The synthesis of a differentially protected oxygenated pyrroline nitrone and its application in routes to hyacinthacine family alkaloids

Glycosidases are involved in a range of important biological processes. The possibility of blocking or modifying these processes using glycosidase-inhibiting sugar mimics for therapeutic or biotechnological applications has attracted much interest. This may have significance in the treatment of cancer, viral infections, diabetes and obesity. Iminosugars are analogues of mono- or disaccharides where the ring oxygen is replaced by a nitrogen atom. These compounds include polyhydroxylated derivatives of monocyclic structures such as piperidines and pyrrolizidines, and also of bicyclic structures such as indolizidines and pyrrolizidines. Routes to nitrone 190 from L-xylose and D-arabinose were explored and the application of nitrone 190 towards the synthesis to hyacinthacine A1 and hyacinthacine B2 were investigated. The differential protection of the C-3 position of nitrone 190 meant that this position would be selectively deprotected after cycloaddition, liberating the C-1 hydroxyl group (hyacinthacine numbering) as a site for inversion. Inversion of the hydroxyl group would then provide the required stereochemical outcome for hyacinthacines A1 and B2, where the stereochemistry at C-1 and C-2 is ci

Caspase-3 Is Transiently Activated without Cell Death during Early Antigen Driven Expansion of CD8+ T Cells In Vivo

Background: CD8 + T cell responses develop rapidly during infection and are swiftly reduced during contraction, wherein.90 % of primed CD8 + T cells are eliminated. The role of apoptotic mechanisms in controlling this rapid proliferation and contraction of CD8 + T cells remains unclear. Surprisingly, evidence has shown non-apoptotic activation of caspase-3 to occur during in vitro T-cell proliferation, but the relevance of these mechanisms to in vivo CD8 + T cell responses has yet to be examined. Methods and Findings: We have evaluated the activity of caspase-3, a key downstream inducer of apoptosis, throughout the entirety of a CD8 + T cell response. We utilized two infection models that differ in the intensity, onset and duration of antigen-presentation and inflammation. Expression of cleaved caspase-3 in antigen specific CD8 + T cells was coupled to the timing and strength of antigen presentation in lymphoid organs. We also observed coordinated activation of additional canonical apoptotic markers, including phosphatidylserine exposure. Limiting dilution analysis directly showed that in the presence of IL7, very little cell death occurred in both caspase-3 hi and caspase-3 low CD8 + T cells. The expression of active caspase-3 peaked before effector phenotype (CD62L low) CD8 + T cells emerged, and was undetectable in effector-phenotype cells. In addition, OVA-specific CD8 + cells remained active caspase-3 low throughout the contraction phase. Conclusions: Our results specifically implicate antigen and not inflammation in driving activation of apoptotic mechanisms without cell death in proliferating CD8 + T cells. Furthermore, the contraction of CD8 + T cell response following expansion i

Blacksmith Fork - Little Bear Watershed Alternative Futures Study

The following project was carried out in conjunction with the Logan River Task Force, under the chairmanship of Dr. Frank Howe. The Logan River Task Force was formed to develop an overall approach for managing the Logan River that balances ecology with people\u27s social values for the river including public safety and property protection. Although the work of the Task Force has focused primarily on the Logan river, the Bioregional Planning graduate students have provided the Task Force with contextual information about the watershed, by exploring alternative futures for the Blacksmith Fork and Little Bear watersheds. This work expands on a previous bioregional planning study of the Logan, Blacksmith Fork and Little Bear watersheds that was carried out by bioregional planning students, Aubrey Christensen and Lyndi Perry in 2014-15. This report represents work that graduate students accomplished during two semesters (Fall 2015- Spring 2016) of the Master of Bioregional Planning (MsBRP) program at Utah State University. During the Fall semester, the MsBRP students collaborated with graduate students in the Landscape Architecture program to develop scenarios that addressed future growth in a portion of the study area, southern Cache Valley. Together they prepare and participate in a Geodesign workshop with community members, experts, faculty at USU. (For an overview of the workshop see the report: South Cache Valley Project- Planning with Geodesign, 2015.) The results of the workshop informed the landscape analysis, and ultimately the alternative futures that were developed for the Blacksmith Fork and Little Bear watersheds.https://digitalcommons.usu.edu/laep_bioregional/1000/thumbnail.jp

Probing magnetic order in EELS of chromite spinels using both multiple scattering (FEFF8.2) and DFT (WIEN2k)

The electron energy loss near edge structure on the O K-edge from chromite spinels contains fine structure from the hybridisation of the O p-orbitals and the Cr d-orbitals. Unlike the aluminates, a non-spin polarised calculation of this fine structure differs significantly from experimental observations. This is due to the large magnetic moment on the Cr. Calculations using simplified collinear ordering of the spins and the local spin density approximation give much improved agreement. A real space multiple scattering formalism and a reciprocal space density functional formalism give results in substantial agreement. In general, the actual spin arrangement of these chromites is not known since they are typically frustrated magnetic systems with ordering temperatures in the 10–20 K range. The calculations are based on the hypothesis that dynamic short range order persists to room temperature over the time scale of the interaction with the fast electron. However, it is possible that the observed effects are due to the strong paramagnetism present at room temperatures but which it is not possible to simulate accurately at present

Non-contrast renal magnetic resonance imaging to assess perfusion and corticomedullary differentiation in health and chronic kidney disease

AIMS Arterial spin labelling (ASL) MRI measures perfusion without administration of contrast agent. While ASL has been validated in animals and healthy volunteers (HVs), application to chronic kidney disease (CKD) has been limited. We investigated the utility of ASL MRI in patients with CKD. METHODS We studied renal perfusion in 24 HVs and 17 patients with CKD (age 22-77 years, 40% male) using ASL MRI at 3.0T. Kidney function was determined using estimated glomerular filtration rate (eGFR). T1 relaxation time was measured using modified look-locker inversion and xFB02;ow-sensitive alternating inversion recovery true-fast imaging and steady precession was performed to measure cortical and whole kidney perfusion. RESULTS T1 was higher in CKD within cortex and whole kidney, and there was association between T1 time and eGFR. No association was seen between kidney size and volume and either T1, or ASL perfusion. Perfusion was lower in CKD in cortex (136 ± 37 vs. 279 ± 69 ml/min/100 g; p < 0.001) and whole kidney (146 ± 24 vs. 221 ± 38 ml/min/100 g; p < 0.001). There was significant, negative, association between T1 longitudinal relaxation time and ASL perfusion in both the cortex (r = -0.75, p < 0.001) and whole kidney (r = -0.50, p < 0.001). There was correlation between eGFR and both cortical (r = 0.73, p < 0.01) and whole kidney (r = 0.69, p < 0.01) perfusion. CONCLUSIONS Significant differences in renal structure and function were demonstrated using ASL MRI. T1 may be representative of structural changes associated with CKD; however, further investigation is required into the pathological correlates of reduced ASL perfusion and increased T1 time in CKD

Programmable Attenuation of Antigenic Sensitivity for a Nanobody-Based EGFR Chimeric Antigen Receptor Through Hinge Domain Truncation

Epidermal growth factor family receptor (EGFR) is commonly overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR)-T therapy, but as EGFR is also expressed at lower levels in healthy tissues a therapeutic strategy must balance antigenic responsiveness against the risk of on-target off-tumor toxicity. Herein, we identify several camelid single-domain antibodies (also known as nanobodies) that are effective EGFR targeting moieties for CARs (EGFR-sdCARs) with very strong reactivity to EGFR-high and EGFR-low target cells. As a strategy to attenuate their potent antigenic sensitivity, we performed progressive truncation of the human CD8 hinge commonly used as a spacer domain in many CAR constructs. Single amino acid hinge-domain truncation progressively decreased both EGFR-sdCAR-Jurkat cell binding to EGFR-expressing targets and expression of the CD69 activation marker. Attenuated signaling in hinge-truncated EGFR-sdCAR constructs increased selectivity for antigen-dense EGFR-overexpressing cells over an EGFR-low tumor cell line or healthy donor derived EGFR-positive fibroblasts. We also provide evidence that epitope location is critical for determining hinge-domain requirement for CARs, as hinge truncation similarly decreased antigenic sensitivity of a membrane-proximal epitope targeting HER2-CAR but not a membrane-distal EGFRvIII-specific CAR. Hinge-modified EGFR-sdCAR cells showed clear functional attenuation in Jurkat-CAR-T cells and primary human CAR-T cells from multiple donors in vitro and in vivo. Overall, these results indicate that hinge length tuning provides a programmable strategy for throttling antigenic sensitivity in CARs targeting membrane-proximal epitopes, and could be employed for CAR-optimization and improved tumor selectivity

Domestic horses (Equus caballus) discriminate between negative and positive human nonverbal vocalisations

The ability to discriminate between emotion in vocal signals is highly adaptive in social species. It may also be adaptive for domestic species to distinguish such signals in humans. Here we present a playback study investigating whether horses spontaneously respond in a functionally relevant way towards positive and negative emotion in human nonverbal vocalisations. We presented horses with positively- and negatively-valenced human vocalisations (laughter and growling, respectively) in the absence of all other emotional cues. Horses were found to adopt a freeze posture for significantly longer immediately after hearing negative versus positive human vocalisations, suggesting that negative voices promote vigilance behaviours and may therefore be perceived as more threatening. In support of this interpretation, horses held their ears forwards for longer and performed fewer ear movements in response to negative voices, which further suggest increased vigilance. In addition, horses showed a right-ear/left-hemisphere bias when attending to positive compared with negative voices, suggesting that horses perceive laughter as more positive than growling. These findings raise interesting questions about the potential for universal discrimination of vocal affect and the role of lifetime learning versus other factors in interspecific communication

Spectroscopic indications of tunnel barrier charging as the switching mechanism in memristive devices

Resistive random access memory is a promising, energy-efficient, low-power “storage class memory” technology that has the potential to replace both flash storage and on-chip dynamic memory. While the most widely employed systems exhibit filamentary resistive switching, interface-type switching systems based on a tunable tunnel barrier are of increasing interest. They suffer less from the variability induced by the stochastic filament formation process and the choice of the tunnel barrier thickness offers the possibility to adapt the memory device current to the given circuit requirements. Heterostructures consisting of a yttria-stabilized zirconia (YSZ) tunnel barrier and a praseodymium calcium manganite (PCMO) layer are employed. Instead of spatially localized filaments, the resistive switching process occurs underneath the whole electrode. By employing a combination of electrical measurements, in operando hard X-ray photoelectron spectroscopy and electron energy loss spectroscopy, it is revealed that an exchange of oxygen ions between PCMO and YSZ causes an electrostatic modulation of the effective height of the YSZ tunnel barrier and is thereby the underlying mechanism for resistive switching in these devices

Tamm Review: Management of mixed-severity fire regime forests in Oregon, Washington, and Northern California

Increasingly, objectives for forests with moderate- or mixed-severity fire regimes are to restore successionally diverse landscapes that are resistant and resilient to current and future stressors. Maintaining native species and characteristic processes requires this successional diversity, but methods to achieve it are poorly explained in the literature. In the Inland Pacific US, large, old, early seral trees were a key historical feature of many young and old forest successional patches, especially where fires frequently occurred. Large, old trees are naturally fire-tolerant, but today are often threatened by dense understory cohorts that create fuel ladders that alter likely post-fire successional pathways. Reducing these understories can contribute to resistance by creating conditions where canopy trees will survive disturbances and climatic stressors; these survivors are important seed sources, soil protectors, and critical habitat elements. Historical timber harvesting has skewed tree size and age class distributions, created hard edges, and altered native patch sizes. Manipulating these altered forests to promote development of larger patches of older, larger, and more widely-spaced trees with diverse understories will increase landscape resistance to severe fires, and enhance wildlife habitat for underrepresented conditions. Closed-canopy, multi-layered patches that develop in hot, dry summer environments are vulnerable to droughts, and they increase landscape vulnerability to insect outbreaks and severe wildfires. These same patches provide habitat for species such as the northern spotted owl, which has benefited from increased habitat area. Regional and local planning will be critical for gauging risks, evaluating trade-offs, and restoring dynamics that can support these and other species. The goal will be to manage for heterogeneous landscapes that include variably-sized patches of (1) young, middle-aged, and old, closed canopy forests growing in upper montane, northerly aspect, and valley bottom settings, (2) a similar diversity of open-canopy, fire-tolerant patches growing on ridgetops, southerly aspects, and lower montane settings, and (3) significant montane chaparral and grassland areas. Tools to achieve this goal include managed wildfire, prescribed burning, and variable density thinning at small to large scales. Specifics on ‘‘how much and where?” will vary according to physiographic, topographic and historical templates, and regulatory requirements, and be determined by means of a socio-ecological process