Circulating antibodies against neonatal cardiac muscarinic acetylcholine receptor in patients with Sjögren's syndrome

Isolated congenital heart block may be associated with Primary Sjogren's Syndrome. In this work we demonstrated that IgG present in the sera ofpatients with Primary Sjogren's Syndrome (PSS) could bind and activate muscarinic acetylcholine receptors of rat neonatal atria. These antibodies were able to inhibit in a irreversible manner the binding of ³H-QNB to muscarinic cholinergic receptors of purified rat atria membranes. Moreover, IgG from PSS individuals could modify biological effects mediated by muscarinic cholinoceptors activation, i.e. decrease contractility and cAMP and increase phosphoinositide turnover and cGMP. Atropine blocked all of these effects and carbachol mimicked them; confirming muscarinic cholinergic receptors-mediated PSS IgG action. Neither binding nor biological effect were obtained using adult instead of neonatal rat atria. IgG from sera of normal women were not effective in the studied system. The prevalence of cholinergic antibody was 100% in PSS and was independent of Ro/SS-A and La/SS-B antibodies. It could be concluded that antibody against muscarinic cholinergic receptors may be another serum factor to be considered in the pathophysiology of the development of congenital heart block.     

Cloning and Characterization of Two Human G Protein-Coupled Receptor Genes (GPR38 and GPR39) Related to the Growth Hormone Secretagogue and Neurotensin Receptors

The recent cloning of a growth hormone secretagogue receptor (GHS-R) from human pituitary gland and brain identified a third G protein-coupled receptor (GPC-R) involved in the control of growth hormone release. The nucleotide sequence of the GHS-R is most closely related to the neurotensin receptor-1 (NT-R1) (35% overall protein identity). Two human GPC-Rs related to both the type 1a GHS-R and NT-Rs were cloned and characterized. Hybridization at low posthybridizational stringency with restriction enzyme-digested human genomic DNA resulted in the identification of a genomic clone encoding a first GHS-R/NT-R family member (GPR38). A cDNA clone was identified encoding a second GHS-R-related gene (GPR39). GPR38 and GPR39 share significant amino acid sequence identity with the GHS-R and NT-Rs 1 and 2. An acidic residue (E124) in TM-3, essential for the binding and activation of the GHS-R by structurally dissimilar GHSs, was conserved in GPR38 and GPR39. GPR38 is encoded by a single gene expressed in thyroid gland, stomach, and bone marrow. GPR39 is encoded by a highly conserved single-copy gene, expressed in brain and other peripheral tissues. Fluorescencein situhybridization localized the genes for GPR38 and GPR39 to separate chromosomes, distinct from the gene encoding the GHS-R and NT-R type 1. The ligand-binding and functional properties of GPR38 and GPR39 remain to be determined.     

SPORE TETRAD STRUCTURES OF POSSIBLE HEPATIC AFFINITY FROM THE AUSTRALIAN LOWER CARBONIFEROUS

Palynological studies of Early Carboniferous (Viséan) sediments of the Bonaparte Gulf Basin, northwestern Australia, reveal the presence of intact tetrahedral spore tetrads (here described as Sagenotetradites gen. nov.) and, more usually, of their disjunct spore portions which had previously been interpreted as dispersed whole-miospore species. Two species of the new tetrad genus are recognized: S. bonapartensis (Playford) comb, nov., as type species; and S. spiritensis (Playford) comb. nov. The species are distinguished, as originally, on the basis of sculptural attributes of their distal exoexines. When intact, both species share a common internal “binding” element (“Cadiospora abrupta” Playford, 1971) composed of the fused proximal exoexinal faces of all four spores of a given tetrad. Morphological comparisons with modern hepatic spores suggest an alliance of the microfossils with the order Sphaerocarpales. The occurrence of Sagenotetradites in exclusively marine sediments suggests that its parent plants grew in close proximity to the marine depositional basin. Moreover, the morphological attributes of the tetrads would appear to have facilitated dissemination by water.     

Detrimental effects of Ulva lactuca (L.) exudates and low oxygen on estuarine crab larvae

Conventional theory postulates that associations between marine macrophytes and animals are generally positive. This paper presents evidence, however, that a common species of green macroalga, Ulva lactuca (L.), is detrimental to estuarine invertebrates due to the production of toxic exudates and low oxygen tensions which occur in the seaweed beds at night. Bioassays of the responses of zoeae of five species of estuarine crabs (Callinectes sapidus Rathbun, Carcinus maenas L., Eurypanopeus depressus Smith, Neopanope texana savi Smith and Rhithropanopeus harissii Gould), using water in which Ulva lactuca was cultured for 24 h, produced 100% mortality after 22 days. No crabs survived the molt into megalopa. Hypoxic water, 0.5 ± 0.3 ppm oxygen, caused a decline in larval activity (movement), but there was no mortality over an 8-h period, Ulva-water purged to 0.4 ± 0.1 ppm oxygen caused 100% mortality in 13–40 min. These synergistic effects could be critical in estuaries where dense U. lactuca beds cause periods of low dissolved oxygen. We hypothesize larval recruitment may be limited in such systems, particularly in areas where flushing is poor.     

Interaction of 2-deamino- and 2-deamino-2-nitroactinomycin D with calf-thymus DNA and formation of ion-radicals

2-Deaminoactinomycin D (3a) and 2-deamino-2-nitroactinomycin D (2a) were prepared in one step from actinomycin D (1a, AMD) by reaction with nitrous acid. New DNA-binding (calf-thymus) data obtained by difference uv and CD spectra and ΔTm were presented. In vitro cell growth inhibitory activity of CCRF-CEM cells was also reported. The 2-deamino analog, 3a, does not bind to DNA strongly nor by intercalation of its chromophore. However, some binding with DNA was indicated by CD which is attributed only to hydrogen bondings of the peptides with the DNA helix; the affinity for binding is in the order 1a ? 2a > 3a. The 2-nitro analog, 2a, is a more potent agent against CCRF-CEM cells than the 2-deaminoactinomycin D, 3a; the potencies are in the order 1a > 2a ? 3a. Furthermore, the microsomes activate the analogs to free radical states which catalyze the production of superoxide, as indicated by electron paramagnetic resonance studies and oxygen consumption experiments.     

In vivo assessment of human vaginal oxygen and carbon dioxide levels during and post menses.

Previous in vitro and in vivo animal studies showed that O(2) and CO(2) concentrations can affect virulence of pathogenic bacteria such as Staphylococcus aureus. The objective of this work was to measure O(2) and CO(2) levels in the vaginal environment during tampon wear using newly available sensor technology. Measurements by two vaginal sensors showed a decrease in vaginal O(2) levels after tampon insertion. These decreases were independent of the type of tampons used and the time of measurement (mid-cycle or during menstruation). These results are not in agreement with a previous study that concluded that oxygenation of the vaginal environment during tampon use occurred via delivery of a bolus of O(2) during the insertion process. Our measurements of gas levels in menses showed the presence of both O(2) and CO(2) in menses. The tampons inserted into the vagina contained O(2) and CO(2) levels consistent with atmospheric conditions. Over time during tampon use, levels of O(2) in the tampon decreased and levels of CO(2) increased. Tampon absorbent capacity, menses loading, and wear time influenced the kinetics of these changes. Colonization with S. aureus had no effect on the gas profiles during menstruation. Taken collectively, these findings have important implications on the current understanding of gaseous changes in the vaginal environment during menstruation and the potential role(s) they may play in affecting bacterial virulence factor production.     

Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay,Hypotonia, Scoliosis,and Cerebellar Atrophy

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.     

The role of sex-differential biology in risk for autism spectrum disorder

Autism spectrum disorder (ASD) is a developmental condition that affects approximately four times as many males as females, a strong sex bias that has not yet been fully explained. Understanding the causes of this biased prevalence may highlight novel avenues for treatment development that could benefit patients with diverse genetic backgrounds, and the expertise of sex differences researchers will be invaluable in this endeavor. In this review, I aim to assess current evidence pertaining to the sex difference in ASD prevalence and to identify outstanding questions and remaining gaps in our understanding of how males come to be more frequently affected and/or diagnosed with ASD. Though males consistently outnumber females in ASD prevalence studies, prevalence estimates generated using different approaches report male/female ratios of variable magnitude that suggest that ascertainment or diagnostic biases may contribute to the male skew in ASD. Here, I present the different methods applied and implications of their findings. Additionally, even as prevalence estimations challenge the degree of male bias in ASD, support is growing for the long-proposed female protective effect model of ASD risk, and I review the relevant results from recurrence rate, quantitative trait, and genetic analyses. Lastly, I describe work investigating several sex-differential biological factors and pathways that may be responsible for females’ protection and/or males’ increased risk predicted by the female protective effect model, including sex steroid hormone exposure and regulation and sex-differential activity of certain neural cell types. However, much future work from both the ASD and sex differences research communities will be required to flesh out our understanding of how these factors act to influence the developing brain and modulate ASD risk.