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Ixodes scapularis , the black-legged tick, is the principal vector of the Lyme disease spirochete, Borrelia burgdorferi , and is responsible for most of the ∼470,000 estimated Lyme disease cases annually in the USA. Ixodes scapularis can transmit six additional pathogens of human health significance. Because of its medical importance, I. scapularis was the first tick genome to be sequenced and annotated. However, the first assembly, I. scapularis Wikel (IscaW), was highly fragmented because of the technical challenges posed by the long, repetitive genome sequences characteristic of arthropod genomes and the lack of long-read sequencing techniques. Although I. scapularis has emerged as a model for tick research because of the availability of new tools such as embryo injection and CRISPR-Cas9-mediated gene editing yet the lack of chromosome-scale scaffolds has slowed progress in tick biology and the development of tools for their control. Here we combine diverse technologies to produce the I. scapularis Gulia-Nuss (IscGN) genome assembly and gene set. We used DNA from eggs and male and female adult ticks and took advantage of Hi-C, PacBio HiFi sequencing, and Illumina short-read sequencing technologies to produce a chromosome-level assembly. In this work, we present the predicted pseudochromosomes consisting of 13 autosomes and the sex pseudochromosomes: X and Y, and a markedly improved genome annotation compared with the existing assemblies and annotations., (© 2023 Nuss et al.)

Ethiopian mustard (Brassica carinata) is an ancient crop with remarkable stress resilience and a desirable seed fatty acid profile for biofuel uses. Brassica carinata is one of six Brassica species that share three major genomes from three diploid species (AA, BB, and CC) that spontaneously hybridized in a pairwise manner to form three allotetraploid species (AABB, AACC, and BBCC). Of the genomes of these species, that of B. carinata is the least understood. Here, we report a chromosome scale 1.31-Gbp genome assembly with 156.9-fold sequencing coverage for B. carinata, completing the reference genomes comprising the classic Triangle of U, a classical theory of the evolutionary relationships among these six species. Our assembly provides insights into the hybridization event that led to the current B. carinata genome and the genomic features that gave rise to the superior agronomic traits of B. carinata. Notably, we identified an expansion of transcription factor networks and agronomically important gene families. Completion of the Triangle of U comparative genomics platform has allowed us to examine the dynamics of polyploid evolution and the role of subgenome dominance in the domestication and continuing agronomic improvement of B. carinata and other Brassica species., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.

Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.

Ovariectomized rats were treated for three weeks with cottonseed oil, estraiol, progesterone, mestranol-norethynodrel, or testosterone, and intact female rats were treated with cottonseed oil, or testosterone. Plasma total cholesterol, plasma triglycerides, and systolic blood pressure were then measured. Estradiol administration resulted in an increase in plasma cholesterol and triglycerides. Administration of testosterone to intact rats produced a decrease in cholesterol. Rats administered estradiol had significantly higher systolic blood pressure than any other group except the contraceptive treated group. By use of the ovariectomized rat model, the individual effects of sex hormones are delineated and it is demonstrated that estrogen has more effect than progestogen on both plasma lipids and systolic blood pressure.

In rabbits, collagen synthesis was studied in five different regions of the vasuclar tree which are subjected to different degrees of pulsatile distention, i.e., cyclic stretching, and mean pressure. The vessels with greatest pulsatile distention had the highest specific activity of hydroxyproline in collagen after incubation with 14C-proline and the inferior vena cava with low pressure and negligible pulsatile distention had the lowest specific activity. The findings suggest a link between mechanical stretching and cellular metabolic function and have significance as to the relationship of pulsatile flow to normal vascular and organ physiology.

Collagen and elastin synthesis was determined in 5 regions of the vascular system in rabbits on (a) normal diet and (b) atherogenic diet. Increased connective tissue synthesis was found in 3 different sections of the aorta and in the pulmonary artery of rabbits on the atherogenic diet. The inferior vena cava showed no difference between the two groups. Regional variation in connective tissue synthesis was found in both normal and atherosclerotic animals, the vessels associated with the greatest degree of pulsatile distention in vivo having the greatest synthesis and the inferior vena cava, a low pressure, low distention vessel having the lowest synthesis. It is concluded that the atherogenic process includes stimulation of collagen and elastin synthesis. It is suggested that in addition to the effect of pressure on connective tissue synthesis, pulsatile distention may be a factor in synthesis and may be related to lesion formation.

Rabbits were fed an atherogenic or normal control diet for 3 months; half of each group were treated with mestranol--norethynodrel (M--N) and half with cottonseed oil vehicle. At the end of the 3-month period rabbits were killed and aortic collagen and elastin synthesis determine. Collagen and elastin synthesis was increased in aortas of rabbits on an atherogenic diet, but those treated with M--N had a lower rate of collagen synthesis and less deposition of cholesterol in the aorta than those administered cottonseed oil. It is suggested that long-term administration of the contraceptive steroid combination may retard the progression of atherosclerosis through the hormone's effect on vascular connective tissue.

The influence of estradiol on deposition of cholesterol in tissues of ovariectomized rats on normal and high lipid diets was studied. Concomitantly the influence of a contraceptive steroid combination was studied in a similar manner in intact rats. It was found that the high lipid diet resulted in increased deposition of cholesterol in aorta, heart, liver and kidney. The presence of either endogenous or exogenous hormones accentuated the deposition of cholesterol in the kidney and resulted in significantly higher systolic blood pressures in these rats. In the rats on a high lipid diet, the concentration of cholesterol in the kidney correlated positively with systolic blood pressure. It is concluded that estrogen and high lipid diet exert a synergistic effect on deposition of cholesterol in kidney. The positive correlation between kidney cholesterol concentration and systolic blood pressure suggests a possible role for kidney lipid deposition in the hypertensive effect of estrogens.

The effects of sex hormones on atherosclerosis and collagen synthesis in blood vessels were studied in rabbits fed an atherogenic diet. Ovariectomy without hormone replacement resulted in significantly greater degree of atherosclerosis and collagen synthesis in the aortic arch when compared with the intact state. The administration of estradiol to ovariectomized rabbits resulted in a degree of atherosclerosis and collagen synthesis similar to that of intact rabbits. Ovariectomized rabbits administered progesterone on the other hand resembled the ovariectomized rabbits without hormone replacement. Specific activity of hydroxyproline in individual specimens of the arch correlated strongly with degree of atherosclerosis. An analysis of regional variation demonstrated declining values for collagen synthesis in the caudal direction along the aorta. Collagen synthesis was much higher in the portal vein as compared with the inferior vena cava. Plasma cholesterol values were higher in the ovariectomized rabbits than in the intact rabbits. Tissue deposition of cholesterol paralleled the degree of atherosclerosis.

The administration of estradiol to both castrated and noncastrated male rats was associated with significantly increased plasma cholesterol levels as compared to controls, the estradiol in the noncastrated rats overriding the tendency of testosterone to lower plasma cholesterol.

Aortic collagen and elastin were quantitated in three groups of castrated and two groups of noncastrated male rats treated by intramuscular injection for 3 wk with oil, testosterone, or estradiol. The greatest differences were found between the castrated rats receiving testosterone and those receiving estradiol, the estradiol-treated rats having significantly lower total collagen, percent collagen, total elastin, and collagen/elastin (C/E), and higher percent elastin than those rats receiving testosterone. In noncastrated rats, administration of estradiol resulted in significantly lower total collagen, percent collagen, total elastin, and C/E. Systolic blood pressure was highest in rats receiving testerone and lowest in rats receiving estradiol. It is concluded that 1) estradiol in the presence or absence of testosterone decreases total accumulation of vascular connective tissue and alters the proportions of collagen and elastin so that the vessel is more distensible, 2) testosterone has an opposite but less marked effect than estradiol on vascular connective tissue, and 3) estradiol and testosterone alter blood pressure in opposite directions in the male rat.