Characterization of Nine Novel Mutations in the CD40 Ligand Gene in Patients with X-Linked Hyper IgM Syndrome of Various Ancestry

X-linked immunodeficiency with hyper-IgM (HIGMX-1) is a rare disorder caused by defective expression of the CD40 ligand (CD40L) by activated T lymphocytes, resulting in inefficient T-B cell cooperation and failure of B cells to undergo immunoglobulin isotype switch. In the present work, we describe nine patients of various ancestry who bear different mutations in the X chromosome–specific CD40L gene. Two of the mutations were nonsense mutations, one each resulting in premature stop codons at amino acid residues 39 and 140. Three patients had single point missense mutations, one each at codons 126, 140, and 144. Another patient had a 4-bp genomic deletion in exon 2, resulting in a frameshift and premature termination. Three patients showed insertions, one each of 1, 2, and 4 nt, probably because of polymerase slippage, resulting in frameshift mutation and premature termination. Overall, these observations confirm the heterogeneity of mutations in HIGMX-1. However, the identification of two patients whose mutation involves codon 140 (previously shown to be altered in two other unrelated subjects) suggests that this may be a hotspot of mutation in HIGMX-1. In two additional patients with clinical and immunological features indistinguishable from canonical HIGMX-1, no mutation was detected in the coding sequence, in the 5' flanking region, or in the 3' UTR.     

Messinian Lago-Mare mollusc fauna from the Gorgona Island slope, Tyrrhenian Sea

Late Miocene Lago-Mare macrofossiliferous sediments were recovered in the northeastern Tyrrhenian Sea by dredging the continental slope off Gorgona Island, Tuscan Archipelago, at 300-470 m depth. The fossil assemblage consists of a rich lymnocardiid bivalve fauna dominated by Pontalmyra ex gr. P. incerta (Deshayes), associated with Dreissena ex gr. D. rostriformis (Deshayes), Pontalmyra cf. partschi (Mayer), “Limnocardium” sp., the gastropods Melanopsis narzolina (D’Archiac), Melanopsis sp. and cf. Saccoia sp. All bivalve taxa recognized at species level are of Paratethyan (Pontian) affinity and widespread in the Late Miocene of the Mediterranean Basin while M. narzolina has so far only recorded from the Mediterranean Basin. This finding represents the most diverse Lago-Mare macrofauna reported thus far from any submerged location in the Mediterranean Basin and documents that the post-evaporitic Cusercoli Formation contributes to the syn-rift neoautochthonous units of this sector of the Northern Tyrrhenian Sea.     

An overview of loggerhead sea turtle (<Emphasis Type="Italic">Caretta caretta</Emphasis>) bycatch and technical mitigation measures in the Mediterranean Sea

This paper reviews the gear parameters responsible for loggerhead sea turtle (Caretta caretta) capture and mortality while taking into account the mitigation measures tested in the Mediterranean Sea. Incidental catch is considered as one of the major threats for turtle survival; however, the loggerhead bycatch estimated in different areas seems to be unrealistic, which highlights the need of a method for homogenising the estimates. Drifting longlines and bottom trawls have the greatest impact on Mediterranean turtle populations, respectively in pelagic and demersal phase, while passive nets (gillnets and trammel nets) seem to be responsible for the highest direct mortality, due to drowning. Most of the experiments available for the Mediterranean are focused on drifting longline. The longline parameters, hook shape and size, bait type, setting position and the reaction to sensory stimuli, strongly affect the sea turtle bycatch and mortality. Circle hooks have the potential to reduce turtle mortality only in certain fisheries and areas; larger hooks are less likely to be swallowed by turtles due to physical constraints of the mouth, reducing the mortality rate and the catch of juveniles; branchlines, once ingested, appear to be one of the major causes of sea turtle mortality; squid bait, which consistently catches more turtles than mackerel, and lightsticks, which strongly attract turtles, should be banned, at least in some areas and seasons. On the contrary only two bottom trawl studies are available from the Mediterranean. Turtle excluder devices have been tested with promising results in Turkey and Italy, even if the loss of large fish should be carefully investigated. For set nets no practical solutions are available at this time. The analysis allows the conclusion that technical parameters affecting turtle bycatch and mortality should only be studied one at a time, in order to avoid inconclusive results, studies on post-release mortality should be implemented and finally fishermen cooperation is paramount in reducing turtle bycatch and mortality.     

Analysis of chromosome damage in circulating lymphocytes of radiological workers affected by thyroid nodules

The aim of our study was to assess whether or not thyroid nodularity in combination with occupational exposure to low levels of ionising radiation would be correlated with chromosome damage in peripheral lymphocytes. Conventional chromosome-aberration analysis was performed on a group of 92 hospital workers with or without thyroid nodules. On the basis of measurements of their exposure levels, the workers were classified into a low (mean total level=0.03 mSv), medium (mean total level=1.04 mSv) or high (mean total level=8.60 mSv) exposure category. Our results indicate that among workers with thyroid nodules, the high-exposed workers showed significantly higher levels of both total (2.35+/-0.34 per 100 cells) and chromosome-type aberrations (1.46+/-0.20 per 100 cells) than medium-exposed (0.98+/-0.42 and 0.68+/-0.25 per 100 cells, respectively) or low-exposed workers (1.11+/-0.29 and 0.58+/-0.17 per 100 cells, respectively). Workers without thyroid nodules had comparable frequencies of chromosome aberrations among the three exposure categories. To our knowledge, this is the first study revealing a slight, but significant increase of chromosome damage in peripheral lymphocytes from hospital workers who developed thyroid nodules under conditions of occupational exposure to radiation well below the threshold limit for the workplace. The existence of a possible association between chromosome aberrations and development of thyroid nodularity will be discussed.     

Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free,low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial

BackgroundWe compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.Methods and findingsATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat.Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m², p = 0.50], and adverse events (AEs) were not significantly different between groups.Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.ConclusionsIn this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00494741","term_id":"NCT00494741"}}NCT00494741; EUDRACT 2006-005604-14.

Piero Ruggenenti and co-workers study maintenance immunosuppression in deceased-donor kidney transplantation.     

Critical behaviour of the stochastic Wilson-Cowan model

Spontaneous brain activity is characterized by bursts and avalanche-like dynamics, with scale-free features typical of critical behaviour. The stochastic version of the celebrated Wilson-Cowan model has been widely studied as a system of spiking neurons reproducing non-trivial features of the neural activity, from avalanche dynamics to oscillatory behaviours. However, to what extent such phenomena are related to the presence of a genuine critical point remains elusive. Here we address this central issue, providing analytical results in the linear approximation and extensive numerical analysis. In particular, we present results supporting the existence of a bona fide critical point, where a second-order-like phase transition occurs, characterized by scale-free avalanche dynamics, scaling with the system size and a diverging relaxation time-scale. Moreover, our study shows that the observed critical behaviour falls within the universality class of the mean-field branching process, where the exponents of the avalanche size and duration distributions are, respectively, 3/2 and 2. We also provide an accurate analysis of the system behaviour as a function of the total number of neurons, focusing on the time correlation functions of the firing rate in a wide range of the parameter space.     

Repeated intraspecific divergence in life span and aging of African annual fishes along an aridity gradient

Life span and aging are substantially modified by natural selection. Across species, higher extrinsic (environmentally related) mortality (and hence shorter life expectancy) selects for the evolution of more rapid aging. However, among populations within species, high extrinsic mortality can lead to extended life span and slower aging as a consequence of condition‐dependent survival. Using within‐species contrasts of eight natural populations of Nothobranchius fishes in common garden experiments, we demonstrate that populations originating from dry regions (with short life expectancy) had shorter intrinsic life spans and a greater increase in mortality with age, more pronounced cellular and physiological deterioration (oxidative damage, tumor load), and a faster decline in fertility than populations from wetter regions. This parallel intraspecific divergence in life span and aging was not associated with divergence in early life history (rapid growth, maturation) or pace‐of‐life syndrome (high metabolic rates, active behavior). Variability across four study species suggests that a combination of different aging and life‐history traits conformed with or contradicted the predictions for each species. These findings demonstrate that variation in life span and functional decline among natural populations are linked, genetically underpinned, and can evolve relatively rapidly.