Some of the most divisive contests shaping the quest for marriage equality occurred not on the culture-war front lines but within the ranks of LGBTQ advocates. Nathaniel Frank tells the dramatic ...story of how an idea that once seemed unfathomable—and for many gays and lesbians undesirable—became a legal and moral right in just half a century.
Some of the most divisive contests shaping the quest for marriage equality occurred not on the culture-war front lines but within the ranks of LGBTQ advocates. Nathaniel Frank tells the dramatic ...story of how an idea that once seemed unfathomable—and for many gays and lesbians undesirable—became a legal and moral right in just half a century.
...he draws sweeping, outlier conclusions (74 studies collected by my research team at Columbia Law School's What We Know Project 2, which aggregates scholarship with public policy implications, have ...found that parent sexual orientation does not affect the wellbeing of children) that can only be reached by fudging the way gay- or lesbian-headed households are discussed and compared to households headed by heterosexuals. All he knows about his dataset is that his subjects, who ranged in age from 12 to 18, spent some of their teenage years with a parent who at some point had a same-sex partner. Since we do not know if that partner was ever actually a parent, legally or otherwise, it is inaccurate to characterize such households as "same-sex parented" as Sullins does eleven times.
Using thrombelastography to gain mechanistic insights, recent investigations have identified enzymes and compounds in
and
species' neurotoxic venoms that are anticoagulant in nature. The neurotoxic ...venoms of the four extant species of
(the Black and green mambas) were noted to be anticoagulant in nature in human blood, but the mechanisms underlying these observations have never been explored. The venom proteomes of these venoms are unique, primarily composed of three finger toxins (3-FTx), Kunitz-type serine protease inhibitors (Kunitz-type SPI) and <7% metalloproteinases. The anticoagulant potency of the four mamba venoms available were determined in human plasma via thrombelastography; vulnerability to inhibition of anticoagulant activity to ethylenediaminetetraacetic acid (EDTA) was assessed, and inhibition of anticoagulant activity after exposure to a ruthenium (Ru)-based carbon monoxide releasing molecule (CORM-2) was quantified. Black mamba venom was the least potent by more than two orders of magnitude compared to the green mamba venoms tested; further, Black Mamba venom anticoagulant activity was not inhibited by either EDTA or CORM-2. In contrast, the anticoagulant activities of the green mamba venoms were all inhibited by EDTA to a greater or lesser extent, and all had anticoagulation inhibited with CORM-2. Critically, CORM-2-mediated inhibition was independent of carbon monoxide release, but was dependent on a putative Ru-based species formed from CORM-2. In conclusion, there was great species-specific variation in potency and mechanism(s) responsible for the anticoagulant activity of
venom, with perhaps all three protein classes-3-FTx, Kunitz-type SPI and metalloproteinases-playing a role in the venoms characterized.
Prey-selective venoms and toxins have been documented across only a few species of snakes. The lack of research in this area has been due to the absence of suitably flexible testing platforms. In ...order to test more species for prey specificity of their venom, we used an innovative taxonomically flexible, high-throughput biolayer interferometry approach to ascertain the relative binding of 29 α-neurotoxic venoms from African and Asian elapid representatives (26
spp.,
,
and four locales of
) to the alpha-1 nicotinic acetylcholine receptor orthosteric (active) site for amphibian, lizard, snake, bird, and rodent targets. Our results detected prey-selective, intraspecific, and geographical differences of α-neurotoxic binding. The results also suggest that crude venom that shows prey selectivity is likely driven by the proportions of prey-specific α-neurotoxins with differential selectivity within the crude venom. Our results also suggest that since the α-neurotoxic prey targeting does not always account for the full dietary breadth of a species, other toxin classes with a different pathophysiological function likely play an equally important role in prey immobilisation of the crude venom depending on the prey type envenomated. The use of this innovative and taxonomically flexible diverse assay in functional venom testing can be key in attempting to understanding the evolution and ecology of α-neurotoxic snake venoms, as well as opening up biochemical and pharmacological avenues to explore other venom effects.
Abstract Objectives To investigate the effect of fluoride (0, 275 and 1250 ppm F; NaF) in combination with normal and low salivary flow rates on enamel surface loss and fluoride uptake using an ...erosion–remineralization–abrasion cycling model. Design Enamel specimens were randomly assigned to 6 experimental groups ( n = 8). Specimens were individually placed in custom made devices, creating a sealed chamber on the enamel surface, connected to a peristaltic pump. Citric acid was injected into the chamber for 2 min followed by artificial saliva at 0.5 (normal flow) or 0.05 (low flow) ml/min, for 60 min. This cycle was repeated 4×/day, for 5 days. Toothbrushing with abrasive suspensions containing fluoride was performed for 2 min (15 s of actual brushing) 2×/day. Surface loss was measured by optical profilometry. KOH-soluble fluoride and enamel fluoride uptake were determined after the cycling phase. Data were analysed by two-way ANOVA. Results No significant interactions between fluoride concentration and salivary flow were observed for any tested variable. Low caused more surface loss than normal flow rate ( p < 0.01). At both flow rates, surface loss for 0 was higher than for 275, which did not differ from 1250 ppm F. KOH-soluble and structurally-bound enamel fluoride uptake were significantly different between fluoride concentrations with 1250 > 275 > 0 ppm F ( p < 0.01). Conclusions Sodium fluoride reduced enamel erosion/abrasion, although no additional protection was provided by the higher concentration. Higher erosion progression was observed in low salivary flow rates. Fluoride was not able to compensate for the differences in surface loss between flow rates.
Snakebite with hemotoxic venom continues to be a major source of morbidity and mortality worldwide. Our laboratory has characterized the coagulopathy that occurs in vitro in human plasma via ...specialized thrombelastographic methods to determine if venoms are predominantly anticoagulant or procoagulant in nature. Further, the exposure of venoms to carbon monoxide (CO) or
-phenylhydroxylamine (PHA) modulate putative heme groups attached to key enzymes has also provided mechanistic insight into the multiple different activities contained in one venom. The present investigation used these techniques to characterize fourteen different venoms obtained from snakes from North, Central, and South America. Further, we review and present previous thrombelastographic-based analyses of eighteen other species from the Americas. Venoms were found to be anticoagulant and procoagulant (thrombin-like activity, thrombin-generating activity). All prospectively assessed venom activities were determined to be heme-modulated except two, wherein both CO and its carrier molecule were found to inhibit activity, while PHA did not affect activity (
and
). When divided by continent, North and Central America contained venoms with mostly anticoagulant activities, several thrombin-like activities, with only two thrombin-generating activity containing venoms. In contrast, most venoms with thrombin-generating activity were located in South America, derived from
species. In conclusion, the kinetomic profiles of venoms obtained from thirty-two Pan-American Pit Viper species are presented. It is anticipated that this approach will be utilized to identify clinically relevant hemotoxic venom enzymatic activity and assess the efficacy of locally delivered CO or systemically administered antivenoms.
The genus
is the most basal branch of the family Elapidae and several species in it have developed highly elongated venom glands. Recent research has shown that
has evolved a seemingly unique toxin ...(calliotoxin) that produces spastic paralysis in their prey by acting on the voltage-gated sodium (Na
) channels. We assembled a transcriptome from
to investigate the molecular characteristics of these toxins and the venom as a whole. We find strong confirmation that this genus produces the classic elapid eight-cysteine three-finger toxins, that δδ-elapitoxins (toxins that resemble calliotoxin) are responsible for a substantial portion of the venom composition, and that these toxins form a distinct clade within a larger, more diverse clade of
three-finger toxins. This broader clade of
toxins also contains the previously named maticotoxins and is somewhat closely related to cytotoxins from other elapids. However, the toxins from this clade that have been characterized are not themselves cytotoxic. No other toxins show clear relationships to toxins of known function from other species.
Within Neotropical pit-vipers, the Mexican/Central-American clade consisting of Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium is a wide-ranging, morphologically and ecologically diverse ...group of snakes. Despite their prevalence, little is known of the functional aspects of their venoms. This study aimed to fill the knowledge gap regarding coagulotoxic effects and to examine the potential of different therapeutic approaches. As a general trait, the venoms were shown to be anticoagulant but were underpinned by diverse biochemical actions. Pseudo-procoagulant activity (i.e., thrombin-like), characterized by the direct cleavage of fibrinogen to form weak fibrin clots, was evident for Atropoides picadoi, Cerrophidiontzotzilorum, Metlapilcoatlus mexicanus, M. nummifer, M. occiduus, M. olmec, and Porthidium porrasi. In contrast, other venoms cleaved fibrinogen in a destructive (non-clotting) manner, with C. godmani and C. wilsoni being the most potent. In addition to actions on fibrinogen, clotting enzymes were also inhibited. FXa was only weakly inhibited by most species, but Cerrophidion godmani and C. wilsoni were extremely strong in their inhibitory action. Other clotting enzymes were more widely inhibited by diverse species spanning the full taxonomical range, but in each case, there were species that had these traits notably amplified relatively to the others. C. godmani and C. wilsoni were the most potent amongst those that inhibited the formation of the prothrombinase complex and were also amongst the most potent inhibitors of Factor XIa. While most species displayed only low levels of thrombin inhibition, Porthidium dunni potently inhibited this clotting factor. The regional polyvalent antivenom produced by Instituto Picado Clodomiro was tested and was shown to be effective against the diverse anticoagulant pathophysiological effects. In contrast to the anticoagulant activities of the other species, Porthidium volcanicum was uniquely procoagulant through the activation of Factor VII and Factor XII. This viperid species is the first snake outside of the Oxyuranus/Pseudonaja elapid snake clade to be shown to activate FVII and the first snake venom of any kind to activate FXII. Interestingly, while small-molecule metalloprotease inhibitors prinomastat and marimastat demonstrated the ability to prevent the procoagulant toxicity of P. volcanicum, neither ICP antivenom nor inhibitor DMPS showed this effect. The extreme variation among the snakes here studied underscores how venom is a dynamic trait and how this can shape clinical outcomes and influence evolving treatment strategies.
Geographic isolation and other factors result in evolution-driven diversity of the enzymatic composition of venom of pit vipers in the same genus. The present investigation sought to characterize ...venoms obtained from such genetically diverse
and
pit vipers utilizing thrombelastographic coagulation kinetic analyses. The coagulation kinetics of human plasma were assessed after exposure to venom obtained from two
and three
species. The potency of each venom was defined (µg/mL required to equivalently change coagulation); additionally, venoms were exposed to carbon monoxide (CO) or a metheme-inducing agent to modulate any enzyme-associated heme. All venoms had fibrinogenolytic activity, with four being CO-inhibitable. While
venoms had similar potency, one demonstrated the presence of a thrombin-like activity, whereas the other demonstrated a thrombin-generating activity. There was a 10-fold difference in potency and 10-fold different vulnerability to CO inhibition between the
species. Metheme formation enhanced fibrinogenolytic-like activity in both
species venoms, whereas the three
species venoms had fibrinogenolytic-like activity enhanced, inhibited, or not changed. This novel "venom kinetomic" approach has potential to identify clinically relevant enzymatic activity and assess efficacy of antivenoms between genetically and geographically diverse species.
PDF
