Genetic variation modifies risk for neurodegeneration based on biomarker status

Background: While a great deal of work has gone into understanding the relationship between CSF biomarkers, brain atrophy, and disease progression, less work has attempted to investigate how genetic variation modifies these relationships. The goal of this study was two-fold. First, we sought to identify high-risk v. low-risk individuals based on their CSF tau and Aβ load and characterize these individuals with regard to brain atrophy in an AD-relevant region of interest. Next, we sought to identify genetic variants that modified the relationship between biomarker classification and neurodegeneration.Methods: Participants were categorized based on established cut-points for biomarker positivity. Mixed model regression was used to quantify longitudinal change in the left inferior lateral ventricle. Interaction analyses between single nucleotide polymorphisms (SNPs) and biomarker group status were performed using a genome wide association study (GWAS) approach. Correction for multiple comparisons was performed using the Bonferroni procedure. Results: One intergenic SNP (rs4866650) and one SNP within the SPTLC1 gene (rs7849530) modified the association between amyloid positivity and neurodegeneration. A transcript variant of WDR11-AS1 gene (rs12261764) modified the association between tau positivity and neurodegeneration. These effects were consistent across the two sub-datasets and explained approximately 3% of variance in ventricular dilation. One additional SNP (rs6887649) modified the association between amyloid positivity and baseline ventricular volume, but was not observed consistently across the sub-datasets.Conclusions: Genetic variation modifies the association between AD biomarkers and neurodegeneration. Genes that regulate the molecular response in the brain to oxidative stress may be particularly relevant to neural vulnerability to the damaging effects of amyloid-β

Layered rare-earth hydroxides as multi-modal medical imaging probes: particle size optimisation and compositional exploration

Recently, layered rare-earth hydroxides (LRHs) have received growing attention in the field of theranostics. We have previously reported the hydrothermal synthesis of layered terbium hydroxide (LTbH), which exhibited high biocompatibility, reversible uptake of a range of model drugs, and release-sensitive phosphorescence. Despite these favourable properties, LTbH particles produced by the reported method suffered from poor size-uniformity (670 ± 564 nm), and are thus not suitable for therapeutic applications. To ameliorate this issue, we first derive an optimised hydrothermal synthesis method to generate LTbH particles with a high degree of homogeneity and reproducibility, within a size range appropriate for in vivo applications (152 ± 59 nm, n = 6). Subsequently, we apply this optimised method to synthesise a selected range of LRH materials (R = Pr, Nd, Gd, Dy, Er, Yb), four of which produced particles with an average size under 200 nm (Pr, Nd, Gd, and Dy) without the need for further optimisation. Finally, we incorporate Gd and Tb into LRHs in varying molar ratios (1 : 3, 1 : 1, and 3 : 1) and assess the combined magnetic relaxivity and phosphorescence properties of the resultant LRH materials. The lead formulation, LGd1.41Tb0.59H, was demonstrated to significantly shorten the T2 relaxation time of water (r2 = 52.06 mM−1 s−1), in addition to exhibiting a strong phosphorescence signal (over twice that of the other LRH formulations, including previously reported LTbH), therefore holding great promise as a potential multi-modal medical imaging probe

Mouse frontal cortex mediates additive multisensory decisions

The brain can combine auditory and visual information to localize objects. However, the cortical substrates underlying audiovisual integration remain uncertain. Here, we show that mouse frontal cortex combines auditory and visual evidence; that this combination is additive, mirroring behavior; and that it evolves with learning. We trained mice in an audiovisual localization task. Inactivating frontal cortex impaired responses to either sensory modality, while inactivating visual or parietal cortex affected only visual stimuli. Recordings from >14,000 neurons indicated that after task learning, activity in the anterior part of frontal area MOs (secondary motor cortex) additively encodes visual and auditory signals, consistent with the mice's behavioral strategy. An accumulator model applied to these sensory representations reproduced the observed choices and reaction times. These results suggest that frontal cortex adapts through learning to combine evidence across sensory cortices, providing a signal that is transformed into a binary decision by a downstream accumulator

Portable Curing Frame

A portable curing frame is provided particularly adapted for use with an automated tobacco harvester. The curing frame includes a substantially rectangular frame member including a series of slotted tracks, in the form of slotted tubes, specially designed for receiving a notched portion of the plant stalks. The slotted track is substantially continuous and thereby allows infinitely variable spacing between the plants and optimization of ventilation for air curing. Legs are also provided on the portable curing frame. The legs are displaceable between a retracted position allowing storage of the frames and loading of the frames with tobacco plants and an extended position for supporting the frames and inverted plants above the ground in the field. A locking mechanism is provided to positively retain the legs in both the retracted and extended positions. A triggering mechanism is also provided to release the locking mechanism and allow the legs to be displaced by gravity from the retracted position to the extended position. The tobacco-laden curing frame may be covered by plastic or other material and left in the field to cure. Once curing is completed the cured plants may be mechanically removed from the frames for optimum speed in handling the plants and bringing the tobacco to market

Gastroduodenal Ulcerations in Patients Receiving Selective Hepatic Artery Infusion Chemotherapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72124/1/j.1572-0241.1985.tb02137.x.pd

Tandem phosphorylation within an intrinsically disordered region regulates ACTN4 function

Phosphorylated residues occur preferentially in the intrinsically disordered regions of eukaryotic proteins. In the disordered amino-terminal region of human a-actinin-4 (ACTN4), Tyr[superscript 4] and Tyr[superscript 31] are phosphorylated in cells stimulated with epidermal growth factor (EGF), and a mutant with phosphorylation-mimicking mutations of both tyrosines exhibits reduced interaction with actin in vitro. Cleavage of ACTN4 by m-calpain, a protease that in motile cells is predominantly activated at the rear, removes the Tyr[superscript 4] site. We found that introducing a phosphomimetic mutation at only Tyr[superscript 31] was sufficient to inhibit the interaction with actin in vitro. However, molecular dynamics simulations predicted that Tyr[superscript 31] is mostly buried and that phosphorylation of Tyr[superscript 4] would increase the solvent exposure and thus kinase accessibility of Tyr[superscript 31]. In fibroblast cells, EGF stimulation increased tyrosine phosphorylation of a mutant form of ACTN4 with a phosphorylation-mimicking residue at Tyr[superscript 4], whereas a truncated mutant representing the product of m-calpain cleavage exhibited EGF-stimulated tyrosine phosphorylation at a background amount similar to that observed for a double phosphomimetic mutant of Tyr[superscript 4] and Tyr[superscript 31]. We also found that inhibition of the receptor tyrosine kinases of the TAM family, such as AXL, blocked EGF-stimulated tyrosine phosphorylation of ACTN4. Mathematical modeling predicted that the kinetics of phosphorylation at Tyr[superscript 31] can be dictated by the kinase affinity for Tyr[superscript 4]. This study suggests that tandem-site phosphorylation within intrinsically disordered regions provides a mechanism for a site to function as a switch to reveal a nearby function-regulating site.National Institutes of Health (U.S.) (Grant R01 GM69668

Examination of Post-Service Health-Related Quality of Life Among Rural and Urban Military Members of the Millennium Cohort Study

Little information exists on the health-related quality of life (HRQL) of U.S. veterans based on rural (versus urban) status, especially those in younger age groups, and whether deployment influences this outcome. We addressed these questions in the Millennium Cohort Study, a prospective investigation of U.S. military personnel assessed first in 2001 and then subsequently every three years via self-administered questionnaires. Participants separated from the military at the time of the most recent survey were eligible (n = 10,738). HRQL was assessed using the SF-36V Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Rural status was assigned from zip codes using the Rural-Urban Commuting Area classification. The mean age of participants was 35 years (SD = 8.98). Compared with urban dwellers, rural residents reported significantly lower unadjusted mean PCS (49.80 vs. 50.42) and MCS (49.97 vs. 50.81) scores, but differences became nonsignificant after covariate adjustment. No interaction was seen between deployment and rural status. Rural status is not independently associated with HRQL among recent U.S. veterans

Type 5 secretion system antigens as vaccines against Gram-negative bacterial infections

Infections caused by Gram-negative bacteria are leading causes of mortality worldwide. Due to the rise in antibiotic resistant strains, there is a desperate need for alternative strategies to control infections caused by these organisms. One such approach is the prevention of infection through vaccination. While live attenuated and heat-killed bacterial vaccines are effective, they can lead to adverse reactions. Newer vaccine technologies focus on utilizing polysaccharide or protein subunits for safer and more targeted vaccination approaches. One promising avenue in this regard is the use of proteins released by the Type 5 secretion system (T5SS). This system is the most prevalent secretion system in Gram-negative bacteria. These proteins are compelling vaccine candidates due to their demonstrated protective role in current licensed vaccines. Notably, Pertactin, FHA, and NadA are integral components of licensed vaccines designed to prevent infections caused by Bordetella pertussis or Neisseria meningitidis. In this review, we delve into the significance of incorporating T5SS proteins into licensed vaccines, their contributions to virulence, conserved structural motifs, and the protective immune responses elicited by these proteins