The Organs of the Parietal Fossa in Elasmobranchs

Davidson, in a paper on the musculature of Heptanchus maculatus (1918), mentions a small shield-shaped organ to be found in the parietal fossa, and in connection with it a pair of small muscles having their origin on the cranium and dorsal longitudinal muscles. He believes that these muscles constrict this sac-like organ

Photoelectric measurement of blood flow during hemodialysis

Accurate measurements of blood flow rate during hemodialysis are essential for determinations of hemodialyzer performance. Despite the availability of a variety of electronic blood flow meters, use of such instruments for determination of blood flow in hemodialysis has never been satisfactory, a situation caused by such factors as the need to recalibrate frequently, the necessity of incorporating transducers into the dialyzer blood circuit and the effect which variables such as hematocrit may have on the accuracy of determination. Furthermore, such devices are expensive and often require the periodic services of an electronics specialist to maintain them in an operable condition.An alternative technique for measuring flow rate in the extracorporeal blood tubing consists of timing the passage of an injected air bubble between two points in the tubing. Since the advent of maintenance dialysis, the “racetrack and bubble time” technique [1] has been widely used for routine determinations of blood flow rate. Data derived from research studies in which this method of flow determination was employed have been published widely, in spite of the relative inaccuracies of the method

Uptake, Distribution and Diffusivity of Reactive Fluorophores in Cells: Implications Toward Target Identification

There is much recent interest in the application of copper-free click chemistry to study a wide range of biological events in vivo and in vitro. Specifically, azide-conjugated fluorescent probes can be used to identify targets which have been modified with bioorthogonal reactive groups. For intracellular applications of this chemistry, the structural and physicochemical properties of the fluorescent azide become increasingly important. Ideal fluorophores should extensively accumulate within cells, have even intracellular distribution, and be free (unbound), allowing them to efficiently participate in bimolecular reactions. We report here on the synthesis and evaluation a set of structurally diverse fluorescent probes to examine their potential usefulness in intracellular click reactions. Total cellular uptake and intracellular distribution profiles were comparatively assessed using both quantitative and qualitative approaches. The intracellular diffusion coefficients were measured using a fluorescence recovery after photobleaching (FRAP)-based method. Many reactive fluorophores exhibited suboptimal properties for intracellular reactions. BODIPY- and TAMRA-based azides had superior cellular accumulation, whereas TAMRA-based probes had the most uniform intracellular distribution and best cytosolic diffusivity. Collectively, these results provide an unbiased comparative evaluation regarding the suitability of azide-linked fluorophores for intracellular click reactions

Mechanical unloading activates FoxO3 to trigger Bnip3‐dependent cardiomyocyte atrophy

BACKGROUND: Mechanical assist device therapy has emerged recently as an important and rapidly expanding therapy in advanced heart failure, triggering in some patients a beneficial reverse remodeling response. However, mechanisms underlying this benefit are unclear. METHODS AND RESULTS: In a model of mechanical unloading of the left ventricle, we observed progressive myocyte atrophy, autophagy, and robust activation of the transcription factor FoxO3, an established regulator of catabolic processes in other cell types. Evidence for FoxO3 activation was similarly detected in unloaded failing human myocardium. To determine the role of FoxO3 activation in cardiac muscle in vivo, we engineered transgenic mice harboring a cardiomyocyte‐specific constitutively active FoxO3 mutant (caFoxO3(flox);αMHC‐Mer‐Cre‐Mer). Expression of caFoxO3 triggered dramatic and progressive loss of cardiac mass, robust increases in cardiomyocyte autophagy, declines in mitochondrial biomass and function, and early mortality. Whereas increases in cardiomyocyte apoptosis were not apparent, we detected robust increases in Bnip3 (Bcl2/adenovirus E1B 19‐kDa interacting protein 3), an established downstream target of FoxO3. To test the role of Bnip3, we crossed the caFoxO3(flox);αMHC‐Mer‐Cre‐Mer mice with Bnip3‐null animals. Remarkably, the atrophy and autophagy phenotypes were significantly blunted, yet the early mortality triggered by FoxO3 activation persisted. Rather, declines in cardiac performance were attenuated by proteasome inhibitors. Consistent with involvement of FoxO3‐driven activation of the ubiquitin‐proteasome system, we detected time‐dependent activation of the atrogenes program and sarcomere protein breakdown. CONCLUSIONS: In aggregate, these data point to FoxO3, a protein activated by mechanical unloading, as a master regulator that governs both the autophagy‐lysosomal and ubiquitin‐proteasomal pathways to orchestrate cardiac muscle atrophy

A new mode of chemical reactivity for metal-free hydrogen activation by Lewis acidic boranes

We herein explore whether tris(aryl)borane Lewis acids are capable of cleaving H2 outside of the usual Lewis acid/base chemistry described by the concept of “frustrated Lewis pairs” (FLPs). Instead of a Lewis base we use a chemical reductant to generate stable radical anions of two highly‐hindered boranes: tris(3,5‐dinitromesityl)borane and tris(mesityl)borane. NMR spectroscopic characterization reveals that the corresponding borane radical anions activate (cleave) dihydrogen, whilst EPR spectroscopic characterization, supported by computational analysis, reveals the intermediates along the hydrogen activation pathway for the first time. This radical–based, redox pathway involves homolytic cleavage of H2, in contrast to conventional models of FLP chemistry which invoke a heterolytic cleavage pathway. This represents a new mode of chemical reactivity for hydrogen activation by borane Lewis acids

Structure-guided design of an Hsp90â N-terminal isoform-selective inhibitor

The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90β, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90β-selective inhibitors as a method to overcome the detriments associated with pan-inhibition

On the possibility of magneto-structural correlations: detailed studies of di-nickel carboxylate complexes

A series of water-bridged dinickel complexes of the general formula [Ni<sub>2</sub>(μ<sub>2</sub>-OH<sub>2</sub>)(μ2- O<sub>2</sub>C<sup>t</sup>Bu)<sub>2</sub>(O<sub>2</sub>C<sup>t</sup>Bu)2(L)(L0)] (L = HO<sub>2</sub>C<sup>t</sup>Bu, L0 = HO<sub>2</sub>C<sup>t</sup>Bu (1), pyridine (2), 3-methylpyridine (4); L = L0 = pyridine (3), 3-methylpyridine (5)) has been synthesized and structurally characterized by X-ray crystallography. The magnetic properties have been probed by magnetometry and EPR spectroscopy, and detailed measurements show that the axial zero-field splitting, D, of the nickel(ii) ions is on the same order as the isotropic exchange interaction, J, between the nickel sites. The isotropic exchange interaction can be related to the angle between the nickel centers and the bridging water molecule, while the magnitude of D can be related to the coordination sphere at the nickel sites