Nucleotide sequence of phenylalanine transfer ribonucleic acid from pea (Pisum sativum, Alaska).

Phenylalanine transfer ribonucleic acid from peas (Pisum sativum, Alaska) was completely digested with beef pancreatic ribonuclease (RNase I) and with ribonuclease T1. The resulting oligonucleotides were compared with those from the corresponding hydrolyses of phenylalanine transfer ribonucleic acid from wheat germ. The structures of both ribonucleic acids appeared to be identical. This report is the first to show that identical structures for the same specific acceptor transfer ribonucleic acid are present in two different plant species.     

Revisiting catalysis by chymotrypsin family serine proteases using peptide substrates and inhibitors with unnatural main chains.

Chymotrypsin family serine proteases play essential roles in key biological and pathological processes and are frequently targets of drug discovery efforts. This large enzyme family is also among the most advanced model systems for detailed studies of enzyme mechanism and structure/function relationships. Productive interactions between these enzymes and their substrates are widely believed to mimic the "canonical" interactions between serine proteases and "standard" inhibitors observed in numerous protease-inhibitor complexes. To test this central hypothesis we have synthesized and characterized a series of peptide analogs, based on model substrates and inhibitors of trypsin, that contain unnatural main chains. These results call into question a long accepted theory regarding the interaction of chymotrypsin family serine proteases with substrates and suggest that the canonical interactions observed between these enzymes and standard inhibitors may represent nonproductive rather than productive, substrate-like interactions.     

American alligator (Alligator mississippiensis) weight gain in captivity and implications for captive reptile body condition

The body condition of an animal is an indicator of health status and is dependent upon many factors, some of which can vary between wild and captive settings. Despite this, there have not been many studies on how captivity affects body condition relative to wild animal populations. This study explores the body condition of captive and wild American alligators (Alligator mississippiensis) because reptiles are frequently overlooked in studies of captive animal health and because alligators are well-represented in captivity. We collected body condition data from 209 captive alligators and 935 wild alligators throughout Florida and southeastern Georgia and compared the relationships between body condition and body length for each group. We found that captive alligators exhibited significantly higher body condition values as they aged, and that this result was driven by the difference between captive and wild males. Body condition values for captive juveniles did not differ from wild juveniles, but they differed when comparing adults. Our results suggest that factors such as diet and movement rates play major roles in determining alligator body condition and that body condition may be an important metric for monitoring captive alligator health, especially for older adult males.     

Regulation of surface topography of mouse peritoneal cells. Formation of microvilli and vesiculated pits on omental mesothelial cells by serum and other proteins

The mesothelial cells of the mouse omentum provide an in vivo model for the study of the mobilization of labile microvilli on the cell surface. These mesothelial cells are sparsely covered with microvilli and large pits 150--400 nm in diameter, termed vesiculated pits. On the unstimulated cell, the microvilli average 44/100 microns2 and pits, 30/100 microns 2 of surface and they are rapidly induced to increase in number by the intraperitoneal injection of isologous mouse serum. After 2 min, microvilli increase threefold, continue to sevenfold at 30 min, and decrease to fourfold at 90 min. Vesiculated pits increased with similar kinetics. Bovine serum albumin and gamma globulin also stimulate the microvilli and pits to form, but the response is a slow, gradual rise to five- or sixfold the normal value at 90 min. Evidence indicates that multiple factors, possibly including insulin and immunoglobulins, are involved in the effect of serum. The close physical and temporal relationship between microvilli and pits suggests that a correlation exists in their mobilization by the cell and it is hypothesized that microvilli function in the regulation of the cortical microfilament network in effecting this mobilization.     

Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models

Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC₅₀ values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3β to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.     

Fractal modeling of human isochronous serial interval production

The Hurst exponent (H) was estimated for series of 256 time intervals produced by human participants, collected in 5 sessions performed on different days. Each series was obtained during the continuation phase following synchronization with 25 isochronous intervals generated by a computer and presented through headphones. Dispersional analysis yielded estimates of H > 0.5. These were sufficiently stable to yield statistically significant differences between participants and between each target interval duration (0.5, 0.8, 1.1, and 1.5s). The results indicate that variability in isochronous serial interval production (ISIP) can be modeled as fractional Gaussian noise, which corroborates and qualifies previous research indicating positive serial dependency or long memory in ISIP data in terms of drift and 1/f noise characteristics. It is concluded that ISIP is a more complex process than is assumed by influential timing models and theories, and that realistic modeling of human timing must account for nonlinear variability patterns.Abbreviations Bm Brownian motion - f frequency - fGn fractional Gaussian noise - H Hurst exponent - ISIP isochronous serial interval production - IOI inter onset interval     

Synthesis and biological activity of macrocyclic inhibitors of hepatitis C virus (HCV) NS3 protease

The 17-membered phenylalanine-based macrocycle 6 was prepared starting from 3-iodo-phenylalanine. Macrocyclization of alkene phenyl iodide 5 was effected through a palladium-catalyzed Heck reaction. The macrocyclic alpha-ketoamides were active inhibitors of the HCV NS3 protease, with the C-terminal acids and amides being more potent than tert-butyl esters.     

Hepatitis C virus NS3-4A serine protease inhibitors: use of a P2-P1 cyclopropyl alanine combination for improved potency

Modification of the P(2) and P(1) side chains of earlier P(3)-capped alpha-ketoamide inhibitor of HCV NS3 serine protease 1 resulted in the discovery of compound 24 with about 10-fold improvement in potency.     

State-dependent heterogeneity in synaptic depression between pyramidal cell pairs

Paired recordings between CA3 pyramidal neurons were used to study the properties of synaptic plasticity in active and silent synapses. Synaptic depression is accompanied by decreases in both AMPAR and NMDAR function. The mechanisms of synaptic depression, and the potential to undergo activity-dependent plastic changes in efficacy, differ depending on whether a synapse is active, recently silent, or potentiated. These results suggest that silent and active synapses represent distinct synaptic "states," and that once unsilenced, synapses express plasticity in a graded manner. The state in which a synapse resides, and the states recently visited, determine its potential and mechanism for undergoing subsequent plastic changes.     

Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation

The activation of silent synapses is a proposed mechanism to account for rapid increases in synaptic efficacy such as long-term potentiation (LTP). Using simultaneous recordings from individual pre- and postsynaptic neurons in organotypic hippocampal slices, we show that two CA3 neurons can be connected entirely by silent synapses. Increasing release probability or application of cyclothiazide does not produce responses from these silent synapses. Direct measurement of NMDAR-mediated postsynaptic responses in all-silent synaptic connections before and after LTP induction show no change in failure rate, amplitude, or area. These data do not support hypotheses that synapse silent results from presynaptic factors or that LTP results from increases in presynaptic glutamate release. LTP is also associated with an increase in postsynaptic responsiveness to exogenous AMPA. We conclude that synapse silence, activation, and expression of LTP are postsynaptic.