Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition

INTRODUCTION: Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. METHODS: We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). RESULTS: We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. CONCLUSION: Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology

Optical resonances on sub-wavelength silver lamellar gratings

Copyright © 2008 Optical Society of America. This paper was published in Optics Express and is made available as an electronic reprint with the permission of OSA. The paper can be found at the following URL on the OSA website: http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-26-22003 Systematic or multiple reproduction or distribution to multiple locations via electronic or other means is prohibited and is subject to penalties under law.The optical response of sub-wavelength silver lamellar gratings has been theoretically investigated. Two distinct types of resonance have been predicted for incident radiation with E-field perpendicular to the long axis of the wires. The first resonance has been identified as a cavity mode resonance that is associated with transmission enhancement. The second resonance has been identified as an entirely new horizontal plasmon resonance on the incident (and transmission) surfaces of the wires of the grating. Normal surface plasmon modes are investigated on discontinuous gratings, and their relation to those found on continuous gratings is highlighted by focusing on the perturbation effect of the discontinuities. It is shown that the new horizontal plasmon mode is in no way related to the well known diffractively coupled surface plasmon, and is shown to have a particle plasmon-like nature. It is therefore termed a horizontal particle plasmon, and may be either an uncoupled horizontal particle plasmon resonance (a 1-dimensional particle plasmon) or a coupled horizontal particle plasmon resonance (a 2-dimensional particle plasmon) depending on the height of the grating. It is shown that this resonance may result in a reflection efficiency that is very high, even when the grating would be optically thin if it were a homogeneous film, therefore, it behaves as an inverse wire grid polariser as it reflects more TM than TE incident radiation

Construing the child reader: a cognitive stylistic analysis of the opening to Neil Gaiman’s The Graveyard Book

Neil Gaiman’s The Graveyard Book (2009) charts the story of Nobody Owens, a boy who is adopted by supernatural entities in the local graveyard after his family is murdered. This article draws on the notion of the “construed reader,” and combines two cognitive stylistic frameworks to analyse the opening section of the novel. In doing so, the article explores the representation and significance of the family home in relation to what follows in the narrative. The analysis largely draws on Text World Theory (Werth, 1999; Gavins, 2007), but also integrates some aspects of Cognitive Grammar (Langacker, 2008), which allows for a more nuanced discussion of textual features. The article pays particular attention to the way Gaiman frames his narrative and positions his reader to view the fictional events from a distinctive vantage point and subsequently demonstrates that a stylistic analysis of children’s literature can lay bare how such writing is designed with a young readership in mind

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica

BACKGROUND:Two platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control. METHODOLOGY/ PRINCIPLE FINDINGS:Here we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 μM) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss. CONCLUSIONS/ SIGNIFICANCE:7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control

Ashfall Tephra in the Ogallala Group of the Great Plains: Characteristics and Significance

The Miocene Ogallala Group blankets the Great Plains east of the Rocky Mountains. This sheet of largely fluvial deposits, lying downwind of major silicic volcanic fields to the west, was ideally located to receive and preserve tephra from these fields. This investigation brings modern methods of tephrochronlogy to bear on the age and identity of Ogallala tephra. Results indicate that ~40 separate tephra layers, ranging in age from ~16.5–5.0 Ma, in the Ogallala. Most tephra came from Yellowstone hotspot sources. The relative frequency of hotspot tephra in the Ogallala matches that in more proximal regions to the west with peak intensities in the intervals ~16.5−15 Ma nd ~13.0−8.5 Ma. About 30 of the Ogallala tephra are correlated with tephra of known age the the Basin and Range to the west. Using the ages of correlative tephra to the west insight into the age of the Ogallala, the correlation of Ogallala tephra from region to region in the Great Plains, and sedimentation rates within the Ogallala. In the Ogallala sedimentation rates vary. The rates are lowest (3–9 m/Ma) in the Cap Rock Mbr. of the Ash Hollow Fm. along the Niobrara River and in undifferentiated Ogallala strata and in the undifferentiated Ogalala Gp. in NW Kansas. Rates of 40–80 m/Ma characterize the Valentine Fm. beneath the Cap Rock Mbr. Finally, one tephra, the 11.37 Ma Cougar Point Tuff XI, is recognized at 6 localies. This key horizon provides the first detailed structure contours within the Ogallala. These contours show a sharply increasing slope of the Ogallala west of 101° W that reflects the post–6 Ma tilt along the western edge of the Ogallala. East of 101º W the gradients mirror the gradients of the major rivers (1.3 to 1.6 m/km.). West of 101º W gradients increase and reach a maximun of 4.6 m/km at the crest of the Gangplank

Ashfall Tephra in the Ogallala Group of the Great Plains: Characteristics and Significance

The Miocene Ogallala Group blankets the Great Plains east of the Rocky Mountains. This sheet of largely fluvial deposits, lying downwind of major silicic volcanic fields to the west, was ideally located to receive and preserve tephra from these fields. This investigation brings modern methods of tephrochronlogy to bear on the age and identity of Ogallala tephra. Results indicate that ~40 separate tephra layers, ranging in age from ~16.5–5.0 Ma, in the Ogallala. Most tephra came from Yellowstone hotspot sources. The relative frequency of hotspot tephra in the Ogallala matches that in more proximal regions to the west with peak intensities in the intervals ~16.5−15 Ma nd ~13.0−8.5 Ma. About 30 of the Ogallala tephra are correlated with tephra of known age the the Basin and Range to the west. Using the ages of correlative tephra to the west insight into the age of the Ogallala, the correlation of Ogallala tephra from region to region in the Great Plains, and sedimentation rates within the Ogallala. In the Ogallala sedimentation rates vary. The rates are lowest (3–9 m/Ma) in the Cap Rock Mbr. of the Ash Hollow Fm. along the Niobrara River and in undifferentiated Ogallala strata and in the undifferentiated Ogalala Gp. in NW Kansas. Rates of 40–80 m/Ma characterize the Valentine Fm. beneath the Cap Rock Mbr. Finally, one tephra, the 11.37 Ma Cougar Point Tuff XI, is recognized at 6 localies. This key horizon provides the first detailed structure contours within the Ogallala. These contours show a sharply increasing slope of the Ogallala west of 101° W that reflects the post–6 Ma tilt along the western edge of the Ogallala. East of 101º W the gradients mirror the gradients of the major rivers (1.3 to 1.6 m/km.). West of 101º W gradients increase and reach a maximun of 4.6 m/km at the crest of the Gangplank

Oral Abstracts 7: RA ClinicalO37. Long-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or ΔmTSS ≤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMS—Provided Expert Advice, Undertaken Trials, AbbVie—AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis—Research Grants, Consultation Fees. S.F., AbbVie—Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB—Research Grants, Consultation Fees. H.K., AbbVie—Employee, Stocks. S.R., AbbVie—Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB—Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharma—Consultation Fees, Research Support. Table 1.Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response ADA + MTX, n/N (%)a PBO + MTX, n/N (%)b Outcome Week 26 Week 52 Week 78 Week 26 Week 52 Week 78 DAS28 (CRP) <3.2 246/466 (53) 304/465 (65) 303/465 (65) 139/460 (30)*** 284/460 (62) 300/460 (65) HAQ-DI <0.5 211/466 (45) 220/466 (47) 224/466 (48) 150/460 (33)*** 203/460 (44) 208/460 (45) ΔmTSS ≤0.5 402/462 (87) 379/445 (86) 382/443 (86) 330/459 (72)*** 318/440 (72)*** 318/440 (72)*** DAS28 (CRP) <3.2 + ΔmTSS ≤0.5 216/462 (47) 260/443 (59) 266/443 (60) 112/459 (24)*** 196/440 (45) 211/440 (48)*** DAS28 (CRP) <3.2 + HAQ-DI <0.5 + ΔmTSS ≤0.5 146/462 (32) 168/443 (38) 174/443 (39) 82/459 (18)*** 120/440 (27)*** 135/440 (31)** aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-squar

Perspectives on Non-Prescription Antibiotic Use among Hispanic Patients in the Houston Metroplex

BACKGROUND: Non-prescription antibiotic use includes taking an antibiotic without medical guidance (e.g., leftovers, from friends/relatives, or purchased without a prescription). Non-prescription use contributes to antimicrobial resistance, adverse drug reactions, interactions, superinfection, and microbiome imbalance. Qualitative studies exploring perspectives regarding non-prescription use among Hispanic patients are lacking. We used the Kilbourne Framework for Advancing Health Disparities Research to identify factors influencing patients\u27 non-prescription use and organize our findings. METHODS: Our study includes Hispanic primary care clinic patients with different types of health insurance coverage in the Houston metroplex who endorsed non-prescription use in a previous survey. Semistructured interviews explored the factors promoting non-prescription use in Hispanic adults. Interviews were conducted remotely, in English or Spanish, between May 2020 and October 2021. Inductive coding and thematic analysis identified motives for non-prescription use. RESULTS: Participants (n = 35) were primarily female (68.6%) and aged 27 to 66. Participants reported obtaining antibiotics through trusted persons, sold under-the-counter in US markets, and purchased without a prescription abroad. Factors contributing to non-prescription use included beliefs that the doctor visit was unnecessary, limited access to healthcare (due to insurance constraints, costs, and clinic wait times), and communication difficulties (e.g., language barriers with clinicians and perceived staff rudeness). Participants expressed confidence in medical recommendations from pharmacists and trusted community members. CONCLUSIONS: Patient, healthcare system, and clinical encounter factors contribute to non-prescription use in Hispanic communities. Antibiotic stewardship interventions that involve pharmacists and trusted persons, improve access to care, and address communication barriers and cultural competency in the clinic may help reduce non-prescription use in these communities