromo-1H-benzimidasole stimulates the Na
+
-dependent taurine influx via the taurine transporter TauT ...in NIH3T3 cells. CK2 inhibition reduces the TauT mRNA level and increases the localization of TauT to ER but has no detectable effect on TauT protein expression. On the other hand, CK2 inhibition increases the affinity of TauT towards Na
+
and reduces the Na
+
/taurine stoichiometry for active taurine uptake. It is suggested that CK2 controls the cellular taurine uptake in unperturbated NIH3T3 cells, i.e., inhibition of CK2 increases the affinity of TauT towards Na
+
and hence Na
+
-dependent taurine uptake.
Recent years have seen a growth in academic literature proposing a variety of ecosocial policies that seek to simultaneously advance environmental and social goals. However, the many proposals ...largely remain fragmented and scattered, making it difficult to see the ecosocial project as a broader coherent political agenda. This paper seeks to address this issue, through a systematic literature review, focusing on ecosocial proposals that directly or indirectly facilitate a downscaling of production and consumption in high-income countries. The review revealed 126 different policy proposals across 73 academic texts. These were categorized into five broad themes: democracy & participation, income & employment, redistributive taxation, consumption regulation, and social services. The categories illustrate the ecosocial project as consisting of unifying goals associated with these five themes. While the existing literature illustrates that the ecosocial project has much to offer in terms of addressing the socio-ecological and democratic crises in high-income countries, considerable gaps remain. Specifically, more research is arguably needed on (1) political strategy (2) detailing of individual policy proposals and (3) policy mixes.
Congenital cytomegalovirus (CMV) infection is a major cause of birth defects ranging from developmental disorders to stillbirth. Most newborns affected by CMV do not present with symptoms at birth ...but are at risk of sequelae at later stages of their childhood. Stored dried blood spots (DBS) taken at birth can be used for retrospective diagnosis of hereditary diseases, but detection of pathogens is challenged by potentially low pathogen concentrations in the small blood volume available in a DBS. Here we test four different extraction methods for optimal recovery of CMV DNA from DBS at low to high CMV titers. The recovery efficiencies varied widely between the different extractions (from 3% to 100%) with the most efficient method extracting up to 113-fold more CMV DNA than the least efficient and 8-fold more than the reference protocol. Furthermore, we amplified four immunomodulatory CMV genes from the extracted DNA: the UL40 and UL111A genes which occur as functional knockouts in some circulating CMV strains, and the highly variable UL146 and US28 genes. The PCRs specifically amplified the CMV genes at all tested titers with sufficient quality for sequencing and genotyping. In summary, we here report an extraction method for optimal recovery of CMV DNA from DBSs that can be used for both detection of CMV and for genotyping of polymorphic CMV genes in congenital CMV infection.
The continued occurrence of more contagious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants and waning immunity over time require ongoing reevaluation of the vaccine ...effectiveness (VE). This study aimed to estimate the effectiveness in 2 age groups (12 to 59 and 60 years or above) of 2 or 3 vaccine doses (BNT162b2 mRNA or mRNA-1273) by time since vaccination against SARS-CoV-2 infection and Coronavirus Disease 2019 (COVID-19) hospitalization in an Alpha-, Delta-, or Omicron-dominated period.
A Danish nationwide cohort study design was used to estimate VE against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha, Delta, or Omicron variant. Information was obtained from nationwide registries and linked using a unique personal identification number. The study included all previously uninfected residents in Denmark aged 12 years or above (18 years or above for the analysis of 3 doses) in the Alpha (February 20 to June 15, 2021), Delta (July 4 to November 20, 2021), and Omicron (December 21, 2021 to January 31, 2022) dominated periods. VE estimates including 95% confidence intervals (CIs) were calculated (1-hazard ratio∙100) using Cox proportional hazard regression models with underlying calendar time and adjustments for age, sex, comorbidity, and geographical region. Vaccination status was included as a time-varying exposure. In the oldest age group, VE against infection after 2 doses was 90.7% (95% CI: 88.2; 92.7) for the Alpha variant, 82.3% (95% CI: 75.5; 87.2) for the Delta variant, and 39.9% (95% CI: 26.3; 50.9) for the Omicron variant 14 to 30 days since vaccination. The VE waned over time and was 73.2% (Alpha, 95% CI: 57.1; 83.3), 50.0% (Delta, 95% CI: 46.7; 53.0), and 4.4% (Omicron, 95% CI: -0.1; 8.7) >120 days since vaccination. Higher estimates were observed after the third dose with VE estimates against infection of 86.1% (Delta, 95% CI: 83.3; 88.4) and 57.7% (Omicron, 95% CI: 55.9; 59.5) 14 to 30 days since vaccination. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 98.1% or above for the Alpha and Delta variants. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 95.5% or above for the Omicron variant. The main limitation of this study is the nonrandomized study design including potential differences between the unvaccinated (reference group) and vaccinated individuals.
Two vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha and Delta variants with protection, notably against infection, waning over time. Two vaccine doses provided only limited and short-lived protection against SARS-CoV-2 infection with Omicron. However, the protection against COVID-19 hospitalization following Omicron SARS-CoV-2 infection was higher. The third vaccine dose substantially increased the level and duration of protection against infection with the Omicron variant and provided a high level of sustained protection against COVID-19 hospitalization among the +60-year-olds.
We generate and characterize entangled states of a register of 20 individually controlled qubits, where each qubit is encoded into the electronic state of a trapped atomic ion. Entanglement is ...generated amongst the qubits during the out-of-equilibrium dynamics of an Ising-type Hamiltonian, engineered via laser fields. Since the qubit-qubit interactions decay with distance, entanglement is generated at early times predominantly between neighboring groups of qubits. We characterize entanglement between these groups by designing and applying witnesses for genuine multipartite entanglement. Our results show that, during the dynamical evolution, all neighboring qubit pairs, triplets, most quadruplets, and some quintuplets simultaneously develop genuine multipartite entanglement. Witnessing genuine multipartite entanglement in larger groups of qubits in our system remains an open challenge.
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