Restricted Ig variable region gene expression among Ly-1+ B cell lymphomas

The majority of the characterized Ly-1+ B cell lymphomas of B10.H-2aH-4bp/Wts origin (the CH series) bear surface Ig related by Ag specificity or idiotype or both. To determine the genetic basis for these structural similarities, we have sequenced the VH and VL region genes expressed by 10 CH lymphomas, and have compared their VH and V kappa gene rearrangements by Southern blot analysis to one another and to those of four other CH lymphomas. Sequence analysis identified only five different VH, and seven different VL genes, and indicated that these V genes are essentially unmutated. CH lymphomas which express the identical VH gene share at least one idiotope. Thus, the basis for shared idiotype and specificity is due in most cases to the use of the same V gene. This restriction in V gene expression is not due to the preferential use of V genes of any particular VH family or VL group, as the expressed V genes belong to four different VH families and four V kappa groups, and include V lambda 1 and V lambda 2. We hypothesize that Ag selection accounts for the restriction in V gene usage among CH lymphomas.     

Antigen-induced lymphomagenesis: identification of a murine B cell lymphoma with known antigen specificity

CH12, a murine B cell lymphoma derived in B10 H-2aH-4bp/Wts mice after transfer of SRBC hyperimmunized spleen cells into an adult-thymectomized, sublethally irradiated, syngeneic recipient, is demonstrated to bear surface IgM specific for a determinant found on SRBC and ChRBC. The Ig specificity has been demonstrated by rosetting assays and complement-dependent hemolysis. The removal of CH12 surface IgM by capping with anti-mu or with anti-CH12 idiotype, but not with anti-gamma or with irrelevant anti-idiotype, eliminated the formation of rosettes between CH12 and SRBC or ChRBC. The absorption of CH12 Ig produced in vitro, with either SRBC or ChRBC but not with HRBC, removed all hemolysin activity against SRBC, demonstrating that only one CH12 product was responsible for the reactivity with both SRBC and ChRBC. CH12 has a surface phenotype of a relatively mature B cell expressing surface Ig (IgM-mu,kappa) and la antigens, but lacking Thy-1 or detectable Fc or C3 receptors. CH12 also expresses the antigen Lyt-1. Growth of CH12 in vivo or in vitro results in the generation of up to 3% direct PFC and serum hemolysin, which shows that CH12 is not irretrievably "frozen". The generation of PFC and serum hemolysin is associated with increased population density, and the rate of PFC and serum hemolysin accumulation cannot be explained by simple cell division. A continuously secreting hybridoma derived from CH12 was used to purify the CH12 IgM to facilitate studies of protein sequence and idiotype.     

mtDNA diversity in rhesus monkeys reveals overestimates of divergence time and paraphyly with neighboring species

Reconstructions of the human-African great ape phylogeny by using mitochondrial DNA (mtDNA) have been subject to considerable debate. One confounding factor may be the lack of data on intraspecific variation. To test this hypothesis, we examined the effect of intraspecific mtDNA diversity on the phylogenetic reconstruction of another Plio- Pleistocene radiation of higher primates, the fascicularis group of macaque (Macaca) monkey species. Fifteen endonucleases were used to identify 10 haplotypes of 40-47 restriction sites in M. mulatta, which were compared with similar data for the other members of this species group. Interpopulational, intraspecific mtDNA diversity was large (0.5%- 4.5%), and estimates of divergence time and branching order incorporating this variation were substantially different from those based on single representatives of each species. We conclude that intraspecific mtDNA diversity is substantial in at least some primate species. Consequently, without prior information on the extent of genetic diversity within a particular species, intraspecific variation must be assessed and accounted for when reconstructing primate phylogenies. Further, we question the reliability of hominoid mtDNA phylogenies, based as they are on one or a few representatives of each species, in an already depauperate superfamily of primates.      

1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists

A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC₅₀ = 4 nM using [¹²⁵I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species.     

Maternal Conditions and Perinatal Characteristics Associated with Autism Spectrum Disorder and Intellectual Disability

Background

As well as being highly comorbid conditions, autism spectrum disorders (ASD) and intellectual disability (ID) share a number of clinically-relevant phenomena. This raises questions about similarities and overlap in diagnosis and aetiological pathways that may exist for both conditions.

Aims

To examine maternal conditions and perinatal factors for children diagnosed with an ASD, with or without ID, and children with ID of unknown cause, compared with unaffected children.

Methods

The study population comprised all live singleton births in Western Australia (WA) between January 1984 and December 1999 (N = 383,153). Univariate and multivariate multinomial logistic regression models were applied using a blocked modelling approach to assess the effect of maternal conditions, sociodemographic factors, labour and delivery characteristics and neonatal outcomes.

Results

In univariate analyses mild-moderate ID was associated with pregnancy hypertension, asthma, urinary tract infection, some types of ante-partum haemorrhage, any type of preterm birth, elective C-sections, breech presentation, poor fetal growth and need for resuscitation at birth, with all factors showing an increased risk. Severe ID was positively associated with poor fetal growth and need for resuscitation, as well as any labour or delivery complication. In the multivariate analysis no maternal conditions or perinatal factors were associated with an increased risk of ASD without ID. However, pregnancy hypertension and small head circumference were associated with a reduced risk (OR = 0.64, 95% CI: 0.43, 0.94; OR = 0.58, 95% CI: 0.34, 0.96, respectively). For ASD with ID, threatened abortion before 20 weeks gestation and poor fetal growth were associated with an increased risk.

Conclusion

Findings show that indicators of a poor intrauterine environment are associated with an elevated risk of ID, while for ASD, and particularly ASD without ID, the associations are much weaker. As such, these findings highlight the importance of accounting for the absence or presence of ID when examining ASD, if we are to improve our understanding of the causal pathways associated with these conditions.     

Assessing the utility of conserving evolutionary history

It is often claimed that conserving evolutionary history is more efficient than species‐based approaches for capturing the attributes of biodiversity that benefit people. This claim underpins academic analyses and recommendations about the distribution and prioritization of species and areas for conservation, but evolutionary history is rarely considered in practical conservation activities. One impediment to implementation is that arguments related to the human‐centric benefits of evolutionary history are often vague and the underlying mechanisms poorly explored. Herein we identify the arguments linking the prioritization of evolutionary history with benefits to people, and for each we explicate the purported mechanism, and evaluate its theoretical and empirical support. We find that, even after 25 years of academic research, the strength of evidence linking evolutionary history to human benefits is still fragile. Most – but not all – arguments rely on the assumption that evolutionary history is a useful surrogate for phenotypic diversity. This surrogacy relationship in turn underlies additional arguments, particularly that, by capturing more phenotypic diversity, evolutionary history will preserve greater ecosystem functioning, capture more of the natural variety that humans prefer, and allow the maintenance of future benefits to humans. A surrogate relationship between evolutionary history and phenotypic diversity appears reasonable given theoretical and empirical results, but the strength of this relationship varies greatly. To the extent that evolutionary history captures unmeasured phenotypic diversity, maximizing the representation of evolutionary history should capture variation in species characteristics that are otherwise unknown, supporting some of the existing arguments. However, there is great variation in the strength and availability of evidence for benefits associated with protecting phenotypic diversity. There are many studies finding positive biodiversity–ecosystem functioning relationships, but little work exists on the maintenance of future benefits or the degree to which humans prefer sets of species with high phenotypic diversity or evolutionary history. Although several arguments link the protection of evolutionary history directly with the reduction of extinction rates, and with the production of relatively greater future biodiversity via increased adaptation or diversification, there are few direct tests. Several of these putative benefits have mismatches between the relevant spatial scales for conservation actions and the spatial scales at which benefits to humans are realized. It will be important for future work to fill in some of these gaps through direct tests of the arguments we define here.     

Epileptic seizures may begin hours in advance of clinical onset: a report of five patients

Mechanisms underlying seizure generation are traditionally thought to act over seconds to minutes before clinical seizure onset. We analyzed continuous 3- to 14-day intracranial EEG recordings from five patients with mesial temporal lobe epilepsy obtained during evaluation for epilepsy surgery. We found localized quantitative EEG changes identifying prolonged bursts of complex epileptiform discharges that became more prevalent 7 hr before seizures and highly localized subclinical seizure-like activity that became more frequent 2 hr prior to seizure onset. Accumulated energy increased in the 50 min before seizure onset, compared to baseline. These observations, from a small number of patients, suggest that epileptic seizures may begin as a cascade of electrophysiological events that evolve over hours and that quantitative measures of preseizure electrical activity could possibly be used to predict seizures far in advance of clinical onset.     

Y Fuse? Sex Chromosome Fusions in Fishes and Reptiles

Chromosomal fusion plays a recurring role in the evolution of adaptations and reproductive isolation among species, yet little is known of the evolutionary drivers of chromosomal fusions. Because sex chromosomes (X and Y in male heterogametic systems, Z and W in female heterogametic systems) differ in their selective, mutational, and demographic environments, those differences provide a unique opportunity to dissect the evolutionary forces that drive chromosomal fusions. We estimate the rate at which fusions between sex chromosomes and autosomes become established across the phylogenies of both fishes and squamate reptiles. Both the incidence among extant species and the establishment rate of Y-autosome fusions is much higher than for X-autosome, Z-autosome, or W-autosome fusions. Using population genetic models, we show that this pattern cannot be reconciled with many standard explanations for the spread of fusions. In particular, direct selection acting on fusions or sexually antagonistic selection cannot, on their own, account for the predominance of Y-autosome fusions. The most plausible explanation for the observed data seems to be (a) that fusions are slightly deleterious, and (b) that the mutation rate is male-biased or the reproductive sex ratio is female-biased. We identify other combinations of evolutionary forces that might in principle account for the data although they appear less likely. Our results shed light on the processes that drive structural changes throughout the genome.