Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871

Quercetin improves and protects Calu-3 airway epithelial barrier function

Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function.Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3.Results: We observed that treating Calu-3 cell layers with quercetin increased transepithelial electrical resistance while simultaneously reducing transepithelial leaks of 14C-D-mannitol (Jm) and 14C-inulin. The effects of quercetin were concentration-dependent and exhibited a biphasic time course. These effects of quercetin occurred with changes in tight junctional protein composition as well as a partial inhibition of cell replication that resulted in decreased linear junctional density. Both of these effects potentially contribute to improved barrier function. Quercetin was equally effective in reducing the barrier compromise caused by the pro-inflammatory cytokine TNF-α, an action that seemed to derive, in part, from reducing the elevation of ERK 1/2 caused by TNF-α.Discussion: Quercetin improved Calu-3 barrier function and reduced TNF-α-induced barrier compromise, mediated in part by changes in the tight junctional complex

TGF-ß Sma/Mab Signaling Mutations Uncouple Reproductive Aging from Somatic Aging

Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15–20 day adulthood. All of the known mutations and treatments that extend C. elegans' reproductive period also regulate longevity, suggesting that reproductive span is normally linked to life span. C. elegans has two canonical TGF-ß signaling pathways. We recently found that the TGF-ß Dauer pathway regulates longevity through the Insulin/IGF-1 Signaling (IIS) pathway; here we show that this pathway has a moderate effect on reproductive span. By contrast, TGF-ß Sma/Mab signaling mutants exhibit a substantially extended reproductive period, more than doubling reproductive span in some cases. Sma/Mab mutations extend reproductive span disproportionately to life span and act independently of known regulators of somatic aging, such as Insulin/IGF-1 Signaling and Dietary Restriction. This is the first discovery of a pathway that regulates reproductive span independently of longevity and the first identification of the TGF-ß Sma/Mab pathway as a regulator of reproductive aging. Our results suggest that longevity and reproductive span regulation can be uncoupled, although they appear to normally be linked through regulatory pathways

Highly Water-Stable Zirconium Metal-Organic Framework UiO-66 Membranes Supported on Alumina Hollow Fibers for Desalination

In this study, continuous zirconium(IV)-based metal-organic framework (Zr-MOF) membranes were prepared. The pure-phase Zr-MOF (i.e., UiO-66) polycrystalline membranes were fabricated on alumina hollow fibers using an in situ solvothermal synthesis method. Single-gas permeation and ion rejection tests were carried out to confirm membrane integrity and functionality. The membrane exhibited excellent multivalent ion rejection (e.g., 86.3% for Ca2+, 98.0% for Mg2+, and 99.3% for Al3+) on the basis of size exclusion with moderate permeance (0.14 L m-2 h-1 bar-1) and good permeability (0.28 L m-2 h-1 bar-1 μm). Benefiting from the exceptional chemical stability of the UiO-66 material, no degradation of membrane performance was observed for various tests up to 170 h toward a wide range of saline solutions. The high separation performance combined with its outstanding water stability suggests the developed UiO-66 membrane as a promising candidate for water desalination

The Spatial Association of Gene Expression Evolves from Synchrony to Asynchrony and Stochasticity with Age

For multicellular organisms, different tissues coordinate to integrate physiological functions, although this systematically and gradually declines in the aging process. Therefore, an association exists between tissue coordination and aging, and investigating the evolution of tissue coordination with age is of interest. In the past decade, both common and heterogeneous aging processes among tissues were extensively investigated. The results on spatial association of gene changes that determine lifespan appear complex and paradoxical. To reconcile observed commonality and heterogeneity of gene changes among tissues and to address evolution feature of tissue coordination with age, we introduced a new analytical strategy to systematically analyze genome-wide spatio-temporal gene expression profiles. We first applied the approach to natural aging process in three species (Rat, Mouse and Drosophila) and then to anti-aging process in Mouse. The results demonstrated that temporal gene expression alteration in different tissues experiences a progressive association evolution from spatial synchrony to asynchrony and stochasticity with age. This implies that tissue coordination gradually declines with age. Male mice showed earlier spatial asynchrony in gene expression than females, suggesting that male animals are more prone to aging than females. The confirmed anti-aging interventions (resveratrol and caloric restriction) enhanced tissue coordination, indicating their underlying anti-aging mechanism on multiple tissue levels. Further, functional analysis suggested asynchronous DNA/protein damage accumulation as well as asynchronous repair, modification and degradation of DNA/protein in tissues possibly contributes to asynchronous and stochastic changes of tissue microenvironment. This increased risk for a variety of age-related diseases such as neurodegeneration and cancer that eventually accelerate organismal aging and death. Our study suggests a novel molecular event occurring in aging process of multicellular species that may represent an intrinsic molecular mechanism of aging

Chemical diversity in a metal-organic framework revealed by fluorescence lifetime imaging

The presence and variation of chemical functionality and defects in crystalline materials, such as metal–organic frameworks (MOFs), have tremendous impact on their properties. Finding a means of identifying and characterizing this chemical diversity is an important ongoing challenge. This task is complicated by the characteristic problem of bulk measurements only giving a statistical average over an entire sample, leaving uncharacterized any diversity that might exist between crystallites or even within individual crystals. Here we show that by using fluorescence imaging and lifetime analysis, both the spatial arrangement of functionalities and the level of defects within a multivariable MOF crystal can be determined for the bulk as well as for the individual constituent crystals. We apply these methods to UiO-67, to study the incorporation of functional groups and their consequences on the structural features. We believe that the potential of the techniques presented here in uncovering chemical diversity in what is generally assumed to be homogeneous systems can provide a new level of understanding of materials properties

Stability and Hydrolyzation of Metal Organic Frameworks with Paddle-Wheel SBUs upon Hydration

Instability of most prototypical metal organic frameworks (MOFs) in the presence of moisture is always a limita- tion for industrial scale development. In this work, we examine the dissociation mechanism of microporous paddle wheel frameworks M(bdc)(ted)0.5 [M=Cu, Zn, Ni, Co; bdc= 1,4-benzenedicarboxylate; ted= triethylenediamine] in controlled humidity environments. Combined in-situ IR spectroscopy, Raman, and Powder x-ray diffraction measurements show that the stability and modification of isostructual M(bdc)(ted)0.5 compounds upon exposure to water vapor critically depend on the central metal ion. A hydrolysis reaction of water molecules with Cu-O-C is observed in the case of Cu(bdc)(ted)0.5. Displacement reactions of ted linkers by water molecules are identified with Zn(bdc)(ted)0.5 and Co(bdc)(ted)0.5. In contrast,. Ni(bdc)(ted)0.5 is less suscept- ible to reaction with water vapors than the other three compounds. In addition, the condensation of water vapors into the framework is necessary to initiate the dissociation reaction. These findings, supported by supported by first principles theoretical van der Waals density functional (vdW-DF) calculations of overall reaction enthalpies, provide the necessary information for de- termining operation conditions of this class of MOFs with paddle wheel secondary building units and guidance for developing more robust units

Cognitive Performances Are Selectively Enhanced during Chronic Caloric Restriction or Resveratrol Supplementation in a Primate

Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus)

Asymmetric Reproductive Isolation between Two Sympatric Annual Killifish with Extremely Short Lifespans

BACKGROUND: Interspecific reproductive isolation is typically achieved by a combination of intrinsic and extrinsic barriers. Behavioural isolating barriers between sympatric, closely related species are often of primary importance and frequently aided by extrinsic factors causing spatial and temporal interspecific separation. Study systems with a severely limited role of extrinsic factors on reproductive isolation may provide valuable insights into how reproductive isolation between sympatric species is maintained. We used no-choice experimental set-up to study reproductive barriers between two closely related sympatric African killifish species, Nothobranchius furzeri and Nothobranchius orthonotus. These fish live in small temporary savannah pools and have complete spatial and temporal overlap in reproductive activities and share a similar ecology. PRINCIPAL FINDINGS: We found that the two species display largely incomplete and asymmetric reproductive isolation. Mating between N. furzeri males and N. orthonotus females was absent under standard experimental conditions and eggs were not viable when fish were forced to mate in a modified experimental setup. In contrast, male N. orthonotus indiscriminately mated with N. furzeri females, the eggs were viable, and offspring successfully hatched. Most spawnings, however, were achieved by male coercion and egg production and embryo survival were low. Behavioural asymmetry was likely facilitated by mating coercion from larger males of N. orthonotus and at relatively low cost to females. Interestingly, the direction of asymmetry was positively associated with asymmetry in post-mating reproductive barriers. SIGNIFICANCE: We showed that, in fish species with a promiscuous mating system and multiple matings each day, selection for strong mate preferences was relaxed. This effect was likely due to the small proportion of resources allocated to each single mating and the high potential cost to females from mating refusal. We highlight and discuss the fact that males of rarer species may often coercively mate with females of a related, more abundant species