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The nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson's disease. Recently, we demonstrated that Nurr1 binds directly to and is regulated by the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI). Unfortunately, DHI is an unstable compound, and thus a poor tool for studying Nurr1 function. Here, we report that 5-chloroindole, an unreactive analog of DHI, binds directly to the Nurr1 ligand binding domain with micromolar affinity and stimulates the activity of Nurr1, including the transcription of genes governing the synthesis and packaging of dopamine.

The nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson’s disease. Recently, we demonstrated that Nurr1 binds directly to and is regulated by the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI). Unfortunately, DHI is an unstable compound, and thus a poor tool for studying Nurr1 function. Here we report that 5-chloroindole, an unreactive analog of DHI, binds directly to the Nurr1 ligand binding domain with micromolar affinity and stimulates the activity of Nurr1, including the transcription of genes governing the synthesis and packaging of dopamine.

Human platelet 12-(S)-Lipoxygenase (12-LOX) is a fatty acid metabolizing oxygenase that plays an important role in platelet activation and cardiometabolic disease. ML355 is a specific 12-LOX inhibitor that has been shown to decrease thrombosis without prolonging hemostasis and protect human pancreatic islets from inflammatory injury. It has an amenable drug-like scaffold with nM potency and encouraging ADME and PK profiles, but its binding mode to the active site of 12-LOX remains unclear. In the current work, we combined computational modeling and experimental mutagenesis to propose a model in which ML355 conforms to the "U" shape of the 12-LOX active site, with the phenyl linker region wrapping around L407. The benzothiazole of ML355 extends into the bottom of the active site cavity, pointing towards residues A417 and V418. However, reducing the active site depth alone did not affect ML355 potency. In order to lower the potency of ML355, the cavity needed to be reduced in both length and width. In addition, H596 appears to position ML355 in the active site through an interaction with the 2-methoxy phenol moiety of ML355. Combined, this binding model suggested that the benzothiazole of ML355 could be enlarged. Therefore, a naphthyl-benzothiazole derivative of ML355, Lox12Slug001, was synthesized and shown to have 7.2-fold greater potency than ML355. This greater potency is proposed to be due to additional van der Waals interactions and pi-pi stacking with F414 and F352. Lox12Slug001 was also shown to be highly selective against 12-LOX relative to the other LOX isozymes and more importantly, it showed activity in rescuing human islets exposed to inflammatory cytokines with comparable potency to ML355. Further studies are currently being pursued to derivatize ML355 in order to optimize the additional space in the active site, while maintaining acceptable drug-like properties.

Culturomics investigates microbial diversity of the human microbiome by combining diversified culture conditions, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene identification. The present study allowed identification of four putative new Clostridium sensu stricto species: ‘Clostridium amazonitimonense’ strain LF2T, ‘Clostridium massilidielmoense’ strain MT26T, ‘Clostridium nigeriense’ strain Marseille-P2414T and ‘Clostridium merdae’ strain Marseille-P2953T, which we describe using the concept of taxonogenomics. We describe the main characteristics of each bacterium and present their complete genome sequence and annotation.

Background: Heat shock proteins (Hsps) are evolutionary ancient and highly conserved molecular chaperons found in prokaryotes as well as eukaryotes. Hsp70 is a predominant member of Hsp family. Microbial Hsp70s (mHsp70s) have acquired special significance in immunity since they have been shown to be potent activators of the innate immune system and generate specific immune responses against tumours and infectious agents. Objectives: The present study was aimed to clone express and purify recombinant Hsp70 from the Mycobacterium tuberculosis and characterise it immunologically. The study also aimed at determining the potential of recombinant M. tuberculosis heat shock protein (rMTB-Hsp70) as adjuvant or antigen carrier. Materials and Methods: Cloning of M. tuberculosis heat shock protein (MTB-Hsp70) amplicon was carried out using the pGEMT-Easy vector although for expression, pProExHTb prokaryotic expression vector was used. Purification of recombinant Hsp70 was carried out by nickel-nitrilotriacetic acid (Ni-NTA) affinity chromatography. For immunological characterization and determining the adjuvant effect of MTB-Hsp70, BALB/c mice were used. The data obtained was statistically analysed. Results: Hsp70 gene was cloned, sequenced and the sequence data were submitted to National Center for Biotechnology Information (NCBI). Recombinant MTB-Hsp70 was successfully over-expressed using the prokaryotic expression system and purified to homogeneity. The protein was found to be immunodominant. Significant adjuvant effect was produced by the rMTB-Hsp70 when inoculated with recombinant outer membrane protein 31; however, effect was less than the conventionally used the Freund′s adjuvant. Conclusion: Protocol standardised can be followed for bulk production of rHsp70 in a cost-effective manner. Significant adjuvant effect was produced by rMTB-Hsp70; however, the effect was than Freund′s adjuvant. Further, studies need to be carried out to explore its applicability as carrier of antigen.

Resume Les anevrismes cerebraux secondaires a la vascularite lupique sont rares. Nous rapportons l’observation d’une patiente hospitalisee pour poussee lupique avec convulsions inaugurales. L’angioscanner revelait une hemorragie sous-arachnoidienne par rupture d’un anevrisme de l’artere cerebelleuse superieure. La patiente presentait apres plusieurs jours, et malgre un traitement associant corticoides et cyclophosphamide, une seconde hemorragie sur rupture d’un nouvel anevrisme au niveau des arteres lenticulo-striees, dont l’issue a ete fatale. Nous discutons ensuite de la frequence et de la prise en charge de cette complication severe du lupus erythemateux systemique.

Geophagy or soil eating is mostly described in pregnant women from Sub-Saharan Africa, South America. Here, we report 12 cases of geophagy associated with severe anemia in non-pregnant Nigerian women.The median age at diagnosis was 34.5 years. The socioeconomic level was average for all patients. The median hemoglobin level at admission was 6.9g/dL (3.3-8.6), median corpuscular volume was 78.3fL (63-106) and median serum ferritin was 9.2ng/mL (3.6-11.2). The reasons of this practice were "desire" (5/12) and tradition (4/12). All patients received psychotherapy and supplementation with intravenous iron.Geophagy is an underestimated practice in developed countries and in non-pregnant women. It can be the cause of severe iron deficiency and must be discussed in patients with anemia, including non-pregnant patients, and in Africa as well as in migration areas, where the practice can be exported.

Cerebral aneurysms secondary to cerebral vasculitis related to systemic lupus erythematosus are rare. We report a 31-year-old woman who presented with a lupus flare associated with inaugural generalized seizures. Computed tomography angiography showed subarachnoid hemorrhage by rupture of a cerebellar artery fusiform aneurysm. Later, despite the initiation of corticosteroids and cyclophosphamide, she presented a second cerebral hemorrhage due to the rupture of a new aneurysm in lenticulostriates arteries. The outcome was fatal. We discuss the frequency and management of this severe complication of systemic lupus erythematosus.

Thin liquid aluminum films (150–500 A) grown in situ on alumina substrates have been studied under U.H.V. conditions in a scanning transmission high-energy electron diffraction system incorporating inelastic filtering. The liquid structure factor was determined (after applying appropriate corrections) by using high-angle fitting and the Krogh-Moe methods. The reliability of the normalization was assessed by the Rahman criterion, giving an accuracy of 1% for the structure factor between Q = 0.5 and 12.0 A−1.

The flow rate of a liquid drainage from the lungs is limited because of the elastic nature of the airways. This study was designed to clarify the relationship between intrapulmonary liquid volume and the development of the flow limitation or choked flow phenomenon as a function of expiratory flow rate during total liquid ventilation with perflubron.Prospective animal study.University research laboratory.Rabbits with a weight of 3.2 +/- 0.3 kg.After the rabbits were killed, the lungs were filled to functional residual capacity with perflubron, followed by administration of an additional volume of 30, 45, or 60 mL of perflubron (initial volume = functional residual capacity + additional volume).In one set of five animals, the intratracheal pressure at the occurrence of choked flow was established at -20 mm Hg. In another set of six animals, we demonstrated that the volume remaining in the lung at the point of development of choked flow (Vch) was stable for the first 40 mins after the animals were killed. Flow rates of 1.25, 2.5, 3.75, 5.0, 7.5, 10.0, and 12.5 mL/sec were then applied at an additional volume of 30, 45, or 60 mL to 34 animals. Vch approximately doubled as the flow rate increased from 1.25 mL/sec to 12.5 mL/sec (p.001). At the same flow, Vch was higher for an additional volume of 60 mL than 30 mL when the flow wasor =2.5 mL/sec.From these data, we conclude that choked flow occurs at intratracheal pressure of less than -20 mm Hg, that Vch is stable for the first 40 mins after the animals are killed, and that Vch is a function of flow rate and initial volume.

Blackwater fever is characterized by severe intravascular hemolysis with renal failure caused by recurrent use of quinine for prophylaxis. Once described in European patients, sporadic cases have been reported more and more often in autochthonous Africans and Asians. Newer antimalarials including aminoalchohol mefloquine, and halofantrine have also been implicated in Blackwater fever. In this report we describe two cases of blackwater fever involving patients with sickle cell anemia (HbSS). Symptoms including fever, acute hemolytic anemia, emesis, back pain, and hemoglobinuria were characteristic of blackwater fever. Both patients died. Although the underlying mechanism of blackwater fever remains unclear, a likely explanation is an immunoallergic reaction to quinine. Association with glucose-6-phosphate dehydrogenase deficiency has often been reported. Our cases suggest that blackwater fever may also be correlated with hemoglobinopathy such as HbSS.

A UHV microparticle gun has been used to accelerate carbonyl iron spheres of diameters ranging from 0.1 to 2 mu m to velocities of 20-100 m s-1 for semi-elastic impact studies on 1/4 mu m diamond polished metal electrodes. The mean values of the microscopic coefficients of restitution have been measured for a range of target materials of varying hardness (lead, copper, nickel, phosphor bronze, iron, titanium, stainless steel and carbon), and are in broad agreement with the previously determined macroscopic behaviour. The considerable scatter associated with the present experimental results has been interpreted in terms of the microtopography of the target surfaces.

1. Distributions of some economically‐important traits in two strains of White Leghorn chickens over six generations were examined. 2. Negative skewness and positive kurtosis were observed for egg production whereas age at first egg showed positive skewness, reflecting an excess of undesirable birds in both the cases. Body weight and egg size showed little or no departure from normal distributions. 3. Such deviations from normality as skewness and kurtosis are associated with characters of relatively low heritability which are more prone to environmental effects. Extremes of gene frequencies and non‐additive genetic effects may also contribute to deviation. 4. Positive kurtosis and skewness cause decreased selection intensity.

Scanning transmission electron diffraction with energy filtering has been used to study thin films of supercooled liquid lead (thickness 5–60 A) grown on graphite substrates under UHV conditions. The liquid structure factor was determined (after applying appropriate corrections) by using the high-angle-fitting and the Krogh-Moe methods. The reliability of the normalization was assessed by the Rahman criterion : this gave an accuracy of 1% for the structure factor for Q = 0·5 to 11·0 A−1.

Distributions of egg weight and egg deformation values of 10,548 eggs, obtained from 530 pullets, were examined. The deviations from normality based on mean values of all eggs from individual pullets over the experimental period were small relative to the estimates obtained when all 10,548 values were used. The effect of these deviations from normality on selection intensities was studied when 5 to 95% of the pullets were hypothetically retained for reproduction. Distribution of both egg weight and deformation using individual data showed considerable departure from presumed normal distribution in the form of positive skewness and positive kurtosis. The nonnormality of distribution tended to over- or underestimate the selection intensities, depending upon the fraction saved and type and extent of deviations from normality.

Constructional and operational details are given of a recently developed UHV low velocity microparticle source that has been incorporated in an experimental system for studying normal incident microparticle 'reflection' processes that occur in a high voltage gap. The measured velocity and charge distributions of the mu m size particle flux range from approximately 1 to 300 m s-1 and 1 to 6 fC respectively, with corresponding mean values of approximately 10 m s-1 and 2 fC. Three types of low velocity particle bouncing process are illustrated.

Carbonyl iron microspheres 0.1-2 mu m diameter, with velocities of 10-100 m s-1 and positive charges of (0.5-5)*10-15 C have been used for a comparative study of the charge reversal that occurs during a bouncing impact with negatively charged copper and stainless steel high-voltage electrodes that are either atomically clean or have approximately 30 AA and approximately >or approximately=150 AA surface oxide films. Argon ion etching and electron bombardment heating were available for in-situ surface cleaning, while an ellipsometric facility was used for characterizing electrode surfaces. Experimental results show that the efficiency of charge reversal is strongly dependent on both the thickness and electrical properties of surface oxide films.

Thin liquid aluminum films (150–500 A) grown in situ on alumina substrates have been studied under U.H.V. conditions in a scanning transmission high-energy electron diffraction system incorporating inelastic filtering. The liquid structure factor was determined (after applying appropriate corrections) by using high-angle fitting and the Krogh-Moe methods. The reliability of the normalization was assessed by the Rahman criterion, giving an accuracy of 1% for the structure factor between Q = 0.5 and 12.0 A−1.

A low-velocity microparticle gun has been developed for a controlled study of the momentum and charge reversal associated with particle bouncing in a high-voltage vacuum gap for impact velocities of 5-200 m s-1. It has been demonstrated that there are a range of experimental conditions for which this mechanism can lead to an enhancement in the kinetic energy of a microparticle. This observation is used in support of a multi-transit model for the initiation of electrical breakdown by the impact of microparticles having velocities in excess of 1500 m s-1.