PTHR1 Loss-of-Function Mutations in Familial, Nonsyndromic Primary Failure of Tooth Eruption

Tooth eruption is a complex developmental process requiring coordinated navigation through alveolar bone and oral epithelium. Primary failure of tooth eruption (PFE) is associated with several syndromes primarily affecting skeletal development, but it is also known as a nonsyndromic autosomal-dominant condition. Teeth in the posterior quadrants of the upper and lower jaw are preferentially affected and usually result in an open bite extending from anterior to posterior. In this study, we show that familial, nonsyndromic PFE is caused by heterozygous mutations in the gene encoding the G protein-coupled receptor for parathyroid hormone and parathyroid hormone-like hormone (PTHR1). Three distinct mutations, namely c.1050-3C > G, c.543+1G > A, and c.463G > T, were identified in 15 affected individuals from four multiplex pedigrees. All mutations truncate the mature protein and therefore should lead to a functionless receptor, strongly suggesting that haplo-insufficiency of PTHR1 is the underlying cause of nonsyndromic PFE. Although complete inactivation of PTHR1 is known to underlie the autosomal-recessive Blomstrand osteochondrodysplasia (BOCD), a lethal form of short-limbed dwarfism, our data now imply that dominantly acting PTHR1 mutations that lead to haplo-insufficiency of the receptor result in a nonsyndromic phenotype affecting tooth development with high penetrance and variable expressivity.     

Endometrial NK cells are special immature cells that await pregnancy

NK cells populate the human endometrium before pregnancy. Unlike decidual NK cells that populate the decidua during pregnancy, the NK cells present in the human endometrium, before pregnancy, have not been fully characterized. In this study, we provide a detailed analysis of the origin, phenotype, and function of endometrial NK cells (eNK). We show that eNK cells have a unique receptor repertoire. In particular, they are negative for NKp30 and chemokine receptor expression, which distinguishes them from any other NK subset described so far. We further show that eNK cells lack NK-specific functional phenotype and activity such as cytokine secretion and cytotoxicity, before IL-15 stimulation. Following such stimulation, endometrial NK cells acquire phenotype and function that are similar to those of decidual NK cells. We therefore suggest that eNK cells are inactive cells (before IL-15 activation and in relation to the known NK activity) that are present in the endometrium before conception, waiting for pregnancy.     

Effect of egg‐phosphatidylcholine on the chilling sensitivity and lipid phase transition of Asian elephant (Elephas maximus) spermatozoa

This study was conducted in an effort to improve our understanding of the response of Asian elephant (Elephas maximus, Em) spermatozoa to chilling. Semen was collected from two elephant bulls by means of the manual rectal stimulation method. Five out of seven semen collections were deemed to be suitable for use based on motility (ranging from 20% to 60%) and membrane integrity. We evaluated the chilling sensitivity by incubating the sperm with a fluorescent dye (5‐carboxyfluorescein diacetate (cFDA)) at 16°C, 12°C, 4°C, and 22°C (control). Cells with an intact membrane retained the dye and were identified as viable. The membrane lipid phase transition (LPT) temperature curve was determined with a Fourier transform infrared (FTIR) spectrometer connected to an FTIR microscope. The LPT center, T_m, was determined by statistical analysis. The LPT and T_m were also assessed in fresh spermatozoa and spermatozoa incubated with egg yolk or egg‐phosphatidylcholine (EPC) liposomes at 16°C, 12°C, 4°C, and 26°C (control). The results show that the membrane integrity of spermatozoa incubated at 16°C, 12°C, and 4°C decreased by 39%, 62%, and 67%, respectively, compared to the control. The LPT temperatures were between room temperature (26°C) and 10°C, with T_m at 14–16°C. The T_m for sperm incubated with liposomes or egg‐yolk extender was below the measured range (2°C). Chilling sensitivity was found at a wide range of temperatures and transition temperatures, suggesting the presence of a wide variety of fatty acids (FAs) in the membrane with a high ratio of saturated‐to‐polyunsaturated FAs. Here we show that the protection afforded by the presence of egg yolk or liposomes in the extender is accomplished by shifting the T_m to below the 4°C point at which chilled semen is maintained for transport, or the point at which fast freezing begins to minimize cellular damage. Zoo Biol 0:1–13, 2005. © 2005 Wiley‐Liss, Inc.     

Hereditary isolated renal magnesium loss maps to chromosome 11q23.

Hypomagnesemia due to isolated renal magnesium loss has previously been demonstrated in two presumably unrelated Dutch families with autosomal dominant mode of inheritance. Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic. In a genomewide linkage study, we first excluded a possible candidate region, on chromosome 9q, that encompasses the gene for intestinal hypomagnesemia with secondary hypocalcemia and, subsequently, found linkage to markers on chromosome 11q23. Detailed haplotype analyses identified a common haplotype segregating in both families, suggesting both their relationship through a common ancestor and the existence of a single, hypomagnesemia-causing mutation within them. The maximum two-point LOD score (Zmax) was found for marker D11S4127 (Zmax=6.41 at a recombination fraction of. 00), whereas a multipoint analysis gave a Zmax of 8.24 between markers D11S4142 and D11S4171. Key recombination events define a 5. 6-cM region between these two markers on chromosome 11q23. We conclude that this region encompasses a gene, involved in renal magnesium handling, that is mutated in our patients and is different from the gene involved in intestinal magnesium handling.     

Pollen tube attrition as related to breeding systems inBrassicaceae

In order to estimate pollen tube attrition and to relate it to the breeding system, numbers of microgametophytes within the stigma and at the bottom of the style were scored in species of theBrassicaceae, 17 sporophytically self-incompatible, 11 predominant inbreeders, 4 facultative outcrossers. Attrition was evident in almost all species. The mean number of tubes at the bottom of the style, and mean number of stylar tubes per ovule were significantly lower in outbreeders. The degree of attrition, measured as attrition rate (the proportion of tubes in the stigma that do not reach the bottom of the style) was higher in outbreeders; it was positively correlated with the pollen : ovule ratios as estimates of the degree of outbreeding in the species involved. In outbreeders, sexual selection seems to be rather effective in inhibiting certain microgametophytic genotypes from reaching the ovules. Because of the low number of tubes per ovule in most cases, we assume that, in theBrassicaceae, female choice may be more effective in sexual selection and in ensuing pollen tube attrition.     

Purification and some properties of the squalene-tetrahymanol cyclase from Tetrahymena thermophila

The membrane-bound enzyme from Tetrahymena thermophila responsible for the conversion of squalene into the quasi-hopanoid tetrahymanol was purified 297-fold to near homogeneity. Purification involved solubilization by octylthioglucoside, chromatography on DEAE-trisacryl, hydroxyapatite and FPLC ion-exchange on Mono Q. The apparent KM was found to be 18 microM. 2,3-Iminosqualene and N,N-dimethyldodecylamine-N-oxide are effective inhibitors of the cyclase with I50 values of 50 and 30 nM, respectively. The cyclase has a molecular mass of 72 kDa as judged by electrophoresis in polyacrylamide gels under denaturating conditions. The optimal enzymatic activity was obtained at pH 7.0 and 30 degrees C. The solubilized enzyme needs the presence of detergent for maintaining activity. The influence of different detergents on cyclase activity was studied. Triton X-100 proved to be a strong inactivator of the enzyme. Solubilization of the cyclase in Tween 80 and digitonin inactivates the enzyme. However, its activity can be recovered by complementation of the assay buffer with octylthioglucoside above its critical micellar concentration. We suggest that this approach might be applicable to other membrane-bound proteins.     

Origins of H-2 polymorphism in the house mouse. II. characterization of a model population and evidence for heterozygous advantage

Comparison of the rate of synonymous and nonsynonymous nucleotide substitutions suggests that certain regions of the functional H-2 genes, which are part of the mouse major histocompatibility complex (Mhc), are under strong positive selection pressure. Thus far, however, little evidence has been provided for the existence of such pressure in natural mouse populations. We have, therefore, initiated experiments designed to test the hypothesis of positive selection acting on H-2 loci. The experiments are being carried out on two natural mouse populations in Jerusalem, Israel. One population occupies a space of about 100 m² in a chicken coop, the other lives in a nearby field in which mouse stations providing food and shelter have been set up. Extensive typing of these two populations revealed the presence of only four H-2 haplotypes. Mice in the two populations breed continually all year around, yet population size varies seasonally, with population maxima in winter and minima in summer. The population in the chicken coop contains a relatively stable nucleus which may be organized in demes with an excess of females over males and limited territorial mobility. The rest of the mice stay in the population for a short time only and then either die or emigrate. The field population is smaller and more loosely organized than the chicken-coop population, with demes probably forming only during population maxima. For the rest of the time breeding in this population is probably panmictic. At a population minimum in the summer of 1984, H-2 homozygotes happened to predominate over heterozygotes. This situation, however, lasted for a short time only and thereafter there was a continuous, statistically highly significant increase in the proportion of H-2 heterozygotes of one or two types. The increase occurred in both populations but was more apparent in the chicken-coop population. This observation provides the first experimental evidence that heterozygous advantage might be one of the mechanisms maintaining high H-2 polymorphism in natural populations of the house mouse.     

Optimal rates of dispersal I. Haploid populations

The problem of how an individual should divide its progeny into dispersed and non-dispersed descendants is investigated for a number of haploid models. In each model, a unique optimal ratio of dispersed to non-dispersed has been found, where the type with this optimal strategy has a selective advantage over all other types. Although the survival ability of a dispersed offspring is reduced (compared to that of a non-dispersed offspring), the optimal strategy implies that a substantial part of the progeny will be dispersed.     

The role of soil Phosphorus in differentiation of edaphic ecotypes in Aegilops peregrina

Summary The role of soil Phosphorus (P) availability on the ecotypic differentiation of plants was investigated. Populations of Aegilops peregrina (Hack.) were collected from four habitats which differed in their soil P. The four soils were: Meron (a P-deficient montmorillonitic xerochrept on dolomite), Malkiya (a P-fertile kaolinitic xerochrept on hard limestone), Har-Hurshan and Bet-Guvrin (lithic xerorthents on soft limestone with appreciable amounts of P, mainly as carbonate-apatite).Plants of the four populations were grown in pots with Meron soil which were previously equilibrated with four different amounts of soluble phosphate to give 1.2, 3.1, 10.7 and 18.9 gP g^-1 soil of sodium-bicarbonate extractable P. Plants originated from Malkiya population produced higher dry matter yields than the other three populations. Dry matter yields of the various populations were analyzed by means of a Mitcherlich's response function, versus sodium-bicarbonate extractable (available) soil P. The analysis revealed that Malkiya population plants had a significant advantage over Meron population plants in the response parameter c: this express the response rate of the plants to phosphate by means of dry matter production. With regard to the parameter Po, which represents the ability of plants to utilize barely-available fractions of soil P, the opposite was true. Har-Hurshan and Bet-Guvrin populations were intermediate in these two parameters. A version of the Mitcherlich response function is proposed, which expresses plant yield as a function of both soil available P and plant age.Meron plants contained the highest percentage of P in plant material, but compared to the other populations, they were the most inefficient in producing dry matter from the already absorbed P. Plants from the calcareous soils, Har-Hurshan and Bet-Guvrin, did not show any apparent trend.In soils which contain moderate amounts of lime, P may become a major limiting growth factor. Plant populations became adapted to low availability of P by (1) improving their ability to utilize barely-available soil P fractions and (2), by decreasing their productivity.     

Taste- and odor-reactivity in elderly demented patients

Previous studies demonstrated that hedonically different chemical(taste or smell) stimuli induceinnate, inherited, differentialand distinct fixed reflectory motion features in the oral andfacial area. In the present study 20 elderly demented patients,suffering from ‘probable’ or ‘possible’Alzheimer's disease, and 20 normally functioning elderly subjectswere tested. The facial expressive behavioral reactions triggeredby a set of common gustatory and olfactory stimuli were videotaped.Both psychophysical and stimulus-dependent behavioral responseswere obtained from the control group, while for the dementedpatients only behavioral reactions were recorded. Results revealedthat: (i) severely demented elderly subjects displayed differentialand distinct orofacial responses indicating ‘acceptance’and ‘aversion’. These were found to be analogousto but less intense than those displayed by control age mates;(ii) the duration of responses induced by aversive tastes islonger than that triggered by pleasant or indifferent ones,for both groups; (iii) all gustatory and olfactory stimuli triggera longer lasting behavioral response in demented than in normalsubjects; and (iv) psychophysical and behavioral responses ofthe control subjects gave similar results for taste- and odor-hedonicsas well as for their intensity. This finding clearly indicatesthe validity of the alternative use of psychophysical and behavioraltesting procedures.