Asymmetric Pendrin Homodimer Reveals its Molecular Mechanism as Anion Exchanger

Pendrin SLC26A4 is an anion exchanger expressed in apical membranes of selected epithelia. Pendrin ablation causes Pendred syndrome, a genetic disorder disease associated with sensorineural hearing loss, hypothyroid goiter, and reduced blood pressure. However, its molecular structure has remained unknown limiting our understanding. Here, we determined the structures of mouse pendrin with symmetric and characteristically asymmetric homodimer conformations by cryo-electron microscopy. The asymmetric homodimer consists of an inward-facing protomer and an intermediate-state protomer, representing the coincident uptake and secretion process, and exhibits the unique state of pendrin as an electroneutral exchanger. This previously unrevealed conformation, together with other conformations we captured, provides an inverted alternate-access mechanism for anion exchange. Furthermore, our structural and functional data disclosed the properties of anion exchange cleft and interpreted the important pathogenetic mutations. These investigations shed light on the pendrin exchange mechanism and extend our structure-guided understanding of pathogenetic mutations.

Why did hunting weapon design change at Abri Pataud? Lithic use-wear data on armature use and hafting around 24,000–22,000 BP

Projectile technology is commonly viewed as a significant contributor to past human subsistence and, consequently, to our evolution. Due to the allegedly central role of projectile weapons in the food-getting strategies of Upper Palaeolithic people, typo-technological changes in the European lithic record have often been linked to supposed developments in hunting weaponry. Yet, relatively little reliable functional data is currently available that would aid the detailed reconstruction of past weapon designs. In this paper, we take a use-wear approach to the backed tool assemblages from the Recent and Final Gravettian layers (Levels 3 and 2) of Abri Pataud (Dordogne, France). Our use of strict projectile identification criteria relying on combinations of low and high magnification features and our critical view of the overlap between production and use-related fractures permitted us to confidently identify a large number of used armatures in both collections. By isolating lithic projectiles with the strongest evidence of impact and by recording wear attributes on them in detail, we could establish that the hunting equipment used during the Level 3 occupations involved both lithic weapon tips and composite points armed with lithic inserts. By contrast, the Level 2 assemblage reflects a heavy reliance on composite points in hunting reindeer and other game. Instead of an entirely new weapon design, the Level 2 collection therefore marks a shift in weapon preferences. Using recent faunal data, we discuss the significance of the observed diachronic change from the point of view of prey choice, seasonality, and social organisation of hunting activities. Our analysis shows that to understand their behavioural significance, typo-technological changes in the lithic record must be viewed in the light of functional data and detailed contextual information.

Bridge closure in the road network of Lombardy: a spatio-temporal analysis of the socio-economic impacts

This paper introduces a methodology to evaluate the socio-economic impacts of closure for maintenance of one or more infrastructures of a large and complex road network. Motivated by a collaboration with Regione Lombardia, we focus on a subset of bridges in the region, although we aim at developing a method scalable to all road infrastructures of the regional network, consisting of more than 10,000 tunnels, bridges and overpasses. The final aim of the endeavor is to help decision-makers in prioritizing their interventions for maintaining and repairing infrastructure segments. We develop two different levels of impact assessment, both providing a unique global score for each bridge closure and investigating its spatio-temporal effects on mobility. We take advantage of a functional data analysis approach enhanced by a complex network theory perspective, thus modelling the roads of Lombardy as a network in which weights attributed to the edges are functional data. Results reveal the most critical bridges of Lombardy; moreover, for each bridge closure, the most impactful hours of the day and the most impacted municipalities of the region are identified. The proposed approach develops a flexible and scalable method for monitoring infrastructures of large and complex road networks.

Evolution and expression of LEAFY genes in ferns and lycophytes

Background The LEAFY (LFY) transcription factors are present in algae and across land plants. The available expression and functional data of these genes in embryophytes suggest that LFY genes control a plethora of processes including the first zygotic cell division in bryophytes, shoot cell divisions of the gametophyte and sporophyte in ferns, cone differentiation in gymnosperms and floral meristem identity in flowering plants. However, their putative plesiomorphic role in plant reproductive transition in vascular plants remains untested. Results We perform Maximum Likelihood (ML) phylogenetic analyses for the LFY gene lineage in embryophytes with expanded sampling in lycophytes and ferns. We recover the previously identified seed plant duplication that results in LEAFY and NEEDLY paralogs. In addition, we recover multiple species-specific duplications in ferns and lycophytes and large-scale duplications possibly correlated with the occurrence of whole genome duplication (WGD) events in Equisetales and Salviniales. To test putative roles in diverse ferns and lycophytes we perform LFY expression analyses in Adiantum raddianum, Equisetum giganteum and Selaginella moellendorffii. Our results show that LFY genes are active in vegetative and reproductive tissues, with higher expression in early fertile developmental stages and during sporangia differentiation. Conclusions Our data point to previously unrecognized roles of LFY genes in sporangia differentiation in lycophytes and ferns and suggests that functions linked to reproductive structure development are not exclusive to seed plant LFY homologs.

Elucidating Macular Structure-Function Correlations in Glaucoma

Correlation between structural data from optical coherence tomography (OCT) and functional data from the visual field (VF) may be suboptimal because of poor mapping of OCT measurement locations to VF test stimuli. We tested the hypothesis that stronger structure-function correlations in the macula can be achieved with fundus-tracking perimetery, by precisely mapping OCT measurements to VF sensitivity at the same location. The conventional 64 superpixel (3°x3°) OCT grid was mapped to VF sensitivities averaged in 40 corresponding VF units with standard automated perimetry (conventional mapped approach, CMA) in 38 glaucoma patients and 10 healthy subjects. Similarly, a 144 superpixel (2°x2°) OCT grid was mapped to each of the 68 VF locations with fundus-tracking perimetry (localized mapped approach, LMA). For each approach, the correlation between sensitivity at each VF unit and OCT superpixel was computed and the maximum value used to generate vector maps. CMA yielded significantly higher structure-function correlations compared to LMA. Only 20% of the vectors with CMA and <5% with LMA were within corresponding mapped OCT superpixels, while most were directed towards loci with structural damage. Measurement variability and patterns of glaucomatous damage are more likely to affect the correlations rather than precise mapping of VF stimuli.

Spatio-Temporal Dynamics of European Innovation—An Exploratory Approach via Multivariate Functional Data Cluster Analysis

We apply a functional data approach for mixture model-based multivariate innovation clustering to identify different regional innovation portfolios in Europe, considering patterns of specialization among innovation types. We combine patent registration data and other innovation and economic data across 225 regions, 13 years, and eight patent classes. The approach allows us to form several regional clusters according to their specific innovation types and captures spatio-temporal dynamics too subtle for most other clustering methods. Consistent with the literature on innovation systems, our analysis supports the value of regionalized clusters that can benefit from flexible policy support to strengthen regions as well as innovation in a systematic context, adding technology specificity as a new criterion to consider. The regional innovation cluster solutions for IPC classes for ‘fixed constructions’ and ‘mechanical engineering’ are highly comparable but relatively less comparable for ‘chemistry and metallurgy’. The clusters for innovations in ‘physics’ and ‘chemistry and metallurgy’ are similar; innovations in ‘electricity’ and ‘physics’ show similar temporal dynamics. For all other innovation types, the regional clustering is different. By taking regional profiles, strengths, and developments into account, options for improved efficiency of location-based regional innovation policy to promote tailored and efficient innovation-promoting programs can be derived.