The capacity of hydrazone bonds to readily undergo component exchange processes sees their extensive utilization in dynamic combinatorial chemistry. The kinetics of hydrazone exchange are optimal at ...pH ∼4.5, which limits the use of hydrazone-based dynamic combinatorial libraries, particularly for biological targets which are only stable at near-neutral pH values. It would thus be advantageous if hydrazone exchange proceeded with faster rates at pH values closer to neutral. We experimentally and computationally evaluated the hypothesis that hydrazones possessing neighbouring acidic or basic functional groups within the carbonyl-derived moitety of the hydrazone would enhance exchange rates. Our work suggests that judiciously placed
N
- or
O
-hydrogen bond acceptors within the carbonyl-derived moiety of the hydrazone stabilize transition states
via
hydrogen bonding interactions, providing a valuable boost to exchange kinetics at near-neutral pH values. We anticipate these findings will be of interest in dynamic combinatorial chemistry, dynamic covalent polymers/materials, functionalized nanoparticles and interlocked molecules, all of which may benefit from hydrazone exchange processes able to operate at near-neutral pH values.
Hydrogen-bond acceptors (A) stabilize the transition state, lowering the energy barrier to rapid hydrazone exchange, without need for exogenous catalyst.
Traditionally, megakaryocytes (MK) are known for platelet generation; with their role as regulators of hematopoietic stem cells (HSC) only recently being appreciated. While it is generally accepted ...high ploidy MK produce platelets, we have now identified that the vast majority of platelets are generated from a novel sub-population of MK, large cytoplasmic MK (LCM). When prospectively isolated from mouse marrow and transplanted, LCM readily form platelets in vivo. We have further characterized LCM using flow cytometry, TEM and performed mitochondrial network analysis via confocal microscopy. Importantly, we have identified this MK sub-population to be critical negative regulators of HSC. Using a mouse model with normal MK numbers, but essentially devoid of LCM (LCMKO), we demonstrate pronounced thrombocytopenia and significantly increased HSC pool concurrent with endogenous mobilization. Furthermore, we identified LCM negative regulation of HSC is via thrombopoietin, platelet factor-4 and thrombin-cleaved osteopontin. Thrombocytopenia, the absence of LCM and an increased HSC pool were recapitulated when HSC isolated from LCMKO mice were used to reconstitute hematopoiesis in irradiated mice. In contrast, following a competitive transplant using minimal numbers of WT HSC with HSC from LCMKO mice, WT HSC were capable of recapitulating the LCM population, preventing thrombocytopenia and resulting in a normal HSC pool. Importantly, we provide evidence that LCM is conserved in humans, where we hypothesize they have similar functions. LCM are an important component of the niche, regulating HSC as well as generating platelets; therefore, therapeutic efforts to increase platelet production needs to specifically increase LCM. Furthermore, by understanding how different MK sub-populations regulate HSC, we will better understand the mechanisms governing steady-state hematopoiesis.
Abstract
Blue food systems are crucial for meeting global social and environmental goals. Both small-scale marine fisheries (SSFs) and aquaculture contribute to these goals, with SSFs supporting ...hundreds of millions of people and aquaculture currently expanding in the marine environment. Here we examine the interactions between SSFs and aquaculture, and the possible combined benefits and trade-offs of these interactions, along three pathways: (1) resource access and rights allocation; (2) markets and supply chains; and (3) exposure to and management of risks. Analysis of 46 diverse case studies showcase positive and negative interaction outcomes, often through competition for space or in the marketplace, which are context-dependent and determined by multiple factors, as further corroborated by qualitative modeling. Results of our mixed methods approach underscore the need to anticipate and manage interactions between SSFs and aquaculture deliberately to avoid negative socio-economic and environmental outcomes, promote synergies to enhance food production and other benefits, and ensure equitable benefit distribution.
The effects of hypothermia on memory formation have been examined extensively, and while it is clear that post-training cooling interferes with the process of consolidation, the nature of the ...temperature sensitive processes disrupted in this way remain poorly defined. Post-training manipulations that disrupt consolidation tend to be effective during specific time-windows of sensitivity, the timing and duration of which are directly related to the mechanism through which the treatment induces amnesia. As such, different treatments that target the same basic processes should be associated with similar time-windows of sensitivity. Using this rationale we have investigated the possibility that cooling induced blockade of long-term memory (LTM) stems from the disruption of protein synthesis. By varying the timing of post-training hypothermia we have determined the critical period during which cooling disrupts the consolidation of appetitive long-term memory in the pond snail
Lymnaea. Post-training hypothermia was found to disrupt LTM only when applied immediately after conditioning, while delaying the treatment by 10
min left the 24
h memory trace intact. This brief (<10
min) window of sensitivity differs from the time-window we have previously described for the protein synthesis inhibitor anisomycin, which was effective during at least the first 30
min after conditioning Fulton, D., Kemenes, I., Andrew, R. J., & Benjamin, P. R. (2005). A single time-window for protein synthesis-dependent long-term memory formation after one-trial appetitive conditioning.
European Journal of Neuroscience, 21, 1347–1358. We conclude that hypothermia and protein synthesis inhibition exhibit distinct time-windows of effectiveness in
Lymnaea, a fact that is inconsistent with the hypothesis that cooling induced amnesia occurs through the direct disruption of macromolecular synthesis.
We report an approach to enhance simultaneously luminescence and SERS signals with a single excitation wavelength by co-encapsulating silicon quantum dots and Au-Ag alloy nanoparticles encoded with ...Raman reporter molecules inside polymeric nanoparticles. The SERS-luminescence enhancement exploits the large Stokes shift of silicon quantum dots, which allows 'room' for the display of a Raman spectrum.
Luminescence and SERS signals are simultaneously enhanced with a single excitation wavelength by co-encapsulating silicon quantum dots and Au-Ag alloy nanoparticles encoded with Raman reporter molecules inside polymeric nanoparticles.
STUDY DESIGN.Prospective population-based cohort study.
OBJECTIVE.To identify early predictors of lumbar spine surgery within 3 years after occupational back injury.
SUMMARY OF BACKGROUND DATA.Back ...injuries are the most prevalent occupational injury in the United States. Few prospective studies have examined early predictors of spine surgery after work-related back injury.
METHODS.Using Disability Risk Identification Study Cohort (D-RISC) data, we examined the early predictors of lumbar spine surgery within 3 years among Washington State workers, with new workers compensation temporary total disability claims for back injuries. Baseline measures included worker-reported measures obtained approximately 3 weeks after claim submission. We used medical bill data to determine whether participants underwent surgery, covered by the claim, within 3 years. Baseline predictors (P < 0.10) of surgery in bivariate analyses were included in a multivariate logistic regression model predicting lumbar spine surgery. The area under the receiver operating characteristic curve of the model was used to determine the modelʼs ability to identify correctly workers who underwent surgery.
RESULTS.In the D-RISC sample of 1885 workers, 174 (9.2%) had a lumbar spine surgery within 3 years. Baseline variables associated with surgery (P < 0.05) in the multivariate model included higher Roland-Morris Disability Questionnaire scores, greater injury severity, and surgeon as first provider seen for the injury. Reduced odds of surgery were observed for those younger than 35 years, females, Hispanics, and those whose first provider was a chiropractor. Approximately 42.7% of workers who first saw a surgeon had surgery, in contrast to only 1.5% of those who saw a chiropractor. The area under the receiver operating characteristic curve of the multivariate model was 0.93 (95% confidence interval, 0.92–0.95), indicating excellent ability to discriminate between workers who would versus would not have surgery.
CONCLUSION.Baseline variables in multiple domains predicted lumbar spine surgery. There was a very strong association between surgery and first provider seen for the injury even after adjustment for other important variables.
In addition to characteristic fatty acid methyl esters (FAMEs), biodiesel produced from Isochrysis sp. contains a significant amount (14%, w/w) of predominantly C37 and C38 long-chain alkenones. ...These compounds are members of a class of lipids known collectively as polyunsaturated long-chain alkenones (PULCAs) that are produced by a range of other prymnesiophyte taxa. The physical properties of alkenones, such as high melting points (∼60 °C), renders the direct product unsuitable for use as a diesel fuel but, nonetheless, represents an important and as yet unexplored renewable carbon feedstock.
Polymer-Scaffolded Dynamic Combinatorial Libraries (PS-DCLs) have been prepared in aqueous solution by the reversible conjugation of two different acylhydrazide residues onto aldehyde-functionalized ...dimethylacrylamide-based polymer scaffolds. PS-DCLs have been shown by super(1)H NMR spectroscopic analysis to adapt their composition in response to addition of three macromolecular template species, namely poly(sodium-4-styrenesulfonate), bovine serum albumin and bovine trypsin. Compositional changes within PS-DCLs in response to template addition may be rationalized in terms of multivalent interactions between members of the PS-DCL and templates. A systematic evaluation of how properties of the polymer scaffold, including molecular weight and density of aldehyde functionalities, affect the behaviour of resultant PS-DCLs is detailed. Increasing the molecular weight of the polymer scaffold has been shown to induce a linear decrease in the amplification of the preferred residue upon template addition. A linear relationship between the molar weight percentage of the aldehyde functionalized monomer and the extent of amplification of the preferred residue upon template addition has also been demonstrated.
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