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A palladium-catalyzed cross-coupling of thioacetates and aryl halides is described herein. Using a catalyst screening kit

Salmonellosis is a leading bacterial cause of foodborne illness, and numerous Salmonella enterica serovars have been responsible for foodborne outbreaks. In the United States outbreaks are often linked to poultry and poultry-related products. The prevalence of Salmonella serovar Infantis has been increasing in poultry processing facilities over the past few years and in 2018 was identified as the causative agent for a large multistate outbreak linked to raw chicken. CRISPR-typing is a subtyping approach based on PCR and the sequencing of two Salmonella loci, CRISPR1 and CRISPR2. CRISPR-typing was used to interrogate 138 recent (2018-2019) isolates and genomes of ser. Infantis. Results show that the CRISPR elements are remarkably conserved in this serovar. The most conserved spacers, and those also unique to ser. Infantis, were used as targets to develop a ser. Infantis-specific qPCR assay. This assay was able to detect ser. Infantis in mixed serovar cultures of Salmonella, down to 0·1% of the population, highlighting the utility of this molecular approach in improving surveillance sensitivity for this important food safety pathogen. SIGNIFICANCE AND IMPACT OF THE STUDY: The incidence of human salmonellosis cases caused by Salmonella enterica serovar Infantis (ser. Infantis) has been increasing, as has its prevalence in broiler chickens, which are a frequent reservoir of Salmonella. A cluster of ser. Infantis genetically linked to an outbreak strain have been identified in numerous processing facilities. A qPCR assay targeting CRISPR elements that are unique to ser. Infantis has been developed and can detect this serovar directly from mixed cultures. This assay is sensitive enough to reveal ser. Infantis within a mixed Salmonella population where it constitutes only 0·1% of the population. The rapid nature of qPCR lends this assay to high-throughput screening of poultry samples to detect this important pathogen.

[Image: see text] As more macrocycle structures are utilized to drug intracellular targets, new platforms are needed to facilitate the discovery of cell permeable compounds in this unique chemical space. Herein, a method is disclosed that allows for the efficient synthesis and permeability evaluation of novel organo-peptide macrocycle libraries. Thoughtful library design allows for the collection of crude permeability data using supercritical fluid chromatography mass spectrometry (SFC-MS) (EPSA) by mass-encoding the stereochemistry, ring size, and organic linker of the desired macrocycles. Library synthesis was aided via the development of a new on-resin N-arylation reaction. Further insights on the permeation of these organo-peptide macrocycles will be discussed, such as the permeability enhancement when utilizing a 2-substituted phenethyl linker versus a 3-substituted phenethyl linker. Lastly, selected macrocycles were scaled up and tested in the MDCK-II permeability assay, and the results of this assay reiterated the permeability trends from the crude SFC-MS data.

[Image: see text] Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD).

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.

[Image: see text] Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.

A metallaphotoredox reaction is described that allows for the efficient exploration of benzyl structure-activity relationships on electron-deficient amines. Typically, accessing a variety of benzyl groups on these substrates can be difficult due to the limited availability of the prerequisite building blocks, namely benzyl halides. However, the use of aryl bromides in this metallaphotoredox reaction allows for greater diversity in the benzyl piece. The reaction scope is discussed herein, including conditions for product scaleup using flow.

Poultry are well recognized as possible carriers of Salmonella species. As part of the local foods movement, backyard poultry flocks have increased in popularity in recent years. Between 1996 and 2012, 45 outbreaks of human Salmonella infections linked to live poultry from mail-order hatcheries were documented. This review examines the history of live poultry-associated salmonellosis in humans in the United States, the current status of the issue, and what can be done to help prevent these illnesses. An integrated One Health approach involving the mail-order hatchery industry, feed stores, healthcare providers, veterinarians, and backyard flock owners is needed to help prevent live poultry-associated salmonellosis.

The Pd-catalyzed coupling of γ-hydroxyalkenes with aryl bromides affords enantiomerically enriched 2-(arylmethyl)tetrahydrofuran derivatives in good yield and up to 96:4 e.r. This transformation was achieved through the development of a new TADDOL/2-arylcyclohexanol-derived chiral phosphite ligand. The transformations are effective with an array of different aryl bromides, and can be used for the preparation of products bearing quaternary stereocenters.

A catalyst composed of Pd2(dba)3 and (S)-Siphos-PE provides excellent results in Pd-catalyzed alkene carboamination reactions between aniline derivatives bearing pendant alkenes and aryl or alkenyl halides. These transformations generate tetrahydroquinolines and tetrahydroquinoxalines that contain quaternary carbon stereocenters with high levels of asymmetric induction. In addition this catalyst also effects the asymmetric synthesis of tetrahydroisoquinolines via related transformations of 2-allylbenzylamines. In contrast to most other approaches to the asymmetric synthesis of these compounds, which frequently involve functional group interconversion or a single C–C or C–N bond-forming event, the carboamination reactions generate both a C–N bond, a C–C bond, and a stereocenter.

A new method to access cyclic peptidomimetics via a Pd-catalyzed macroamination reaction is presented. Natural amino acid amines are revealed as proficient coupling partners in these transformations. With a commercially available CPhos G3 catalyst system and substrates bearing diverse amino acid and aryl halide backbones, the unique head to side-chain (or side-chain mimic) macrocycles are afforded with ring sizes from 11 to 23 members in yields up to 84%.

The Pd-catalyzed coupling of γ-hydroxyalkenes with aryl bromides affords enantiomerically enriched 2-(arylmethyl)tetrahydrofuran derivatives in good yield and up to 96:4 e.r. This transformation was achieved through the development of a new TADDOL/2-arylcyclohexanol-derived chiral phosphite ligand. The transformations are effective with an array of different aryl bromides, and can be used for the preparation of products bearing quaternary stereocenters.

Positive water effect: A catalyst composed of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and (S)-Siphos-PE is effective for the enantioselective coupling of N-allyl ureas with aryl bromides to afford 4-substituted imidazolidin-2-ones. Added water leads to significantly improved enantioselectivities with electron-poor aryl halide substrates. It is suggested that the C-C bond-forming reductive elimination is the enantiodetermining step in these reactions.

Outbreaks of human salmonella infections are increasingly associated with contact with live poultry, but effective control measures are elusive. In 2005, a cluster of human salmonella Montevideo infections with a rare pattern on pulsed-field gel electrophoresis (the outbreak strain) was identified by PulseNet, a national subtyping network.In cooperation with public health and animal health agencies, we conducted multistate investigations involving patient interviews, trace-back investigations, and environmental testing at a mail-order hatchery linked to the outbreak in order to identify the source of infections and prevent additional illnesses. A case was defined as an infection with the outbreak strain between 2004 and 2011.From 2004 through 2011, we identified 316 cases in 43 states. The median age of the patient was 4 years. Interviews were completed with 156 patients (or their caretakers) (49%), and 36 of these patients (23%) were hospitalized. Among the 145 patients for whom information was available, 80 (55%) had bloody diarrhea. Information on contact with live young poultry was available for 159 patients, and 122 of these patients (77%) reported having such contact. A mail-order hatchery in the western United States was identified in 81% of the trace-back investigations, and the outbreak strain was isolated from samples collected at the hatchery. After interventions at the hatchery, the number of human infections declined, but transmission continued.We identified a prolonged multistate outbreak of salmonellosis, predominantly affecting young children and associated with contact with live young poultry from a mail-order hatchery. Interventions performed at the hatchery reduced, but did not eliminate, associated human infections, demonstrating the difficulty of eliminating salmonella transmission from live poultry.

Substrate electron effects and additives greatly affect the levels of asymmetric induction in the reactions of N-allyl urea substrates with aryl bromides.

SUMMARY. After necropsy of the surviving turkeys in a comparative vaccine study for fowl cholera, in the turkeys with only one lung lobe consolidated, a significantly (P < 0.01, chi square test) higher number of turkeys were found with a consolidation of the left lung lobe than with the right lung lobe. When the circumferences of the left and right pulmonary arteries 0.5 cm rostral from the bifurcation were measured and converted to cross-sectional area, the left pulmonary artery had an average area of 29.6 + 2.8 mm2, and the right pulmonary artery had an average area of only 22.9 + 2.8 mm2, which was nearly one-fourth smaller. This finding suggests that the left lung lobe receives more blood than the right lobe and that, during an acute Pasteurella multocida septicemia, it would receive more of this organism than the right lung lobe.

The chromosomal DNA of 29 field isolants of Pasteurella multocida from commercial turkey farms in Missouri and the avirulent Clemson University (CU) and M-9 vaccine strains of P. multocida were tested using the arbitrarily primed polymerase chain reaction (AP-PCR) in combination with 32P-labeled deoxycytidine triphosphate (dCTP) and high-resolution gel electrophoresis. The 29 field isolants of P. multocida were isolated from outbreaks of fowl cholera in turkey flocks in which vaccination with the CU vaccine had been performed within 2 weeks of the isolation, and it was suspected that the outbreak could have been due to the use of the live CU vaccine. The results of this study showed that: 1) the use of the live CU vaccine can lead to the isolation of the vaccine strain if the outbreak occurs within 2 weeks of vaccination; 2) a higher proportion of field isolants collected during 1983 and 1984, when the usage of the CU vaccine strain was highest on Missouri turkey farms, had PCR-amplified product profiles similar or identical to those of the CU vaccine strain compared with the period between 1987 and 1992, when its use was less; and 3) there was no relationship between the PCR-amplified product profiles and the serotype.

SUMMARY. The live avirulent PM-1 Pasteurela multocida vaccine, grown in brain-heart infusion broth, was evaluated and compared in two experiments with the Clemson University (CU) vaccine, which had been shown to be effective in preventing fowl cholera in turkeys. Experiment 1 was performed during warm environmental temperatures and Expt. 2 during cooler environmental temperatures. The PM-1 vaccine was comparable with the CU vaccine in protecting turkeys against challenge with virulent P. multocida but was considered no less virulent than the CU because turkeys died after vaccination with both the PM-1 and the CU vaccines. A significantly (P < 0.05) higher percentage of unvaccinated turkeys challenged during the cooler environmental temperatures died than did unvaccinated turkeys challenged during the warmer temperatures. A microtiter agglutination test demonstrated a significant (P < 0.01) correlation between the level of serum anti-?P multocida antibody found 1 wk after vaccination and survival after challenge with virulent P multocida in Expt. 1 and a significant (P < 0.05) correlation between these parameters in Expt. 2. However, there was a significant (P < 0.01) negative correlation between serum anti-?P multocida antibody titer 1 wk after vaccination and body weight gained 4 wk after vaccination, but before challenge, in Expt. 1, suggesting that vaccination with the live vaccines may have had a negative effect on body weight gain. At 4 wk after challenge or 8 wk after vaccination in Expt. 2, there was also a highly significant (P < 0.001) negative correlation between these parameters in the surviving turkeys.

SUMMARY. An eighteen-month-old female rhea (Rhea americana) was presented dead for necropsy. The owner reported having observed blood in the droppings. Gross examination revealed a rhea in good body condition with a copious amount of frank blood in the cloaca. Large masses of matted fescue grass (Festuca spp.) distended the ventriculus and jejunum. No hemorrhage was evident in the digestive tract, which was otherwise void of ingesta. The kidneys were dark brown in color. Renal histopathology revealed a severe accumulation of eosinophilic pigment in the tubular epithelial cells of the proximal convoluted tubules, with tubular nephrosis and eosinophilic casts in the collecting tubules. It was concluded that the renal pigment was hemoglobin and not myoglobin, based on lack of evidence of muscle injury and the severe erythrophagocytosis evident in hepatic macrophages. The renal pigment also stained positive with the hemoglobin-specific Okajima stain. Hemoglobinuric nephrosis has not previously been reported in an avian species. RESUMEN. Reporte de Caso-Nefrosis hemoglobinfirica en un fiandu (Rhea americana). Se practico la necropsia de una hembra iiandfu (Rhea americana) de 18 meses de edad. El propietario reporto haber observado sangre en la materia fecal. El examen macroscopico revelo una copiosa cantidad de sangre en la cloaca. Grandes masas de pasto puntero (Festuca spp.) distendian el proventriculo y yeyuno. No se encontr6 hemorragia en el tracto digestivo, que ademfas estaba sin contenido alimenticio. Los rifnones estaban de color cafe oscuro. La histopatologia renal revelo una acumulacion severa de pigmento eosinofilico en las celulas epiteliales tubulares de los tubulos proximales, con nefrosis tubular y cilindros eosinofllicos en los tuibulos colectores. Se concluyo que el pigmento renal era hemoglobina y no mioglobina, basado en la ausencia de heridas musculares y la eritrofagocitosis severa evidente en los macrofagos hepafticos. La nefrosis hemoglobinurica no ha sido reportada previamente en las especies aviares.