Wavelength comparisons have indicated that circadian phase-shifting and enhancement of subjective and EEG-correlates of alertness have a higher sensitivity to short wavelength visible light. The aim ...of the current study was to test whether polychromatic light enriched in the blue portion of the spectrum (17,000 K) has increased efficacy for melatonin suppression, circadian phase-shifting, and alertness as compared to an equal photon density exposure to a standard white polychromatic light (4000 K). Twenty healthy participants were studied in a time-free environment for 7 days. The protocol included two baseline days followed by a 26-h constant routine (CR1) to assess initial circadian phase. Following CR1, participants were exposed to a full-field fluorescent light (1 × 1014 photons/cm2/s, 4000 K or 17,000 K, n = 10/condition) for 6.5 h during the biological night. Following an 8 h recovery sleep, a second 30-h CR was performed. Melatonin suppression was assessed from the difference during the light exposure and the corresponding clock time 24 h earlier during CR1. Phase-shifts were calculated from the clock time difference in dim light melatonin onset time (DLMO) between CR1 and CR2. Blue-enriched light caused significantly greater suppression of melatonin than standard light ((mean ± SD) 70.9 ± 19.6% and 42.8 ± 29.1%, respectively, p < 0.05). There was no significant difference in the magnitude of phase delay shifts. Blue-enriched light significantly improved subjective alertness (p < 0.05) but no differences were found for objective alertness. These data contribute to the optimization of the short wavelength-enriched spectra and intensities needed for circadian, neuroendocrine and neurobehavioral regulation.
Triamcinolone acetonide (TA), an intermediate acting corticosteroid, is used in the treatment of posterior ocular diseases, such as inflammation, posterior uveitis, and diabetic macular edema. The ...objective of this investigation was to prepare TA-loaded solid lipid nanoparticles (TA-SLNs) and in situ gel (TA-SLN-IG) formulations for delivery into the deeper ocular tissues through the topical route. TA-SLNs were prepared by hot homogenization and ultrasonication method using glyceryl monostearate and Compritol
888ATO as solid lipids and Tween
80 and Pluronic
F-68 as surfactants. TA-SLNs were optimized and converted to TA-SLN-IG by the inclusion of gellan gum and evaluated for their rheological properties.
transcorneal permeability and
ocular distribution of the TA-SLNs and TA-SLN-IG were studied using isolated rabbit corneas and New Zealand albino rabbits, respectively, and compared with TA suspension, used as control (TA-C). Particle size, PDI, zeta potential, assay, and entrapment efficiency of TA-SLNs were in the range of 200⁻350 nm, 0.3⁻0.45, -52.31 to -64.35 mV, 70⁻98%, and 97⁻99%, respectively. TA-SLN-IG with 0.3% gellan gum exhibited better rheological properties. The transcorneal permeability of TA-SLN and TA-SLN-IG was 10.2 and 9.3-folds higher compared to TA-C. TA-SLN-IG showed maximum tear concentration at 2 h, indicating an improved pre-corneal residence time, as well as higher concentrations in aqueous humor, vitreous humor and cornea at 6 h, suggesting sustained delivery of the drug into the anterior and posterior segment ocular tissues, when compared to TA-SLN and TA-C. The results, therefore, demonstrate that the lipid based nanoparticulate system combined with the
gelling agents can be a promising drug delivery platform for the deeper ocular tissues.
TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD). Namely, both diseases feature aggregated and phosphorylated TDP-43 containing ...inclusions in the cytoplasm and a loss of nuclear TDP-43 in affected neurons. It has been reported that tau tubulin kinase (TTBK)1/2 phosphorylate TDP-43 and TTBK1/2 overexpression induced neuronal loss and behavioral deficits in a C. elegans model of ALS. Here we aimed to elucidate the molecular mechanisms of TTBK1 in TDP-43 pathology. TTBK1 levels were observed to be elevated in ALS patients' post-mortem motor cortex. Also, TTBK1 was found to phosphorylate TDP-43 at disease-relevant sites in vitro directly, and this phosphorylation accelerated TDP-43 formation of high molecular species. Overexpression of TTBK1 in mammalian cells induced TDP-43 phosphorylation and the construction of high molecular species, concurrent with TDP-43 mis-localization and cytoplasmic inclusions. In addition, when TTBK1 was knocked down or pharmacologically inhibited, TDP-43 phosphorylation and aggregation were significantly alleviated. Functionally, TTBK1 knockdown could rescue TDP-43 overexpression-induced neurite and neuronal loss in iPSC-derived GABAergic neurons. These findings suggest that phosphorylation plays a critical role in the pathogenesis of TDP-43 pathology and that TTBK1 inhibition may have therapeutic potential for the treatment of ALS and FTLD.
•TTBK1 levels are elevated in ALS patient post-mortem motor cortex.•Phosphorylated recombinant TDP-43 has accelerated aggregation.•TTBK1 overexpression induced TDP-43 phosphorylation, formation of high molecular species, and mis-localization.•TTBK1 knock-down or pharmacological inhibition reduced TDP-43 pathology.•TTBK1 knock-down reduced TDP-43 overexpression-induced toxicity in iPSC neurons.
Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are ...available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor‐protein (MCP), C3 and factor B (CFB). At 5 years, death‐censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M‐TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence‐related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.
This study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence‐related graft loss.
Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. ...Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.
Summary
•
Reproductive traits are key characteristics for predicting the response of communities and ecosystems to global change.
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We used meta‐analysis to integrate data on eight reproductive ...traits from 159 CO 2 enrichment papers that provided information on 79 species.
•
Across all species, CO 2
enrichment (500–800 µl l
−1
) resulted in more flowers (+19%), more fruits (+18%), more seeds (+16%), greater individual seed mass (+4%), greater total seed mass (+25%), and lower seed nitrogen concentration, (N) (−14%). Crops and undomesticated (wild) species did not differ in total mass response to elevated CO
2
(+31%), but crops allocated more mass to reproduction and produced more fruits (+28% vs +4%) and seeds (+21% vs +4%) than did wild species when grown at high CO
2
. Seed N was not affected by high CO
2 concentrations in legumes, but declined significantly in most nonlegumes.
•
Our results provide robust estimates of average plant reproductive responses to CO 2
enrichment and demonstrate important differences among individual taxa and among functional groups. In particular, crops were more responsive to elevated CO
2 than were wild species. These differences and the substantial decline in seed N in many species have broad implications for the functioning of future natural and agro‐ecosystems.
Glaucoma is a leading cause of permanent vision loss and current drugs do not halt disease progression. Thus, new therapies targeting different drug targets with novel mechanisms of action are ...urgently needed. Previously, we identified CACNA2D1 as a novel modulator of intraocular pressure (IOP) and demonstrated that a topically applied CACNA2D1 antagonist—pregabalin (PRG)—lowered IOP in a dose-dependent manner. To further validate this novel IOP modulator as a drug target for IOP-lowering pharmaceutics, a homology model of CACNA2D1 was built and docked against the NCI library, which is one of the world’s largest and most diverse compound libraries of natural products. Acivicin and zoledronic acid were identified using this method and together with PRG were tested for their plausible IOP-lowering effect on Dutch belted rabbits. Although they have inferior potency to PRG, both of the other compounds lower IOP, which in turn validates CACNA2D1 as a valuable drug target in treating glaucoma.
Protein quality control is essential for clearing misfolded and aggregated proteins from the cell, and its failure is associated with many neurodegenerative disorders. Here, we identify two genes, ...ufd-2 and spr-5, that when inactivated, synergistically and robustly suppress neurotoxicity associated with misfolded proteins in Caenorhabditis elegans. Loss of human orthologs ubiquitination factor E4 B (UBE4B) and lysine-specific demethylase 1 (LSD1), respectively encoding a ubiquitin ligase and a lysine-specific demethylase, promotes the clearance of misfolded proteins in mammalian cells by activating both proteasomal and autophagic degradation machineries. An unbiased search in this pathway reveals a downstream effector as the transcription factor p53, a shared substrate of UBE4B and LSD1 that functions as a key regulator of protein quality control to protect against proteotoxicity. These studies identify a new protein quality control pathway via regulation of transcription factors and point to the augmentation of protein quality control as a wide-spectrum antiproteotoxicity strategy.
We prove a generalization of a theorem of Borel-Harish-Chandra on closed orbits of linear actions of reductive groups. Consider a real reductive algebraic group 𝐺 acting linearly and rationally on a ...real vector space 𝑉. The group 𝐺 can be viewed as the real points of a complex reductive group 𝐺C which acts on 𝑉 C := 𝑉 ⊗ C. In 2 it was shown that 𝐺C · 𝑣 ∩ 𝑉 is a finite union of 𝐺-orbits; moreover, 𝐺C · 𝑣 is closed if and only if 𝐺 · 𝑣 is closed, see 20. We show that the same result holds not just for closed orbits but for the so-called distinguished orbits. An orbit is called distinguished if it contains a critical point of the norm squared of the moment map on a projective space. Our main result compares the complex and real settings to show that 𝐺 · 𝑣 is distinguished if and only if 𝐺C · 𝑣 is distinguished.
In addition, we show that, if an orbit is distinguished, then under the negative gradient flow of the norm squared of the moment map, the entire 𝐺-orbit collapses to a single 𝐾-orbit. This result holds in both the complex and real settings.
We finish with applications to the study of left-invariant geometry of Lie groups; of particular interest are left-invariant Einstein and Ricci soliton metrics on solvable and nilpotent Lie groups. Using the above theorems, we obtain a procedure for recovering Ricci soliton metrics on nilpotent Lie groups.
This paper describes a new class of saturable absorber device based on single-wall carbon nanotube (SWNT)-the saturable absorber incorporating nano tube (SAINT). The device possesses ultrafast ...optical properties comparable to that of the industrial standard semiconductor saturable absorber mirror (SESAM). Passively mode-locked picosecond fiber lasers in different configurations are demonstrated using SAINTs as mode lockers. This is the first demonstration of optical pulsed lasers based on the carbon nanotube technology, and the first practical application of carbon nanotubes in the field of applied optics.
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