How do morphological sharpness measures relate to puncture performance in viperid snake fangs?

It makes intuitive sense that you need a sharp tool to puncture through a tough material. The typical approach to evaluating sharpness in biological puncturing tools is to treat morphological measurements as a proxy for puncture ability. However, there are multiple approaches to measuring sharpness, and the relative influence of morphology on function remains unclear. Our goal is to determine what aspects of tip morphology have the greatest impact on puncture ability, using ( a) viper fangs and ( b) engineered punches to isolate the effects of different sharpness measures. Our results indicate that tip included angle is the strongest predictor of puncture performance in both viper fangs and engineered punches. For puncture tools with small included angles, sharpness index (based on the radius of curvature) also affects puncture ability. Finally, we found that punches serve as good predictors of fang performance at small angles and sharpness index values.

The influence of cactus spine surface structure on puncture performance and anchoring ability is tuned for ecology.

Spines are common morphological features found in almost all major biological groups offering an opportunity to explore large-scale evolutionary convergence across disparate clades. As an example, opuntioid cacti have spines with barbed ornamentation that is remarkably similar in form and scale to that found on porcupine quills, suggesting specific biomechanical convergence across the animal and plant kingdoms. While the mechanics of porcupine quills as defensive mechanisms has been previously tested, the mechanics of cactus spines (which have evolved to fill a number of functions including defence, climbing and dispersal) has not been characterized. Here we study the puncturing and anchoring ability of six species of cactus, including both barbed and non-barbed spines. We found that barbed spines require less work to puncture a variety of targets than non-barbed spines. Barbed spines also require more work than non-barbed spines to withdraw from biological materials, owing to their barbs engaging with tissue fibres. These results closely match those found previously for barbed versus non-barbed porcupine quills, implying biomechanical convergence. The variation in performance of barbed versus non-barbed spines, as well as between barbed spines from different species, is probably tied to the diversity of ecological functions of cactus spines.

The comparative hydrodynamics of rapid rotation by predatory appendages.

Countless aquatic animals rotate appendages through the water, yet fluid forces are typically modeled with translational motion. To elucidate the hydrodynamics of rotation, we analyzed the raptorial appendages of mantis shrimp (Stomatopoda) using a combination of flume experiments, mathematical modeling and phylogenetic comparative analyses. We found that computationally efficient blade-element models offered an accurate first-order approximation of drag, when compared with a more elaborate computational fluid-dynamic model. Taking advantage of this efficiency, we compared the hydrodynamics of the raptorial appendage in different species, including a newly measured spearing species, Coronis scolopendra The ultrafast appendages of a smasher species (Odontodactylus scyllarus) were an order of magnitude smaller, yet experienced values of drag-induced torque similar to those of a spearing species (Lysiosquillina maculata). The dactyl, a stabbing segment that can be opened at the distal end of the appendage, generated substantial additional drag in the smasher, but not in the spearer, which uses the segment to capture evasive prey. Phylogenetic comparative analyses revealed that larger mantis shrimp species strike more slowly, regardless of whether they smash or spear their prey. In summary, drag was minimally affected by shape, whereas size, speed and dactyl orientation dominated and differentiated the hydrodynamic forces across species and sizes. This study demonstrates the utility of simple mathematical modeling for comparative analyses and illustrates the multi-faceted consequences of drag during the evolutionary diversification of rotating appendages.

Mechanical sensitivity reveals evolutionary dynamics of mechanical systems.

A classic question in evolutionary biology is how form-function relationships promote or limit diversification. Mechanical metrics, such as kinematic transmission (KT) in linkage systems, are useful tools for examining the evolution of form and function in a comparative context. The convergence of disparate systems on equivalent metric values (mechanical equivalence) has been highlighted as a source of potential morphological diversity under the assumption that morphology can evolve with minimal impact on function. However, this assumption does not account for mechanical sensitivity-the sensitivity of the metric to morphological changes in individual components of a structure. We examined the diversification of a four-bar linkage system in mantis shrimp (Stomatopoda), and found evidence for both mechanical equivalence and differential mechanical sensitivity. KT exhibited variable correlations with individual linkage components, highlighting the components that influence KT evolution, and the components that are free to evolve independently from KT and thereby contribute to the observed pattern of mechanical equivalence. Determining the mechanical sensitivity in a system leads to a deeper understanding of both functional convergence and morphological diversification. This study illustrates the importance of multi-level analyses in delineating the factors that limit and promote diversification in form-function systems.

Beyond Description: The Many Facets of Dental Biomechanics.

Teeth lie at the interface between an animal and its environment and, with some exceptions, act as a major component of resource procurement through food acquisition and processing. Therefore, the shape of a tooth is closely tied to the type of food being eaten. This tight relationship is of use to biologists describing the natural history of species and given the high instance of tooth preservation in the fossil record, is especially useful for paleontologists. However, correlating gross tooth morphology to diet is only part of the story, and much more can be learned through the study of dental biomechanics. We can explore the mechanics of how teeth work, how different shapes evolved, and the underlying forces that constrain tooth shape. This review aims to provide an overview of the research on dental biomechanics, in both mammalian and non-mammalian teeth, and to synthesize two main approaches to dental biomechanics to develop an integrative framework for classifying and evaluating dental functional morphology. This framework relates food material properties to the dynamics of food processing, in particular how teeth transfer energy to food items, and how these mechanical considerations may have shaped the evolution of tooth morphology. We also review advances in technology and new techniques that have allowed more in-depth studies of tooth form and function.

Yellow fever vaccination, avian leukosis virus, and cancer risk in man.

Comparison was made between 2659 veterans who died of cancer, during 1950 to 1954 or 1959 to 1963, and matched controls, based on the frequency of yellow fever immunization during World War II. The vaccine was produced from chick embryos that almost certainly contained avian leukosis-sarcoma viruses. Among the veterans, no relation was found between vaccination and leukemia, lymphoma, or other cancer.

Rapid stimulation of diacylglycerol production in Xenopus oocytes by microinjection of H-ras p21.

The p21 products of ras proto-oncogenes are thought to be important components in pathways regulating normal cell proliferation and differentiation. These proteins acquire transforming properties as a result of activating lesions that convert ras genes to oncogenes in a wide array of malignancies. In Xenopus laevis oocytes, microinjection of transforming ras p21 is a potent inducer of maturation, whereas microinjection of a monoclonal antibody to ras p21 inhibits normal maturation induced by hormones. The phosphoinositide pathway is a ubiquitous system that appears to play a key role in diverse cellular functions. By use of the Xenopus oocyte system, it was possible to quantitate the effects of ras p21 microinjection on individual components of the phosphoinositide pathway. Within 20 minutes of microinjection, levels of phosphatidylinositol 4,5-bisphosphate, inositol 1-phosphate, and inositol bisphosphate increased 1.5- to 2-fold. The most striking effects were on diacylglycerol, which increased 5-fold under the same conditions. In contrast, the normal ras p21 protein induced no detectable alteration in any of the metabolites analyzed. The earliest effects of the transforming p21 on phosphoinositol turnover were observable within 2 minutes, implying a very rapid effect of ras p21 on the enzymes involved in phospholipid metabolism.

Expression of the Aplysia californica rho gene in Escherichia coli: purification and characterization of its encoded p21 product.

A new family of highly conserved genes, designated rho, has recently been isolated and characterized (P. Madaule and R. Axel, Cell 41:31-40, 1985). These genes have been found in Saccharomyces cerevisiae, Drosophila melanogaster, rats, and humans, and their 21,000-dalton products are highly homologous. The rho p21 protein shares 35% amino acid homology with the Harvey ras p21 protein and on this basis has been proposed to be a G protein. We expressed the Aplysia californica rho gene in Escherichia coli and purified its p21 protein to more than 90% purity. The availability of the rho protein in high quantities made it possible to establish its high affinity for guanine nucleotides. The rho p21 protein had nucleotide-binding properties similar to those of the ras p21 protein. However, a comparison of these proteins revealed some important differences regarding their specificities and affinities. Finally, the rho p21 protein had GTPase activity almost identical to that of a normal ras p21 protein, the rates being 0.106 and 0.105 mol/min per mol of p21, respectively. Thus, the results suggest that the degree of homology found between the ras and rho genes products most likely is related to the conservation of sequences relevant to their ability to bind and hydrolyze guanine nucleotides. The fact that the rho p21 protein binds and hydrolyzes GTP strongly suggests that it is a G protein with a potential regulatory function conserved in evolution.

Point of impact: the effect of size and speed on puncture mechanics.

The use of high-speed puncture mechanics for prey capture has been documented across a wide range of organisms, including vertebrates, arthropods, molluscs and cnidarians. These examples span four phyla and seven orders of magnitude difference in size. The commonality of these puncture systems offers an opportunity to explore how organisms at different scales and with different materials, morphologies and kinematics perform the same basic function. However, there is currently no framework for combining kinematic performance with cutting mechanics in biological puncture systems. Our aim here is to establish this framework by examining the effects of size and velocity in a series of controlled ballistic puncture experiments. Arrows of identical shape but varying in mass and speed were shot into cubes of ballistic gelatine. Results from high-speed videography show that projectile velocity can alter how the target gel responds to cutting. Mixed models comparing kinematic variables and puncture patterns indicate that the kinetic energy of a projectile is a better predictor of penetration than either momentum or velocity. These results form a foundation for studying the effects of impact on biological puncture, opening the door for future work to explore the influence of morphology and material organization on high-speed cutting dynamics.

Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors.

BACKGROUND: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability. RESULTS: We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation. CONCLUSIONS: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.

The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma.

Colony-stimulating factor 1 (CSF-1) is a homodimeric growth factor that humorally regulates the growth and differentiation of mononuclear phagocytes, and locally regulates maternal-fetal interactions during pregnancy. It exerts these actions through a transmembrane tyrosine kinase receptor, colony-stimulating factor 1 receptor (CSF-1R), the product of the c-fms proto-oncogene. Recent studies have demonstrated overexpression of CSF-1 and its receptor in breast, ovarian, and endometrial adenocarcinomas. To further investigate the possible role of CSF-1 and its receptor in the pathogenesis of endometrial adenocarcinoma, a prospective study was undertaken to study CSF-1 expression in benign and neoplastic endometrial epithelium and to compare serum CSF-1 levels in endometrial adenocarcinoma patients with healthy perimenopausal women. The mean serum levels of CSF-1 in 71 patients with endometrial cancer (4.9 +/- 1.8 microgram/liter) were significantly elevated compared with levels found in the 32 controls (3.5 +/- 1.1 microgram/liter). Within the endometrial adenocarcinoma group, circulating CSF-1 levels were significantly elevated in patients with large tumor volume, high grade, myometrial invasion, residual disease, and circulating CA-125 levels. High serum levels of serum CSF-1 were associated with elevated serum CA19-9 and CA-125 levels. Immunohistochemistry results revealed in tumor epithelium intense staining for CSF-1R (27 of 54 cases, 50%) and elevated staining for CSF-1 (41 of 54 cases, 75.9%), with intense staining of CSF-1 in 16 of 54 cases (29.6%). Staining was significantly greater in intensity and number of cells involved in malignant compared with benign epithelium for CSF-1R and CSF-1 (P = 0.05 and <0.0001, respectively). A positive correlation between amount and intensity of CSF-1 and CSF-1R staining in endometrial adenocarcinoma tissue was also demonstrated (P = 0.007). CSF-1 and CSF-1R mRNA was also detected in the tumor samples, confirming the expression of the protein in these tissues. Reverse transcription-PCR demonstrated the presence of mRNA for both the transmembrane and secreted forms of CSF-1 in all tumors analyzed. These results therefore support the hypotheses that CSF-1 and CSF-1R are overexpressed in endometrial adenocarcinoma, that levels of expression significantly correlate with clinicopathological risk factors for poor outcome, and that CSF-1 in association with its receptor via autocrine, juxtacrine, and/or paracrine interactions has a causal role in endometrial adenocarcinoma development and proliferation.

Diabetes, parental diabetes, and obesity in Oklahoma Indians.

The relationship between diabetes and parental diabetes status and obesity in Oklahoma Indians was studied. Data from 2095 adult Oklahoma Indians (1085 type II diabetic subjects and 1010 nondiabetic subjects) through a complete physical examination and personal interview showed a strong association between diabetes and parental diabetes status. Frequency of diabetes among siblings was significantly higher in families with affected parents than those without diabetic parents. No significant difference was found between families with one diabetic parent and those with two diabetic parents. The diabetic individuals were more obese than the nondiabetic individuals at age 18 and at interview. Obesity was defined as percent body mass index greater than 120. After adjusting for possible age and sex effects, the risk of diabetes for the obese was estimated as almost twice that for the nonobese.

Effects of a potent carbonic anhydrase inhibitor on bone resorption in organ culture.

We have examined the effects of a potent inhibitor of carbonic anhydrase (CA), 5-(3-hydroxybenzoyl)2-thiophenesulfonamide (HTS), and compared them with the effects of acetazolamide (AZ) and ethoxzolamide (EX) on bone resorption in organ cultures in fetal rat long bones under control unstimulated conditions and in response to PTH, prostaglandin E2 (PGE2), 1,25-dihydroxyvitamin D [1,25-(OH)2D3], and interleukin-1 (IL-1). The relative potencies of HTS, EX, and AZ for inhibition of CA and bone resorption were similar. HTS inhibited control resorption at 10(-5) to 3 X 10(-5) M, while EX at 10(-4) M inhibited and AZ was ineffective. In the presence of PTH, the inhibitory effect of HTS was seen at concentrations as low as 3 X 10(-6) M and was maximal at 3 X 10(-5) M. EX was inhibitory at 10(-5) M and maximal at 10(-4) M, while AZ at 10(-4) M only partially inhibited PTH-stimulated bone resorption. The responses to PGE2 (10(-7) M), 1,25-(OH)2D3 (10(-9) M), and IL-1 (50 U/ml) were inhibited by HTS at 10(-5) M, while AZ at 10(-4) M was ineffective against PGE2 and 1,25-(OH)2D3. The effect of HTS did not appear to be due to nonspecific toxicity, since after 2 days of treatment at 3 X 10(-5) M and 3 days of recovery, the bone resorptive response to PTH was completely restored. Moreover, HTS at 3 X 10(-5) M did not inhibit the incorporation of labeled proline or thymidine into fetal rat long bones. HTS was more potent as an inhibitor when the CO2 concentration in the gas phase was reduced from 5% to 2% and the pH was increased from 7.2 to 7.5, consistent with an effect on CA-mediated hydrogen ion generation.

A structurally unique, potent, and selective oxytocin antagonist derived from Streptomyces silvensis.

The in vitro and in vivo oxytocin/arginine vasopressin (OT/AVP) antagonist properties of two cyclic hexapeptides derived from a newly discovered natural product (L-156,373) of Streptomyces silvensis are described. In radioligand binding assays, L-156,373 [cyclo(L-Pro-D-Phe-N-OH-L-Ile-D-piperazyl-L-piperazyl-N-Me-D -Phe)] exhibited moderate affinity for rat uterine OT receptors (Ki, 150 nM), with some selectivity (approximately 20-fold) vs. liver AVP-V1 and kidney AVP-V2 receptors. Dehydroxylation of N-hydroxyisoleucine and oxidation of the piperazic acid residues of L-156-373 produced an interesting derivative, L-365,209. These structural modifications increased OT receptor affinity and selectivity by 20- and 2.5-5-fold, respectively. In the isolated rat uterus, L-365,209 was a potent (apparent dissociation constant, 1.7 nM) and competitive OT antagonist. L-365,209 also blocked the effects of AVP at both AVP-V1 (phosphatidylinositol turnover in rat hepatocytes) and AVP-V2 (adenylate cyclase in rat kidney medulla) receptors, but only at low micromolar concentrations. L-365,209, given iv to anesthetized rats, antagonized the action of exogenous OT on the uterus (ID50, 460 micrograms/kg) with a relatively long duration of action. L-365,209 represents a unique class of compounds that provides an entirely new approach for the design of antagonists for these neurohypophyseal hormones.

Plasma apolipoprotein B and VLDL-, LDL-, and HDL-cholesterol as risk factors in the development of coronary artery disease in male patients examined by angiography.

To assess the potential use of plasma apolipoprotein B (ApoB) as a risk factor for coronary artery disease, this apolipoprotein was quantified by electroimmunoassay in 161 male patients with angiographically documented coronary atherosclerosis and 72 male patients with normal coronary arteries. In addition to ApoB, the analyzed lipoprotein profile included plasma total cholesterol, plasma triglyceride and VLDL-, LDL- and HDL-cholesterol levels. Age, plasma cholesterol, triglyceride, and VLDL- and LDL-cholesterol were significantly greater (P less than 0.05) for patients with coronary artery disease than for patients with normal arteries. In contrast, there was no difference in the mean levels of HDL-cholesterol between these 2 groups of patients. However, patients with HDL-cholesterol les than 40 mg/dl had a higher rate of coronary artery disease than those with HDL-cholesterol greater than 40 mg/dl (P less than 0.05). The results of multivariate analysis showed that age and plasma cholesterol were the 2 variables most significantly (P less than 0.01) related to the presence of coronary artery disease. However, in a subgroup of patients with plasma cholesterol less than 265 mg/dl, the most reliable variable was ApoB (P less than 0.01). For patients under 50 years of age ApoB and LDL-cholesterol were the most significant variables (P less than 0.05), whereas for patients at 50 years of age or older VLDL-cholesterol was the most significant variable (P less than 0.01). Results of this study indicate that measurement of ApoB may offer important predictive value for coronary artery disease, especially at lower levels of plasma cholesterol. Whether this and other conclusions also apply to general population, remains to be established in future studies.

Pelvic exenteration for cervix cancer: would additional intraoperative interstitial brachytherapy improve survival?

OBJECTIVE: Improved local control with the addition of brachytherapy to pelvic exenteration for recurrent cervical cancer has been reported to improve survival. We examined the sites of recurrence after pelvic exenteration to determine if these patients might have been salvaged by the improved local control promised by interstitial brachytherapy. We sought to identify risk factors available intraoperatively or perioperatively which might predict decreased local control. METHODS: A retrospective review of 26 patients with recurrent cervical cancer who underwent total pelvic exenteration since 1988 at our institution was performed. RESULTS: Overall, the mean follow-up was 29.5 months (range 6.1-81.6). Of the 26 patients, 14 had no evidence of disease (NED), 1 was alive with disease (AWD), 9 were dead of disease (DOD), and 2 died of unrelated causes (DOC). Seven of 26 patients (27%) had margins < or = 5 mm, of whom 2 were NED, 4 DOD, and 1 AWD. Seven of 26 (27%) patients had lymphovascular involvement (LVI) or perineural invasion (PNI) with clear margins. Three of the seven with LVI or PNI and clear margins were NED, and four DOD. Of the 10 failures, 9 (90%) had close margins, PNI, or LVI. CONCLUSION: Our data reveal that 9 of 14 (64%) patients with close margins, LVI, or PNI were DOD or AWD, and 6 of 9 of those patients suffered local regional failure alone. Brachytherapy has the potential to cure 6 of 14 (43%) patients with these risk factors. Further study of brachytherapy at the time of pelvic extenteration is warranted.

Synthesis and orexigenic activity of some 1-methyl-4-piperidylidene-Substituted pyrrolo[2,1-g][3] benzazepine and dibenzocycloheptene derivatives.

The synthesis and orexigenic activity of some unsubstituted and Bz-carboxylic acid substituted 1-methyl-4-piperidylidenepyrrolo[2,1-b][3]benzazepine and dibenzocycloheptene derivatives are described. 10,11-Dihydro-3-carboxycyproheptadine (7c) has been selected for clinical evaluation as a orexigenic agent based on its low threshold dose for increasing food consumption in cats (0.031 mg/kg po) and its lack of undesirable central nervous system activity. The levorotatory enantiomer of 3-carboxycyproheptadine (1d) and the 9-carboxypyrrolobenzazepine derivative 4f also possess orexigenic activity, but with these compounds such activity diminishes sharply below 0.25 mg/kg po. The unsubstituted 1-methyl-4-(5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidine (4d) and its 6,11-dihydroanalogue (4a) are comparable to cyproheptadine (1a) in promoting hyperphagia in cats.

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 4. Side chain ester derivatives of mevinolin.

Modification of the 2(S)-methylbutyryl moiety of mevinolin led to a series of side chain ester derivatives. A systematic exploration of the structure-activity relationships showed that the introduction of an additional aliphatic group on the carbon alpha to the carbonyl group increased potency. This observation led to the synthesis of compound 16, which has about 2.5 times the intrinsic inhibitory activity of mevinolin.

Cyclic amidine inhibitors of indolamine N-methyltransferase.

Syntheses of a large number of mono- and bicyclic, as well as a few tricyclic, amidine derivatives related to 2,3,4,6,7,8,-hexahydropyrrolo[1,2-a]pyrimidine (DBN) are reported. In vitro potencies for inhibition of the enzyme indolamine N-methyltransferase (INMT) from rabbit and human lung are presented. Four bicyclic amidine derivatives and 11 monocyclic derivatives were found to be equal or superior to DBN in in vitro potencies. With the bicyclic amidines, increasing ring size or introduction of substituents reduced activity. Among the monocyclic analogues, the most potent representatives were five- or six-membered systems with an exocyclic imino group, combined with methyl of ethyl substituents on the endocyclic nitrogen. Introduction of additonal substituents decreased inhibitory potency. 2,3,5,6-Tetrahydro-8H-imidazo[2,1-c][1,4]thiazine and 3-methyl-2-iminothiazolidine have been shown to cause inhibition of lung INMT when administered orally to rabbits.