A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(GC) in c9ALS/FTD via the nuclear RNA exosome.

A hexanucleotide repeat expansion in intron 1 of the gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(GC), causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(GC) and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models.

Development of a putative Zn-chelating but highly selective MMP-13 inhibitor.

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn ion for chelating the metal ion.

Prospective analysis of Artisan aphakia intraocular lens implantation for nontraumatic ectopia lentis in children.

Purpose: To report long-term outcomes of iris claw aphakia intraocular lens (IOL) implantation for nontraumatic ectopia lentis (EL) in children.

Methods: In this prospective study, children who underwent Artisan Aphakia IOL placement were included if they have a minimum of 1-year follow-up after implantation. Main outcome measures were: best-corrected distance visual acuity, reoperations, change in central corneal thickness (CCT), and corneal endothelial cell counts (ECC).

Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(GC) repeat expansion in vitro and in vivo ALS models.

The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded GC RNA repeat [r(GC)] in chromosome 9 open reading frame 72 (), which elicits pathology through several mechanisms. Here, we developed and characterized a small molecule for targeted degradation of r(GC). The compound was able to selectively bind r(GC)’s structure and to assemble an endogenous nuclease onto the target, provoking removal of the transcript by native RNA quality control mechanisms.

Increases in glucocorticoids are sufficient but not necessary to increase cooperative burrowing in Damaraland mole-rats.

Despite widespread interest in the evolution of cooperative behaviour, the physiological mechanisms shaping their expression remain elusive. We tested the hypothesis that glucocorticoid (GC) hormones affect cooperative behaviour using captive Damaraland mole-rats (Fukomys damarensis), a cooperatively breeding mammal. Within groups, individuals routinely contribute to public goods that include foraging tunnels, which provide all group members access to the tubers of desert plants they feed on, communal food stores and nests.

Host-Derived Matrix Metalloproteinase-13 Activity Promotes Multiple Myeloma-Induced Osteolysis and Reduces Overall Survival.

Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts.

Activity-Based Protein Profiling (ABPP) of Oxidoreductases.

Over the last two decades, activity-based protein profiling (ABPP) has been established as a tremendously useful proteomic tool for measuring the activity of proteins in their cellular context, annotating the function of uncharacterized proteins, and investigating the target profile of small-molecule inhibitors. Unlike hydrolases and other enzyme classes, which exhibit a characteristic nucleophilic residue, oxidoreductases have received much less attention in ABPP. In this minireview, the state of the art of ABPP of oxidoreductases is described and the scope and limitations of the existing approaches are discussed.

Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties.

Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4.

Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity - indications of immune cell activation.

Birth by Cesarean section increases the risk of developing type 1 diabetes later in life. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system. To investigate Cesarean section effects, we analyzed longitudinal gene expression profiles from peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes.

The Hairpin Form of r(GC) in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules.

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded GC repeat [(GC)] in C9ORF72. ALS/FTD-associated toxicity has been traced to the RNA transcribed from the repeat expansion [r(GC)], which sequesters RNA-binding proteins (RBPs) and undergoes repeat-associated non-ATG (RAN) translation to generate toxic dipeptide repeats. Using in vitro and cell-based assays, we identified a small molecule (4) that selectively bound r(GC), prevented sequestration of an RBP, and inhibited RAN translation.

Development of matrix metalloproteinase-13 inhibitors - A structure-activity/structure-property relationship study.

A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 μM, and a permeability coefficient greater than 20 × 10 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (C = 56.

Allele-specific methylation of type 1 diabetes susceptibility genes.

The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype.

Case Series Analysis of Myopic Progression Control With a Unique Extended Depth of Focus Multifocal Contact Lens.

Objectives: To determine the rate of myopia progression in children fit with a commercially available extended depth of focus (center distance) multifocal soft contact lens with attributes theoretically expected to slow the progression of myopia.

Methods: A retrospective case series analysis of 32 patients (ages 6-19 years, mean 10.98±2.

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g.

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases.

The design of selective matrix metalloproteinase (MMP) inhibitors that also possess favorable solubility properties has proved to be especially challenging. A prior approach using collagen-model templates combined with transition state analogs produced a first generation of triple-helical peptide inhibitors (THPIs) that were effective in vitro against discrete members of the MMP family. These THPI constructs were also highly water-soluble.

Virtual High-Throughput Screening for Matrix Metalloproteinase Inhibitors.

Structure-based virtual screening (SBVS) is a common method for the fast identification of hit structures at the beginning of a medicinal chemistry program in drug discovery. The SBVS, described in this manuscript, is focused on finding small molecule hits that can be further utilized as a starting point for the development of inhibitors of matrix metalloproteinase 13 (MMP-13) via structure-based molecular design. We intended to identify a set of structurally diverse hits, which occupy all subsites (S1'-S3', S2, and S3) centering the zinc containing binding site of MMP-13, by the virtual screening of a chemical library comprising more than ten million commercially available compounds.

Precise temperature control of donor cornea tissue with reusable passive thermal container.

Purpose: To describe a new reusable passive thermal shipping container for domestic and international transport of human donor cornea, which maintains air temperature for 72 consecutive hours of harsh hypothermic and hyperthermic environmental challenges.

Methods: The passive thermal container (PTC) was prepared by storing the device at -30°C for 8 hours. On full activation of the biphasic wax-based compound, 2 human corneas for research and future histological studies were secured in either of 2 similarly prepared PTCs or 2 polystyrene containers with wet ice.

Properties of type II quadratic solitons excited by imbalanced fundamental waves.

It was shown experimentally for type II second-harmonic generation in KTP that the family of quadratic spatial solitons exists over a wide range of imbalances for the two fundamental wave inputs. The threshold for soliton formation was measured as a function of both phase mismatch and relative input fraction of the energy in the two fundamental polarizations. Launching unequal fundamental inputs led to an imbalanced three-coupled-field output composition.

Quadratic spatial soliton generation by seeded downconversion of a strong harmonic pump beam.

Two-dimensional quadratic spatial solitons were generated experimentally near phase-matching conditions for type II frequency doubling in KTP by the seeding of a strong second-harmonic field with a weak input at the fundamental wavelength. The self-trapped beams were shown to be insensitive to the energy, phase, and polarization of the fundamental-frequency seed input beam.

Toward soliton emission in asymmetric GaAs/AlGaAs multiple-quantum-well waveguide structures below the half-bandgap.

We report what is to our knowledge the first experimental evidence of nonlinear beam displacement in a strip-loaded GaAs/AlGaAs multiple-quantum-well waveguide with an asymmetric, nonlinear cladding. An intensity-dependent spatial displacement of ~2 mum was observed for the guided mode at a wavelength of 1.55 mum.

Two-dimensional type I quadratic spatial solitons in KNbO(3) near noncritical phase matching.

Experiments on the properties of quadratic, two-dimensional spatial soliton properties in KNbO(3) near and at noncritical phase matching (NCPM) are reported. The NCPM geometry leads to unique features such as a large angular bandwidth for soliton generation, weak dependence of soliton composition on intensity and incidence angle, and unique multisoliton-generation properties.

The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q.

We present the first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder (BPAD), using a large linkage data set (52 families of European descent; 448 participants and 259 affected individuals). Our results provide the strongest interaction evidence between BPAD genes on chromosomes 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions (nonparametric LOD [NPL] scores of 7.55 on 2q and 7.

Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24.

We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.