Subwavelength anti-diffracting beams propagating over more than 1,000 Rayleigh lengths

Propagating light beams with widths down to and below the optical wavelength require bulky large-aperture lenses and remain focused only for micrometric distances. Here, we report the observation of light beams that violate this localization/depth- of-focus law by shrinking as they propagate, allowing resolution to be maintained and increased over macroscopic propagation lengths. In nanodisordered ferroelectrics we observe a non-paraxial propagation of a sub-micrometre-sized beam for over 1,000 diffraction lengths, the narrowest visible beam reported to date. This unprecedented effect is caused by the nonlinear response of a dipolar glass, which transforms the leading opticalwave equation into a Klein-Gordon-type equation that describes a massive particle field. Our findings open the way to high-resolution optics over large depths of focus, and a route to merging bulk optics into nanodevices

SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane \u3b1-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure-function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport

Functional over-redundancy and high functional vulnerability in global fish faunas on tropical reefs

When tropical systems lose species, they are often assumed to be buffered against declines in functional diversity by the ability of the species-rich biota to display high functional redundancy: i.e., a high number of species performing similar functions. We tested this hypothesis using a ninefold richness gradient in global fish faunas on tropical reefs encompassing 6,316 species distributed among 646 functional entities (FEs): i.e., unique combinations of functional traits. We found that the highest functional redundancy is located in the Central Indo-Pacific with a mean of 7.9 species per FE. However, this overall level of redundancy is disproportionately packed into few FEs, a pattern termed functional over-redundancy (FOR). For instance, the most speciose FE in the Central Indo-Pacific contains 222 species (out of 3,689) whereas 38% of FEs (180 out of 468) have no functional insurance with only one species. Surprisingly, the level of FOR is consistent across the six fish faunas, meaning that, whatever the richness, over a third of the species may still be in overrepresented FEs whereas more than one third of the FEs are left without insurance, these levels all being significantly higher than expected by chance. Thus, our study shows that, even in high-diversity systems, such as tropical reefs, functional diversity remains highly vulnerable to species loss. Although further investigations are needed to specifically address the influence of redundant vs. vulnerable FEs on ecosystem functioning, our results suggest that the promised benefits from tropical biodiversity may not be as strong as previously thought

An in silico structural approach to critical quality attributes assessment of biopharmaceutical products

\u201cQuality by design\u201d (QbD) is a key approach in modern pharmaceutical development, applied during the development, the manufacturing and the whole life cycle of the product, included the post approval phase, for assuring the quality in terms of efficacy and safety. In detail, QbD process includes the critical quality attributes (CQAs) assessment, providing a comprehensive understanding of the product itself and the manufacturing process. CQAs are defined as \u201call the physical, chemical, biological, or microbiological properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality\u201d (ICH Q8). They have a potential impact on bioactivity, PK, immunogenicity and safety and are associated with the drug substance and drug product. In the context of biotechnological products, the introduction of a structural investigation in an early identification of potential CQAs (pCQAs) can be very useful to QbD approach. Identification of pCQAs of biomolecules can lead the characterization process during the development phase in order to ensure the desired drug quality profile. Monoclonal antibodies (mAbs), fusion proteins and antibody-drug conjugates (ADC) represent one of the most innovative class of biopharmaceuticals, due to their ability to specifically recognize unique epitopes inducing specific therapeutic responses. CQAs assessment for these biopharmaceuticals is a complex analysis due to the lack of structural information. Actually, there is only one fully-crystallized human IgG1 (PDB entry: 1HZH) and, in absence of whole structures, it is challenging to understand the impact of structural insights on the therapeutic response. On these basis, the purpose of this study was to develop an in silico strategy to build the atomistic model of the whole structure of an IgG1, focusing on lambda and kappa light chains. To reach this goal, we used a structural chimeric approach that, using the Homology Modeling (HM) tool by MOE software, allowed us to build the full atomistic model of two therapeutic and commercially available IgG1: adalimumab (kappa chain) and avelumab (lambda chain). This allowed us to investigate structural differences between two isotypes, kappa and lambda, and understand the impact of these different characteristics on the antibody structure and function. Our results try to fill the gap between biological and structural properties on biotechnological products, created by lack of full immunoglobulin crystal structures. Moreover, this innovative structural approach can be used in CQAs assessment during the pharmaceutical development and production phases, giving an important resource to pharmaceutical companies. DISCLOSURES Merck Serono, Guidonia Montecelio-Rome, Italy is an affiliate of Merck KGaA, Darmstadt, Germany. Please note that avelumab has been approved in various countries for the treatment of metastatic Merkel cell carcinoma and in the US for treatment of advanced urothelial carcinoma progressed after platinum-containing treatment

Ecological dependencies make remote reef fish communities most vulnerable to coral loss

yEcosystems face both local hazards, such as over-exploitation, and global hazards, such as climate change. Since the impact of local hazards attenuates with distance from humans, local extinction risk should decrease with remoteness, making faraway areas safe havens for biodiversity. However, isolation and reduced anthropogenic disturbance may increase ecological specialization in remote communities, and hence their vulnerability to secondary effects of diversity loss propagating through networks of interacting species. We show this to be true for reef fish communities across the globe. An increase in fish-coral dependency with the distance of coral reefs from human settlements, paired with the far-reaching impacts of global hazards, increases the risk of fish species loss, counteracting the benefits of remoteness. Hotspots of fish risk from fish-coral dependency are distinct from those caused by direct human impacts, increasing the number of risk hotspots by similar to 30% globally. These findings might apply to other ecosystems on Earth and depict a world where no place, no matter how remote, is safe for biodiversity, calling for a reconsideration of global conservation priorities.Peer reviewe

Global tropical reef fish richness could decline by around half if corals are lost

Reef fishes are a treasured part of marine biodiversity, and also provide needed protein for many millions of people. Although most reef fishes might survive projected increases in ocean temperatures, corals are less tolerant. A few fish species strictly depend on corals for food and shelter, suggesting that coral extinctions could lead to some secondary fish extinctions. However, secondary extinctions could extend far beyond those few coral-dependent species. Furthermore, it is yet unknown how such fish declines might vary around the world. Current coral mass mortalities led us to ask how fish communities would respond to coral loss within and across oceans. We mapped 6964 coral-reef-fish species and 119 coral genera, and then regressed reef-fish species richness against coral generic richness at the 1 degrees scale (after controlling for biogeographic factors that drive species diversification). Consistent with small-scale studies, statistical extrapolations suggested that local fish richness across the globe would be around half its current value in a hypothetical world without coral, leading to more areas with low or intermediate fish species richness and fewer fish diversity hotspots.Peer reviewe

Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis

The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPC-neuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents