Cinematic reflectometry using QIKR, the quite intense kinetics reflectometer.

The Quite Intense Kinetics Reflectometer (QIKR) will be a general-purpose, horizontal-sample-surface neutron reflectometer. Reflectometers measure the proportion of an incident probe beam reflected from a surface as a function of wavevector (momentum) transfer to infer the distribution and composition of matter near an interface. The unique scattering properties of neutrons make this technique especially useful in the study of soft matter, biomaterials, and materials used in energy storage. Exploiting the increased brilliance of the Spallation Neutron Source Second Target Station, QIKR will collect specular and off-specular reflectivity data faster than the best existing such machines. It will often be possible to collect complete specular reflectivity curves using a single instrument setting, enabling "cinematic" operation, wherein the user turns on the instrument and "films" the sample. Samples in time-dependent environments (e.g., temperature, electrochemical, or undergoing chemical alteration) will be observed in real time, in favorable cases with frame rates as fast as 1 Hz. Cinematic data acquisition promises to make time-dependent measurements routine, with time resolution specified during post-experiment data analysis. This capability will be deployed to observe such processes as in situ polymer diffusion, battery electrode charge-discharge cycles, hysteresis loops, and membrane protein insertion into lipid layers.

The Direction of response selectivity between conspecific and heterospecific auditory stimuli varies with response metric.

Species recognition is an essential behavioral outcome of social discrimination, flocking, mobbing, mating, and/or parental care. In songbirds, auditory species recognition cues are processed through specialized forebrain circuits dedicated to acoustic discrimination. Here we addressed the direction of behavioral and neural metrics of zebra finches' (Taeniopygia guttata) responses to acoustic cues of unfamiliar conspecifics vs. heterospecifics. Behaviorally, vocal response rates were greater for conspecific male zebra finch songs over heterospecific Pin-tailed Whydah (Vidua macroura) songs, which paralleled greater multiunit spike rates in the auditory forebrain in response to the same type of conspecific over heterospecific auditory stimuli. In contrast, forebrain activation levels were reversed to species-specific song playbacks during two functional magnetic resonance imaging experiments: we detected consistently greater responses to whydah songs over finch songs and did so independently of whether subjects had been co-housed or not with heterospecifics. These results imply that the directionality of behavioral and neural response selectivity metrics are not always consistent and appear to be experience-independent in this set of stimulus-and-subject experimental paradigms.

Influence of early-life nutritional stress on songbird memory formation.

In birds, vocal learning enables the production of sexually selected complex songs, dialects and song copy matching. But stressful conditions during development have been shown to affect song production and complexity, mediated by changes in neural development. However, to date, no studies have tested whether early-life stress affects the neural processes underlying vocal learning, in contrast to song production. Here, we hypothesized that developmental stress alters auditory memory formation and neural processing of song stimuli. We experimentally stressed male nestling zebra finches and, in two separate experiments, tested their neural responses to song playbacks as adults, using either immediate early gene (IEG) expression or electrophysiological response. Once adult, nutritionally stressed males exhibited a reduced response to tutor song playback, as demonstrated by reduced expressions of two IEGs (Arc and ZENK) and reduced neuronal response, in both the caudomedial nidopallium (NCM) and mesopallium (CMM). Furthermore, nutritionally stressed males also showed impaired neuronal memory for novel songs heard in adulthood. These findings demonstrate, for the first time, that developmental conditions affect auditory memories that subserve vocal learning. Although the fitness consequences of such memory impairments remain to be determined, this study highlights the lasting impact early-life experiences can have on cognitive abilities.

A Upf3b-mutant mouse model with behavioral and neurogenesis defects.

Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders.

Relating surface roughness and magnetic domain structure to giant magneto-impedance of Co-rich melt-extracted microwires.

Understanding the relationship between the surface conditions and giant magneto-impedance (GMI) in Co-rich melt-extracted microwires is key to optimizing their magnetic responses for magnetic sensor applications. The surface magnetic domain structure (SMDS) parameters of ~45 µm diameter Co69.25Fe4.25Si13B13.5-xZrx (x = 0, 1, 2, 3) microwires, including the magnetic domain period (d) and surface roughness (Rq) as extracted from the magnetic force microscopy (MFM) images, have been correlated with GMI in the range 1-1000 MHz. It was found that substitution of B with 1 at. % Zr increased d of the base alloy from 729 to 740 nm while retaining Rq from ~1 nm to ~3 nm. A tremendous impact on the GMI ratio was found, increasing the ratio from ~360% to ~490% at an operating frequency of 40 MHz. Further substitution with Zr decreased the high frequency GMI ratio, which can be understood by the significant increase in surface roughness evident by force microscopy. This study demonstrates the application of the domain period and surface roughness found by force microscopy to the interpretation of the GMI in Co-rich microwires.

Ferromagnetic glass-coated microwires with good heating properties for magnetic hyperthermia.

The heating properties of Fe71.7Si11B13.4Nb3Ni0.9 amorphous glass-coated microwires are explored for prospective applications in magnetic hyperthermia. We show that a single 5 mm long wire is able to produce a sufficient amount of heat, with the specific loss power (SLP) reaching a value as high as 521 W/g for an AC field of 700 Oe and a frequency of 310 kHz. The large SLP is attributed to the rectangular hysteresis loop resulting from a peculiar domain structure of the microwire. For an array of parallel microwires, we have observed an SLP improvement by one order of magnitude; 950 W/g for an AC field of 700 Oe. The magnetostatic interaction strength essential in the array of wires can be manipulated by varying the distance between the wires, showing a decreasing trend in SLP with increasing wire separation. The largest SLP is obtained when the wires are aligned along the direction of the AC field. The origin of the large SLP and relevant heating mechanisms are discussed.

Tooth agenesis and orofacial clefting: genetic brothers in arms?

Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFß3, TGFßR1, TGFßR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.

Boosted Hyperthermia Therapy by Combined AC Magnetic and Photothermal Exposures in Ag/Fe3O4 Nanoflowers.

Over the past two decades, magnetic hyperthermia and photothermal therapy are becoming very promising supplementary techniques to well-established cancer treatments such as radiotherapy and chemotherapy. These techniques have dramatically improved their ability to perform controlled treatments, relying on the procedure of delivering nanoscale objects into targeted tumor tissues, which can release therapeutic killing doses of heat either upon AC magnetic field exposure or laser irradiation. Although an intense research effort has been made in recent years to study, separately, magnetic hyperthermia using iron oxide nanoparticles and photothermal therapy based on gold or silver plasmonic nanostructures, the full potential of combining both techniques has not yet been systematically explored. Here we present a proof-of-principle experiment showing that designing multifunctional silver/magnetite (Ag/Fe3O4) nanoflowers acting as dual hyperthermia agents is an efficient route for enhancing their heating ability or specific absorption rate (SAR). Interestingly, the SAR of the nanoflowers is increased by at least 1 order of magnitude under the application of both an external magnetic field of 200 Oe and simultaneous laser irradiation. Furthermore, our results show that the synergistic exploitation of the magnetic and photothermal properties of the nanoflowers reduces the magnetic field and laser intensities that would be required in the case that both external stimuli were applied separately. This constitutes a key step toward optimizing the hyperthermia therapy through a combined multifunctional magnetic and photothermal treatment and improving our understanding of the therapeutic process to specific applications that will entail coordinated efforts in physics, engineering, biology, and medicine.

Protein stability changes of the novel p.Arg180Cys mutant A glycosyltransferase resulted in a weak A phenotype.

A novel A subgroup allele (c.538C>T p.Arg180Cys) showing weak A phenotype was found in a 30-year-old Korean woman with ABO discrepancy. Using 3D structural analysis, protein stability prediction and flow cytometric analysis of ABO antigen expression on HeLa cells transfected with plasmids containing the p.Arg180Cys mutant, we found that the Arg180 residue in the loop region of the A glycosyltransferases (GTA) structure plays significant role in stabilizing its closed conformation, which is required for substrate binding and catalysis study.

Strain- and host species-specific inflammasome activation, IL-1ß release, and cell death in macrophages infected with uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) is the main etiological agent of urinary tract infections (UTIs). Little is known about interactions between UPEC and the inflammasome, a key innate immune pathway. Here we show that UPEC strains CFT073 and UTI89 trigger inflammasome activation and lytic cell death in human macrophages. Several other UPEC strains, including two multidrug-resistant ST131 isolates, did not kill macrophages. In mouse macrophages, UTI89 triggered cell death only at a high multiplicity of infection, and CFT073-mediated inflammasome responses were completely NLRP3-dependent. Surprisingly, CFT073- and UTI89-mediated responses only partially depended on NLRP3 in human macrophages. In these cells, NLRP3 was required for interleukin-1ß (IL-1ß) maturation, but contributed only marginally to cell death. Similarly, caspase-1 inhibition did not block cell death in human macrophages. In keeping with such differences, the pore-forming toxin α-hemolysin mediated a substantial proportion of CFT073-triggered IL-1ß secretion in mouse but not human macrophages. There was also a more substantial α-hemolysin-independent cell death response in human vs. mouse macrophages. Thus, in mouse macrophages, CFT073-triggered inflammasome responses are completely NLRP3-dependent, and largely α-hemolysin-dependent. In contrast, UPEC activates an NLRP3-independent cell death pathway and an α-hemolysin-independent IL-1ß secretion pathway in human macrophages. This has important implications for understanding UTI in humans.

From core/shell to hollow Fe/γ-Fe2O3 nanoparticles: evolution of the magnetic behavior.

High quality Fe/γ-Fe2O3 core/shell, core/void/shell, and hollow nanoparticles with two different sizes of 8 and 12 nm were synthesized, and the effect of morphology, surface and finite-size effects on their magnetic properties including the exchange bias (EB) effect were systematically investigated. We find a general trend for both systems that as the morphology changes from core/shell to core/void/shell, the magnetization of the system decays and inter-particle interactions become weaker, while the effective anisotropy and the EB effect increase. The changes are more drastic when the nanoparticles become completely hollow. Noticeably, the morphological change from core/shell to hollow increases the mean blocking temperature for the 12 nm particles but decreases for the 8 nm particles. The low-temperature magnetic behavior of the 12 nm particles changes from a collective super-spin-glass system mediated by dipolar interactions for the core/shell nanoparticles to a frustrated cluster glass-like state for the shell nanograins in the hollow morphology. On the other hand for the 8 nm nanoparticles core/shell and hollow particles the magnetic behavior is more similar, and a conventional spin glass-like transition is obtained at low temperatures. In the case of the hollow nanoparticles, the coupling between the inner and outer spin layers in the shell gives rise to an enhanced EB effect, which increases with increasing shell thickness. This indicates that the morphology of the shell plays a crucial role in this kind of exchange-biased systems.

A novel cis-AB variant allele arising from a de novo nucleotide substitution c.796A>G (p.M266V) in the B glycosyltransferase gene.

BACKGROUND: Cis-AB, a rare ABO variant, is the result of a mutated ABO gene that produces a glycosyltransferase enzyme with dual A and B glycosyltransferase activity. It may lead to ABO discrepancies and a delay in establishing the blood group. To date, there have been no reports of a de novo mutation leading to a cis-AB allele. OBJECTIVES AND METHODS: Sequencing of the ABO gene using blood and hair follicle cells from the proposita were performed along with blood from her parents. To establish maternity and paternity, short tandem repeat (STR) analysis was also performed. The A and B enzyme activities of the novel enzyme were measured in an in vitro expression study. RESULTS: A novel cis-AB allele arising from nucleotide substitution c.796A>G (p.M266V) in the B glycosyltransferase gene were discovered in the blood and hair follicle cells from the proposita, which was absent from her parents. In all 15 autosomal STR loci analysed, the probability of maternity and paternity were 0.999999 and 0.999989, respectively. The novel enzyme created 33.1% and 60.2% of A and B antigen compared to wild type A and B glycosyltransferases. CONCLUSION: A novel mechanism leading to a cis-AB allele was discovered.

Magnetocaloric effect and critical behavior in Pr0.5Sr0.5MnO3: an analysis of the validity of the Maxwell relation and the nature of the phase transitions.

The Maxwell relation, the Clausius-Clapeyron equation, and a non-iterative method to obtain the critical exponents have been used to characterize the magnetocaloric effect (MCE) and the nature of the phase transitions in Pr0.5Sr0.5MnO3, which undergoes a second-order paramagnetic to ferromagnetic (PM-FM) transition at TC ~ 247 K, and a first-order ferromagnetic to antiferromagnetic (FM-AFM) transition at TN ~ 165 K. We find that around the second-order PM-FM transition, the MCE (as represented by the magnetic entropy change, ΔSM) can be precisely determined from magnetization measurements using the Maxwell relation. However, around the first-order FM-AFM transition, values of ΔSM calculated with the Maxwell relation deviate significantly from those calculated by the Clausius-Clapeyron equation at the magnetic field and temperature ranges where a conversion between the AFM and FM phases occurs. A detailed analysis of the critical exponents of the second-order PM-FM transition allows us to correlate the short-range type magnetic interactions with the MCE. Using the Arrott-Noakes equation of state with the appropriate values of the critical exponents, the field- and temperature-dependent magnetization [Formula: see text] curves, and hence the [Formula: see text] curves, have been simulated and compared with experimental data. A good agreement between the experimental and simulated data has been found in the vicinity of the Curie temperature TC, but a noticeable discrepancy is present for [Formula: see text]. This discrepancy arises mainly from the coexistence of AFM and FM phases and the presence of ferromagnetic clusters in the AFM matrix.

Exchange bias effect in Au-Fe3O4 nanocomposites.

We report exchange bias (EB) effect in the Au-Fe3O4 composite nanoparticle system, where one or more Fe3O4 nanoparticles are attached to an Au seed particle forming 'dimer' and 'cluster' morphologies, with the clusters showing much stronger EB in comparison with the dimers. The EB effect develops due to the presence of stress at the Au-Fe3O4 interface which leads to the generation of highly disordered, anisotropic surface spins in the Fe3O4 particle. The EB effect is lost with the removal of the interfacial stress. Our atomistic Monte Carlo studies are in excellent agreement with the experimental results. These results show a new path towards tuning EB in nanostructures, namely controllably creating interfacial stress, and opens up the possibility of tuning the anisotropic properties of biocompatible nanoparticles via a controllable exchange coupling mechanism.

Detection of HPAI H5N1 viruses in ducks sampled from live bird markets in Vietnam.

In Vietnam, highly pathogenic avian influenza (HPAI) H5N1 infections in poultry often occur without concomitant clinical signs and outbreaks are not consistently reported. Live bird markets represent a convenient site for surveillance that does not rely on farmers' notifications. Two H5N1 surveys were conducted at live bird markets/slaughter points in 39 districts (five provinces) in the Red River, Mekong delta, and central Vietnam during January and May 2011. Oropharyngeal and rectal swab samples from 12 480 ducks were tested for H5N1 by reverse transcription-polymerase chain reaction in pools of five. Traders and stallholders were interviewed using standardized questionnaires; 3·3% of pools tested positive. The highest prevalence (6·6%) corresponded to the Mekong delta, and no H5N1 was detected in the two Red River provinces. The surveys identified key risk behaviours of traders and stallholders. It is recommended that market surveys are implemented over time as a tool to evaluate progress in HPAI control in Vietnam.

Evidence of a canted magnetic state in self-doped LaMnO(3+δ) (δ = 0.04): a magnetocaloric study.

We report a detailed investigation of the magnetocaloric properties of self-doped polycrystalline LaMnO(3+δ) with δ = 0.04. Due to the self-doping effect, the system exhibits a magnetic transition from a paramagnetic to ferromagnetic-like canted magnetic state (CMS) at ~120 K, which is associated with an appreciably large magnetocaloric effect (MCE). The CMS is an inhomogeneous magnetic phase developing due to a steady growth of antiferromagnetic correlation in its predominant ferromagnetic state below ∼120 K. The stabilization of CMS in this material is concluded from a comprehensive analysis of magnetocaloric data using Landau theory, which is in excellent agreement with our neutron diffraction study. The magnetic entropy change versus temperature curves for different applied fields collapse into a single curve, revealing a universal behavior of MCE. Our studies suggest that investigation of MCE is an effective technique to acquire fundamental understanding about the basic magnetic structure of a system with complex competing interactions.

Pharmacological characterization of KLYP961, a dual inhibitor of inducible and neuronal nitric-oxide synthases.

Nitric oxide (NO) derived from neuronal nitric-oxide synthase (nNOS) and inducible nitric-oxide synthase (iNOS) plays a key role in various pain and inflammatory states. KLYP961 (4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one) inhibits the dimerization, and hence the enzymatic activity of human, primate, and murine iNOS and nNOS (IC(50) values 50-400 nM), with marked selectivity against endothelial nitric-oxide synthase (IC(50) >15,000 nM). It has ideal drug like-properties, including excellent rodent and primate pharmacokinetics coupled with a minimal off-target activity profile. In mice, KLYP961 attenuated endotoxin-evoked increases in plasma nitrates, a surrogate marker of iNOS activity in vivo, in a sustained manner (ED(50) 1 mg/kg p.o.). KLYP961 attenuated pain behaviors in a mouse formalin model (ED(50) 13 mg/kg p.o.), cold allodynia in the chronic constriction injury model (ED(50) 25 mg/kg p.o.), or tactile allodynia in the spinal nerve ligation model (ED(50) 30 mg/kg p.o.) with similar efficacy, but superior potency relative to gabapentin, pregabalin, or duloxetine. Unlike morphine, the antiallodynic activity of KLYP961 did not diminish upon repeated dosing. KLYP961 also attenuated carrageenin-induced edema and inflammatory hyperalgesia and writhing response elicited by phenylbenzoquinone with efficacy and potency similar to those of celecoxib. In contrast to gabapentin, KLYP961 did not impair motor coordination at doses as high as 1000 mg/kg p.o. KLYP961 also attenuated capsaicin-induced thermal allodynia in rhesus primates in a dose-related manner with a minimal effective dose (≤ 10 mg/kg p.o.) and a greater potency than gabapentin. In summary, KLYP961 represents an ideal tool with which to probe the physiological role of NO derived from iNOS and nNOS in human pain and inflammatory states.

Discovery of dual inducible/neuronal nitric oxide synthase (iNOS/nNOS) inhibitor development candidate 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one (KD7332) part 2: identification of a novel, potent, and selective series of benzimidazole-quinolinone iNOS/nNOS dimerization inhibitors that are orally active in pain models.

Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimerization inhibitors that although potent, suffered from high clearance and limited exposure in vivo. By conformationally restricting the amide of this progenitor series, we describe the identification of a novel series of benzimidazole-quinolinone dual iNOS/nNOS inhibitors with low clearance and sustained exposure in vivo. Compounds were triaged utilizing an LPS challenge assay coupled with mouse and rhesus pharmacokinetics and led to the identification of 4,7-imidazopyrazine 42 as the lead compound. 42 (KD7332) (J. Med. Chem. 2009, 52, 3047 - 3062) was confirmed as an iNOS dimerization inhibitor and was efficacious in the mouse formalin model of nociception and Chung model of neuropathic pain, without showing tolerance after repeat dosing. Further 42 did not affect motor coordination up to doses of 1000 mg/kg, demonstrating a wide therapeutic margin.

Patients with thrombolysed stroke in Vietnam have an excellent outcome: results from the Vietnam Thrombolysis Registry.

BACKGROUND AND PURPOSE: We present the early experience in thrombolysis in three major centers of Ho Chi Minh city, namely 115 People Hospital, Gia Dinh Hospital, and An Binh Hospital. METHODS: A prospective study of consecutive patients treated with intravenous tPA with a treatment protocol similar to that of the National Institute of Neurological Disorders and Stroke (NINDS) trial. National Institutes of Health Stroke Scale (NIHSS) scores on admission and Modified Rankin Scale (MRS) scores at 3 months were measured for all patients. Intracranial and systemic hemorrhagic complications were recorded. RESULT: A total of 121 of 6171 (2%) patients with acute IS received thrombolysis over 3 years. Mean age was 57 years (range 18-78) and initial median NIHSS score was 12 (range 5-23). The mean delay between symptom onset and treatment was 143 min (range 50-210). Seventy-three (60.3%) patients received the standard dose with the remaining 48 patients (36.9%) treated with a lower dose, a mean calculated dose of 0.62 mg/kg (range, 0.6-0.86 mg/kg). Over half (56.3%) of the patients receiving low dose achieved functional independence (mRS score 0-1) at 3 months compared with 34.2% in the standard-dose group (P = 0.01). The 3-month mortality rate was also higher in the standard-dose group (2.1% vs. 12.5% with standard-dose tPA; P = 0.04). Symptomatic intracranial hemorrhage was noted in four patients of standard-dose group and one patient of low-dose group (P = 0.36). CONCLUSION: Intravenous thrombolysis, particularly in a lower dose, is safe and feasible in the treatment of acute IS in our selected Vietnamese population.

Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models.

There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42--potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.