The Impacts of Sex Differences and Sex Hormones on Fear Extinction.

Fear extinction memories are strongly modulated by sex and hormonal status, but the exact mechanisms are still being discovered. In humans, there are some basal and task-related features in which male and female individuals differ in fear conditioning paradigms. However, analyses considering the effects of sex hormones demonstrate a role for estradiol in fear extinction memory consolidation. Translational studies are taking advantage of the convergent findings between species to understand the brain structures implicated. Nevertheless, the human brain is complex and the transfer of these findings into the clinics remains a challenge. The promising advances in the field together with the standardization of fear extinction methodologies in humans will benefit the design of new personalized therapies.

Emergence of the Synucleins.

This study establishes the origin and evolutionary history of the synuclein genes. A combination of phylogenetic analyses of the synucleins from twenty-two model species, characterization of local synteny similarities among humans, sharks and lampreys, and statistical comparisons among lamprey and human chromosomes, provides conclusive evidence for the current diversity of synuclein genes arising from the whole-genome duplications (WGDs) that occurred in vertebrates. An ancestral synuclein gene was duplicated in a first WGD, predating the diversification of all living vertebrates. The two resulting genes are still present in agnathan vertebrates. The second WGD, specific to the gnathostome lineage, led to the emergence of the three classical synuclein genes, SNCA, SNCB and SNCG, which are present in all jawed vertebrate lineages. Additional WGDs have added new genes in both agnathans and gnathostomes, while some gene losses have occurred in particular species. The emergence of synucleins through WGDs prevented these genes from experiencing dosage effects, thus avoiding the potential detrimental effects associated with individual duplications of genes that encode proteins prone to aggregation. Additional insights into the structural and functional features of synucleins are gained through the analysis of the highly divergent synuclein proteins present in chondrichthyans and agnathans.

Improvement of intermediate vision with new monofocal intraocular lenses: A systematic review and meta-analysis.

PURPOSE: Monofocal intraocular lenses (IOLs) used in cataract surgery are designed to improve visual acuity (VA). The available evidence of new monofocal IOLs" functional benefits is limited. The aim of this meta-analysis was to analyze the improvement in VA using Tecnis Eyhance monofocal IOLs compared to standard monofocal IOLs Tecnis ZCB00. METHODS: MEDLINE, Web of Science and Scopus were searched for studies assessing improvement in intermediate VA using Tecnis Eyhance IOLs versus Tecnis ZCB00 IOLs. Studies evaluating post-operative VA in patients who underwent cataract surgery were selected. This meta-analysis followed PRISMA guidelines and was registered in PROSPERO. The Cochrane Risk of Bias Tool 2.0. was used to assess the methodological quality of the included studies, risk of selection bias and comparability of cohorts and outcomes. RESULTS: The search resulted in 1153 articles. Five studies met the inclusion criteria and were included in the meta-analysis. A total of 604 eyes were evaluated, of which 309 received Tecnis Eyhance IOLs and 295 were implanted with Tecnis ZCB00 IOLs. Mean binocular distant-corrected intermediate VA with Tecnis Eyhance IOLs at 2 weeks-1 month showed a significant difference of -0,21 logMAR, p < 0.001; and mean binocular distance-corrected intermediate VA with Tecnis Eyhance IOLs at 6 months showed a significant difference of -0,11 logMAR, p < 0.001. CONCLUSION: Near VA could not be assessed in this meta-analysis as it was measured in very few studies. Preliminary pooled evidence indicates that intermediate VA improved with Tecnis Eyhance IOLs. Further studies evaluating near VA and with longer follow-up are still necessary.

Modification of Corneal Biomechanics and Intraocular Pressure Following Non-Penetrating Deep Sclerectomy.

Changes in the cornea can influence outcomes in patients with primary open-angle glaucoma (POAG). We aimed to evaluate the relevance of changes in corneal biomechanics and intraocular pressure (IOP) in patients undergoing non-penetrating deep sclerectomy (NPDS) with the Esnoper V2000 implant® (AJL Ophthalmic S.A., Gasteiz, Spain). We included 42 eyes of 42 patients with POAG scheduled for NPDS with the Esnoper V2000 implant. Biomechanical properties were measured by Ocular Response Analyzer® G3 (ORA; Reichert Inc., Depew, NY, USA). Corneal hysteresis (CH), corneal resistance factor (CRF), corneal compensated IOP (IOPcc), and Goldmann-correlated IOP (IOPg) were measured the day before surgery and on day 1, 7, and 30 and 2 and 3 months after surgery. CH initially increased, fell below the presurgical value at 30 days after the surgery, and increased again at 2 and 3 months. CRF, IOPcc, and IOPg decreased on the first day after surgery, then followed a trend of increasing but stayed below pre-surgery levels. All values reached statistical significance. While observed changes in corneal biomechanics after NPDS and Esnoper V2000 implant were significant, more studies are needed if we are to understand their influence on corneal biomechanics and their clinical relevance in POAG.

Influence of tomographic and biomechanical corneal indexes on myopic refractive surgery indications: A multicenter study.

PURPOSE: To evaluate the influence of corneal tomographic and biomechanical indexes on the refractive technique indication. METHODS: A total of 251 eyes from 251 patients interested in refractive surgery were enrolled in this cross-sectional and multicenter study. Previous to the surgeon decision, a preoperative protocol was performed by refractive optometrists, containing four sections: refraction, biometry, corneal tomography and biomechanics. The refractive surgeons made a first decision based only on refraction, biometric and tomographic information. Biomechanical indexes were revealed, and refractive surgeons made a second indication. Additionally, for Laser-Assisted in-situ Keratomileusis cases, the percent tissue altered were calculated. Possible indications were no refractive surgery, photorefractive keratectomy, Laser-Assisted in-situ Keratomileusis or intraocular Collamer lens. RESULTS: After the first surgery indication, the distribution was photorefractive keratectomy (47.4%), Laser-Assisted in-situ Keratomileusis (48.2%) while intraocular Collamer lens achieved 2.8%. This proportion changed significantly after the second indication regarding corneal biomechanics and photorefractive keratectomy and Laser-Assisted in-situ Keratomileusis decreased by 24% while intraocular Collamer lens increased 19%. A total of 69 eyes changed the indication (27.5%) and 182 eyes (72.5%) remained unchanged. All indications changes were from photorefractive keratectomy or Laser-Assisted in-situ Keratomileusis to intraocular Collamer lens or no surgery. Indication changes to intraocular Collamer lens were observed in 49 eyes (71%). Tomographic, biomechanical indexes, ablation depth and percent tissue altered achieved statistically significant differences between eyes without and with indication changes (all, P < .01). CONCLUSION: New corneal biomechanical indexes could change the indication decision regarding biometric and tomographic data alone. Intraocular Collamer len was the preferred indication for eyes at risk of ectasia or with subclinical keratoconus due to corneal biomechanical parameters.

Tumor Necrosis Factor Superfamily: Ancestral Functions and Remodeling in Early Vertebrate Evolution.

The evolution of the tumor necrosis factor superfamily (TNFSF) in early vertebrates is inferred by comparing the TNFSF genes found in humans and nine fishes: three agnathans, two chondrichthyans, three actinopterygians, and the sarcopterygian Latimeria chalumnae. By combining phylogenetic and synteny analyses, the TNFSF sequences detected are classified into five clusters of genes and 24 orthology groups. A model for their evolution since the origin of vertebrates is proposed. Fifteen TNFSF genes emerged from just three progenitors due to the whole-genome duplications (WGDs) that occurred before the agnathan/gnathostome split. Later, gnathostomes not only kept most of the genes emerged in the WGDs but soon added several tandem duplicates. More recently, complex, lineage-specific patterns of duplications and losses occurred in different gnathostome lineages. In agnathan species only seven to eight TNFSF genes are detected, because this lineage soon lost six of the genes emerged in the ancestral WGDs and additional losses in both hagfishes and lampreys later occurred. The orthologs of many of these lost genes are, in mammals, ligands of death-domain-containing TNFSF receptors, indicating that the extrinsic apoptotic pathway became simplified in the agnathan lineage. From the patterns of emergence of these genes, it is deduced that both the regulation of apoptosis and the control of the NF-κB pathway that depends in modern mammals on TNFSF members emerged before the ancestral vertebrate WGDs.

Characteristics of inflammatory bowel disease in patients of Roma/Gypsy ethnicity. A case-control study.

BACKGROUND: Peculiarities of inflammatory bowel disease (IBD) have been explored in ethnic groups, such as Asians, Hispanics, and Afro-Americans, but not in other ethnic minorities, such as Roma/Gypsies. METHODS: In a retrospective, hospital-based study, all adult Roma/Gypsy patients included in the IBD databases of seven Spanish centres were identified as cases. For each Roma/Gypsy patient, a Caucasian patient, matched for several demographic features, was searched as a control. Data on phenotypic features, therapeutic requirements, and familial aggregation were recorded. RESULTS: Sixty-eight Roma/Gypsy patients were identified, 29 of them being women. The mean age at diagnosis of IBD was 24.9±9.5years, and the mean time elapsed since diagnosis was 96.6±72.2months. Roma/Gypsy IBD patients showed a significantly higher rate of familial aggregation (43%) than their Caucasian controls (9%) (p=0.00001). CD in Roma/Gypsies had more often a complicated pattern (mainly penetrating) while UC patients showed a marked trend to more often developing extraintestinal manifestations. In addition, Roma/Gypsy IBD patients had a somewhat greater need for immunosuppressants, biological agents or surgery. CONCLUSIONS: These are the first data on IBD in Roma/Gypsy patients. Familial aggregation is the most prominent feature in these patients, suggesting a predominant role of genetics in its pathogenesis.

Origin and evolution of fungal HECT ubiquitin ligases.

Ubiquitin ligases (E3s) are basic components of the eukaryotic ubiquitination system. In this work, the emergence and diversification of fungal HECT ubiquitin ligases is described. Phylogenetic and structural data indicate that six HECT subfamilies (RSP5, TOM1, UFD4, HUL4, HUL4A and HUL5) existed in the common ancestor of all fungi. These six subfamilies have evolved very conservatively, with only occasional losses and duplications in particular fungal lineages. However, an early, drastic reduction in the number of HECT genes occurred in microsporidians, in parallel to the reduction of their genomes. A significant correlation between the total number of genes and the number of HECT-encoding genes present in fungi has been observed. However, transitions from unicellularity to multicellularity or vice versa apparently had no effect on the evolution of this family. Likely orthologs or co-orthologs of all fungal HECT genes have been detected in animals. Four genes are deduced to be present in the common ancestor of fungi, animals and plants. Protein-protein interactions detected in both the yeast Saccharomyces cerevisiae and humans suggest that some ancient functions of HECT proteins have been conserved since the animals/fungi split.

Origin and Diversification of Meprin Proteases.

Meprins are astacin metalloproteases with a characteristic, easily recognizable structure, given that they are the only proteases with both MAM and MATH domains plus a transmembrane region. So far assumed to be vertebrate-specific, it is shown here, using a combination of evolutionary and genomic analyses, that meprins originated before the urochordates/vertebrates split. In particular, three genes encoding structurally typical meprin proteins are arranged in tandem in the genome of the urochordate Ciona intestinalis. Phylogenetic analyses showed that the protease and MATH domains present in the meprin-like proteins encoded by the Ciona genes are very similar in sequence to the domains found in vertebrate meprins, which supports them having a common origin. While many vertebrates have the two canonical meprin-encoding genes orthologous to human MEP1A and MEP1B (which respectively encode for the proteins known as meprin α and meprin ß), a single gene has been found so far in the genome of the chondrichthyan fish Callorhinchus milii, and additional meprin-encoding genes are present in some species. Particularly, a group of bony fish species have genes encoding highly divergent meprins, here named meprin-F. Genes encoding meprin-F proteins, derived from MEP1B genes, are abundant in some species, as the Amazon molly, Poecilia formosa, which has 7 of them. Finally, it is confirmed that the MATH domains of meprins are very similar to the ones in TRAF ubiquitin ligases, which suggests that meprins originated when protease and TRAF E3-encoding sequences were combined.

Identification of HECT E3 ubiquitin ligase family genes involved in stem cell regulation and regeneration in planarians.

E3 ubiquitin ligases constitute a large family of enzymes that modify specific proteins by covalently attaching ubiquitin polypeptides. This post-translational modification can serve to regulate protein function or longevity. In spite of their importance in cell physiology, the biological roles of most ubiquitin ligases remain poorly understood. Here, we analyzed the function of the HECT domain family of E3 ubiquitin ligases in stem cell biology and tissue regeneration in planarians. Using bioinformatic searches, we identified 17 HECT E3 genes that are expressed in the Schmidtea mediterranea genome. Whole-mount in situ hybridization experiments showed that HECT genes were expressed in diverse tissues and most were expressed in the stem cell population (neoblasts) or in their progeny. To investigate the function of all HECT E3 ligases, we inhibited their expression using RNA interference (RNAi) and determined that orthologs of huwe1, wwp1, and trip12 had roles in tissue regeneration. We show that huwe1 RNAi knockdown led to a significant expansion of the neoblast population and death by lysis. Further, our experiments showed that wwp1 was necessary for both neoblast and intestinal tissue homeostasis as well as uncovered an unexpected role of trip12 in posterior tissue specification. Taken together, our data provide insights into the roles of HECT E3 ligases in tissue regeneration and demonstrate that planarians will be a useful model to evaluate the functions of E3 ubiquitin ligases in stem cell regulation.

Comparative study of primary intention lacrimal probing with and without nasal endoscopy.

OBJECTIVE: Our objective was to compare the results of probing with and without endoscopy in cases of congenital nasolacrimal duct obstruction without prior probing. METHODS: This was a retrospective analysis on 2 non-randomized cohorts, 36 simple soundings (group 1) and 36 soundings with endoscope (group 2), between January 2011 and January 2013. Both groups were similar in age and had no previous surgery. The age of the patients studied ranged between 8 and 27 months in the first group and between 7 and 30 months in the second group. RESULTS: The procedure was successful in 50% of the conventional probing group and in 97.22% in the endoscopy probing group. In this group 16.67% of patients with tight inferior turbinate and 11.11% of those where the probe passed into the submucosal space were diagnosed and corrected intraoperatively. Some anomaly was observed in 30.56% of patients undergoing endoscopy. CONCLUSION: Although nasal endoscopy is classically reserved for unsuccessful probing, its use in primary intention increases the success rate of the procedure. In our study, 97.22% of eyes had complete resolution of symptoms, avoiding a second surgery and the use of more expensive materials and techniques. Nasal endoscopy helps intraoperative visualisation, understanding and management of congenital nasolacrimal duct obstruction and is the only method that confirms the correct anatomic position of the catheterisation in real time.

The ubiquilin gene family: evolutionary patterns and functional insights.

BACKGROUND: Ubiquilins are proteins that function as ubiquitin receptors in eukaryotes. Mutations in two ubiquilin-encoding genes have been linked to the genesis of neurodegenerative diseases. However, ubiquilin functions are still poorly understood. RESULTS: In this study, evolutionary and functional data are combined to determine the origin and diversification of the ubiquilin gene family and to characterize novel potential roles of ubiquilins in mammalian species, including humans. The analysis of more than six hundred sequences allowed characterizing ubiquilin diversity in all the main eukaryotic groups. Many organisms (e. g. fungi, many animals) have single ubiquilin genes, but duplications in animal, plant, alveolate and excavate species are described. Seven different ubiquilins have been detected in vertebrates. Two of them, here called UBQLN5 and UBQLN6, had not been hitherto described. Significantly, marsupial and eutherian mammals have the most complex ubiquilin gene families, composed of up to 6 genes. This exceptional mammalian-specific expansion is the result of the recent emergence of four new genes, three of them (UBQLN3, UBQLN5 and UBQLNL) with precise testis-specific expression patterns that indicate roles in the postmeiotic stages of spermatogenesis. A gene with related features has independently arisen in species of the Drosophila genus. Positive selection acting on some mammalian ubiquilins has been detected. CONCLUSIONS: The ubiquilin gene family is highly conserved in eukaryotes. The infrequent lineage-specific amplifications observed may be linked to the emergence of novel functions in particular tissues.

SurpriseMe: an integrated tool for network community structure characterization using Surprise maximization.

SUMMARY: Detecting communities and densely connected groups may contribute to unravel the underlying relationships among the units present in diverse biological networks (e.g. interactomes, coexpression networks, ecological networks). We recently showed that communities can be precisely characterized by maximizing Surprise, a global network parameter. Here, we present SurpriseMe, a tool that integrates the outputs of seven of the best algorithms available to estimate the maximum Surprise value. SurpriseMe also generates distance matrices that allow visualizing the relationships among the solutions generated by the algorithms. We show that the communities present in small- and medium-sized networks, with up to 10 000 nodes, can be easily characterized: on standard PC computers, these analyses take less than an hour. Also, four of the algorithms may rapidly analyze networks with up to 100 000 nodes, given enough memory resources. Because of its performance and simplicity, SurpriseMe is a reference tool for community structure characterization. AVAILABILITY AND IMPLEMENTATION: SurpriseMe is implemented in Perl and C/C++. It compiles and runs on any UNIX-based operating system, including Linux and Mac OS/X, using standard libraries. The source code is freely and publicly available under the GPL 3.0 license at http://github.com/raldecoa/SurpriseMe/releases.

Exploring the limits of community detection strategies in complex networks.

The characterization of network community structure has profound implications in several scientific areas. Therefore, testing the algorithms developed to establish the optimal division of a network into communities is a fundamental problem in the field. We performed here a highly detailed evaluation of community detection algorithms, which has two main novelties: 1) using complex closed benchmarks, which provide precise ways to assess whether the solutions generated by the algorithms are optimal; and, 2) A novel type of analysis, based on hierarchically clustering the solutions suggested by multiple community detection algorithms, which allows to easily visualize how different are those solutions. Surprise, a global parameter that evaluates the quality of a partition, confirms the power of these analyses. We show that none of the community detection algorithms tested provide consistently optimal results in all networks and that Surprise maximization, obtained by combining multiple algorithms, obtains quasi-optimal performances in these difficult benchmarks.

Evolution of plant HECT ubiquitin ligases.

HECT ubiquitin ligases are key components of the ubiquitin-proteasome system, which is present in all eukaryotes. In this study, the patterns of emergence of HECT genes in plants are described. Phylogenetic and structural data indicate that viridiplantae have six main HECT subfamilies, which arose before the split that separated green algae from the rest of plants. It is estimated that the common ancestor of all plants contained seven HECT genes. Contrary to what happened in animals, the number of HECT genes has been kept quite constant in all lineages, both in chlorophyta and streptophyta, although evolutionary recent duplications are found in some species. Several of the genes found in plants may have originated very early in eukaryotic evolution, given that they have clear similarities, both in sequence and structure, to animal genes. Finally, in Arabidopsis thaliana, we found significant correlations in the expression patterns of HECT genes and some ancient, broadly expressed genes that belong to a different ubiquitin ligase family, called RBR. These results are discussed in the context of the evolution of the gene families required for ubiquitination in plants.

Surprise maximization reveals the community structure of complex networks.

How to determine the community structure of complex networks is an open question. It is critical to establish the best strategies for community detection in networks of unknown structure. Here, using standard synthetic benchmarks, we show that none of the algorithms hitherto developed for community structure characterization perform optimally. Significantly, evaluating the results according to their modularity, the most popular measure of the quality of a partition, systematically provides mistaken solutions. However, a novel quality function, called Surprise, can be used to elucidate which is the optimal division into communities. Consequently, we show that the best strategy to find the community structure of all the networks examined involves choosing among the solutions provided by multiple algorithms the one with the highest Surprise value. We conclude that Surprise maximization precisely reveals the community structure of complex networks.

Origin and diversification of TRIM ubiquitin ligases.

Most proteins of the TRIM family (also known as RBCC family) are ubiquitin ligases that share a peculiar protein structure, characterized by including an N-terminal RING finger domain closely followed by one or two B-boxes. Additional protein domains found at their C termini have been used to classify TRIM proteins into classes. TRIMs are involved in multiple cellular processes and many of them are essential components of the innate immunity system of animal species. In humans, it has been shown that mutations in several TRIM-encoding genes lead to diverse genetic diseases and contribute to several types of cancer. They had been hitherto detected only in animals. In this work, by comprehensively analyzing the available diversity of TRIM and TRIM-like protein sequences and evaluating their evolutionary patterns, an improved classification of the TRIM family is obtained. Members of one of the TRIM subfamilies defined, called Subfamily A, turn to be present not only in animals, but also in many other eukaryotes, such as fungi, apusozoans, alveolates, excavates and plants. The rest of subfamilies are animal-specific and several of them originated only recently. Subfamily A proteins are characterized by containing a MATH domain, suggesting a potential evolutionary connection between TRIM proteins and a different type of ubiquitin ligases, known as TRAFs, which contain quite similar MATH domains. These results indicate that the TRIM family emerged much earlier than so far thought and contribute to our understanding of its origin and diversification. The structural and evolutionary links with the TRAF family of ubiquitin ligases can be experimentally explored to determine whether functional connections also exist.

Closed benchmarks for network community structure characterization.

Characterizing the community structure of complex networks is a key challenge in many scientific fields. Very diverse algorithms and methods have been proposed to this end, many working reasonably well in specific situations. However, no consensus has emerged on which of these methods is the best to use in practice. In part, this is due to the fact that testing their performance requires the generation of a comprehensive, standard set of synthetic benchmarks, a goal not yet fully achieved. Here, we present a type of benchmark that we call "closed," in which an initial network of known community structure is progressively converted into a second network whose communities are also known. This approach differs from all previously published ones, in which networks evolve toward randomness. The use of this type of benchmark allows us to monitor the transformation of the community structure of a network. Moreover, we can predict the optimal behavior of the variation of information, a measure of the quality of the partitions obtained, at any moment of the process. This enables us in many cases to determine the best partition among those suggested by different algorithms. Also, since any network can be used as a starting point, extensive studies and comparisons can be performed using a heterogeneous set of structures, including random ones. These properties make our benchmarks a general standard for comparing community detection algorithms.

Deciphering network community structure by surprise.

The analysis of complex networks permeates all sciences, from biology to sociology. A fundamental, unsolved problem is how to characterize the community structure of a network. Here, using both standard and novel benchmarks, we show that maximization of a simple global parameter, which we call Surprise (S), leads to a very efficient characterization of the community structure of complex synthetic networks. Particularly, S qualitatively outperforms the most commonly used criterion to define communities, Newman and Girvan's modularity (Q). Applying S maximization to real networks often provides natural, well-supported partitions, but also sometimes counterintuitive solutions that expose the limitations of our previous knowledge. These results indicate that it is possible to define an effective global criterion for community structure and open new routes for the understanding of complex networks.