Antibody-based screening of cell wall matrix glycans in ferns reveals taxon, tissue and cell-type specific distribution patterns.

Background: While it is known that complex tissues with specialized functions emerged during land plant evolution, it is not clear how cell wall polymers and their structural variants are associated with specific tissues or cell types. Moreover, due to the economic importance of many flowering plants, ferns have been largely neglected in cell wall comparative studies. Resutls: To explore fern cell wall diversity sets of monoclonal antibodies directed to matrix glycans of angiosperm cell walls have been used in glycan microarray and in situ analyses with 76 fern species and four species of lycophytes. All major matrix glycans were present as indicated by epitope detection with some variations in abundance. Pectic HG epitopes were of low abundance in lycophytes and the CCRC-M1 fucosylated xyloglucan epitope was largely absent from the Aspleniaceae. The LM15 XXXG epitope was detected widely across the ferns and specifically associated with phloem cell walls and similarly the LM11 xylan epitope was associated with xylem cell walls. The LM5 galactan and LM6 arabinan epitopes, linked to pectic supramolecules in angiosperms, were associated with vascular structures with only limited detection in ground tissues. Mannan epitopes were found to be associated with the development of mechanical tissues. We provided the first evidence for the presence of MLG in leptosporangiate ferns. Conclusions: The data sets indicate that cell wall diversity in land plants is multifaceted and that matrix glycan epitopes display complex spatio-temporal and phylogenetic distribution patterns that are likely to relate to the evolution of land plant body plans

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

BACKGROUND: Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. MAIN BODY: Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. SHORT CONCLUSION: Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED

Giant phonon anomalies and central peak due to charge density wave formation in YBa2_2Cu3_3O6.6_{6.6}

The electron-phonon interaction is a major factor influencing the competition between collective instabilities in correlated-electron materials, but its role in driving high-temperature superconductivity in the cuprates remains poorly understood. We have used high-resolution inelastic x-ray scattering to monitor low-energy phonons in YBa$_2$Cu$_3$O$_{6.6}$ (superconducting $\bf T_c = 61$ K), which is close to a charge density wave (CDW) instability. Phonons in a narrow range of momentum space around the CDW ordering vector exhibit extremely large superconductivity-induced lineshape renormalizations. These results imply that the electron-phonon interaction has sufficient strength to generate various anomalies in electronic spectra, but does not contribute significantly to Cooper pairing. In addition, a quasi-elastic "central peak" due to CDW nanodomains is observed in a wide temperature range above and below $\bf T_c$, suggesting that the gradual onset of a spatially inhomogeneous CDW domain state with decreasing temperature is a generic feature of the underdoped cuprates

The effect of temperature, gradient and load carriage on oxygen consumption, posture and gait characteristics

Purpose The purpose of this experiment was to evaluate the effect of load carriage in a range of temperatures to establish the interaction between cold exposure, the magnitude of change from unloaded to loaded walking and gradient. Methods Eleven participants (19-27 years) provided written informed consent before performing six randomly ordered walking trials in six temperatures (20°C, 10°C, 5°C, 0°C, -5°C and -10°C). Trials involved two unloaded walking bouts before and after loaded walking (18.2 kg) at 4 km.hr⁻¹, on 0% and 10% gradients in 4 minute bouts. Results The change in absolute oxygen consumption (V̇O₂) from the first unloaded bout to loaded walking was similar across all six temperatures. When repeating the second unloaded bout, V̇O₂ at both -5°C and-10°C was greater compared to the first. At -10°C, V̇O₂ was increased from 1.60 ± 0.30 L.min⁻¹ to 1.89 ± 0.51 L.min⁻¹. Regardless of temperature, gradient had a greater effect on V̇O₂ and heart rate (HR) than backpack load. HR was unaffected by temperature. Stride length (SL) decreased with decreasing temperature but trunk forward lean was greater during cold exposure. Conclusion Decreased ambient temperature did not influence the magnitude of change in V̇O₂ from unloaded to loaded walking. However, in cold temperatures, V̇O₂ was significantly higher than in warm conditions. The increased V̇O₂ in colder temperatures at the same exercise intensity is predicted to ultimately lead to earlier onset of fatigue and cessation of exercise. These results highlight the need to consider both appropriate clothing and fitness during cold exposure

Comparison of In vitro Nanoparticles Uptake in Various Cell Lines and In vivo Pulmonary Cellular Transport in Intratracheally Dosed Rat Model

In present study, the potential drug delivery of nanoformulations was validated via the comparison of cellular uptake of nanoparticles in various cell lines and in vivo pulmonary cellular uptake in intratracheally (IT) dosed rat model. Nanoparticles were prepared by a bench scale wet milling device and incubated with a series of cell lines, including Caco-2, RAW, MDCK and MDCK transfected MDR1 cells. IT dosed rats were examined for the pulmonary cellular uptake of nanoparticles. The processes of nanoparticle preparation did not alter the crystalline state of the material. The uptake of nanoparticles was observed most extensively in RAW cells and the least in Caco-2 cells. Efflux transporter P-gp did not prevent cell from nanoparticles uptake. The cellular uptake of nanoparticles was also confirmed in bronchoalveolar lavage (BAL) fluid cells and in bronchiolar epithelial cells, type II alveolar epithelial cells in the intratracheally administrated rats. The nanoparticles uptake in MDCK, RAW cells and in vivo lung epithelial cells indicated the potential applications of nanoformulation for poorly soluble compounds. The observed limited direct uptake of nanoparticles in Caco-2 cells suggests that the improvement in oral bioavailability by particle size reduction is via increased dissolution rate rather than direct uptake

Designing Focused Chemical Libraries Enriched in Protein-Protein Interaction Inhibitors using Machine-Learning Methods

Protein-protein interactions (PPIs) may represent one of the next major classes of therapeutic targets. So far, only a minute fraction of the estimated 650,000 PPIs that comprise the human interactome are known with a tiny number of complexes being drugged. Such intricate biological systems cannot be cost-efficiently tackled using conventional high-throughput screening methods. Rather, time has come for designing new strategies that will maximize the chance for hit identification through a rationalization of the PPI inhibitor chemical space and the design of PPI-focused compound libraries (global or target-specific). Here, we train machine-learning-based models, mainly decision trees, using a dataset of known PPI inhibitors and of regular drugs in order to determine a global physico-chemical profile for putative PPI inhibitors. This statistical analysis unravels two important molecular descriptors for PPI inhibitors characterizing specific molecular shapes and the presence of a privileged number of aromatic bonds. The best model has been transposed into a computer program, PPI-HitProfiler, that can output from any drug-like compound collection a focused chemical library enriched in putative PPI inhibitors. Our PPI inhibitor profiler is challenged on the experimental screening results of 11 different PPIs among which the p53/MDM2 interaction screened within our own CDithem platform, that in addition to the validation of our concept led to the identification of 4 novel p53/MDM2 inhibitors. Collectively, our tool shows a robust behavior on the 11 experimental datasets by correctly profiling 70% of the experimentally identified hits while removing 52% of the inactive compounds from the initial compound collections. We strongly believe that this new tool can be used as a global PPI inhibitor profiler prior to screening assays to reduce the size of the compound collections to be experimentally screened while keeping most of the true PPI inhibitors. PPI-HitProfiler is freely available on request from our CDithem platform website, www.CDithem.com