Smart implants as a novel strategy to regenerate well-founded cartilage

Here we explore a new generation of smart, living implants, combining not only active therapeutics but also stem cells, as a novel strategy to regenerate stabilised cartilage and avoid prostheses. This process can regenerate the subchondral bone foundation, which is currently difficult in the clinic

Role of hypoxia inducible factor-1α (HIF-1α) in innate defense against uropathogenic Escherichia coli infection

Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTI) affecting approximately 150 million people worldwide. Here, we revealed the importance of transcriptional regulator hypoxia-inducible factor-1 α subunit (HIF-1α) in innate defense against UPEC-mediated UTI. The effects of AKB-4924, a HIF-1α stabilizing agent, were studied using human uroepithelial cells (5637) and a murine UTI model. UPEC adherence and invasion were significantly reduced in 5637 cells when HIF-1α protein was allowed to accumulate. Uroepithelial cells treated with AKB-4924 also experienced reduced cell death and exfoliation upon UPEC challenge. In vivo, fewer UPEC were recovered from the urine, bladders and kidneys of mice treated transurethrally with AKB-4924, whereas increased bacteria were recovered from bladders of mice with a HIF-1α deletion. Bladders and kidneys of AKB-4924 treated mice developed less inflammation as evidenced by decreased pro-inflammatory cytokine release and neutrophil activity. AKB-4924 impairs infection in uroepithelial cells and bladders, and could be correlated with enhanced production of nitric oxide and antimicrobial peptides cathelicidin and β-defensin-2. We conclude that HIF-1α transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1α boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI

Controlling Volatility and Nonvolatility of Memristive Devices by Sn Alloying

Memristive devices have attracted significant attention due to their downscaling potential, low power operation, and fast switching performance. Their inherent properties make them suitable for emerging applications such as neuromorphic computing, in-memory computing, and reservoir computing. However, the different applications demand either volatile or nonvolatile operation. In this study, we demonstrate how compliance current and specific material choices can be used to control the volatility and nonvolatility of memristive devices. Especially, by mixing different materials in the active electrode, we gain additional design parameters that allow us to tune the devices for different applications. We found that alloying Ag with Sn stabilizes the nonvolatile retention regime in a reproducible manner. Additionally, our alloying approach improves the reliability, endurance, and uniformity of the devices. We attribute these advances to stabilization of the filament inside the switching medium by the inclusion of Sn in the filament structure. These advantageous properties of alloying were found by investigating a choice of six electrode materials (Ag, Cu, AgCu-1, AgCu-2, AgSn-1, AgSn-2) and three switching layers (SiO$_2$, Al$_2$O$_3$, HfO$_2$)

Improved Biodistribution and Extended Serum Half-Life of a Bacteriophage Endolysin by Albumin Binding Domain Fusion

The increasing number of multidrug-resistant bacteria intensifies the need to develop new antimicrobial agents. Endolysins are bacteriophage-derived enzymes that degrade the bacterial cell wall and hold promise as a new class of highly specific and versatile antimicrobials. One major limitation to the therapeutic use of endolysins is their often short serum circulation half-life, mostly due to kidney excretion and lysosomal degradation. One strategy to increase the half-life of protein drugs is fusion to the albumin-binding domain (ABD). By high-affinity binding to serum albumin, ABD creates a complex with large hydrodynamic volume, reducing kidney excretion and lysosomal degradation. The aim of this study was to investigate the in vitro antibacterial activity and in vivo biodistribution and half-life of an engineered variant of the Staphylococcus aureus phage endolysin LysK. The ABD sequence was introduced at different positions within the enzyme, and lytic activity of each variant was determined in vitro and ex vivo in human serum. Half-life and biodistribution were assessed in vivo by intravenous injection of europium-labeled proteins into C57BL/6 wild-type mice. Our data demonstrates that fusion of the endolysin to ABD improves its serum circulation half-life and reduces its deposition in the kidneys in vivo. The most active construct reduced S. aureus counts in human serum ex vivo by 3 logs within 60 min. We conclude that ABD fusions provide an effective strategy to extend the half-life of antibacterial enzymes, supporting their therapeutic potential for treatment of systemic bacterial infections

Nano-Engineered Scaffold for Osteoarticular Regenerative Medicine

In the last decade, regenerative medicine has benefited from the exponential development of nanomaterial sciences, tissue engineering and cell-based therapies. More and more sophisticated designed structures and surface topologies are being developed to basically mimic the extracellular matrix of native tissues such as cartilage and bone. Here we give an overview of the progress made in osteochondral lesion repair, with nano-engineered scaffolds comprising building blocks such as nanoparticles, nanotubes, layer-by-layer nano-assemblies, molecular self-assembly, nanopatterned surfaces…. This nano-engineering technology is coupled with bio-functionalization, by the use of adhesion peptides, growth factors, or deoxyribonucleic acid, to drive cell adhesion, proliferation and behavior towards tissue regeneration. In osteochondral regeneration, the challenge is the simultaneous development of chondrocytes and cartilage extracellular matrix on the one side and a well vascularized bone tissue with osteoblasts on the other sid

Advanced nanostructured medical device combining mesenchymal cells and VEGF nanoparticles for enhanced engineered tissue vascularization.

AIM: Success of functional vascularized tissue repair depends on vascular support system supply and still remains challenging. Our objective was to develop a nanoactive implant enhancing endothelial cell activity, particularly for bone tissue engineering in the regenerative medicine field. MATERIALS & METHODS: We developed a new strategy of tridimensional implant based on cell-dependent sustained release of VEGF nanoparticles. These nanoparticles were homogeneously distributed within nanoreservoirs onto the porous scaffold, with quicker reorganization of endothelial cells. Moreover, the activity of this active smart implant on cells was also modulated by addition of osteoblastic cells. RESULTS & CONCLUSION: This sophisticated active strategy should potentiate efficiency of current therapeutic implants for bone repair, avoiding the need for bone substitutes

Ancient Migratory Events in the Middle East: New Clues from the Y-Chromosome Variation of Modern Iranians

Knowledge of high resolution Y-chromosome haplogroup diversification within Iran provides important geographic context regarding the spread and compartmentalization of male lineages in the Middle East and southwestern Asia. At present, the Iranian population is characterized by an extraordinary mix of different ethnic groups speaking a variety of Indo-Iranian, Semitic and Turkic languages. Despite these features, only few studies have investigated the multiethnic components of the Iranian gene pool. In this survey 938 Iranian male DNAs belonging to 15 ethnic groups from 14 Iranian provinces were analyzed for 84 Y-chromosome biallelic markers and 10 STRs. The results show an autochthonous but non-homogeneous ancient background mainly composed by J2a sub-clades with different external contributions. The phylogeography of the main haplogroups allowed identifying post-glacial and Neolithic expansions toward western Eurasia but also recent movements towards the Iranian region from western Eurasia (R1b-L23), Central Asia (Q-M25), Asia Minor (J2a-M92) and southern Mesopotamia (J1-Page08). In spite of the presence of important geographic barriers (Zagros and Alborz mountain ranges, and the Dasht-e Kavir and Dash-e Lut deserts) which may have limited gene flow, AMOVA analysis revealed that language, in addition to geography, has played an important role in shaping the nowadays Iranian gene pool. Overall, this study provides a portrait of the Y-chromosomal variation in Iran, useful for depicting a more comprehensive history of the peoples of this area as well as for reconstructing ancient migration routes. In addition, our results evidence the important role of the Iranian plateau as source and recipient of gene flow between culturally and genetically distinct population

Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy.

Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High- resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, eluci- dating mechanisms that may underlie genetic susceptibility to heart failure in human populations

Advancing research for seamless Earth system prediction

Whether on an urban or planetary scale, covering time scales of a few minutes or a few decades, the societal need for more accurate weather, climate, water, and environmental information has led to a more seamless thinking across disciplines and communities. This challenge, at the intersection of scientific research and society’s need, is among the most important scientific and technological challenges of our time. The “Science Summit on Seamless Research for Weather, Climate, Water, and Environment” organized by the World Meteorological Organization (WMO) in 2017, has brought together researchers from a variety of institutions for a cross-disciplinary exchange of knowledge and ideas relating to seamless Earth system science. The outcomes of the Science Summit, and the interactions it sparked, highlight the benefit of a seamless Earth system science approach. Such an approach has the potential to break down artificial barriers that may exist due to different observing systems, models, time and space scales, and compartments of the Earth system. In this context, the main future challenges for research infrastructures have been identified. A value cycle approach has been proposed to guide innovation in seamless Earth system prediction. The engagement of researchers, users, and stakeholders will be crucial for the successful development of a seamless Earth system science that meets the needs of society

Genetic Association and Altered Gene Expression of Mir-155 in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation, demyelination, and axonal damage. As microRNA (miRNA)-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response, miRNA deregulation may result in defects in immune tolerance. In this frame, we sought to explore the possible involvement of miRNAs in MS pathogenesis by monitoring the differential expression of 22 immunity-related miRNAs in peripheral blood mononuclear cells of MS patients and healthy controls, by using a microbead-based technology. Three miRNAs resulted >2 folds up-regulated in MS vs controls, whereas none resulted down-regulated. Interestingly, the most up-regulated miRNA (mir-155; fold change = 3.30; P = 0.013) was previously reported to be up-regulated also in MS brain lesions. Mir-155 up-regulation was confirmed by qPCR experiments. The role of mir-155 in MS susceptibility was also investigated by genotyping four single nucleotide polymorphisms (SNPs) mapping in the mir-155 genomic region. A haplotype of three SNPs, corresponding to a 12-kb region encompassing the last exon of BIC (the B-cell Integration Cluster non-coding RNA, from which mir-155 is processed), resulted associated with the disease status (P = 0.035; OR = 1.36, 95% CI = 1.05–1.77), suggesting that this locus strongly deserves further investigations