Do DH Librarians Need to Be in the Library?: DH Librarianship in Academic Units

Michigan State University sought to bolster digital humanities pedagogy and research by hiring two digital humanities specialists to work within disciplinary units. The two specialists hired, one at the College level and another situated between two departments, are both librarians by training. Over the past two years, these two specialists, Kristen Mapes and Brandon Locke, have been practicing digital humanities in disciplinary units in a manner that is heavily imbued with the values of librarianship. Mapes and Locke bring a focus on literacy, scholarly communication, sustainability, ethics, and access and serve as advocates for libraries and librarianship. This piece is intended to examine the value of librarianship in disciplinary units, and to illustrate benefits of deeply embedded librarianship nested within academic units - either through librarians as specialists, hybrid positions, or embedded librarianship. This piece is also a call for more partnerships where librarians are an expected part of the process and are engaged throughout the life of the course or research project. Digital humanities librarianship can succeed in any unit through active participation in courses, community-building activities, and individual research consultations, all while promoting the central values of librarianship and librarians throughout the process

Variants in WFS1 and Other Mendelian Deafness Genes are Associated with Cisplatin-Associated Ototoxicity

Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P=1.4x10-8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P=0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n=18,620 patients, Bonferroni adjusted P\u3c0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P-values in the GWAS (P=0.048). Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pre-therapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses

Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms

Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n= 762) were dichotomized to cases (moderate/severe tinnitus; n=154) and controls (none; n=608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in GWAS following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P=0.007) and cumulative cisplatin dose (P=0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared to 300 (P=0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P<0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P<0.0001), and reported more vertigo (OR=6.47; P<0.0001) and problems hearing in a crowd (OR=8.22; P<0.0001) than controls. Cases reported poorer health (P=0.0005) and greater psychotropic medication use (OR=2.4; P=0.003). GWAS suggested a variant near OTOS (rs7606353, P=2×10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P=0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q=0.007). Conclusions: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells

Ranger Subdivision Design

Ingenium, LLC is designing The Ranger Subdivision is a series of multi-family dwellings to be located on a 2.36 acres parcel in West Boise, northeast of the Wildwood Street and Fairview Avenue intersection. The subdivision’s design will maximize the number of dwelling units on the site along with associated parking spaces, and recreational features. The overall design will meet codes and requirements set by the federal, state, and local regulatory agencies. Structural floor plans, parking lots, and sidewalks will be designed in compliance with the American’s with Disabilities Act (ADA).The critical design tasks include utilities layout, and a transportation plan and roadway design, and structural and foundation design of a typical dwelling unit. The remaining key elements of the project include an environmental site assessment, stormwater runoff plan, stormwater pollution prevention plan and documentation of all applicable permitting

Structure–Function Analysis of the Non-Muscle Myosin Light Chain Kinase (nmMLCK) Isoform by NMR Spectroscopy and Molecular Modeling: Influence of <i>MYLK</i> Variants

<div><p>The <i>MYLK</i> gene encodes the multifunctional enzyme, myosin light chain kinase (MLCK), involved in isoform-specific non-muscle and smooth muscle contraction and regulation of vascular permeability during inflammation. Three <i>MYLK</i> SNPs (P21H, S147P, V261A) alter the N-terminal amino acid sequence of the non-muscle isoform of MLCK (nmMLCK) and are highly associated with susceptibility to acute lung injury (ALI) and asthma, especially in individuals of African descent. To understand the functional effects of SNP associations, we examined the N-terminal segments of nmMLCK by ¹H-¹⁵N heteronuclear single quantum correlation (HSQC) spectroscopy, a 2-D NMR technique, and by <i>in silico</i> molecular modeling. Both NMR analysis and molecular modeling indicated SNP localization to loops that connect the immunoglobulin-like domains of nmMLCK, consistent with minimal structural changes evoked by these SNPs. Molecular modeling analysis identified protein-protein interaction motifs adversely affected by these <i>MYLK</i> SNPs including binding by the scaffold protein 14-3-3, results confirmed by immunoprecipitation and western blot studies. These structure-function studies suggest novel mechanisms for nmMLCK regulation, which may confirm <i>MYLK</i> as a candidate gene in inflammatory lung disease and advance knowledge of the genetic underpinning of lung-related health disparities.</p></div

Selection of the N-terminal segments of nmMLCK1.

<p>The segment of 1-494aa was initially selected for protein expression within the N-terminal sequence of nmMLCK1, containing three ALI-associated SNPs and two phosphorylatable Tyr sites, Y464 and Y471. This sequence generates a protein of ca. 53 kDa, within a suitable range of size for practical bacterial protein expression and survived preliminary NMR trials. Included in this ca. 500aa protein are three immunoglobulin C-2 type (IGc2) domains and a low-complexity region (preceding the 3rd IGc2 domain) as predicted by SMART. Subsequently, a shorter 1-264aa segment of ca. 28 kDa was also generated spanning the three ALI-associated SNPs (two IGc2 domains) and exhibited advantages for NMR-based structural determination.</p