Dinitrogen Reduction to Ammonium at Rhenium Utilizing Light and Proton-Coupled Electron Transfer.

The direct scission of the triple bond of dinitrogen (N2) by a metal complex is an alluring entry point into the transformation of N2 to ammonia (NH3) in molecular catalysis. Reported herein is a pincer-ligated rhenium system that reduces N2 to NH3 via a well-defined reaction sequence involving reductive formation of a bridging N2 complex, photolytic N2 splitting, and proton-coupled electron transfer (PCET) reduction of the metal-nitride bond. The new complex (PONOP)ReCl3 (PONOP = 2,6-bis(diisopropylphosphinito)pyridine) is reduced under N2 to afford the trans,trans-isomer of the bimetallic complex [(PONOP)ReCl2]2(µ-N2) as an isolable kinetic product that isomerizes sequentially upon heating into the trans,cis and cis,cis isomers. All isomers are inert to thermal N2 scission, and the trans,trans-isomer is also inert to photolytic N2 cleavage. In striking contrast, illumination of the trans,cis and cis,cis-isomers with blue light (405 nm) affords the octahedral nitride complex cis-(PONOP)Re(N)Cl2 in 47% spectroscopic yield and 11% quantum yield. The photon energy drives an N2 splitting reaction that is thermodynamically unfavorable under standard conditions, producing a nitrido complex that reacts with SmI2/H2O to produce a rhenium tetrahydride complex (38% yield) and furnish ammonia in 74% yield.

Chemical Oxidation of a Coordinated PNP-Pincer Ligand Forms Unexpected Re-Nitroxide Complexes with Reversal of Nitride Reactivity.

Because of the thermodynamic demands of N2 cleavage, N2-derived nitride complexes are often unreactive. The development of multistep N2 functionalization reactions hinges on methods for modulating nitride reactivity with supporting ligands. Here, we describe the reactions of N2-derived Re-nitride complexes, including the first Re nitrides supported by a nitroxide-containing pincer ligand, and unusual examples of Re6+-nitride complexes. The previously reported N2-derived complex (PNP)Re(N)(Cl) (PNP = N(CH2CH2PtBu2)2) can be oxidized by O atom transfer to the backbone amide to form a novel nitroxide-pincer complex or by 1e- to form a rare S = 1/2 Re6+-nitride complex. The Re-nitrido interaction in a series of Re- and ligand-oxidized complexes is characterized using 15N NMR spectroscopy, IR spectroscopy, and DFT calculations, and shows changes in the Re-N bond order from both ligand- and metal-centered oxidations. Chemical oxidation of the supporting ligand to form a nitroxide-pincer ligand results in subtle electronic changes at Re and a more electron-deficient nitride ligand. Combined ligand- and metal-centered oxidation to form a Re6+-nitroxide complex results in a reversal of reactivity at the nitride ligand from nucleophilic to electrophilic. These systematic electronic structure and reactivity studies demonstrate methods for inducing reactivity in N2-derived nitride complexes.

Coordination chemistry insights into the role of alkali metal promoters in dinitrogen reduction.

The Haber-Bosch process is a major contributor to fixed nitrogen that supports the world's nutritional needs and is one of the largest-scale industrial processes known. It has also served as a testing ground for chemists' understanding of surface chemistry. Thus, it is significant that the most thoroughly developed catalysts for N2 reduction use potassium as an electronic promoter. In this review, we discuss the literature on alkali metal cations as promoters for N2 reduction, in the context of the growing knowledge about cooperative interactions between N2, transition metals, and alkali metals in coordination compounds. Because the structures and properties are easier to characterize in these compounds, they give useful information on alkali metal interactions with N2. Here, we review a variety of interactions, with emphasis on recent work on iron complexes by the authors. Finally, we draw conclusions about the nature of these interactions and areas for future research.

A methodology for using Lambda phages as a proxy for pathogen transmission in hospitals.

BACKGROUND: One major concern in hospitalized patients is acquiring infections from pathogens borne on surfaces, patients, and healthcare workers (HCWs). Fundamental to controlling healthcare-associated infections is identifying the sources of pathogens, monitoring the processes responsible for their transmission, and evaluating the efficacy of the procedures employed for restricting their transmission. AIM: To present a method using the bacteriophage Lambda (λ) to achieve these ends. METHODS: Defined densities of multiple genetically marked λ phages were inoculated at known hotspots for contamination on high-fidelity mannequins. HCWs then entered a pre-sanitized simulated hospital room and performed a series of patient care tasks on the mannequins. Sampling occurred on the scrubs and hands of the HCWs, as well as previously defined high-touch surfaces in hospital rooms. Following sampling, the rooms were decontaminated using procedures demonstrated to be effective. Following the conclusion of the simulation, the samples were tested for the presence, identity, and densities of these λ phages. FINDINGS: The data generated enabled the determination of the sources and magnitude of contamination caused by the breakdown of established infection prevention practices by HCWs. This technique enabled the standardized tracking of multiple contaminants during a single episode of patient care. Unlike other biological surrogates, λ phages are susceptible to common hospital disinfectants, and allow for a more accurate evaluation of pathogen transmission. CONCLUSION: Whereas our application of these methods focused on healthcare-associated infections and the role of HCW behaviours in their spread, these methods could be employed for identifying the sources and sites of microbial contamination in other settings.

Facile conversion of ammonia to a nitride in a rhenium system that cleaves dinitrogen.

Rhenium complexes with aliphatic PNP pincer ligands have been shown to be capable of reductive N2 splitting to nitride complexes. However, the conversion of the resulting nitride to ammonia has not been observed. Here, the thermodynamics and mechanism of the hypothetical N-H bond forming steps are evaluated through the reverse reaction, conversion of ammonia to the nitride complex. Depending on the conditions, treatment of a rhenium(iii) precursor with ammonia gives either a bis(amine) complex [(PNP)Re(NH2)2Cl]+, or results in dehydrohalogenation to the rhenium(iii) amido complex, (PNP)Re(NH2)Cl. The N-H hydrogen atoms in this amido complex can be abstracted by PCET reagents which implies that they are quite weak. Calorimetric measurements show that the average bond dissociation enthalpy of the two amido N-H bonds is 57 kcal mol-1, while DFT computations indicate a substantially weaker N-H bond of the putative rhenium(iv)-imide intermediate (BDE = 38 kcal mol-1). Our analysis demonstrates that addition of the first H atom to the nitride complex is a thermochemical bottleneck for NH3 generation.

Updates on therapeutic targets and agents in castration-resistant prostate cancer.

Prostate cancer (PCa) is the most commonly diagnosed noncutaneous cancer in men accounting for 28% of all newly diagnosed cancer cases and it is the second to third most common cause of cancer death in the Western world. Nearly all patients with metastatic disease will eventually experience disease progression despite castration as the median duration of response is between 18-24 months. Hence, development of castration-resistant prostate cancer (CRPC) is only a matter of time in these patients. CRPC is defined by disease progression despite androgen-deprivation therapy. CRPC presents a spectrum of disease ranging from rising PSA levels to metastases and significant debilitation from cancer symptoms. Prognosis is associated with several factors, including performance status, presence of bone pain, extent of disease on bone scan, and serum levels of alkaline phosphatase. Based on our enhanced understanding of tumor biology, including the role of tumor, host, and hormonal signaling, there has been rational development of new therapies for CRPC. Over the last decade, several clinical trials have been launched to study novel agents targeting different mechanisms of PCa progression, and have culminated success of new agents for CRPC (docetaxel, cabazitaxel, sipuleucel-T, denosumab, and abiraterone acetate) and several more molecules are on the horizon. The purpose of this review is to discuss the new therapeutic targets in CRPC focusing on new promising agents.

Asymmetry of chimpanzee planum temporale: humanlike pattern of Wernicke's brain language area homolog.

The anatomic pattern and left hemisphere size predominance of the planum temporale, a language area of the human brain, are also present in chimpanzees (Pan troglodytes). The left planum temporale was significantly larger in 94 percent (17 of 18) of chimpanzee brains examined. It is widely accepted that the planum temporale is a key component of Wernicke's receptive language area, which is also implicated in human communication-related disorders such as schizophrenia and in normal variations such as musical talent. However, anatomic hemispheric asymmetry of this cerebrocortical site is clearly not unique to humans, as is currently thought. The evolutionary origin of human language may have been founded on this basal anatomic substrate, which was already lateralized to the left hemisphere in the common ancestor of chimpanzees and humans 8 million years ago.

Protonation and electrochemical reduction of rhodium- and iridium-dinitrogen complexes in organic solution.

Protonation and reduction of pincer-ligated Rh- and Ir-N2 complexes have been studied by NMR spectroscopy and cyclic voltammetry to assess the capability of these complexes to activate or reduce N2. Protonation, which is a prerequisite to electrochemical reduction, results in a cationic metal-hydride that loses N2 under an atmosphere of Ar. Reduction of the metal-hydride results in fast disproportionation of an unobserved transient Ir2+ species. These studies suggest that the regioselectivity of initial protonation is a strong determinant for the ability of a system to facilitate the reduction of N2.

An inducible acid phosphatase from the yeast Pichia pastoris: characterization of the gene and its product.

To develop the budding yeast Pichia pastoris (Pp) as a model system for the study of protein secretion, we have characterized a secreted acid phosphatase (Pho1p) from this yeast. Pho1p can be induced 100-fold by starvation for phosphate. The enzyme was purified to homogeneity from a cell-wall extract by DEAE-Sepharose chromatography. We selected mutants that lacked extracellular phosphatase activity and the gene (PHO1) encoding Pho1p was isolated from a recombinant plasmid library of Pp DNA by complementation of the mutant defect. PHO1 encodes a protein of 468 amino acids (aa) with homology to repressible acid phosphatases from other yeast species. The sequence contains a 15-aa N-terminal signal sequence and six potential N-linked glycosylation sites. Antiserum to Pho1p was used to show that Pho1p transits the Pp secretory pathway in less than 5 min.

5-HT1A receptor localization on the axon hillock of cervical spinal motoneurons in primates.

Serotonin (5-HT) has direct and specific effects on the activity of spinal cord motoneurons. The 5-HT1A receptor has been shown to mediate motoneuron responses in spinal reflex pathways using the highly selective 5-HT1A receptor agonist 8-OH-DPAT. We have developed an antipeptide antibody that recognizes a specific region (the second external loop) of the 5-HT1A receptor. This 5-HT1A receptor antibody labels populations of neurons and glia in the primate cervical spinal cord. The highest receptor density is present in the superficial lamina of the dorsal horn, around the central canal, and on the axon hillock of large ventral horn motoneurons. The cellular labeling pattern on motoneurons shows a single, densely stained, tapering process emanating from the perikaryon. A more diffuse label is also present throughout the soma. Dendritic labeling was not apparent. These results suggest that post-synaptic 5-HT1A receptors may be involved in modulating spinal motoneuron activity at the key site of action potential initiation, the axon hillock.

Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells.

Activation of 5HT1A receptors produces many different physiologic responses, which may be due to their localization on diverse cells in the brain. A 5-HT1A receptor antipeptide (aa170-186) antibody was produced that showed both high titer for peptide binding and immunocytochemical staining. Studies performed in perfusion-fixed brain tissue showed immunoreactive neurons, glial, and ependymal cells in the rat, mouse, cat, and monkey. Results from our studies of Macaca fascicularis brains are presented. We observed two main neuronal labeling patterns in the primate brain: (1) A general, diffuse somatodendritic distribution of 5-HT1A receptor immunoreactivity is seen in the raphe nuclei where the dendritic shaft, its branches and spines, and the entire perikaryon are immunolabeled. This pattern is also observed in the nucleus locus coeruleus, in scattered large brainstem reticular neurons, and in dentate gyrus hilar interneurons. (2) A discrete localization of 5-HT1A receptor immunoreactivity on the initial axon segment (axon hillock) is noted in pyramidal neurons of layer III and V of cerebral cortex, Cornu Ammonus (1-4) of the hippocampus, and in most brainstem and cervical spinal cord motoneurons. In addition to neuronal labeling, 5-HT1A receptor immunoreactivity is seen in the cell body and processes of astrocytes, and other nonneuronal cells. This pattern is particularly evident in the white matter of cerebral cortex and spinal cord, the pontine nuclei, the brainstem tectum, and the hilus of the dentate gyrus. The clinical implications of 5-HT1A cellular localization are briefly discussed.

Isolation of human peripheral blood lymphocytes: modification of a double discontinuous density gradient of Ficoll-Hypaque.

Incubation of whole blood with adenosine diphosphate (ADP) and carbonyl iron prior to layering on a double discontinuous gradient of Ficoll-Hypaque selectively reduced the number of platelets and monocytes found at the upper lymphocyte interface after centrifugation. This modification in combination with a double discontinuous gradient results in a lymphocyte isolation method that is simple, rapid and reproducible.

Predictors of perioperative myocardial infarction in coronary artery operation.

Postoperative graft patency and thirteen perioperative variables were evaluated as potential risk factors for perioperative myocardial infarction (MI) in 102 consecutive patients undergoing coronary artery bypass grafting. Also, the incidence of perioperative MI and the amount of CK-MB released in the postoperative period were compared in three groups of patients selected according to the myocardial preservation technique employed: (1) topical hypothermia with and (2) without aortic cross-clamping and (3) cardioplegia. A perioperative MI as detected by electrocardiogram, enzymes, and myocardial scintigraphy with technetium 99 developed in 15 patients. Most important predictors of perioperative MI were found to be (1) left main and triple-vessel coronary artery disease, (2) a left ventricular end-diastolic pressure greater than or equal to 15 mm Hg, (3) a decreased ejection fraction (p < 0.05), and (4) cardiopulmonary bypass time > 120 minutes (p < 0.01). The incidence of perioperative MI was 50% in patients with three or more risk factors and 7% in those with less than three risk factors (p < 0.001). Graft patency was similar in patients with or without perioperative MI. Differing myocardial preservation techniques did not influence CK-MB release or the incidence of perioperative MI. Thus, the severity of ischemic heart disease and the length of the cardiopulmonary bypass time were important predictors of perioperative MI while graft patency and myocardial preservation technique did not appear to be related to its incidence in this study.

A specialized innervation of the tensor tympani muscle in Macaca fascicularis.

The innervation of the tensor tympani muscle of the middle ear in Macaca fascicularis (cynomolgus monkey) was studied using the horseradish peroxidase (HRP) neural tracing technique. A compact column of small trigeminal motoneurons was labeled ipsilaterally following intramuscular application of HRP to the tensor tympani muscle. This column is located ventral and lateral to the dorsolateral division of the trigeminal motor nucleus, and just medial to the descending trigeminal nerve rootlets. No labeled neurons were present in the trigeminal mesencephalic nucleus or any other brainstem nucleus. Results are compared with those previously reported in several non-primate mammalian species, and in detail with that of the cat. A possible differential role of the tensor tympani muscle in acoustic modulation/middle ear aeration between primate and non-primate mammals is discussed.

Efficacy of oral hydergine (ergoloid mesylates) in alcohol related encephalopathy.

A pilot-study to explore the efficacy of oral hydergine in seven cases of alcohol-related encephalopathy was undertaken. It showed significant improvement in symptoms of depression, plus some improvement in sleep disturbance and agitation, as measured by the Geriatric Profile (GP).

Frequency of cerebral vasospasm in patients treated with endovascular occlusion of intracranial aneurysms.

UNLABELLED: The purpose of this study was to retrospectively compare a group of 19 patients treated with craniotomy and aneurysmal clipping with a group of 18 patients who were treated via endovascular occlusion with Guglielmi detachable coils in regard to frequency and severity of cerebral vasospasm. METHODS: All patients were treated within 48 hours of ictus. In the endovascular group, nine patients had Hunt and Hess grade I subarachnoid hemorrhage, five patients had grade II aneurysms, and four patients had grade III. According to the Fisher classification, one aneurysm was grade I, nine were grade II, and eight were grade III. Twelve of the aneurysms were on the anterior circulation and seven were on the posterior circulation. In the surgical group, 10 patients had Hunt and Hess grade I hemorrhage, seven had grade II aneurysms, and two had grade III. Nine of these were Fisher grade II and 10 were grade III. Eighteen aneurysms were on the anterior circulation and one was on the posterior circulation. Endovascularly treated patients were medically treated identically to those in the surgical group, with prophylactic volume expansion and hemodilution immediately after endovascular occlusion, except that they also received 48 hours of full heparinization followed by 24 hours of dextran infusion after endovascular occlusion. RESULTS: All four patients in the endovascular group in whom delayed neurologic deficits developed as a result of vasospasm responded to elevation of blood pressure and did not require either mechanical or chemical angioplasty to reverse their symptomatology. In the surgical group, 14 of 19 developed clinical vasospasm, with elevation of their transcranial Doppler velocities, and required maximum triple-H (hypertensive, hypervolemic, hemodilutional) therapy. Three of these patients required mechanical and pharmacologic angioplasty. No surgical complications were incurred as a direct result of the craniotomy. One patient in the endovascular group developed a femoral pseudoaneurysm as a complication of the procedure and postocclusion anticoagulation. No thromboembolic events were noted in this group. CONCLUSION: In patients with similar Hunt and Hess grades and Fisher grades, preliminary data suggest that the frequency and severity of cerebral vasospasm may be reduced in those treated by endovascular occlusion of their aneurysm as compared with those treated by direct surgical clipping.

Atlas of serotonergic cell bodies in the cat brainstem: an immunocytochemical analysis.

The localization and relative number of serotonergic (5HT) cell bodies in the brainstem of the cat were studied through the use of a specific immunocytochemical technique. A surprisingly large number of 5HT cells were found in regions in addition to the classical raphe nuclei (obscurus, pallidus, magnus, centralis superior, and dorsalis). Foremost among these were: the ventral medulla, just dorsal to the pyramidal tract and inferior olivary complex, and especially the area in and around the lateral reticular nucleus; the dorsal pons, surrounding the central reticular core, and in the central gray area; and a region in the mesencephalon, in and around the interpeduncular nucleus. The advantages and disadvantages of the existing schemas for subdividing and labeling groups of brain 5HT neurons are discussed.

Therapeutic modalities for the management of cerebral vasospasm: timing of endovascular options.

OBJECTIVES: To determine if a window of time could be defined during which angioplasty would be most effective in reversing neurological decline and ultimately improving outcome. METHODS: Of a group of 466 patients, 93 underwent endovascular management of clinical vasospasm that was medically refractory. Eighty-four of the 93 patients were available for follow-up for at least 6 months. All patients underwent mechanical angioplasty using compliant microballoon systems and, if distal spasm was present, the administration of papaverine. RESULTS: Fifty-one patients underwent endovascular management within a 2-hour window, and 33 patients underwent treatment more than 2 hours after the development of their symptoms. Compared with the group treated more than 2 hours after neurological decline (P < 0.01; chi2 = 8.02), the group that underwent endovascular management within a 2-hour window after the development of symptoms demonstrated sustained clinical improvement. CONCLUSION: When a patient develops symptomatic vasospasm and is unresponsive to traditional measures of critical care management, angioplasty may be effective in improving the patient's neurological status if this procedure is performed as early as possible. The results indicate that a 2-hour window may exist for restoration of blood flow to ultimately improve the patient's outcome.

Acutely thrombosed aneurysm of the middle cerebral artery presenting as intracranial hemorrhage in a 3-year-old child. Case report.

Spontaneous thrombosis of aneurysms occurs rarely in children, and, to our knowledge, there are no reports of aneurysms presenting as an embolic event in a child. We describe the case of a 3-year-old boy whose symptoms initially suggested an ischemic event to the dominant hemisphere. Initial computerized tomography scans indicated an intracranial hemorrhage. Subsequent radiographic study revealed evidence of emboli and, at exploration, a large acutely thrombosed aneurysm of the left middle cerebral artery associated with arterial occlusion was found. Entrapment of the aneurysm and thrombectomy provided excellent operative results.

The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis.

This chapter has reviewed biochemical and morphological studies of the human and monkey serotonergic system. In addition, the serotonin-producing neurons of M fascicularis were analyzed, using immunocytochemistry, radioautography, and measurements of synaptosomal serotonin reuptake and supernatant tryptophan hydroxylase activity. The major sections of the chapter covered cell bodies, pathways, subcortical distribution, and cortical distribution, and a gross brain dissection guide of M fascicularis is included. An atlas of the 5-HT-IR cell bodies was presented in Figures 7 to 33. Rostral and caudal groups of nuclei were discussed. The rostral group consists principally of the nuclei raphe dorsalis (B7 and B6), centralis superior (B8, B5, and part of B7), and prosupralemniscus (B9). These groups ascend mainly in tracts lying outside the medial forebrain bundle (MFB). In M fascicularis, 25% of the fibers within the MFB are myelinated. The caudal 5-HT-IR nuclei consist principally of the nuclei in a dorsal cluster (raphe obscurus, B2) and in a ventral cluster (pallidus, B1, and magnus B3). The dorsal 5-HT-IR cells in raphe obscurus are associated with the MLF, and cells extend into cervical spinal cord (lamina IX and X) with the descending MLF and the TTS. Fibers from the raphe obscurus innervate the motoneurons in both the cranial nuclei (X, XII) and the ventral horn. The ventral 5-HT-IR cells lie mainly medial to the medial leminiscal fibers. A large number of these cells extend laterally into paragigantocellularis lateralis and here extend caudally lying below the lateral reticular nuclei. Cells from this group are seen dorsally joining the internal arcuate fibers. The raphe magnus of the ventral cluster projects to the dorsal horn and is believed to mediate the serotonin-induced analgesia. The descending fibers from both of these clusters are occasionally myelinated. Also, in our tryptophan- and pargyline-pretreated monkeys, small 5 HT-IR cells were visible in the area postrema. Human and monkey biochemical data (detailed summary in Tables 1-6) provide evidence for the presence of serotonin fibers in all cortical and subcortical regions. In subcortical regions, the midbrain, medulla, amygdala, and substantia nigra have the highest, whereas the cerebellum, spinal cord, and ventral pons have the lowest amount of serotonin and its metabolite, 5-HIAA. In the basal ganglion, the globus pallidus has the highest rate of 5-HT synthesis. The temporal lobe receives the most serotonin of the major cortical lobes.(ABSTRACT TRUNCATED AT 400 WORDS)