Is there a relationship between sex of cystic fibrosis carriers and sex ratio of their offspring?

Summary Data on the offspring of 198 aunts and 179 uncles of 100 cystic fibrosis index cases were analyzed. Aunts showed higher average number of liveborn sons than uncles. No significant difference was observed in the number of liveborn female offspring. When the sample was subdivided with respect to family size, the proportion of liveborn sons of aunts appeared higher than that of uncles in all classes.The present observations suggest that a female carrier may have a higher probability of male offspring than a male carrier and that she may be mainly responsible for the sex ratio deviations previously reported in sibships of cystic fibrosis patients.     

Intrinsic predisposition of na?ve cystic fibrosis T cells to differentiate towards a Th17 phenotype

Background

Cystic fibrosis (CF) is a complex, multi-system, life-shortening, autosomal recessive disease most common among Caucasians. Pulmonary pathology, the major cause of morbidity and mortality in CF, is characterized by dysregulation of cytokines and a vicious cycle of infection and inflammation. This cycle causes a progressive decline in lung function, eventually resulting in respiratory failure and death. The Th17 immune response plays an active role in the pathogenesis of CF pulmonary pathology, but it is not known whether the pathophysiology of CF disease contributes to a heightened Th17 response or whether CF naïve CD4+ T lymphocytes (Th0 cells) intrinsically have a heightened predisposition to Th17 differentiation.

Methods

To address this question, Th0 cells were isolated from the peripheral blood of CF mice, human CF subjects and corresponding controls. Murine Th0 cells were isolated from single spleen cell suspensions using fluorescence-activated cell sorting. Lymphocytes from human buffy coats were isolated by gradient centrifugation and Th0 cells were further isolated using a human naïve T cell isolation kit. Th0 cells were then assessed for their capacity to differentiate along Th17, Th1 or Treg lineages in response to corresponding cytokine stimulation. The T cell responses of human peripheral blood cells were also assessed ex vivo using flow cytometry.

Results

Here we identify in both mouse and human CF an intrinsically enhanced predisposition of Th0 cells to differentiate towards a Th17 phenotype, while having a normal propensity for differentiation into Th1 and Treg lineages. Furthermore, we identify an active Th17 response in the peripheral blood of human CF subjects.

Conclusions

We propose that these novel observations offer an explanation, at least in part, for the known increased Th17-associated inflammation of CF and the early signs of inflammation in CF lungs before any evidence of infection. Moreover, these findings point towards direct modulation of T cell responses as a novel potential therapeutic strategy for combating excessive inflammation in CF.     

Frequency of the cystic fibrosis ΔF508 mutation in a large sample of the French population

Summary We have determined the frequency of the cystic fibrosis (CF) ΔF508 mutation in a large sample of CF patients originating from different areas of France, including the greater Paris, Brittany, Alsace, Lorraine and Rh?ne-Alpes regions. A total of 422 CF chromosomes were studied, and the defect was found to account for 75% of the mutant alleles. In the course of the survey, a rare nucleotide sequence polymorphism leading to an isoleucine to valine substitution at position 506 of the CF transmembrane conductance regulator protein has been characterized in an unaffected individual. Our data enable the evaluation of the probabilities that a chromosome negative for the ΔF508 mutation carriers another CF defect.     

The mutation ΔF508 on Dutch cystic fibrosis chromosomes: frequency and relation to patients age at diagnosis

Summary We tested 190 chromosomes from Dutch cystic fibrosis (CF) patients and carriers for the presence or absence of the major CF mutation ΔF508. This mutation was found on 77% of the Dutch CF chromosomes. We observed a significant difference in the distribution of the ages at diagnosis between homozygotes for ΔF508 and the other patients. ΔF508 homozygotes tend to be identified as patients at neonatal or infantile age. The age at diagnosis of patients with at least one unknown allele, on the other hand, ranged between neonatal and young adult age.     

Can tobacco have a potentially beneficial effect to our health?

With urgent pressure to clean up the contaminated environment, new approaches are needed. Phyto- and rhizoremediation using plants and related bacteria is a promising approach, but has its inborn limitations. To overcome the slow performance of the process, transgenic plants have been prepared specifically tailored for phytoremediation purposes. Our projects addressed a group of widespread synthetic organic xenobiotics, polychlorinated biphenyls (PCBs), and heavy metals as representatives of inorganic contaminants. Beside basic research studies in the field of phyto/rhizoremediation of the mentioned toxicants we focused on genetically modified plants as a highly promising tool for these purposes. We tried to prepare tobacco plants expressing the bacterial enzyme responsible for cleaving PCBs, coded by the gene bphC from the bacterial biphenyl operon. The expression of bphC product in fusion with the green fluorescent protein is described together with evaluation of the twice increased resistance of transgenic seeds towards PCBs. The other model is addressing improvement of cadmium accumulation by preparing plants bearing fused transgenes of metal binding protein (yeast metallothionein) with an introduced additional metal binding domain--polyhistidine anchor with high affinity to metals. The genetically modified plants exhibit 190% Cd accumulation of the control in harvestable parts, higher resistance and lower Cd content in roots. The performance of the plants in real contaminated soil is also evaluated.     

Rapid detection of single nucleotide deletions: application to the β 6 (-A) mutation of the β-globin gene and to cystic fibrosis

The formation of heteroduplexes from the amplified products of homologous alleles has been shown to be useful in the identification of heterozygotes carrying deletion or insertion mutations. Here, we describe an improved procedure that allows the detection of single base pair (bp) deletions on nondenaturing polyacrylamide gels. Carriers for a common Mediterranean -thalassemic mutation, 6 (-A), could be easily detected by use of this method, as could carriers of a 1-bp deletion in the cystic fibrosis gene.     

Are small RNAs a big help to plants?

The discovery of RNA interference (RNAi) has augmented our knowledge of gene regulation and presents a fascinating technology that has a great potential for application in genetic analysis, disease therapy, plant protection, and many other areas. In this review, we will focus on the biological functions of RNAi and its application in agriculture with a brief introduction to the history of its discovery and molecular mechanism. Supported by National Natural Sciences of China (Grant No. 30630008) and National Key Basic Research and Development Program of China (Grant No. 2007CB108800).     

Do we need nasal vaccines against COVID 19 to suppress the transmission of infections?

Covid-19 vaccines have within the first year prevented about 14 million deaths but did not induce a strong mucosal immune response. Data from US, UK, Singapore and Israel showed a variable and mostly modest effects of vaccination on virus excretion during breakthrough infections. Contact studies showed decreased transmission of infection from vaccinated index cases, but the effect varied according to dominant virus type, with study type and the nature of the contact group and diminished with time after vaccination. Some researchers suspect that it is unlikely to stop the pandemic with injected vaccines alone. Promising animal experiments were conducted with mucosal vaccines. Mice nasally immunized with a chimpanzee adenovirus vector mounted a mucosal immune response, were protected against viral challenge after a single vaccine dose and suppressed nasal replication of the challenge virus. Phage T4 expressing SARS-CoV-2 spike and nucleocapsid induced a sterilizing lung immunity in nasally vaccinated mice. Also hamsters intranasally immunized with the prefusion-stabilized spike protein showed no infectious virus in nasal turbinates upon challenge. Other studies showed that intranasal vaccination with an adenovirus vaccine reduced but did not eliminated viral transmission from infected to naïve hamsters. Intranasal vaccination of rhesus macaques with adenovirus vaccines also substantially reduced or even suppressed viral replication in the upper and lower respiratory tract. Human data on mucosal SARS-CoV-2 vaccines are so far limited to safety and immunogenicity studies. Aerosolized adenovirus vaccines given either as a booster or as primary immunization were safe and induced similar or superior immune response than injected vaccines while an aerosolized influenza vectored vaccine induced only a weak humoral and cellular immune response. Overall 100 mucosal SARS-CoV-2 vaccines are in development and 20 are in clinical trials. First human trials demonstrate that this will not be an easy task.     

Are transcriptional responses to inbreeding a functional response to alleviate inbreeding depression?

Previous studies addressing the relationship between gene regulation and inbreeding depression did not allow for discerning the changes that alleviate the depression from those that generate it. We directly addressed this question by analyzing changes in gene expression, using Affymetrix 2.0 arrays in Drosophila melanogaster inbred sublines differing in their magnitudes of inbreeding depression relative to the expression in an outbred control. The total number of arrays analyzed was 27, with 9,133 probe sets showing a significant signal of expression. We found that for those genes differentially expressed between inbred and outbred sublines, most of them showed a pattern of expression consistent with a protective role against inbreeding effects. The observed increase in depression was presumably related to an inability of the genome to do the appropriate expression adjustments. Expression changes detected in our study showed a clear specificity of RNA-splicing and energy derivation functions. Thus, it appears that most of the observed changes in gene expression associated with inbreeding may occur predominantly to alleviate inbreeding depression, i.e., as a protection against the effects of inbreeding.     

CCN2/decorin interactions: a novel approach to combating fibrosis?

CCN2 (connective tissue growth factor, CTGF), a member of the CCN family is overexpressed in fibrotic disease and is essential for the development of experimental fibrosis. Drugs targeting CCN2 action may therefore prove to be useful anti-fibrotic approaches. CCN2 acts via integrins and heparan sulfate-containing proteoglycans (HSPGs). In a recent study, Vial and colleagues (2011) show that decorin can bind CCN2. A peptide corresponding to the leucine rich repeats peptide 12 region of decorin can neutralize CCN2-mediated activity on C2C12 cells in vitro. Thus it is conceivable that this peptide could be used in the future as a novel antifibrotic approach.     

Is leaf-level photosynthesis related to plant success in a highly productive grassland?

We addressed the question: “Are short-term, leaf-level measurements of photosynthesis correlated with long-term patterns of plant success?” in a productive grassland where interspecific competitive interactions are important. To answer this question, seasonal patterns of leaf-level photosynthesis were measured in 27 tallgrass prairie species growing in sites that differed in species composition and productivity due to differences in fire history. Our specific goals were to assess the relationship between gas exchange under field conditions and success (defined as aerial plant cover) for a wide range of species, as well as for these species grouped as dominant and sub-dominant grasses, forbs, and woody plants. Because fire increases productivity and dominance by grasses in this system, we hypothesized that any relationship between photosynthesis and success would be strongest in annually burned sites. We also predicted that regardless of fire history, the dominant species (primarily C₄ grasses) would have higher photosynthetic rates than the less successful species (primarily C₃ grasses, forbs and woody plants). Because forbs and woody species are less abundant in annually burned sites, we expected that these species would have lower photosynthetic rates in annually burned than in infrequently burned sites. As expected, the dominant C₄?grasses had the highest cover on all sites, relative to?other growth forms, and they had the highest maximum and seasonally averaged photosynthetic rates (17.6 ± 0.42 μmol m^?2 s^?1). Woody species had the lowest average cover as well as the lowest average photosynthetic rates, with subdominant grasses and forbs intermediate in both cover and photosynthesis. Also as predicted, the highest overall photosynthetic rates were found on the most productive annually burned site. Perhaps most importantly, a positive relationship was found between leaf-level photosynthesis and cover for a core group of species when data were combined across all sites. These data support the hypothesis that higher instantaneous rates of leaf-level photosynthesis are indicative of long-term plant success in this grassland. However, in contrast to our predictions, the subdominant grasses, forbs and woody species on the annually burned site had higher photosynthetic rates than in the less frequently burned sites, even though their average cover was lower on annually burned sites, and hence they were less successful. The direct negative effect of fire on plant cover and species-specific differences in the availability of resources may explain why photosynthesis was high but cover was low in some growth forms in annually burned sites.     

Human cystic hydatidosis in Italy: a public health emergency? Past to present

Starting from 1991 the Central Office of Statistics ISTAT, according to changed regulations on notification of infective diseases, stopped reporting official national data on human hydatidosis. On the other hand until then notified data, concerning only about a hundred cases per year in mean during the last decades and just 36 in 1991, appeared unreliable, suggesting a diffusion far from the actual. Owing to specific studies on different research groups it is possible to try to describe a not exhaustive but indicative pattern of trend of human hydatidosis in Italy. More recent publications regarding different regions report an annual mean incidence rate of surgical cases of 9.77/100,000 inhabitants in Sardinia, of 1.57 in Emilia Romagna, of 2.30 in Sicily and of 2.33 in Apulia, the latter encompassing only hepatic cysts treated in the region, irrespective of residence of subjects. A comparison with previous studies regarding the period between 1948-1952 and 1980-84 respectively, indicates an increase in the more recent surveys. However, as even underlined by Authors, former surveys were not all-embracing (for example not including patients from private Clinics etc). On the other hand during time, improvements in surgical as well in anaesthesiological skills have made surgery possible in patients previously inoperable, and particularly in old subjects. Conversely, at present, availability of alternative therapies such as chemotherapy, PAIR or modified PAIR-based techniques may allow cases to avoide surgical surveys. However, actual parasite burden in humans may be estimated by assessing the trend of likely young cysts, as due to recent infections. Rate of pulmonary cysts, that are sure to be young, was of 48.6%/100,000 inhab. in 1952 in Italy, then falling to 18.2 in 1980-84 in the 9 considered regions, to 12.7 in Sicily (1989-91), 6.5 in Emilia-Romagna (1989-93) and 15.7 in Sardinia (1990-95). Another "class" of surely young cysts regards all cysts in young age group that necessarily have been recently infected. Ratio of infection rates in the old/young people was around 1 in 1941-52 but was exceeding 3 in 1980-84. In addition available data from more recent surveys indicate that ratio is at present still relatively low in Sardinia (3.9), where sheep-breeding is widespread, and dog-livestock-man interaction is most likely to exist, and conversely is very high in Emilia-Romagna (5.75) where pastoral economy is not prevalent (just 92,000 sheep). Actual trend both parasitological and in terms of public health would ameliorate if studies were provided with long temporary series. In Sardinia all hydatid cases surgically treated from 1969 to 1995 have been registered and analysed with a standardized methodology. During the considered period incidence appears nearly unvaried (16.9 in 1969 vs 15.8 in 1985), with a fall only for the last 5 years (9.1 in 1995), and with an increase regarding 1984-88 period. Analysis according to cyst localization strongly suggests that fall in the last period is only weakly related to hepatic cysts, that conversely are near completely responsible of rise in 1984-88. On the contrary for pulmonary cysts, i.e. young cysts, a slow but continuous and significant decrease (from 6.5 in 1969 to 1.4 in 1995) is evident. In the same way the above- mentioned old/young ratio rises from 1.7 (1969-79) to 3.9 (1990-95). On the whole analysed data suggest that although parasitic burden, strong in central-south Italy for decades, is now slow lowering due to structural changes and improvements in general conditions of life rather to specific preventive actions, human hydatidosis still represents a public health problem that will continue in the future as, because of latency, incidence rates will stay long relevant.     

What makes a species vulnerable to extinction? Comparative life-history traits of two sympatric snakes

Although it is well known that species vary in their vulnerability to extinction, the reasons are poorly understood. Theory predicts that long-lived species with slow life histories (small litters, slow growth, late maturation) should be at greater risk than short-lived species with high potential rates of increase. This hypothesis was tested by comparing life-history traits of two species of sympatric, elapid snakes: the endangered broad-headed snake, Hoplocephalus bungaroides, and common small-eyed snake, Cryptophis nigrescens. From 1992 to 2000 a mark–recapture study of both species was undertaken in Morton National Park, south-eastern Australia, and this information was used to construct transition matrices for each species. The endangered H. bungaroides was found to mature late (6 years of age), had a high juvenile (54.7%) and adult (81.6%) survival rate, and a long generation length (10.4 years). In striking contrast, the common C. nigrescens matured early (within 3 years), had a lower juvenile (30.4%) and adult (74.4%) survival rate (but higher recruitment rate), and a substantially shorter generation length (5.9 years). Elasticity analyses revealed that H. bungaroides was considerably more sensitive to survival past the age of 2 years (68.6%) than C. nigrescens (37.4%). These results provide support for the hypothesis that species with slow life histories are more vulnerable to extinction.     

The frequency of the ΔF508 mutation on cystic fibrosis chromosomes in Israeli families: correlation to CF haplotypes in Jewish communities and Arabs

Summary We have analysed the distribution of the ΔF508 mutation and the haplotypes of cystic fibrosis (CF) bearing chromosomes among the Israeli CF population. The population was classified according to its ethnic origin and included 3 groups, Ashkenazi Jews, Sephardic/Oriental Jews and Arabs. Haplotype B (KM19 allele 2, XV2c allele 1) was found to be the predominant haplotype in all groups but in each of them the haplotype distribution was different. The ΔF508 mutation was present in all groups and accounts for 32% of the CF mutations. It was mainly associated with the B haplotype but only one third of the CF chromosomes with this haplotype carry the ΔF508 mutation. This work is dedicated to Dr. Ruth Voss who initiated the CF study in Israel and was tragically killed in a car accident on 7 August 1988     

Isodisomy of chromosome 7 in a patient with cystic fibrosis: could uniparental disomy be common in humans?

Maternal isodisomy for chromosome 7 was observed in a 4-year-old cystic fibrosis patient with very short stature. In an examination of 11 DNA polymorphisms spanning the entire length of chromosome 7, no paternal contribution could be shown in seven informative loci. Paternity was examined with probes for five polymorphic loci on the Y chromosome, for the pseudo beta-globin locus on chromosome 11 and by Jeffreys's hypervariable probes. The results with the latter gave a probability of 3.7 x 10(-9) for nonpaternity. Chromosomal examination revealed a centromeric heteromorphism of chromosome 7 in the mother, for which the proband was homozygous. Isodisomy of the patient was thus shown for the entire length of a maternal chromosome 7. The mechanisms leading to this isodisomy involve at least two events of abnormal cell division, events that may be meiotic, postzygotic, or both. This proband is the second reported maternal isodisomy; both were detected through homozygosity for CF. Both patients had short stature, which could have been caused by parental imprinting, since similar results have been observed in isodisomic mice. Homozygosity due to uniparental descent in man should be kept in mind as a mechanism for recessive disorders, especially for chromosome 7.