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Context: The relationship between resveratrol and histone acetylation in renal cell carcinoma (RCC) has not yet been reported. Objective: To explore the functional role of resveratrol in RCC. Materials and methods: Functional experiments were performed to determine proliferatio n of ACHN cells with treatment of resveratrol (0, 7.8125, 15.625, 31.25 and 62.5 μg/mL, for 12, 24 and 48 h of culture) or 0.1 μM SAHA. The enzyme activities of MMP-2/-9 were measured by gelatine zymography and histone acetylation by Western blot. Results: When the cells were treated with 15.625, 31.25 and 62.5 μg/mL resveratrol, ACHN cells viability was 73.2 ± 3.5%, 61.4 ± 3.1%, 50.2 ± 4.7% for 12 h, 62.7 ± 4.5%, 52.4 ± 5.5%, 40.2 ± 3.8% for 24 h, and 60.8 ± 3.7%, 39.4 ± 5.1%, 37.6 ± 2.7% for 48 h, and the wound closure (%) of migration was increased from 0.6 to 0.7, 0.85, 0.9 for 12 h and from 0.23 to 0.3, 0.48, 0.59 for 24 h. The invasion rate was 8.5 ± 0.9%, 7.4 ± 0.3% and 5.8 ± 0.6%, and cell cycle was arrested at G1 from 42.5 ± 2.9% to 55.3 ± 5.7%, 59.8 ± 3.4%, 68.7 ± 4.6%. MMP-2/-9 expression (p

Inhibitory neurons take on many forms and functions. How this diversity contributes to memory function is not completely known. Previous formal studies indicate inhibition differentiated by local and global connectivity in associative memory networks functions to rescale the level of retrieval of excitatory assemblies. However, such studies lack biological details such as a distinction between types of neurons (excitatory and inhibitory), unrealistic connection schemas, and nonsparse assemblies. In this study, we present a rate-based cortical model where neurons are distinguished (as excitatory, local inhibitory, or global inhibitory), connected more realistically, and where memory items correspond to sparse excitatory assemblies. We use this model to study how local-global inhibition balance can alter memory retrieval in associative memory structures, including naturalistic and artificial structures. Experimental studies have reported inhibitory neurons and their subtypes uniquely respond to specific stimuli and can form sophisticated, joint excitatory-inhibitory assemblies. Our model suggests such joint assemblies, as well as a distribution and rebalancing of overall inhibition between two inhibitory subpopulations, one connected to excitatory assemblies locally and the other connected globally, can quadruple the range of retrieval across related memories. We identify a possible functional role for local-global inhibitory balance to, in the context of choice or preference of relationships, permit and maintain a broader range of memory items when local inhibition is dominant and conversely consolidate and strengthen a smaller range of memory items when global inhibition is dominant. This model, while still theoretical, therefore highlights a potentially biologically-plausible and behaviorally-useful function of inhibitory diversity in memory.

International audience; In bivalves, no clear-cut functional role of microbiota has yet been identified, although many publications suggest that they could be involved in nutrition or immunity of their host. In the context of climate change, integrative approaches at the crossroads of disciplines have been developed to explore the environment-host-pathogen microbiota system. Here, we attempt to synthesize work on (1) the current methodologies to analyse bivalve microbiota, (2) the comparison of microbiota between species, between host compartments and their surrounding habitat, (3) how the bivalve microbiota are governed by environmental factors and host genetics and (4) how host-associated microorganisms act as a buffer against pathogens and/or promote recovery, and could thereby play a role in the prevention of disease or mortalities.

This paper presents creative geometry research focusing on computational design exploration to improve the eco-performance of concrete blocks used as a building material. To provide a positive eco-performance, an optimized concrete block was designed to be more efficient than a conventional concrete block with respect to the materials used and the space occupied during storage and transport. The results prove that the form is cost-effective and that the environmental impact caused by associated production and distribution processes would be comparatively reduced. Computational research based on parametric design thinking enabled the relationship between form properties as selected design parameters to be evaluated, with the aim of ensuring that efficiency does not compromise technical requirements and that the overall functional role of the concrete block is appropriate when used as a constituent material in nonstructural wall construction. Volumetric-based measurements were employed using Rhinoceros modeling software with a Grasshopper plug-in to assess the eco-performance of the concrete block based on selected indicators. The results show that the folded S-shape concrete block with a width of 40 mm consumes only 43% of the main material and 14% of the auxiliary material relative to a conventional concrete block with a width of 100 mm. When arranged horizontally, a standard container can hold 60% more of the optimized concrete block units compared to conventional ones. Additional findings were also made that suggest future research potential, including use of the concrete blocks as building elements in passive design strategies.

Genital traits are among the fastest to evolve, and the processes that drive their evolution are intensively studied. Spiders are characterized by complex genitalia, but the functional role of the different structures during genital coupling is largely unknown. Members of one of the largest spider groups, the retrolateral tibial apophysis (RTA) clade, are characterized by a RTA on the male palp, which is thought to play a crucial role during genital coupling. However, the RTA was lost in several families including the species-rich wolf spiders (Lycosidae) leading to the hypothesis that the genital coupling is achieved by alternative mechanisms. Here, we investigate the genital interactions during copulation in the wolf spider Agalenocosa pirity (Zoicinae) on cryofixed mating pairs using electron, optical and X-ray microscopy and compare our findings with other lycosids and entelegyne spiders. We found an unprecedented coupling mechanism for lycosid spiders involving the palea and a membranous cuticle folding adjacent to the epigynal plate. Additionally, we show an uncommon coupling between the median apophysis and the contralateral genital opening, and confirmed that the terminal apophysis acts as functional conductor, as previously hypothesized for males of Zoicinae. Phylogenetic mapping of RTA indicated that the basal tibial process found in Agalenocosa is a secondary acquisition rather than a modified RTA. Fil: Poy, Dante. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentina Fil: Ramirez, Martin Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentina Fil: Michalik, Peter. ERNST MORITZ ARNDT UNIVERSITÄT GREIFSWALD (UG); Fil: Piacentini, Luis Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentina

As águas superficiais do domí­nio Cerrado do Brasil central abrigam elevada biodiversidade e endemismo. Esta revisão teve como objetivo realizar um levantamento de novas ocorrências de Cladocera nestas águas e verificar tendências atuais do tema. A pesquisa foi realizada por meio de busca em literatura (2008-2018). Houve registro de 26 novas ocorrências, com a maioria exclusiva a determinada área. Chydoridae foi dominante nestes registros, o que reflete a heterogeneidade ambiental nos ecossistemas aquáticos do Cerrado e o papel funcional desta famí­lia. Estudos taxonômicos foram indispensáveis para a obtenção de resultados mais acurados em biodiversidade e análise ecológica de Cladocera. Com base na potencialidade destes novos registros serem indicadores de áreas pristinas e endêmicas, esta revisão permite reconhecer a distribuição do grupo e também contribuiu para reduzir lacunas de amostragem. A partir destes registros nestas áreas, subsí­dios são gerados para proteção mais efetiva de mananciais em áreas de divisores de bacias e mais vulneráveis a alterações antrópicas no Cerrado do Brasil Central.

Serial dependence is a perceptual bias where current perception is biased towards prior visual input. This bias occurs when perceiving visual attributes, such as facial identity, and has been argued to play an important functional role in vision, stabilising the perception of objects through integration. In face identity recognition, this bias could assist in building stable representations of facial identity. If so, then individual variation in serial dependence could contribute to face recognition ability. To investigate this possibility, we measured both the strength of serial dependence and the range over which individuals showed this bias (the tuning) in 219 adults, using a new measure of serial dependence of facial identity. We found that better face recognition was associated with stronger serial dependence and narrower tuning, that is, showing serial dependence primarily when sequential faces were highly similar. Serial dependence tuning was further found to be a significant predictor of face recognition abilities independently of both object recognition and face identity aftereffects. These findings suggest that the extent to which serial dependence is used selectively for similar faces is important to face recognition. Our results are consistent with the view that serial dependence plays a functional role in face recognition.

miR-615-3p has previously been described as up-regulated in prostate cancer (PC) tissue samples compared with nonmalignant controls; however, its prognostic potential and functional role in PC remain largely unknown. In this study, we investigated the clinical and biological relevance of miR-615-3p in PC. The expression of miR-615-3p was measured in PC tissue specimens from 239 men who underwent radical prostatectomy (RP), and it was investigated if miR-615-3p could predict postoperative biochemical recurrence (BCR). These findings were subsequently validated in three independent RP cohorts (n = 222, n = 273, and n = 387) and functional overexpression studies conducted in PC cells (PC3M). High miR-615-3p expression was significantly associated with BCR in four independent PC patient cohorts (P < 0.05, log-rank test). In addition, high miR-615-3p expression was a significant predictor of PC-specific survival in univariate (hazard ratio, 3.75; P < 0.001) and multivariate (hazard ratio, 2.66; P = 0.008) analysis after adjustment for the Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) nomogram in a merged RP cohort (n = 734). Moreover, overexpression of miR-615-3p in PC cells (PC3M) significantly increased cell viability, proliferation, apoptosis, and migration. Together, our results suggest that miR-615-3p is a significant predictor of postoperative BCR and PC-specific survival and has oncogenic functions in PC cells.

Lymphatic vessels mediate fluid flows that affect antigen distribution and delivery, lymph node stromal remodeling, and cell-cell interactions, to thus regulate immune activation. Here we review the functional role of lymphatic transport and lymph node biomechanics in immunity. We present experimental tools that enable quantitative analysis of lymphatic transport and lymph node dynamics in vitro and in vivo. Finally, we discuss the current understanding for how changes in lymphatic transport and lymph node biomechanics contribute to pathogenesis of conditions including cancer, aging, neurodegeneration, and infection., Graphical Abstract, Lymphology; Biophysics; Biomechanics; Biological Sciences Tools

Temporal nesting of cortical slow oscillations, thalamic spindles, and hippocampal ripples indicates multiregional neuronal interactions required for memory consolidation. However, how the thalamic activity during spindles organizes hippocampal dynamics remains largely undetermined. We analyzed simultaneous recordings of anterodorsal thalamus and CA1 in male mice to determine the contribution of thalamic spindles in cross-regional synchronization. Our results indicated that temporal hippocampo-thalamocortical coupling was more enhanced during slower and longer thalamic spindles. Additionally, spindles occurring closer to slow oscillation trough were more strongly coupled to ripples. We found that the temporal association between CA1 spiking/ripples and thalamic spindles was stronger following spatial exploration compared with baseline sleep. We further developed a hippocampal-thalamocortical model to explain the mechanism underlying the duration and frequency-dependent coupling of thalamic spindles to hippocampal activity. Our findings shed light on our understanding of the functional role of thalamic activity during spindles on multiregional information transfer. SIGNIFICANCE STATEMENT The contribution of thalamic spindles with differential properties to cross-regional synchronization and information transfer still remains poorly understood. Using simultaneous anterodorsal thalamic and hippocampal recordings from naturally sleeping mice before and after exploration, we found strong coupling of CA1 units to anterodorsal thalamic spindles and increase of this coupling following spatial experience. We further showed that the temporal coupling of CA1 units and hippocampal ripples with thalamic spindles and the spindle-associated modulation of CA1 units with ripples were stronger for spindles with slower frequency of oscillations. Our experimental as well as computational findings using a hippocampal-thalamocortical model provide the first demonstration that spindle frequency and duration can provide valuable information about the underlying multiregional interactions essential for memory consolidation computations.

Osteosarcoma, which arises from bone tissue, is considered to be one of the most common types of cancer in children and teenagers. As the etiology of osteosarcoma has not been fully elucidated, the overall prognosis for patients is generally poor. In recent years, the development of bioinformatical technology has allowed researchers to identify numerous molecular biological characteristics associated with the prognosis of osteosarcoma using online databases. In the present study, Gene Expression Omnibus (GEO) database was used and three microarray datasets were obtained. The GEO2R web tool was utilized and differentially expressed genes (DEGs) in osteosarcoma tissue were identified. Venn analysis was performed to determine the intersection of the DEG profiles. DEGs were analyzed by Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Protein-protein interactions (PPIs) between these DEGs were analyzed using the Search Tool for the Retrieval of Interacting Genes database, and the PPI network was then visualized using Cytoscape software. The top ten genes were identified based on measurement of degree, density of maximum neighborhood component, maximal clique centrality and mononuclear cell counts in the PPI network, and five overlapping genes [origin recognition complex subunit 6 (ORC6), IGF-binding protein 5 (IGFBP5), minichromosome maintenance 10 replication initiation factor (MCM10), MET proto-oncogene, receptor tyrosine kinase (MET) and centromere protein F (CENPF)] were identified. Additionally, three module networks were analyzed by Molecular Complex Detection (MCODE), and six key genes [ORC6, MCM10, DEP domain containing 1 (DEPDC1), CENPF, TIMELESS interacting protein (TIPIN) and shugoshin 1 (SGOL1)] were screened. Combined with the results from Cytoscape and MCODE, eight hub genes (ORC6, MCM10, DEPDC1, CENPF, TIPIN, SGOL1, MET and IGFBP5) were obtained. Furthermore, Kaplan-Meier plotter survival analysis was used to evaluate the prognostic value of these eight hub genes in patients with osteosarcoma. Oncomine and GEPIA databases were applied to further confirm the expression levels of hub genes in tissue. Finally, the functional roles of the core gene CENPF were investigated using Cell Counting Kit-8, wound healing and Transwell assays, which indicated that CENPF knockdown inhibited the proliferation, migration and invasion of osteosarcoma cells. These results provided potential prognostic markers, as well as a basis for further investigation of the mechanism underlying osteosarcoma.

Mitochondria are one of the most exhaustively investigated organelles in the cell and most attention has been paid to the components of the mitochondrial electron transport chain (ETC) in the last 100 years. The ETC collects electrons from NADH or FADH2 and transfers them through a series of electron carriers within multiprotein respiratory complexes (complex I to IV) to oxygen, therefore generating an electrochemical gradient that can be used by the F1-F0-ATP synthase (also named complex V) in the mitochondrial inner membrane to synthesize ATP. The organization and function of the ETC is a continuous source of surprises. One of the latest is the discovery that the respiratory complexes can assemble to form a variety of larger structures called super-complexes (SCs). This opened an unexpected level of complexity in this well-known and fundamental biological process. This review will focus on the current evidence for the formation of different SCs and will explore how they modulate the ETC organization according to the metabolic state. Since the field is rapidly growing, we also comment on the experimental techniques used to describe these SC and hope that this overview may inspire new technologies that will help to advance the field, MINECO: SAF2015-65633-R, MCIU: RTI2018-099357-B-I00, CIBERFES (CB16/10/00282) and HFSP (RGP0016/2018). The CNIC is supported by the Ministry Science and Innovation (MSI) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MSI award SEV-2015-0505)

Microorganisms form symbiotic relationships with the majority of animals and plants on earth and are integral to their health and functioning in the ecosystem. Coral reefs in particular, one of the most productive ecosystems in the world, depend upon a plethora of organisms (e.g., corals, sponges, and macroalgae) and their microbial symbionts to exist. Yet, little is known about the metabolic basis of microbial symbiosis in these reef holobionts. A wide array of molecular techniques to characterise symbiotic microbial communities and map their metabolic interactions can now be exploited to reveal the extent to which microorganisms underpin both holobiont and ecosystem functioning. However, despite their utility in revealing and validating the functional role of specific microbes, ‘omic’ tools, stable isotope probing, and advanced imaging approaches such as NanoSIMS and Raman spectroscopy are rarely utilised in complex environmental settings like coral reefs. In this review, we describe molecular techniques and experimental approaches that can be employed to provide insight into microbial interactions and symbiotic function in coral reef holobionts. We further describe the inherent challenges involved in their application and suggest methods to solve these challenges to unravel the metabolic interactions underpinning these complex reef symbioses.

The actual tendency exhibits continuous increment to use alginate polysaccharides in drug delivery and tissue engineering fields due to its attractive properties. Alginate pH-sensitiveness and its fabrication techniques have been extensively reported in the literature. However, in this review, the essential role of crosslinking process in the scaffold design will be highlighted. We discuss the possibility to use a different type of crosslinking to create proper biomimetic alginate hydrogels, emphasizing the possibility to improve alginate mechanical properties through chemical modification by covalent crosslinking or ionic combination with other polymeric materials. At the same time, the relevance of the degradation process and biocompatibility in these applications is also detailed described.

RRS1(human regulator of ribosome synthesis 1), a critical nuclear protein participated in ribosome biogenesis, plays important roles in the genesis and development of breast cancer. Here, we reported that RRS1 was highly expressed in cisplatin resistant breast cancer cell MCF-7/DDP than that in parent MCF-7. RRS1 silencing increased the sensitivity of MCF-7/DDP cells to cisplatin, inhibited proliferation, affected cell cycle distribution and promoted apoptosis. Furthermore, in nude mice xenograft study, the content of RRS1 in cisplatin treatment group was significantly higher than that in saline treatment group. In addition, we found that RRS1 could bind to AEG-1 and subsequently strengthened AEG-1 abundance in breast cancer cells. Although AEG-1 did not affect AEG-1 gene transcription, it inhibited ubiquitination and subsequent proteasome-mediated degradation of AEG-1 protein. Our research in current study documented for the first time that RRS1 participated in the sensitivity of breast cancer cells to cisplatin through binding to AEG-1, indicating that RRS1 may be a promising target for the therapy of breast cancer.

Microbial eukaryotes are ubiquitous in the environment and play important roles in key ecosystem processes, including accounting for a significant portion of global primary production. Yet, our tools for assessing the functional capabilities of eukaryotic microbes in the environment are quite limited because many microbes have yet to be grown in culture. Maximum growth rate is a fundamental parameter of microbial lifestyle that reveals important information about an organism9s functional role in a community. We developed and validated a genomic estimator of maximum growth rate for eukaryotic microbes, enabling the assessment of growth potential for both cultivated and yet-to-be-cultivated organisms. We produced a database of over 700 growth predictions from genomes, transcriptomes, and metagenome-assembled genomes, and found that closely related and/or functionally similar organisms tended to have similar maximal growth rates. By comparing the maximal growth rates of existing culture collections with environmentally-derived genomes we found that, unlike for prokaryotes, culture collections of microbial eukaryotes are only minimally biased in terms of growth potential. We then extended our tool to make community-wide estimates of growth potential from over 500 marine metagenomes, mapping growth potential across the global oceans. We found that prokaryotic and eukaryotic communities have highly correlated growth potentials near the ocean surface, but that this relationship disappears deeper in the water column. This suggests that fast growing eukaryotes and prokaryotes thrive under similar conditions at the ocean surface, but that there is a decoupling of these communities as resources become scarce deeper in the water column.

The brain is a hugely diverse, heterogeneous structure. Whether or not heterogeneity at the neural level plays a functional role remains unclear, and has been relatively little explored in models which are often highly homogeneous. We compared the performance of spiking neural networks trained to carry out tasks of real-world difficulty, with varying degrees of heterogeneity, and found that heterogeneity substantially improved task performance. Learning with heterogeneity was more stable and robust, particularly for tasks with a rich temporal structure. In addition, the distribution of neuronal parameters in the trained networks is similar to those observed experimentally. We suggest that the heterogeneity observed in the brain may be more than just the byproduct of noisy processes, but rather may serve an active and important role in allowing animals to learn in changing environments., The authors show that heterogeneity in spiking neural networks improves accuracy and robustness of prediction for complex information processing tasks, results in optimal parameter distribution similar to experimental data and is metabolically efficient for learning tasks at varying timescales.

Simple Summary The role of non-coding RNA, and particularly of circular RNA, in the DNA damage response and repair network is underappreciated. Given the vital role of this network in preserving the genomic integrity and consequently cellular homeostasis, the constantly increasing numbers of discovered circular RNAs and the increasing implication of these molecules in the function of this network unravel a new important field that may open new therapeutic opportunities, but also require detailed investigation. Abstract Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications.

Plant trait- based ecology is a powerful extension of the attempt of community ecolo -gists to unveil assembly mechanisms. However, the two main expected determinants of community assembly, niche and neutral processes, can be confused under this framework. Here, we propose to move from trait- based to phenotype- based commu-nity ecology, accounting for the variation between individuals (phenotypes affected by the abiotic and biotic environment, and vice versa), and explicitly considering their ability to compete with or facilitate its neighbours. This would shift our focus from species’ niche responses to niche specialization of phenotypes, reducing the space for neutrality at the finest scales. The current assembly framework, based mainly on niche complementarity and using species-average functional traits, has been devel -oped exploring mega- diverse communities, but it fails at describing poor plant com -munities. Under this framework, monospecificity would be interpreted as an arena where functionally similar individuals compete, consequently leading to regular pat -terns, which are rarely found in nature. Our niche specialization framework could help explaining coexistence in rich plant communities, where the higher fraction of functional variation is found between species, whereas the intraspecific trait varia -tion dominates in poor species and monospecific communities. We propose a guide to conduct massive phenotyping at the community scale based on the use of visible and near- infrared spectroscopy. We also discuss the need to integrate the so- called plant's eye perspective based on the use of spatial pattern statistics in the current community ecology toolbox., This work was supported by the Ministerio de Economía y Competitividad of the Spanish Government [PHENOTYPES PGC2018-099115-B-I00] and by Comunidad de Madrid Government [REMEDINAL-TE- CM P2018/EMT-4338].

Οι μεταφορείς, είναι διαμεμβρανικές πρωτεΐνες μέσω των οποίων πραγματοποιείται η διακίνηση θρεπτικών συστατικών, μορίων σηματοδοτών ή άλλων ουσιών εντός και εκτός του κυττάρου. Αυτό τις καθιστά απαραίτητα μόρια για την επικοινωνία του κυττάρου με το περιβάλλον. Τα τελευταία χρόνια, γενετικά, βιοχημικά και βιοφυσικά δεδομένα που προέρχονται από τη μελέτη αρκετών μεταφορέων, συνέβαλλαν στην κατανόηση των σχέσεων δομής λειτουργίας και των μηχανισμών αναγνώρισης και μεταφοράς υποστρώματος. Παρά τις εξελικτικές, δομικές και λειτουργικές διαφορές τους, όλοι οι μεταφορείς χρησιμοποιούν έναν κοινό μηχανισμό εναλλασσόμενης πρόσβασης, όπου μια θέση πρόσδεσης υποστρώματος εναλάσσεται μεταξύ πολλαπλών διαμορφώσεων προκειμένου να μεταφέρει ένα υπόστρωμα από τη μία πλευρά της μεμβράνης στην άλλη. Αυτός ο βασικός μηχανισμός που διεξάγεται από δυναμικές κινήσεις του κύριου διαμεμβρανικού σώματος και υποβοηθείται από την ευελιξία υδρόφιλων βρόχων, συναντάται σε διάφορες παραλλαγές, γνωστές ως rocker-switch, rocking-bundle και μηχανισμός elevator. Μία από τις μεγαλύτερες οικογένειες δευτερογενών μεταφορέων είναι η υπεροικογένεια amino acid/polyamine/organocation (APC), η οποία περιλαμβάνει μεταφορείς που λειτουργόυν ως συμμεταφορείς διαλυτής ουσίας κατιόντος και αντιμεταφορείς διαλυτών ουσιών με μεγάλη ποικιλία υποστρωμάτων. Η οικογένεια Nucleobase Cation Symporter 1 (NCS1) αποτελεί μία από τις πιο καλά μελετημένες υποοικογένειες της APC υπεροικογένειας, και εκπρόσωποί της συναντώνται σε προκαρυωτικούς οργανισμούς, μύκητες και μερικά φυτά. Αυτό οφείλεται στην πληθώρα γενετικών και βιοχημικών δεδομένων που αφορούν μέλη της οικογένειας σε μύκητες, καθώς και σε εκτεταμένες δομικές και βιοφυσικές μελέτες ενός βακτηριακού ομολόγου, του συμμεταφορέα υδαντοΐνης/Na+, Mhp1. Η οικογένεια NCS1 δεν έχει αντιπροσώπους στα θηλαστικά, κάτι που την καθιστά ιδανική για τη στόχευση ειδικών φαρμάκων κατά των μικροβιακών παθογόνων. Οι μεταφορείς της οικογένειας NCS1 αποτελούνται από 12 διαμεμβρανικά τμήματα (ΔΤ) με δομή α έλικας, που συνδέονται με σχετικά μικρές ενδιάμεσες αλληλουχίες και έχουν κυτταροπλασματικά αμινο και καρβοξυτελικά άκρα. Τα ΔΤ1 10 οργανώνονται σε μια δομή ανεστραμμένης επανάληψης ανά 5 (5-helix intertwined inverted repeat; 5HIRT) που ονομάζεται αλλιώς και LeuT-fold, και συναντάται σε μεταφορείς πολλών διαφορετικών οικογενειών που εμπλέκονται στη μεταφορά νευροδιαβιβαστών, σακχάρων, αμινοξέων ή φαρμάκων. Τα δύο τελευταία διαμεμβρανικά τμήματα (11 και 12) μερικών μεταφορέων που έχουν παρόμοια δομή με τον LeuT, φαίνεται να εμπλέκονται στον ολιγομερισμό, παρά στο μηχανισμό λειτουργίας τους αυτό καθαυτό. Παρόλα αυτά, δεν υπάρχουν επαρκή δεδομένα για το δομικό ή/και λειτουργικό τους ρόλο. Μεταφορείς που ανήκουν στην οικογένεια NCS1 στους μύκητες, είναι από τους πιο καλά μελετημένους σε γενετικό, βιοχημικό και κυτταρικό επίπεδο. Δομικά μοντέλα μυκητιακών μεταφορέων NCS1 βασίζονται σε πολλές διακριτές κρυσταλλικές δομές του βακτηριακού ομολόγου Mhp1 και υποστηρίζονται από γενετικές μελέτες που προκαθόρισαν τη θέση δέσμευσης του υποστρώματος και τα πιθανά στοιχεία που δρουν σαν πύλες, καθορίζοντας την εξειδίκευση. Πιο συγκεκριμένα, ένα σημαντικό εύρημα που προέρχεται από έρευνα του εργαστηρίου μας πάνω στους μυκητιακούς μεταφορείς της NCS1 οικογένειας (τόσο σε μέλη της Fcy όσο και της Fur υποοικογένειας) είναι ότι η εξειδίκευση δεν καθορίζεται μόνο από κατάλοιπα που βρίσκονται στο σημείο πρόσδεσης του υποστρώματος (ΔΤ1, ΔΤ3, ΔΤ6 ή ΔΤ8) αλλά και από δυναμικές κινήσεις του τμήματος ΔΤ9 ΔΤ10 που δρα σαν εξωκυτταρική πύλη.Σε αυτή τη διατριβή, παρέχουμε πειραματικά και in silico δεδομένα που αποδεικνύουν ότι η ενδοκύτωση, η λειτουργία και περιέργως η εξειδίκευση του FurE, ενός μεταφορέα του Aspergillus nidulans που ανήκει στην NCS1 οικογένεια και μεταφέρει ουρακίλη-αλλαντοΐνη και ουρικό οξύ, εξαρτάται από δυναμικές αλληλεπιδράσεις των άμινο και καρβοξυτελικών άκρων μεταξύ τους και με το βασικό σώμα του μεταφορέα. Πιο συγκεκριμένα, τα καρβοξυτελικά άκρα εμπλέκονται σε ενδομοριακές δυναμικές αλληλεπιδράσεις που είναι απαραίτητες για την εκλεπτυσμένη ρύθμιση των πυλών που ελέγχουν την επιλογή των υποστρωμάτων. Πραγματοποιώντας Μοριακές Δυναμικές (ΜΔ) και αναλύσεις μεταλλαγών στο γονίδιο του μεταφορέα, υποθέσαμε ότι αυτό συμβαίνει μέσω αλληλεπιδράσεων των κυτταροπλασματικών ουρών με ενδοκυττάριες θηλιές, οι οποίες με τη σειρά τους επηρεάζουν τη διαδικασία διαλογής υποστρωμάτων μέσω των πυλών στην εξωκυττάρια πλευρά της πλασματικής μεμβράνης. Επιπρόσθετα, τα αποτελέσματά μας έδειξαν ότι αυτές οι αλληλεπιδράσεις εξαρτώνται άμεσα από το pH. Στη συνέχεια, αξιοποιώντας τις πληροφορίες από εκτεταμένες αναλύσεις ΜΔ, πραγματοποιήσαμε συστηματική και στοχευμένη λειτουργική ανάλυση μεταλλαγών στο μόριο του μεταφορέα FurΕ, προκειμένου να χαρακτηρίσουμε το μονοπάτι μετατόπισης του υποστρώματος κατά τη διάρκεια της μετάβασής του από τις διακριτές διαμορφώσεις του. Επιπροσθέτως, παρέχουμε πειραματικά στοιχεία που δείχνουν πως η ταυτότητα των αμινοξέων που απαρτίζουν τα δύο τελευταία ΔΤ του FurE, δεν καθορίζει την κατάλυση της μεταφοράς. Ωστόσο, ένα συντηρημένο κατάλοιπο τυροσίνης είναι απολύτως απαραίτητο για τη σωστή στόχευση του μεταφορέα στην πλασματική μεμβράνη. Στο τελευταίο μέρος αυτής της δουλειάς, συνδυάζουμε βιοφυσικές τεχνικές και υπολογιστικές μεθόδους για να καταλάβουμε σε βάθος το μηχανισμό που διέπει το λειτουργικό ρόλο των κυτταροπλασματικών άκρων στη διαλογή και μεταφορά του υποστρώματος, κάτι που φαίνεται να αντικατοπτρίζει ένα γενικότερο μηχανισμό που χαρακτηρίζει τους μεταφορείς της APC υπεροικογένειας. Το σύνολο της διατριβής αυτής, υποστηρίζει την ευρύτερη ιδέα ότι το μέγεθος των άκρων των ευκαρυωτικών μεταφορέων αυξήθηκε κατά τη διάρκεια της εξέλιξης, προσδίδοντας περισσότερους διακριτούς τρόπους ρύθμισης της λειτουργίας τους.

Since the discovery of protein arginine methyltransferase 5 (PRMT5) and the resolution of its structure, an increasing number of papers have investigated and delineated the structural and functional role of PRMT5 in diseased conditions. PRMT5 is a type II arginine methyltransferase that catalyzes symmetric dimethylation marks on histones and non-histone proteins. From gene regulation to human development, PRMT5 is involved in many vital biological functions in humans. The role of PRMT5 in various cancers is particularly well-documented, and investigations into the development of better PRMT5 inhibitors to promote tumor regression are ongoing. Notably, emerging studies have demonstrated the pathological contribution of PRMT5 in the progression of inflammatory diseases, such as diabetes, cardiovascular diseases, and neurodegenerative disorders. However, more research in this direction is needed. Herein, we critically review the position of PRMT5 in current literature, including its structure, mechanism of action, regulation, physiological and pathological relevance, and therapeutic strategies.

Males and females present differences in complex traits and in the risk of a wide array of diseases. Genotype by sex (GxS) interactions are thought to account for some of these differences. However, the extent and basis of GxS are poorly understood. In the present study, we provide insights into both the scope and the mechanism of GxS across the genome of about 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits. We also found that, in some cases, sex-agnostic analyses may be missing trait-associated loci and looked into possible improvements in the prediction of high-level phenotypes. Finally, we studied the potential functional role of the differences observed through sex-biased gene expression and gene-level analyses. Our results suggest the need to consider sex-aware analyses for future studies to shed light onto possible sex-specific molecular mechanisms.

Certain neurophysiological characteristics of sleep, in particular slow oscillations (SO), sleep spindles, and their temporal coupling, have been well characterized and associated with human memory formation. Delta waves, which are somewhat higher in frequency and lower in amplitude compared to SO, have only recently been found to play a critical role in memory processing of rodents, through a competitive interplay between SO-spindle and delta-spindle coupling. However, human studies that comprehensively address delta waves, their interactions with spindles and SOs as well as their functional role for memory are still lacking.Electroencephalographic data were acquired across three naps of 33 healthy older human participants (17 female) to investigate delta-spindle coupling and the interplay between delta and SO-related activity. Additionally, we determined intra-individual stability of coupling measures and their potential link to the ability to form novel memories.Our results revealed weaker delta-spindle compared to SO-spindle coupling. Contrary to our initial hypothesis, we found that increased delta activity was accompanied by stronger SO-spindle coupling. Moreover, we identified the ratio between SO- and delta-nested spindles as the sleep parameter that predicted ability to form novel memories best.Our study suggests that SOs, delta waves and sleep spindles should be jointly considered when aiming to link sleep physiology and memory formation in aging.Significance statementInterrelations between delta waves, slow oscillations and sleep spindles have recently been causally linked to the balance between consolidation and forgetting in rats using optogenetics. In humans, SO-spindle coupling has been intensively investigated, but delta waves and their interaction with spindles were only studied jointly as SWA. Here we delineate the coupling of delta waves to spindles, investigate interactions of delta- and SO-related activity and investigate their role for the ability to form novel memories in healthy older individuals. Our results show differences as well as dependencies between SO- and delta-related activities including spindle coupling. Further, our results indicate that the ratio of SO- to delta-nested spindles might be the most informative sleep parameter for memory formation of older adults.

Conformational conversion of the α-helix-rich cellular prion protein into the misfolded, β-rich, aggregated, scrapie form underlies the molecular basis of prion diseases that represent a class of invariably fatal, untreatable, and transmissible neurodegenerative diseases. However, despite the extensive and rigorous research, there is a significant gap in understanding molecular mechanisms that contribute to prion pathogenesis. In this review, we describe the historical perspective of the development of the prion concept and the current state of knowledge of prion biology including structural, molecular, and cellular aspects of the prion protein. We then summarize the putative functional role of the N-terminal intrinsically disordered segment of the prion protein. We next describe the ongoing efforts in elucidating the prion phase behavior and the emerging role of liquid-liquid phase separation that can have potential functional relevance and can offer an alternate non-canonical pathway involving conformational conversion into a disease-associated form. We also attempt to shed light on the evolutionary perspective of the prion protein highlighting the potential role of intrinsic disorder in prion protein biology and summarize a few important questions associated with the phase transitions of the prion protein. Delving deeper into these key aspects can pave the way for a detailed understanding of the critical molecular determinants of the prion phase transition and its relevance to physiology and neurodegenerative diseases.

The epithelial-to-mesenchymal transition (EMT), an embryonic program relaunched during wound healing and in pathological conditions such as fibrosis and cancer, continues to gain the attention of the research community, as testified by the exponential trend of publications since its discovery in the seventies. From the first description as a mesenchymal transformation, the concept of EMT has been substantially refined as an in-depth comprehension of its functional role has recently emerged thanks to the implementation of novel mouse models as well as the use of sophisticated mathematical modeling and bioinformatic analysis. Nevertheless, attempts to targeting EMT in fibrotic diseases are at their infancy and continue to pose several challenges. The aim of this mini review is to recapitulate the most recent concepts in the EMT field and to summarize the different strategies which have been exploited to target EMT in fibrotic disorders.

INTRODUCTION AND OBJECTIVE:Members of the forkhead transcription factor (FOX) family mediate embryonic development and are altered in many cancers. The functional role of FOXF1 in bladder cancer pr...

Summary The manufacturing of commercial lithium-ion batteries (LIBs) involves a number of sophisticated production processes. Various cell defects can be induced, and, depending on their structural and chemical characteristics, they could lead to acute failure and/or chronic degradation. Although tremendous efforts have been devoted to develop a robust quality control (QC) procedure, the functional role of the cell defects is not well understood. Here, we address this question through a systematic experimental study of commercial 18650-type LIBs that have failed the QC inspection due to a self-discharging effect. We identify and recover the defective regions from the cell and conduct a comprehensive investigation from the chemical, structural, and morphological perspectives. Our results reveal how the structural defects affect the cell performance, which is highly important to industry-scale battery production.

INTRODUCTION AND OBJECTIVE:The aging bladder phenotype in detrusor overactivity, detrusor underactivity or detrusor hyperactivity with impaired contractility patients is characterized by detrusor i...

The telomeric transcriptome of Chironomus riparius has been involved in thermal stress response. One of the telomeric transcripts, the so-called CriTER-A variant, is highly overexpressed upon heat shock. On the other hand, its homologous variant CriTER-B, which is the most frequently encoded noncoding RNA in the telomeres of C. riparius, is only slightly affected by thermal stress. Interestingly, both transcripts show high sequence homology, but less is known about their folding and how this could influence their differential behaviour. Our study suggests that CriTER-A folds as two different conformers, whose relative proportion is influenced by temperature conditions. Meanwhile, the CriTER-B variant shows only one dominant conformer. Thus, a temperature-dependent conformational equilibrium can be established for CriTER-A, suggesting a putative functional role of the telomeric transcriptome in relation to thermal stress that could rely on the structure–function relationship of the CriTER-A transcripts.

The cerebellum has been traditionally disregarded in relation to nonmotor functions, but recent findings indicate it may be involved in language, affective processing, and social functions. Mentalizing, or Theory of Mind (ToM), is the ability to infer mental states of others and this skill relies on a distributed network of brain regions. Here, we leveraged large-scale multimodal neuroimaging data to elucidate the structural and functional role of the cerebellum in mentalizing. We used functional activations to determine whether the cerebellum has a domain-general or domain-specific functional role, and effective connectivity and probabilistic tractography to map the cerebello-cerebral mentalizing network. We found that the cerebellum is organized in a domain-specific way and that there is a left cerebellar effective and structural lateralization, with more and stronger effective connections from the left cerebellar hemisphere to the right cerebral mentalizing areas, and greater cerebello-thalamo-cortical and cortico-ponto-cerebellar streamline counts from and to the left cerebellum. Our study provides novel insights to the network organization of the cerebellum, an overlooked brain structure, and mentalizing, one of humans’ most essential abilities to navigate the social world.

Hepatitis E virus (HEV), a major cause of acute hepatitis worldwide, infects approximately 20 million individuals annually. HEV can infect a wide range of mammalian and avian species, and cause frequent zoonotic spillover, increasingly raising public health concerns. To establish a successful infection, HEV needs to usurp host machineries to accomplish its life cycle from initial attachment to egress. However, relatively little is known about the HEV life cycle, especially the functional role(s) of cellular organelles and their associated proteins at different stages of HEV infection. Here, we summarize current knowledge regarding the relation of HEV with the different cell organelles during HEV infection. Furthermore, we discuss the underlying mechanisms by which HEV infection is precisely regulated in infected cells and the modification of host cell organelles and their associated proteins upon HEV infection.

The cardiac hyperpolarization-activated “funny” current (If), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of If in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human If formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of If reduction with the total inward depolarising current (Itotal) during diastolic depolarization. Replacing the rabbit If formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% If reduction (a level close to the inhibition of If by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit If formulation; however, the effect was doubled (~12.4%) for the human If formulation, even though the latter has smaller If density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% If reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of Itotal during diastolic depolarization phase: a smaller If in the model resulted in a smaller Itotal amplitude, resulting in a slower pacemaking rate; and the same reduction in If resulted in a more significant change of CL in the cell model with a smaller Itotal. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.

Sphingomyelins, the most abundant sphingolipids in most mammalian cells, appear to be among the most represented polar lipids in breast milk. Despite the variability of the data reported in the literature, human milk sphingomyelins are qualitatively unique and their quantities are five times higher than in most formula milk. The structural and functional role within the milk fat globule membranes, the involvement in neonatal neurological maturation both in neuro-typical development and in some pathological circumstances, together with the possible contribution in the intestinal development of newborns, are certainly among the main characteristics that have fueled the curiosity of the scientific world. Metabolomics studies, providing a unique metabolic fingerprint, allow an in-depth analysis of the role of these molecules in the extreme variability and uniqueness of breast milk. In the perspective of preventive medicine, at the base of which there is certainly personalized nutrition, it is possible, in the presence of particular conditions, such as neonatal growth retardation or in preterm infants, to consider supplementation of some target nutrients, such as certain sphingomyelins. Nevertheless, further studies are needed to more accurately assess whether and how the type and quantity of sphingomyelins present in breast milk could affect the metabolic health of newborns.HIGHLIGHTSBreast milk is the golden standard for infants' nutritionSphingomyelins are the most represented polar lipids in breast milkThese molecules are involved in both intestinal and neural developments of newbornsMetabolomics is a very useful tool to investigate their precise roleFurther studies are needed to provide eventual nutritional treatment.

Quorum sensing (QS) is one of the most studied cell-cell communication mechanisms in fungi. Research in the last 20 years has explored various fungal QS systems that are involved in a wide range of biological processes, especially eukaryote- or fungus-specific behaviors, mirroring the significant contribution of QS regulation to fungal biology and evolution. Based on recent progress, we summarize in this review fungal QS regulation, with an emphasis on its functional role in behaviors unique to fungi or eukaryotes. We suggest that using fungi as genetically amenable eukaryotic model systems to address why and how QS regulation is integrated into eukaryotic reproductive strategies and molecular or cellular processes could be an important direction for QS research.

Visual acuity is better for vertical and horizontal compared to other orientations. This cross-species phenomenon is often explained by “efficient coding”, whereby more neurons show sharper tuning for the orientations most common in natural vision. However, it is unclear if experience alone can account for such biases. Here, we measured orientation representations in a convolutional neural network, VGG-16, trained on modified versions of ImageNet (rotated by 0°, 22.5°, or 45° counter-clockwise of upright). Discriminability for each model was highest near the orientations that were most common in the network’s training set. Furthermore, there was an over-representation of narrowly tuned units selective for the most common orientations. These effects emerged in middle layers and increased with depth in the network. Our results suggest that biased orientation representations can emerge through experience with a non-uniform distribution of orientations, supporting the efficient coding hypothesis. Author Summary Observers tend to have more precise vision for items that are oriented vertically or horizontally compared to items oriented diagonally. This perceptual bias may be an adaptation to the statistics of the visual environment, where items such as trees, buildings, and the horizon naturally create horizontal and vertical edges. Here, we tested this hypothesis by taking a popular computational model of the visual system (a convolutional neural network, or CNN), and training it to perform object recognition on images that were either upright or rotated. Measuring orientation representations in the trained model revealed that orientation discriminability was highest near whichever orientations were most common in the training image set, and more neural network units showed a preference for those orientations. These results support the hypothesis that orientation biases reflect an adaptation to environmental statistics.

Lateralization is a hallmark of somatosensory processing in the mammalian brain. However, in addition to their contralateral representation, unilateral tactile stimuli also modulate neuronal activity in somatosensory cortices of the ipsilateral hemisphere. The cellular organization and functional role of these ipsilateral stimulus responses in awake somatosensory cortices, especially regarding stimulus coding, are unknown. Here, we targeted silicon probe recordings to the vibrissa region of primary (S1) and secondary (S2) somatosensory cortex of awake head-fixed mice of either sex while delivering ipsilateral and contralateral whisker stimuli. Ipsilateral stimuli drove larger and more reliable responses in S2 than in S1, and activated a larger fraction of stimulus-responsive neurons. Ipsilateral stimulus-responsive neurons were rare in layer 4 of S1, but were located in equal proportion across all layers in S2. Linear classifier analyses further revealed that decoding of the ipsilateral stimulus was more accurate in S2 than S1, while S1 decoded contralateral stimuli most accurately. These results reveal substantial encoding of ipsilateral stimuli in S1 and especially S2, consistent with the hypothesis that higher cortical areas may integrate tactile inputs across larger portions of space, spanning both sides of the body.S1ignificance StatementTactile information obtained by one side of the body is represented in the activity of neurons of the opposite brain hemisphere. However unilateral tactile stimulation also modulates neuronal activity in the other, or ipsilateral, brain hemisphere. This ipsilateral activity may play an important role in the representation and processing of tactile information, in particular when the sense of touch involves both sides of the body. Our work in the whisker system of awake mice reveals that neocortical ipsilateral activity, in particular that of deep layer excitatory neurons of secondary somatosensory cortex (S2), contains information about the presence and the velocity of unilateral tactile stimuli, which supports a key role for S2 in integrating tactile information across both body sides.

Current scientific literature has identified the infant gut microbiota as a multifaceted organ influencing a range of aspects of host-health and development. Many scientific studies have focused on characterizing the main microbial taxa that constitute the resident bacterial population of the infant gut. This has generated a wealth of information on the bacterial composition of the infant gut microbiota, and on the functional role/s exerted by their key microbial members. In this context, one of the most prevalent, abundant and investigated microbial taxon in the human infant gut is the genus Bifidobacterium, due to the purported beneficial activities is bestows upon its host. This review discusses the most recent findings regarding the infant gut microbiota with a particular focus on the molecular mechanisms by which bifidobacteria impact on host health and well-being.

Over one third of biomolecules rely on metal ions to exert their cellular functions. Metal ions can play a structural role by stabilizing the structure of biomolecules, a functional role by promoting a wide variety of biochemical reactions, and a regulatory role by acting as messengers upon binding to proteins regulating cellular metal-homeostasis. These diverse roles in biology ascribe critical implications to metal-binding proteins in the onset of many diseases. Hence, it is of utmost importance to exhaustively unlock the different mechanistic facets of metal-binding proteins and to harness this knowledge to rationally devise novel therapeutic strategies to prevent or cure pathological states associated with metal-dependent cellular dysfunctions. In this compendium, we illustrate how the use of a computational arsenal based on docking, classical, and quantum-classical molecular dynamics simulations can contribute to extricate the minutiae of the catalytic, transport, and inhibition mechanisms of metal-binding proteins at the atomic level. This knowledge represents a fertile ground and an essential prerequisite for selectively targeting metal-binding proteins with small-molecule inhibitors aiming to (i) abrogate deregulated metal-dependent (mis)functions or (ii) leverage metal-dyshomeostasis to selectively trigger harmful cells death.