An Alteration in ELMOD3, an Arl2 GTPase-Activating Protein,Is Associated with Hearing Impairment in Humans

Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468. The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss. ELMOD3 belongs to the engulfment and cell motility (ELMO) family, which consists of six paralogs in mammals. Several members of the ELMO family have been shown to regulate a subset of GTPases within the Ras superfamily. However, ELMOD3 is a largely uncharacterized protein that has no previously known biochemical activities. We found that in rodents, within the sensory epithelia of the inner ear, ELMOD3 appears most pronounced in the stereocilia of cochlear hair cells. Fluorescently tagged ELMOD3 co-localized with the actin cytoskeleton in MDCK cells and actin-based microvilli of LLC-PK1-CL4 epithelial cells. The p.Leu265Ser mutation in the ELMO domain impaired each of these activities. Super-resolution imaging revealed instances of close association of ELMOD3 with actin at the plasma membrane of MDCK cells. Furthermore, recombinant human GST-ELMOD3 exhibited GTPase activating protein (GAP) activity against the Arl2 GTPase, which was completely abolished by the p.Leu265Ser mutation. Collectively, our data provide the first insights into the expression and biochemical properties of ELMOD3 and highlight its functional links to sound perception and actin cytoskeleton.     

Isolated Lung Perfusion as an Adjuvant Treatment of Colorectal Cancer Lung Metastases: A Preclinical Study in a Pig Model

Background

The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP.

Methods

First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria.

Results

In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent.

Conclusions

GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique.     

Side Effects of Being Blue: Influence of Sad Mood on Visual Statistical Learning

It is well established that mood influences many cognitive processes, such as learning and executive functions. Although statistical learning is assumed to be part of our daily life, as mood does, the influence of mood on statistical learning has never been investigated before. In the present study, a sad vs. neutral mood was induced to the participants through the listening of stories while they were exposed to a stream of visual shapes made up of the repeated presentation of four triplets, namely sequences of three shapes presented in a fixed order. Given that the inter-stimulus interval was held constant within and between triplets, the only cues available for triplet segmentation were the transitional probabilities between shapes. Direct and indirect measures of learning taken either immediately or 20 minutes after the exposure/mood induction phase revealed that participants learned the statistical regularities between shapes. Interestingly, although participants from the sad and neutral groups performed similarly in these tasks, subjective measures (confidence judgments taken after each trial) revealed that participants who experienced the sad mood induction showed increased conscious access to their statistical knowledge. These effects were not modulated by the time delay between the exposure/mood induction and the test phases. These results are discussed within the scope of the robustness principle and the influence of negative affects on processing style.     

Integrative Biology of Idas iwaotakii (Habe, 1958), a ‘Model Species’ Associated with Sunken Organic Substrates

The giant bathymodioline mussels from vents have been studied as models to understand the adaptation of organisms to deep-sea chemosynthetic environments. These mussels are closely related to minute mussels associated to organic remains decaying on the deep-sea floor. Whereas biological data accumulate for the giant mussels, the small mussels remain poorly studied. Despite this lack of data for species living on organic remains it has been hypothesized that during evolution, contrary to their relatives from vents or seeps, they did not acquire highly specialized biological features. We aim at testing this hypothesis by providing new biological data for species associated with organic falls. Within Bathymodiolinae a close phylogenetic relationship was revealed between the Bathymodiolus sensu stricto lineage (i.e. “thermophilus” lineage) which includes exclusively vent and seep species, and a diversified lineage of small mussels, attributed to the genus Idas, that includes mostly species from organic falls. We selected Idas iwaotakii (Habe, 1958) from this latter lineage to analyse population structure and to document biological features. Mitochondrial and nuclear markers reveal a north-south genetic structure at an oceanic scale in the Western Pacific but no structure was revealed at a regional scale or as correlated with the kind of substrate or depth. The morphology of larval shells suggests substantial dispersal abilities. Nutritional features were assessed by examining bacterial diversity coupled by a microscopic analysis of the digestive tract. Molecular data demonstrated the presence of sulphur-oxidizing bacteria resembling those identified in other Bathymodiolinae. In contrast with most Bathymodiolus s.s. species the digestive tract of I. iwaotakii is not reduced. Combining data from literature with the present data shows that most of the important biological features are shared between Bathymodiolus s.s. species and its sister-lineage. However Bathymodiolus s.s. species are ecologically more restricted and also display a lower species richness than Idas species.     

Instrumental Rotation for Persistent Fetal Occiput Posterior Position: A Way to Decrease Maternal and Neonatal Injury?

Objective

To evaluate immediate perineal and neonatal morbidity associated with instrumental rotations performed with Thierry’s spatulas for the management of persistent posterior occiput (OP) positions.

Methods

Retrospective study including all persistent occiput posterior positions with vaginal OP delivery, from August 2006 to September 2007. Occiput anterior deliveries following successful instrumental rotation were included as well. We compared maternal and neonatal immediate outcomes between spontaneous deliveries, rotational and non rotational assisted deliveries, using χ² and Anova tests.

Results

157 patients were enrolled, comprising 46 OP spontaneous deliveries, 58 assisted OP deliveries and 53 deliveries after rotational procedure. Instrumental rotation failed in 9 cases. Mean age and parity were significantly higher in the spontaneous delivery group, while labor duration was shorter. There were no significant differences in the rate of severe perineal tears and neonatal adverse outcomes between the 3 groups.

Conclusion

Instrumental rotation using Thierry’s spatulas was not associated with a reduced risk of maternal and neonatal morbidity for persistent OP deliveries. Further studies are required to define the true interest of such procedure in modern obstetrics.     

Length-weight relationship of twelve mesopelagic fishes from the western Tropical Atlantic

Length-weight relationship parameters were calculated for twelve mesopelagic fish species from the western Tropical Atlantic: Diretmus argenteus, Melamphaes polylepis, Bolinichthys distofax, Diaphus lucidus, Diaphus splendidus, Electrona risso, Hygophum taaningi, Taaningichthys bathyphilus, Melanolagus bericoides, Winteria telescopa, Diplophos taenia, Astronesthes similus. Data was collected off northeastern Brazil from April 9th to May 6th, 2017. Hauls were conducted during day and night at 47 stations by using a micronekton trawl (body mesh: 40 mm, cod-end mesh: 10 mm) from 10 to 1,113 m depth. The material was fixed in a 4% formalin solution for 1 month and then preserved in a 70% alcohol solution for proximally 6 months before processing for length (nearest 0.1 cm of standard length) and weight (nearest 0.01 g of total weight). A new maximum standard length for Winteria telescopa is also provided.     

Ascertaining the biochemical function of an essential pectin methylesterase in the gut microbe Bacteroides thetaiotaomicron

Pectins are a major dietary nutrient source for the human gut microbiota. The prominent gut microbe Bacteroides thetaiotaomicron was recently shown to encode the founding member (BT1017) of a new family of pectin methylesterases essential for the metabolism of the complex pectin rhamnogalacturonan-II (RG-II). However, biochemical and structural knowledge of this family is lacking. Here, we showed that BT1017 is critical for the metabolism of an RG-II–derived oligosaccharide ΔBT1017oligoB generated by a BT1017 deletion mutant (ΔBT1017) during growth on carbohydrate extract from apple juice. Structural analyses of ΔBT1017oligoB using a combination of enzymatic, mass spectrometric, and NMR approaches revealed that it is a bimethylated nonaoligosaccharide (GlcA-β1,4-(2-O-Me-Xyl-α1,3)-Fuc-α1,4-(GalA-β1,3)-Rha-α1,3-Api-β1,2-(Araf-α1,3)-(GalA-α1,4)-GalA) containing components of the RG-II backbone and its side chains. We showed that the catalytic module of BT1017 adopts an α/β-hydrolase fold, consisting of a central twisted 10-stranded β-sheet sandwiched by several α-helices. This constitutes a new fold for pectin methylesterases, which are predominantly right-handed β-helical proteins. Bioinformatic analyses revealed that the family is dominated by sequences from prominent genera of the human gut microbiota, including Bacteroides and Prevotella. Our re-sults not only highlight the critical role played by this family of enzymes in pectin metabolism but also provide new insights into the molecular basis of the adaptation of B. thetaiotaomicron to the human gut.     

FAM111A Mutations Result in Hypoparathyroidism and Impaired Skeletal Development

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.     

Turkey as a crossroad for Greater Flamingos Phoenicopterus roseus: evidence from population trends and ring-resightings (Aves: Phoenicopteridae)

The Greater Flamingo Phoenicopterus roseus is a waterbird commonly found in saline and brackish lagoons throughout the Mediterranean Region. We have gathered existing data on Greater Flamingos in Turkey and carried out field surveys to present the most up to date information on wintering (1999–2014) and breeding (1969– 2014). The wintering population of flamingos shows an increasing trend with 54,947±20,794 individuals mainly concentrated in the Gediz, Büyük Menderes and Çukurova deltas, respectively. Breeding attempts were recorded in at least seven wetlands in Turkey in the past, yet after 1999 most of the colonies were abandoned due to basin scale intensive water management practices in Central Anatolia. Currently, only Tuz Lake and Gediz Delta are used as regular breeding sites, while breeding has been recorded sporadically in Ac?göl and Ak?ehir Lakes. The breeding colony of Tuz Lake is of prime importance at the Mediterranean scale, with the number of young chicks in 2011, 2012 and 2013 accounting for the highest number of fledglings in the Mediterranean Region and West Africa (18,418, 20,274 and 20,292 respectively). Finally, building upon the previous findings about Turkey and the western Mediterranean metapopulation links, recent resightings of Turkish flamingos (despite the limited numbers) confirm post-fledging and natal dispersal reaching the western Mediterranean Basin and West Africa. Flamingos from Turkey were also found to disperse to Israel and to a region outside the known flyways of the western Mediterranean and West African flamingos (i.e. to Israel and UAE). Thus, Turkey, due to its geographic position, appears to be a crossroad between the western and eastern Mediterranean Region and southwest Asia.