2024 GLA Advocacy Division Update

Updates from the Georgia Library Association\u27s Advocacy Division, including Print Day at the Capitol and Legislative Updates

A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient Cavalier King Charles Spaniels is amenable to exon 51 skipping

BACKGROUND Duchenne muscular dystrophy (DMD), which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion "hot spot" is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD) model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD "hot spot". METHODOLOGY/PRINCIPAL FINDINGS Here we describe the severe phenotype, histopathological findings, and molecular analysis of Cavalier King Charles Spaniels with dystrophin-deficient muscular dystrophy (CKCS-MD). The dogs harbour a missense mutation in the 5' donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein. Antisense oligonucleotide-mediated skipping of exon 51 in cultured myoblasts from an affected dog restored the reading frame and protein expression. CONCLUSIONS/SIGNIFICANCE Given the small size of the breed, the amiable temperament and the nature of the mutation, we propose that CKCS-MD is a valuable new model for clinical trials of antisense oligonucleotide-induced exon skipping and other therapeutic approaches for DMD

Evidence for a Partially Stalled γ Rotor in F

F1-ATPase uses ATP hydrolysis to drive rotation of the γ subunit. The γ C-terminal helix constitutes the rotor tip that is seated in an apical bearing formed by α3β3. It remains uncertain to what extent the γ conformation during rotation differs from that seen in rigid crystal structures. Existing models assume that the entire γ subunit participates in every rotation. Here we interrogated E. coli F1-ATPase by hydrogen-deuterium exchange (HDX) mass spectrometry. Rotation of γ caused greatly enhanced deuteration in the γ C-terminal helix. The HDX kinetics implied that most F1 complexes operate with an intact rotor at any given time, but that the rotor tip is prone to occasional unfolding. A molecular dynamics (MD) strategy was developed to model the off-axis forces acting on γ. MD runs showed stalling of the rotor tip and unfolding of the γ C-terminal helix. MD-predicted H-bond opening events coincided with experimental HDX patterns. Our data suggest that in vitro operation of F1-ATPase is associated with significant rotational resistance in the apical bearing. These conditions cause the γ C-terminal helix to get stuck (and unfold) sporadically while the remainder of γ continues to rotate. This scenario contrasts the traditional greasy bearing model that envisions smooth rotation of the γ C-terminal helix. The fragility of the apical rotor tip in F1-ATPase is attributed to the absence of a c10 ring that stabilizes the rotation axis in intact FoF1. Overall, the MD/HDX strategy introduced here appears well suited for interrogating the inner workings of molecular motors

Effect of Liquidity on Performance of Deposit Money Banks

The study examines the effect of liquidity management on the performance of DMBs in Nigeria. The objective of the study is to determine the extent of relationship that exists between liquidity mechanism and DMBs performance in Nigeria from 2000 to 2015. The study employs Augmented Dickey Fuller Unit Root Test, OLS regression and Granger Causality. The result of the study revealed that liquidity mechanism is not significantly related to DMBs performance in the short run and long run. The granger result proves that liquidity mechanism hinder DMBs performance within the period under review in the study. Hence, the study recommends that DMBs should be given leverage of plugging back funds into investment to booster profitability while maintaining a level of liquidity ratio. Keywords: DMBs, Liquidity, Banks Performanc

Bank Credit and Economic Growth in a Recessed Economy

The study examines the extent to which Bank Credit relates to economic growth in a recessed economy. The objective of the study is to determine the extent of relationship that exist between Bank Credit and economic growth of selected Small Scale Enterprises in Nigeria from 1992 to 2015. The study employs Philip-Peron and Augmented Dickey Fuller Unit Root Test, Johansen Co-integration, OLS regression and Granger Causality. The result of the study revealed that Bank credit to Small Scale Enterprises significantly related to economic growth in the short run and long run. Hence, the study recommends that Bank Credit to Small Scale Enterprises should be increased to grow the economy like the developed economy that thrives on Small Scale Enterprises. Keywords: Bank Credit, Small Scale enterprises, GD

PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy

Pancreatic ductal adenocarcinoma (PDAC) is considered a non‐immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD‐L1 expression in a JAK/Stat1‐dependent manner. In vitro, PD‐L1 inhibition did not alter radio‐ and chemosensitivity. In vivo, addition of anti‐PD‐L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD‐L1 blockade was associated with reduced CD11b+Gr1+ myeloid cell infiltration and enhanced CD45+CD8+ T‐cell infiltration with concomitant upregulation of T‐cell activation markers including CD69, CD44, and FasL, and increased CD8:Treg ratio. Depletion of CD8+ T cells abrogated radiosensitization by anti‐PD‐L1. Blockade of PD‐L1 further augmented the effect of high RT doses (12 Gy) in preventing development of liver metastases. Exploring multiple mathematical models reveals a mechanism able to explain the observed synergy between RT and anti‐PD‐L1 therapy. Our findings provide a rationale for testing the use of immune checkpoint inhibitors with RT in PDAC

The Locust Standard Brain: A 3D Standard of the Central Complex as a Platform for Neural Network Analysis

Many insects use the pattern of polarized light in the sky for spatial orientation and navigation. We have investigated the polarization vision system in the desert locust. To create a common platform for anatomical studies on polarization vision pathways, Kurylas et al. (2008) have generated a three-dimensional (3D) standard brain from confocal microscopy image stacks of 10 male brains, using two different standardization methods, the Iterative Shape Averaging (ISA) procedure and the Virtual Insect Brain (VIB) protocol. Comparison of both standardization methods showed that the VIB standard is ideal for comparative volume analysis of neuropils, whereas the ISA standard is the method of choice to analyze the morphology and connectivity of neurons. The central complex is a key processing stage for polarization information in the locust brain. To investigate neuronal connections between diverse central-complex neurons, we generated a higher-resolution standard atlas of the central complex and surrounding areas, using the ISA method based on brain sections from 20 individual central complexes. To explore the usefulness of this atlas, two central-complex neurons, a polarization-sensitive columnar neuron (type CPU1a) and a tangential neuron that is activated during flight, the giant fan-shaped (GFS) neuron, were reconstructed 3D from brain sections. To examine whether the GFS neuron is a candidate to contribute to synaptic input to the CPU1a neuron, we registered both neurons into the standardized central complex. Visualization of both neurons revealed a potential connection of the CPU1a and GFS neurons in layer II of the upper division of the central body

Resident Training Curriculum in Adolescent Depression and Suicide Screening

Introduction: Routine screening of adolescents for depression and suicide risk is now considered best clinical practice. However, due to a lack of training, many physicians do not engage in screening. The goal of this curriculum is to improve learner knowledge of and comfort in adolescent depression and suicide risk assessment and management. Methods: The didactic session typically takes 60-90 minutes to complete. In addition to a teaching PowerPoint that provides instruction in both the assessment and management of adolescent depression and suicide risk, the curriculum also includes a suicide assessment and management protocol. This protocol outlines an algorithm that assists in distinguishing between individuals at high and low risk of suicide. The algorithm enables clinicians to determine the most appropriate management plan based on the assessed level of suicide risk. Results: Outcome measures indicate that the majority of residents improved their self-perceived knowledge and comfort in assessing and managing depression and suicide risk, with an average of 61.7% of residents moving from the novice to the proficient group at the conclusion of the rotation. These results reflect learners obtaining 4 weeks of supervised clinical experience after the didactic session. Discussion: This curriculum was designed for use with pediatric and internal medicine–pediatric residents during their adolescent medicine rotation but could easily be adapted for use with other learners in different settings