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Background and Purpose: Glucocorticoids are powerful anti‐inflammatory drugs, but are associated with many side‐effects. Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal suppression. 5α‐Tetrahydrocorticosterone (5αTHB) is a potential selective anti‐inflammatory with reduced metabolic effects. Here, the efficacy and side‐effect profile of 5αTHB were compared with hydrocortisone in preclinical models of irritant dermatitis. Experimental Approach: Acute irritant dermatitis was invoked in ear skin of male C57BL/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5αTHB and hydrocortisone. Side‐effects of 5αTHB and hydrocortisone were assessed following chronic topical steroid treatment (28 days) to non‐irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5αTHB and hydrocortisone were measured following intravenous and oral administration. Key Results: 5αTHB suppressed ear swelling in mice, with ED50 similar to hydrocortisone (23 μg vs. 13 μg). Chronic application of 5αTHB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5αTHB (8× ED50). 5αTHB was rapidly cleared from the systemic circulation. Conclusions and Implications: Topical 5αTHB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin. [ABSTRACT FROM AUTHOR]

Objective: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID‐19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID‐19 and with post‐COVID symptoms have glucocorticoid and sex hormone deficiencies. Design/Patients: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID‐19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow‐up 5 months after hospitalisation (Post‐hospitalisation COVID‐19 study). Measurements: Plasma steroids were quantified by liquid chromatography–mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). Results: In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p <.001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p <.001). In the follow‐up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121–192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in‐hospital severity, perception of recovery, or patient‐reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in‐hospital severity, perception of recovery or symptom scores. Conclusions: Circulating glucocorticoids in patients hospitalised with COVID‐19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post‐COVID symptoms suggests steroid insufficiency does not play a causal role in this condition. [ABSTRACT FROM AUTHOR]

The article focuses on the diagnostic challenges of malignant spinal cord compression (MSCC) in emergency settings. Topics include the prevalence and typical presentation of MSCC, issues with false localizing signs and diagnostic imaging, and the rapid progression of symptoms leading to delays in diagnosis and treatment.

Glucocorticoids (GC) are prescribed for periods > 3 months to 1%–3% of the UK population; 10%–50% of these patients develop hypothalamus‐pituitary–adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of the pituitary and hypothalamus is necessary for recovery of adrenal function. We developed a mouse model of dexamethasone (DEX)‐induced HPA axis dysfunction aiming to further explore recovery in the pituitary. Adult male wild‐type C57BL6/J or Pomc‐eGFP transgenic mice were randomly assigned to receive DEX (approximately 0.4 mg kg–1 bodyweight day–1) or vehicle via drinking water for 4 weeks following which treatment was withdrawn and tissues were harvested after another 0, 1, and 4 weeks. Corticotrophs were isolated from Pomc‐eGFP pituitaries using fluorescence‐activated cell sorting, and RNA extracted for RNA‐sequencing. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced at time 0, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment, with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whereas only two genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and in six genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress. [ABSTRACT FROM AUTHOR]

Among these patients, 784 patients had at least two GEP performed during their disease course including 147 patients with a paired diagnosis and relapse sample. Keywords: gene expression; myeloma; risk factors EN gene expression myeloma risk factors 283 286 4 10/12/21 20211015 NES 211015 Clustering of gene expression profiling (GEP) signatures at diagnosis identified a number of distinct biological subgroups that correlate with clinical outcome in multiple myeloma (MM).1-4 Some of these clusters are defined by an aetiologic genetic event whereas others, such as the proliferation cluster (PR) and GEP70 risk, relate to acquired transcriptional patterns associated with adverse clinical behaviour irrespective of the underlying disease subgroup.1,2 Much has been written about the GEP70 risk classification but less has been presented about the PR cluster which is of particular importance as it was identified by the very first unsupervised clustering analysis2 and confirmed in other datasets.5 Key features of this group include the expression of typical proliferation genes and an adverse clinical outcome.6 The evolutionary behaviour of MM is now more clearly understood as is the natural history of MM which is associated with increasingly short periods of remission. High-risk transcriptional profiles in multiple myeloma are an acquired feature that can occur in any subtype and more frequently with each subsequent relapse. [Extracted from the article]

Circulating cell‐free DNA (cfDNA) has the potential to capture spatial genetic heterogeneity in myeloma (MM) patients. We assessed whether cfDNA levels vary according to risk status defined by the 70 gene expression profile (GEP70). cfDNA levels in 77 patients were significantly higher in the GEP70 high‐risk (HR) group compared to the low‐risk (LR) group and correlated weakly with clinical markers including lactate dehydrogenase, β2‐microglobulin, and ISS. Patients with high cfDNA levels were associated with a worse PFS (hazard ratio 6.4; 95% CI of ratio 1.9‐22) and OS (hazard ratio 4.4; 95% CI of ratio 1.2‐15.7). Circulating tumor DNA (ctDNA) was elevated in the HR group and ctDNA correlated strongly with GEP70 risk score (Spearman r =.69, P =.0027). cfDNA concentrations were significantly elevated between days 3‐5 after chemotherapy before falling back to baseline levels. ctDNA in two patients showed a similar spike in levels between days 3 and 5 after chemotherapy with a concomitant increase in allele fraction of KRAS mutations. We assessed cfDNA levels in 25 patients with smoldering myeloma with serial samples and showed increased allele fraction of mutated KRAS at progression in cfDNA. Our study shows that cfDNA is a dynamic tool to capture genetic events in myeloma. [ABSTRACT FROM AUTHOR]

Summary: Single agent daratumumab has shown clinical activity in relapsed, refractory multiple myeloma (RRMM). The Intergroupe Francophone du Myélome 2014‐04 trial was designed to further investigate daratumumab in combination with dexamethasone in triple RRMM patients. Patients received daratumumab infusions in combination with weekly dexamethasone until disease progression or unacceptable toxicity. Fifty‐seven patients were included in the trial and evaluable for response. The overall response rate and the clinical benefit rate were 33% (n = 19) and 48% (n = 27), respectively. Five (8·8%) patients achieved a very good partial response or better. The median time to response was 4 weeks. For responding patients, the median progression‐free survival was 6·6 months, compared to 3·7 months (3·0–5·5) for those with a minimal or stable disease. The median overall survival (OS) for all patients was 16·7 months (11·2–24·0). For responding patients, the median OS was 23·23 months, whereas that of patients with progressive disease was 2·97 months. The incidence of infusion‐related reactions was 37%; all cases were manageable and did not lead to dose reduction or permanent treatment discontinuation. These data demonstrate that treatment with daratumumab and dexamethasone results in a meaningful long‐term benefit with an acceptable safety profile for patients with triple RRMM. [ABSTRACT FROM AUTHOR]

A significant obstacle to evaluating the importance of mangrove habitat to coral reef fishes has been the difficulty of disentangling its effects from other subtidal/nearshore habitats or human population pressures. Florida’s seascape, unlike most others, has been extensively surveyed and mapped, and there are reliable estimates of human population density. Despite many studies that have correlated reef fish abundance with nearby mangrove habitat, some researchers continue to question the importance of mangroves to reef fishes. Previous studies that have investigated the mangrove–reef fish subsidy effect have applied methods that either compared averages or examined linear relationships; yet there is a body of literature that indicates that the effects of habitat are characterized by thresholds and limiting functions. Here, we employed a generalized additive model to investigate whether species richness of 106 mangrove-associated reef fishes is related to thresholds in the extent of nearby mangrove forests along the Florida Keys Reef Tract. In addition, we used linear discriminant analyses (LDAs) to examine the relationships between the occurrence of 77 reef fish species and extent of Florida mangrove forests. We found that after accounting for confounding factors, at scales <20 km2 , species richness declines with decreasing mangrove extent, whereas richness increases with increasing mangrove extent at scales >80 km2. Results of our LDA suggested that at least 49 reef fish species (64% of focal species) were associated with higher nearby mangrove forest extent. Our results indicate that of all habitat attributes considered, mangroves played the most substantial role in the diversity of nearby reef fish populations. These apparent thresholds (i.e., non-linearities) in the extent of mangrove forests should be incorporated into fisheries critical habitat management and emphasize the need to consider non-linear relationships between fishes and their habitat. [ABSTRACT FROM AUTHOR]

Background and Purpose: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11β-HSD1 inhibitors as potential medicines for the treatment of AD.Experimental Approach: Medicinal chemistry optimization of a series of amido-thiophene analogues was performed to identify potent and selective 11β-HSD1 inhibitors with optimized oral pharmacokinetics able to access the brain. Single and multiple ascending dose studies were conducted in healthy human subjects to determine the safety, pharmacokinetic and pharmacodynamic characteristics of the candidate compound.Results: UE2343 was identified as a potent, orally bioavailable, brain-penetrant 11β-HSD1 inhibitor and selected for clinical studies. No major safety issues occurred in human subjects. Plasma adrenocorticotropic hormone was elevated (a marker of systemic enzyme inhibition) at doses of 10 mg and above, but plasma cortisol levels were unchanged. Following multiple doses of UE2343, plasma levels were approximately dose proportional and the terminal t1/2 ranged from 10 to 14 h. The urinary tetrahydrocortisols/tetrahydrocortisone ratio was reduced at doses of 10 mg and above, indicating maximal 11β-HSD1 inhibition in the liver. Concentrations of UE2343 in the CSF were 33% of free plasma levels, and the peak concentration in CSF was ninefold greater than the UE2343 IC50 .Conclusions and Implications: UE2343 is safe, well tolerated and reaches the brain at concentrations predicted to inhibit 11β-HSD1. UE2343 is therefore a suitable candidate to test the hypothesis that 11β-HSD1 inhibition in brain improves memory in patients with AD. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance ( MGUS) is a benign condition with an approximate 1% annual risk of symptomatic plasma cell disorder development, mostly to multiple myeloma ( MM). We performed genomewide screening of copy-number alterations ( CNAs) in 90 MGUS and 33 MM patients using high-density DNA microarrays. We identified CNAs in a smaller proportion of MGUS (65.6%) than in MM (100.0%, P = 1.31 × 10−5) and showed median number of CNAs is lower in MGUS (3, range 0-22) than in MM (13, range 4-38, P = 1.82 × 10−10). In the MGUS cohort, the most frequent losses were located at 1p (5.6%), 6q (6.7%), 13q (30.0%), 14q (14.4%), 16q (8.9%), 21q (5.6%), and gains at 1q (23.3%), 2p (6.7%), 6p (13.3%), and Xq (7.8%). Hyperdiploidy was detected in 38.9% of MGUS cases, and the most frequent whole chromosome gains were 3 (25.6%), 5 (23.3%), 9 (37.8%), 15 (23.3%), and 19 (32.2%). We also identified CNAs such as 1p, 6q, 8p, 12p, 13q, 16q losses, 1q gain and hypodiploidy, which are potentially associated with an adverse prognosis in MGUS. In summary, we showed that MGUS is similar to MM in that it is a genetically heterogeneous disorder, but overall cytogenetic instability is lower than in MM, which confirms that genetic abnormalities play important role in monoclonal gammopathies. [ABSTRACT FROM AUTHOR]

Objective Opioid analgesia has been implicated as a cause of secondary adrenal insufficiency, but little is known of the prevalence of this potentially serious adverse effect in patients with chronic pain. Design Cross-sectional study of chronic pain patients on long-term opioid analgesia. Patients Patients attending tertiary chronic pain clinics at the Western General Hospital, Edinburgh, treated with long-term opioid analgesia ( n = 48) with no recent exposure to exogenous glucocorticoids. Results Four patients (8·3%) had basal morning plasma cortisol concentrations below 100 nmol/l, of whom three failed to achieve a satisfactory cortisol response to exogenous ACTH1-24 stimulation (peak cortisol >430 nmol/l). Basal cortisol was positively associated with age ( R = 0·398, P = 0·005) and negatively associated with BMI ( R = −0·435, P = 0·002). Conclusions Suppression of the hypothalamic−pituitary−adrenal axis is present in a clinically significant proportion of chronic pain patients treated with opioid analgesia. Studies of larger populations should be conducted to better define the prevalence and potential clinical consequences of adrenal insufficiency in this context. [ABSTRACT FROM AUTHOR]

Retrospective analysis is used to reconstruct fish body size at previous ages, with size and growth assumed to be accurately reflected by scale circuli and otolith increments. Using a 122-d laboratory experiment, this study validated the relationship between fish body size and growth with scale circuli and otolith daily growth increments for age-0 Chinook SalmonOncorhynchus tshawytscha. Somatic growth was accurately reflected by growth in scale radius and growth in otolith diameter, indicating that growth in these two measures was proportional to growth in fish length. Although the width between scale circuli reflected somatic growth, daily growth was not accurately reflected by the width between corresponding otolith daily increments. Study results showed that fish deposited new otolith increments on a daily basis, but that new scale circuli were deposited at each successive increase of 5 to 6 mm in total length. These findings provide a foundation for future retrospective growth analyses involving Chinook Salmon and allow for the conversion of otolith and scale measurements into fish lengths, which are meaningful in studies of growth and survival. Received November 5, 2015; accepted April 8, 2016 Published online August 26, 2016 [ABSTRACT FROM PUBLISHER]

Objective Hypogonadotrophic hypogonadism ( HH) is commonly associated with ageing, obesity and type 2 diabetes. The indications for pituitary imaging are controversial, and current guidelines are based on small case series. Design Retrospective case series from a secondary/tertiary endocrinology referral centre. Patients All men presenting to the Edinburgh Centre for Endocrinology and Diabetes with hypogonadotrophic hypogonadism (testosterone <10 nmol/l and normal prolactin) from 2006 to 2013, in whom pituitary MRI was performed ( n = 281). All HH patients referred in 2011 ( n = 86) were reviewed to assess differences between those selected for pituitary MRI and those who were not scanned. Results Pituitary MRI was normal in 235 men (83·6%), with 24 microadenomas (8·5%), 5 macroadenomas (1·8%) and 1 craniopharyngioma (0·4%) identified. The remaining 16 (5·7%) comprised a range of minor pituitary abnormalities including small cysts and empty sella. All men with abnormal imaging studies had otherwise normal pituitary function. Imaging abnormalities were associated with a significantly lower age at presentation (50 vs 54 years, P = 0·02), but no differences in testosterone or gonadotrophin levels were observed. Current Endocrine Society guidelines would have prompted imaging in only three of six patients with significant pituitary pathology. Conclusions Structural pituitary disease is more common in isolated HH than in the general population, and current guidelines do not accurately identify 'at-risk' individuals. Full anterior pituitary function testing has a low yield in patients presenting with hypogonadism. The optimal strategy for determining the need for pituitary imaging remains uncertain. [ABSTRACT FROM AUTHOR]

ABSTRACT Arctic weather in spring is unpredictable and can also be extreme, so Arctic-breeding birds must be flexible in their breeding to deal with such variability. Unpredictability in weather conditions will only intensify with climate change and this in turn could affect reproductive capability of migratory birds. Adjustments to coping strategies are therefore crucial, so here we examined the plasticity of the adrenocorticotropic stress response in two Arctic songbird species-the snow bunting ( Plectrophenax nivalis) and Lapland longspur ( Calcarius lapponicus)-breeding in northwest Greenland. Across the breeding season, the stress response was strongest at arrival and least robust during molt in male snow buntings. Snow bunting females had higher baseline but similar stress-induced corticosterone levels compared to males. Modification of the stress response was not due to adrenal insensitivity, but likely regulated at the anterior pituitary gland. Compared to independent nestlings and adult snow buntings, parental-dependent chicks had a more robust stress response. For Lapland longspurs, baseline corticosterone was highest at arrival in both male and females, and arriving males displayed a higher stress response compared to arriving females. Comparison of male corticosterone profiles collected at arrival in Greenland (76°N) and Alaska (67-71°N;) reveal that both species have higher stress responses at the more northern location. Flexibility in the stress response may be typical for birds nesting at the leading edges of their range and this ability will become more relevant as global climate change results in major shifts of breeding habitat and phenology for migratory birds. J. Exp. Zool. 323A: 266-275, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Semiconductor nanocrystals are promising materials for printed optoelectronic devices, but their high surface areas are susceptible to forming defects that hinder charge carrier transport. Furthermore, correlation of chalcogenide nanocrystal (NC) material properties with solar cell operation is not straightforward due to the disorder often induced into NC films during processing. Here, an improvement in long-range ordering of PbSe NCs symmetry that results from halide surface passivation is described, and the effects on chemical, optical, and photovoltaic device properties are investigated. Notably, this passivation method leads to a nanometer-scale rearrangement of PbSe NCs during ligand exchange, improving the long-range ordering of nanocrystal symmetry entirely with inorganic surface chemistry. Solar cells constructed with a variety of architectures show varying improvement and suggest that triplet formation and ionization, rather than carrier transport, is the limiting factor in singlet fission solar cells. Compared to existing protocols, our synthesis leads to PbSe nanocrystals with surface-bound chloride ions, reduced sub-bandgap absorption and robust materials and devices that retain performance characteristics many hours longer than their unpassivated counterparts. [ABSTRACT FROM AUTHOR]

OBJECTIVESThe commonest side-effects of GH replacement therapy relate to sodium retention but its mechanism is unclear. In rats, GH inhibits renal and hepatic 11β–hydroxysteroid dehydrogenase (11β–HSD) activities. In man, this action might impair inactivation of cortisol to cortisone in the distal nephron thereby allowing cortisol to activate mineralocorticoid receptors. In this study, we examined the effects of GH replacement on cortisol metabolism. DESIGNA randomized double-blind study comparing 6 months GH replacement with placebo in adults with GH deficiency due to pituitary or hypothalamic disease. PATIENTS6 men and 8 women received placebo and 8 men and 9 women received GH. MEASUREMENTSCortisol and its metabolites were measured in overnight urine samples and in a fasting morning plasma sample at baseline and at 6 months. RESULTSFive patients withdrew from the study, 4 because of adverse effects of GH. Amongst those who completed the study, the effects of GH on cortisol metabolism differed between patients with and without ACTH deficiency. Amongst those receiving hydrocortisone replacement (n = 18), GH had no effect on plasma cortisol/cortisone ratio, or urine tetrahydrocortisols/tetrahydrocortisone ratio, but produced a substantial reduction in total urinary cortisol metabolites (from 1326±191 to 777±229 μg/mmol creatinine; P < 0.01) and an increase in urinary free cortisol/cortisone ratio (from 0.88±0.10 to 2.57±0.74; P < 0.02). By contrast, GH had none of these effects in patients with normal ACTH secretion. There were no changes in blood pressure or plasma electrolytes, aldosterone, or renin activity with GH, and no changes in any variables with placebo. CONCLUSIONSThe increase in cortisol/cortisone ratio in urine but not in plasma, and the lack of effect on hepatic cortisol metabolites, suggests that GH inhibits both the conversion of cortisol to cortisone by renal 11β–HSD2 and the conversion... [ABSTRACT FROM AUTHOR]

ABSTRACT Penguin colonies are highly visited worldwide. Although several studies have addressed how penguins behaviorally respond to tourist visitation at a point in time, nothing is known about their response across the entire breeding season. Furthermore, behavioral responses are driven by complex physiological processes and the basal physiological state of the individual might affect the way it responds to stimuli. To test the hypothesis that annual changes in corticosterone result from animals having different requirements for expressing (or not) the glucocorticoid-mediated behaviors at different times of the year in the context of tourist visitation, we examined circulating and stress-induced corticosterone in Magellanic penguins ( Spheniscus magellanicus) from non-visited areas from the San Lorenzo colony, Peninsula Valdes, Argentina across the breeding season. We also examined the behavioral responses of penguins to a pedestrian approach in tourist-visited and non-visited areas of the colony across the season. Our results showed that circulating levels of corticosterone did not vary across the season; however, stress-induced corticosterone was lowest during molt. Our behavioral results showed that penguins displayed different behavior responses at varying distances depending on the area (visited or non-visited) and stage in the season. Penguins in the tourist area were more tolerant to a human approach than penguins in the non-tourist area. During settlement and molt, penguins showed higher occurrence of behaviors related to self-survival (such as standing, moving farther into the nest, and fleeing), whereas during incubation and chick rearing, penguins displayed mostly a behavior associated with defense and vigilance (such as alternate head turns). Furthermore, penguins allowed a closer approach during incubation, but elicited a subsequent behavior quicker than in the rest of the stages, suggesting that they would be particularly sensitive in this stage. Overall, our results suggest that corticosterone release across the season is more associated with penguins' survival in an extreme environment than with behavioral regulation. From a conservation perspective, we identified that penguins were more sensitive to human approach during incubation, but also molt should be considered as a vulnerable stage because corticosterone secretion is suppressed. © 2014 The Wildlife Society. [ABSTRACT FROM AUTHOR]

Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-associated cell derived cathepsin S. The most significant impact on tumor development was obtained when the protease was depleted from both sources. Further characterization revealed that the loss of cathepsin S led to impaired tumor vascularization, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumor growth. Analysis of cell types showed that in addition to the tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumor-associated cells can positively contribute to developing tumors and highlight cathepsin S as a therapeutic target in cancer. [ABSTRACT FROM AUTHOR]

Multiple myeloma ( MM) is a heterogeneous disease. International Staging System/fluorescence hybridization ( ISS/ FISH)-based model and gene expression profiles ( GEP) are effective approaches to define clinical outcome, although yet to be improved. The discovery of a class of small non-coding RNAs (micro RNAs, mi RNAs) has revealed a new level of biological complexity underlying the regulation of gene expression. In this work, 163 presenting samples from MM patients were analysed by global mi RNA profiling, and distinct mi RNA expression characteristics in molecular subgroups with prognostic relevance (4p16, MAF and 11q13 translocations) were identified. Furthermore we developed an 'outcome classifier', based on the expression of two mi RNAs ( MIR17 and MIR886-5p), which is able to stratify patients into three risk groups (median OS 19·4, 40·6 and 65·3 months, P = 0·001). The mi RNA-based classifier significantly improved the predictive power of the ISS/ FISH approach ( P = 0·0004), and was independent of GEP-derived prognostic signatures ( P < 0·002). Through integrative genomics analysis, we outlined the potential biological relevance of the mi RNAs included in the classifier and their putative roles in regulating a large number of genes involved in MM biology. This is the first report showing that mi RNAs can be built into molecular diagnostic strategies for risk stratification in MM. [ABSTRACT FROM AUTHOR]

11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74–76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages. [ABSTRACT FROM AUTHOR]

We have been engaged in the microwave-solid phase peptide synthesis (SPPS) synthesis of the phenylglycine (Phg)-containing pentapeptide H-Ala-Val-Pro-Phg-Tyr-NH2 (1) previously demonstrated to bind to the so-called BIR3 domain of the anti-apoptotic protein XIAP. Analysis of the target peptide by a combination of RP-HPLC, ESI-MS, and NMR revealed the presence of two diastereoisomers arising out of the racemisation of the Phg residue, with the percentage of the LLLDL component assessed as 49%. We performed the synthesis of peptide (1) using different microwave and conventional stepwise SPPS conditions in attempts to reduce the level of racemisation of the Phg residue and to determine at which part of the synthetic cycle the epimerization had occurred. We determined that racemisation occurred mainly during the Fmoc-group removal and, to a much lesser extent, during activation/coupling of the Fmoc-Phg-OH residue. We were able to obtain the desired peptide with a 71% diastereomeric purity (29% LLLDL as impurity) by utilizing microwave-assisted SPPS at 50 °C and power 22 Watts, when the triazine-derived coupling reagent DMTMM-BF4 was used, together with NMM as an activator base, for the incorporation of this residue and 20% piperidine as an Fmoc-deprotection base. In contrast, the phenylalanine analogue of the above peptide, H-Ala-Val-Pro-Phe-Tyr-NH2 (2), was always obtained as a single diastereoisomer by using a range of standard coupling and deprotection conditions. Our findings suggest that the racemisation of Fmoc-Phg-OH, under both microwave-SPPS and stepwise conventional SPPS syntheses conditions, is very facile but can be limited through the use of the above stated conditions. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim To characterize and map temporal changes in the biological and clinical phenotype during a 21-day experimental gingivitis study. Materials and Methods Experimental gingivitis was induced over 21 days in healthy human volunteers ( n = 56), after which normal brushing was resumed (resolution phase). Gingival and plaque indices were assessed. Gingival crevicular fluid was collected from four paired test and contra-lateral control sites in each volunteer during induction (Days 0, 7, 14 and 21) and resolution (Days 28 and 42) of experimental gingivitis. Fluid volumes were measured and a single analyte was quantified from each site-specific, 30s sample. Data were evaluated by analysis of repeated measurements and paired sample tests. Results Clinical indices and gingival crevicular fluid volumes at test sites increased from Day 0, peaking at Day 21 (test/control differences all p < 0.0001) and decreased back to control levels by Day 28. Levels of four inflammatory markers showed similar patterns, with significant differences between test and control apparent at Day 7 (substance P, cathepsin G, interleukin-1β, elastase: all p < 0.03) and peaking at Day 21 (all p < 0.002). Levels of α-1-antitrypsin showed no pattern. Conclusions Levels of substance P, cathepsin G, interleukin-1β and neutrophil elastase act as objective biomarkers of gingival inflammation induction and resolution that typically precede phenotypical changes. [ABSTRACT FROM AUTHOR]

Productivity enhancement has traditionally been the main focus of agricultural research to alleviate poverty and enhance food security of poor farmers in the developing world. Recently, the harmful impact of climate change, economic volatility, and other external shocks on poor farmers has led to concern that resilience should feature alongside productivity as a major objective of research. The applicability of recent work on resilient social-ecological systems to the problems of poor farmers is reviewed, and proposals are made for issues that need to be addressed in determining when and how enhanced resilience might become an objective of research. [ABSTRACT FROM AUTHOR]

Black South African women are more insulin resistant than BMI-matched white women. The objective of the study was to characterize the determinants of insulin sensitivity in black and white South African women matched for BMI. A total of 57 normal-weight (BMI 18–25 kg/m2) and obese (BMI > 30 kg/m2) black and white premenopausal South African women underwent the following measurements: body composition (dual-energy X-ray absorptiometry), body fat distribution (computerized tomography (CT)), insulin sensitivity (SI, frequently sampled intravenous glucose tolerance test), dietary intake (food frequency questionnaire), physical activity (Global Physical Activity Questionnaire), and socioeconomic status (SES, demographic questionnaire). Black women were less insulin sensitive (4.4 ± 0.8 vs. 9.5 ± 0.8 and 3.0 ± 0.8 vs. 6.0 ± 0.8 × 10−5/min/(pmol/l), for normal-weight and obese women, respectively, P < 0.001), but had less visceral adipose tissue (VAT) (P = 0.051), more abdominal superficial subcutaneous adipose tissue (SAT) (P = 0.003), lower SES (P < 0.001), and higher dietary fat intake (P = 0.001) than white women matched for BMI. SI correlated with deep and superficial SAT in both black (R = −0.594, P = 0.002 and R = 0.495, P = 0.012) and white women (R = −0.554, P = 0.005 and R = −0.546, P = 0.004), but with VAT in white women only (R = −0.534, P = 0.005). In conclusion, body fat distribution is differentially associated with insulin sensitivity in black and white women. Therefore, the different abdominal fat depots may have varying metabolic consequences in women of different ethnic origins.Obesity (2009) 17 8, 1506–1512. doi:10.1038/oby.2009.73 [ABSTRACT FROM AUTHOR]

The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue-specific manner by the isozymes of 11beta-hydroxysteroid dehydrogenase. Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11beta-hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11beta-hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11beta-hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro-inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11beta-hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study aimed at assessing the effect of growth factors on proteasome activity in normal myeloid progenitor cells and chronic myeloid leukemia cell lines using recombinant granulocyte-colony stimulating factor (G-CSF) and Epo.

Many cellular processes converge on the proteasome, and its key regulatory role is increasingly being recognized. Proteasome inhibition allows the manipulation of many cellular pathways including apoptotic and cell cycle mechanisms. The proteasome inhibitor bortezomib has enhanced responses in newly diagnosed patients with myeloma and provides a new line of therapy in relapsed and refractory patients. Malignant cells are more sensitive to proteasome inhibition than normal haematopoietic cells. Proteasome inhibition enhances many conventional therapies and its role in leukaemia is promising. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents the findings of a study on the link of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and glucocorticoid receptor (Grα) in four adipose depots and obesity. 11βHSD1 and messenger ribonucleic acid (mRNA) were higher in abdominal and omental depots and correlated with body mass index (BMI) and adiposity in all depots. Omental 11βHSD1 was correlated with body fat, fat cell size and plasma triglycerides. GRα and mRNA were higher in omental fat.

Objective Causes of visceral fat accumulation include glucocorticoid excess or decreased oestrogen/androgen ratio either in plasma or within adipose tissue. In obese subjects, the intra-adipose cortisol-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is increased, but information on sex steroid signalling is sparse. We aimed to test associations between body fat or fat distribution and mRNA transcript levels for androgen and oestrogen receptors and for enzymes metabolizing sex steroids in adipose tissue. Design A cross-sectional study. Patients Forty-five healthy men and women with body mass index (BMI) 21–36 kg/m2. Measurements In subcutaneous adipose biopsies we measured mRNAs for enzymes metabolizing local oestrogens (aromatase) and androgens [5α-reductase type 1; AKR1C2 (3α-HSD3); AKR1C3 (17β-HSD5, 3α-HSD2)] and for sex steroid receptors [oestrogen receptor (ER)-α and androgen receptor (AR)]. We related these to body fat mass and distribution. Results Generalized obesity (BMI) was associated with increased aromatase mRNA ( r = 0·35, P < 0·05). Central obesity (waist : hip ratio) was associated with mRNA for AKR1C2 ( r = 0·28, P < 0·05) and AKR1C3 ( r = 0·38, P < 0·01) but not aromatase ( r = 0·06). 5α-Reductase type 1, ER and AR mRNA levels did not predict fat amount or its distribution. Conclusion These data on transcript levels suggest that, in idiopathic obesity, increased intra-adipose oestrogen generation by aromatase predicts peripheral fat distribution, while androgen metabolism by AKR1C isoforms predicts central fat distribution, supporting the hypothesis that intra-adipose sex steroid metabolism is a determinant of gynoid vs. android patterns of body fat. [ABSTRACT FROM AUTHOR]

A series of synthetic peptides in which the C-terminal carboxyl grouping (-CO2H) of each has been chemically converted into a variety of ene dione derivatives (-CO-CH=CH-CO-X; X = -H, -Me, -OBut, -OEt, -OMe, -CO-OMe), have been prepared and tested as inactivators against typical members of the serine and cysteine protease families. For example, the sequences Cbz-Pro-Phe-CH=CH-CO-OEt (I) which fulfils the known primary and secondary specificity requirements of the serine protease chymotrypsin, and Cbz-Phe-Ala-CH=CH-CO-OEt (II) which represents a general recognition sequence for cysteine proteases such as cathepsins B, L and S, have been tested as putative irreversible inactivators of their respective target proteases. It was found that, whereas II, for example, functioned as a time-dependent, irreversible inactivator of each of the cysteine proteases, I behaved only as a modest competitive reversible inhibitor of chymotrypsin. Within the simple ester sequences Cbz-Phe-Ala-CH=CH-CO-R, the rank order of inhibitor effectiveness decreases in the order R = -OMe > -OEt >> -OBut. It was also found that the presence of both an unsaturated double bond and an ester (or α-keto ester) moiety were indispensable for obtaining irreversible inactivators. Of the irreversible inactivators synthesized, Cbz-Phe-Ala-CH=CH-CO-CO-OEt (which contains a highly electrophilic α-keto ester grouping) was found to be the most effective exhibiting, for example, second-order rate constants of approximately 1.7 × 106m−1min−1 and approximately 4.9 × 104m−1min−1 against recombinant human cathepsin S and human spleenic cathepsin B, respectively. This initial study thus holds out the promise that this class of inactivator may well be specific for the cysteine protease subclass. [ABSTRACT FROM AUTHOR]

Activation of intracellular glucocorticoid receptors is determined not only by the plasma concentrations of cortisol, under the influence of the hypothalamic-pituitary-adrenal (HPA) axis, but also by 11HSD enzymes within the target cell which interconvert cortisol with its inert metabolite cortisone. Data from cells in culture, isolated tissues, and transgenic mouse models have established that 11HSD type 1 regenerates glucocorticoids and amplifies glucocorticoid receptor activation. In humans, the rate of cortisol regeneration in peripheral tissues is of similar magnitude to adrenal secretion of cortisol at most times of day, and occurs principally in the splanchnic circulation. Approximately two-thirds of the splanchnic activity appears to reside in visceral adipose tissue, sufficient to allow visceral adipose tissue to “deliver” cortisol to the liver via the portal vein. In obesity, 11HSD1 activity in subcutaneous adipose tissue is increased, putatively explaining the link between obesity and other features of the metabolic syndrome. The regulation of 11HSD1, and the basis for its upregulation in obesity, are now being explored. Against this background, inhibition of 11HSD1 has become a major therapeutic target in metabolic syndrome. Preclinical results with novel selective 11HSD1 inhibitors are encouraging, and clinical proof of principle has been achieved with the nonselective inhibitor carbenoxolone. Although the parallels between metabolic syndrome and Cushing's syndrome were originally drawn with reference to patients with elevated plasma cortisol concentrations, it now appears that manipulating tissue concentrations of cortisol will allow the subtle level of control required for long-term therapy to reduce the risks of cardiovascular disease. [ABSTRACT FROM AUTHOR]

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Objective The metabolic syndrome is more prevalent in South Asians in Britain than in the general population. Furthering our understanding of the underlying mechanisms is important because of the increased risk of cardiovascular disease associated with the metabolic syndrome. As it has been proposed that increased activity of the hypothalamic pituitary adrenal axis might underlie the metabolic syndrome, we hypothesized that plasma cortisol levels would be higher in South Asians and that increased cortisol levels would be associated with cardiovascular risk factors comprising the metabolic syndrome. The aim of the study was to examine ethnic differences in cortisol levels and to compare the relationships between cortisol levels and cardiovascular risk factors in men from different ethnic groups. Design Cross-sectional population-based study, Newcastle upon Tyne, UK. (Newcastle Heart project). Participants One hundred men, 40–67 years old, of European and South Asian (Indian, Pakistani, Bangladeshi) ancestry, with and without cardiovascular risk factors of the metabolic syndrome. Measurements Measurement of plasma cortisol and corticosteroid binding globulin in stored sera. Results After adjustment for age and the presence of cardiovascular risk factors, mean cortisol was 27% (95% CI, 10%, 40%) lower in South Asians compared to Europeans. Cortisol levels were higher in all men with cardiovascular risk factors than those without. Conclusions Cortisol levels are lower in South Asian than in European men resident in the UK. Despite lower cortisol levels in South Asians, the relations between cortisol and cardiovascular risk factors remain strong. [ABSTRACT FROM AUTHOR]

Ecotourism is increasing worldwide; hence, it is important to know how wildlife are affected behaviorally and physiologically by human visitation. We studied the effects of human visitation on the Magellanic Penguins (Spheniscus magellanicus ) at Punta Tombo, Argentina, by monitoring changes in defensive head turns and plasma corticosterone (a hormone secreted in response to stress) for penguins with and without a history of tourist visitation. Habituation to human visitation was rapid. In penguins with no previous exposure to tourists, the number of defensive head turns and level of plasma corticosterone decreased significantly within 5 days of one 15-minute visit/day. Penguins living in tourist-visited and undisturbed areas secreted more corticosterone when captured and restrained than penguins visited by a person. Penguins in tourist areas, however, did not show as strong a corticosterone response to capture and restraint as did penguins in areas without tourists. This difference was due to a decreased capability of the adrenocortical tissue to secrete corticosterone in tourist-visited birds. Although our data show no direct negative effects of tourism on Magellanic Penguins at Punta Tombo, consequences of a modification of physiological capabilities (e.g., adrenocortical function) may not become apparent until much later in life. The physiological differences between tourist-visited and undisturbed groups of Magellanic Penguins emphasize the importance of monitoring the effects of anthropogenic disturbances on wildlife at multiple levels. [ABSTRACT FROM AUTHOR]

Studies examining anthropogenic effects on wildlife typically focus on adults and on behavioral responses rather than the physiological consequences of human disturbances. Here we examined how Magellanic Penguin ( Spheniscus magellanicus ) chicks living in either tourist-visited or undisturbed areas of a breeding colony were affected by human visitation by comparing the baseline and stress-induced levels of corticosterone during three periods of the breeding season. Newly hatched chicks in visited areas had higher corticosterone stress responses than newly hatched chicks in undisturbed areas (p = 0.007), but baseline levels were similar (p = 0.61). By 40–50 days of age and around fledging time, both visited and undisturbed chicks showed a robust corticosterone stress response to capture. Tourist-visited chicks did not flee when approached by humans, however, whereas undisturbed chicks fled significantly sooner (i.e., when approached no closer than 9 m; p < 0.0001). Although it is unknown whether Magellanic Penguin chicks raised in visited areas suffer negative consequences from the elevation of the corticosterone stress response at hatching, they do exhibit behavioral habituation to human contact by the time they are ready to fledge. Unlike adults living in tourist areas, however, fledging chicks in visited areas do not have a decreased stress response to capture and restraint. Our results show that the coupling of behavioral and physiological habituation in Magellanic Penguins is complex and life-history context may greatly affect the ability of wildlife to adapt to anthropogenic disturbances. [ABSTRACT FROM AUTHOR]

Biological diversity appears to enhance the resilience of desirable ecosystem states, which is required to secure the production of essential ecosystem services. The diversity of responses to environmental change among species contributing to the same ecosystem function, which we call response diversity, is critical to resilience. Response diversity is particularly important for ecosystem renewal and reorganization following change. Here we present examples of response diversity from both terrestrial and aquatic ecosystems and across temporal and spatial scales. Response diversity provides adaptive capacity in a world of complex systems, uncertainty, and human-dominated environments. We should pay special attention to response diversity when planning ecosystem management and restoration, since it may contribute considerably to the resilience of desired ecosystem states against disturbance, mismanagement, and degradation. [ABSTRACT FROM AUTHOR]

Investigates the role of glucocorticoids in human insulin resistance. Mechanisms of insulin resistance; Pathological conditions associated with insulin resistance; Mechanisms of glucocorticoid-induced insulin resistance.

Summary objective Among babies born at term, intrauterine growth retardation (IUGR) predicts adult hypertension and hyperglycaemia. This might be due to elevated circulating glucocorticoids in adulthood, as described in animal models and in several cohorts of men who were low birthweight at term. Recently, we found that premature low birthweight babies also have adult cardiovascular risk factors, irrespective of IUGR. We have now investigated cortisol secretion in this group. design patients and measurements We studied 29 women and 23 men aged 22–25 years who had been recruited at birth as either normal term (mean birthweight 3·1 kg, gestation 39 weeks), premature appropriate for gestational age (AGA; 1·7 kg, 32 weeks), or premature IUGR (1·7 kg, 35 weeks) babies. Body composition was measured by dual-energy X-ray absorptiometry (DEXA); plasma was obtained at 0900 h after overnight fast; and cortisol metabolites were measured in a 24-h urine sample by gas chromatography/mass spectrometry (GCMS). results Cortisol metabolites were different in men and women, so results were analysed separately. Among women, adult body composition did not differ between groups. Plasma cortisol was not different, but total urinary cortisol metabolite excretion was lower in AGA (3·29 ± 1·91 mg/day, n = 7, P < 0·02) than in either normals (6·77 ± 4·10, n = 14) or IUGR (9·47 ± 8·84, n = 8). Relative excretion of cortisol and cortisone metabolites was not different. Statistically significant differences in cortisol parameters between groups were not seen in men. conclusions Premature AGA baby girls have lower cortisol secretion in adulthood but normal plasma cortisol, suggesting impaired metabolic clearance of cortisol. By contrast, premature IUGR babies maintain normal cortisol secretion as adults, suggesting that IUGR, rather than premature delivery, is responsible for programmed activation of the... [ABSTRACT FROM AUTHOR]

OBJECTIVE The aetiology of enhanced adrenal androgen secretion in polycystic ovary syndrome is poorly understood. Previous reports suggest that enhanced peripheral metabolism of cortisol results in decreased negative feedback suppression of ACTH secretion, either by enhanced inactivation of cortisol by 5α-reductase or impaired reactivation of cortisol by 11β–hydroxysteroid dehydrogenase type 1 (11β–HSD1). Endogenous inhibitors of hepatic 11β–HSD1 can be extracted from urine. We have tested the hypothesis that these are increased in patients with polycystic ovary syndrome. DESIGN A case-control study. PATIENTS 57 patients with polycystic ovary syndrome and 27 healthy control women. MEASUREMENTS Aliquots from 24 h urine samples were extracted with Sep-Paks and incubated with rat liver microsomes in which 11β–HSD1 activity was quantified by conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone. RESULTS Inhibition of 11β–HSD1 activity was not different in extracts from patients compared with controls (40.8 ± 18.9 arbitrary units in patients vs. 42.7 ± 16.6 in controls, mean (± SEM, P > 0.60) and did not correlate with ratios of cortisol metabolites in urine or with body mass index. CONCLUSIONS The altered cortisol metabolism in polycystic ovarian syndrome, which is consistent with impaired 11β–HSD1 activity, cannot be accounted for by increased production of measurable endogenous inhibitors of this enzyme. [ABSTRACT FROM AUTHOR]

Some years ago, we used out data for class I genes, proteins and peptide-binding specificities to develop the hypothesis that the chicken B-F/B-L region represents a "minimal essential MHC". In this view, the B locus contains the classical (highly expressed and polymorphic) class I α and class II β multigene families, which are reduced to one or two members, with many other genes moved away or deleted from the chicken genome together. We found that a single dominantly expressed class I gene determines the immune response to certain infectious pathogens, due to peptide-binding specificity and cell-surface expression level. This stands in stark contrast to well-studied mammals like humans and mice, in which every haptotype is more-or-less responsive to every pathogen and vaccine, presumably due to the multigene family of MHC molecules present. In order to approach the basis for a single dominantly expressed class I molecule, we have sequenced a portion of the B complex and examined the location and polymorphism of the class I (B-F) &alpha, TAP and class II (B-L) β genes. The region is remarkably compact and simple, with many of the genes expected from the MHC of mammals absent, including LMP, class II α and DO genes as we as most class III region genes. However, unexpected genes were present, including tapasin and putative natural killer receptor genes. The region is also organized differently from mammals, with the TAPs in between the class I genes, the tapasin gene in between the class II (B-L) β genes, and the C4 gene outside of the class I α and class II β genes. The close proximity of TAP and class I &alpha genes leads to the possibility of co-evolution, which can drive the use of single dominantly expressed class I molecule with peptide-binding specificity like the... [ABSTRACT FROM AUTHOR]