Hydrologic Resources Management Program and Underground Test Area Project FY2005 Progress Report

This report describes FY 2005 technical studies conducted by the Chemical Biology and Nuclear Science Division (CBND) at Lawrence Livermore National Laboratory (LLNL) in support of the Hydrologic Resources Management Program (HRMP) and the Underground Test Area Project (UGTA). These programs are administered by the U.S. Department of Energy, National Nuclear Security Administration, Nevada Site Office (NNSA/NSO) through the Defense Programs and Environmental Restoration Divisions, respectively. HRMP-sponsored work is directed toward the responsible management of the natural resources at the Nevada Test Site (NTS), enabling its continued use as a staging area for strategic operations in support of national security. UGTA-funded work emphasizes the development of an integrated set of groundwater flow and contaminant transport models to predict the extent of radionuclide migration from underground nuclear testing areas at the NTS. The report is organized on a topical basis and contains five chapters that highlight technical work products produced by CBND. However, it is important to recognize that most of this work involves collaborative partnerships with the other HRMP and UGTA contract organizations. These groups include the Energy and Environment Directorate at LLNL (LLNL-E&E), Los Alamos National Laboratory (LANL), the Desert Research Institute (DRI), the U.S. Geological Survey (USGS), Stoller-Navarro Joint Venture (SNJV), and Bechtel Nevada (BN)

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

\ua9 The Author(s) 2024.In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery

An Evaluation of Innovative Transportation Financing Techniques for Indiana

Innovative financing techniques can complement current methods of financing highway projects in Indiana. Annual federal apportionments and Indiana state revenues are not sufficient to maintain and improve state highways, so innovative approaches in transportation project financing should be sought. There are several available innovative financing techniques associated with the use of federal funds. Although, they do not provide new sources of revenue and cannot create enough funds for all identified projects, they provide flexibility in the use of available funds that can expedite the implementation of individual projects. The main objective of this study was to evaluate the major innovative financing techniques associated with federal funds, and their applicability for transportation projects in Indiana. The legal, financial, and operational issues of various alternatives were examined, and the economic impacts were investigated in terms of user benefits and debt service of the transportation agency. Possible revenue sources for debt service payment also were identified, and from a legal perspective, factors such as eligibility, authorization parties, and administration of financing assistance were addressed. Innovative financing techniques considered in the study include: the Test and Evaluation Project 045 (TE-045 program), Grant Anticipation Revenue Vehicle Bonds (GARVEE), the Transportation Infrastructure Finance and Innovation Act (TIFIA), and the State Infrastructure Bank (SIB). Four actual INDOT projects were used as case studies in the analysis. The study provides a framework for the evaluation of the use of innovative financing techniques described in this report. With detailed project specific data project-by-project analysis can be done to find the optimal solution for individual project financing

Clinical Evaluation of Pink Esthetic Score of Immediately Impressed Posterior Dental Implants

Purpose: While comparative outcome results for peri-implant crestal bone levels, mucosal margin position, and peri-implant indices have been reported, no studies are available that evaluate and compare the esthetic result of impressions performed immediately at implant placement with that of impressions performed on healed implants. The purpose of this cross-sectional study was to evaluate the pink esthetic score of posterior implants restored with an immediate impression workflow compared to implants restored with a delayed impression workflow. Material and Methods: Twenty-eight eligible participants who had received a single implant crown either in the premolar or molar regions at least 4 months before the study, were identified by an electronic health record review and scheduled for a single-visit study appointment. Esthetic outcomes were measured using the pink esthetic score. Several local- and prosthesis-related factors were recorded and their association with the selected outcome was assessed. Two-sample t-test was used for comparisons between the groups. Results: Pink esthetic score ranged between 4 and 12 (mean: 8). No significant difference between immediate (8.36 ±1.12) and delayed (7.76 ±2.14) impression workflow groups were seen for the total PES (p = 0.25). In addition, individual comparisons between immediately and delayed impressed implants for mesial papilla (1.27 ±0.47; 0.88 ±0.78), distal papilla (0.73 ±0.65; 0.76 ±0.83), tissue margin (1.73 ±0.47; 1.47 ±0.51), tissue contour (1.27 ±0.65; 0.82 ±0.64), alveolar process (0.82 ±0.60; 1.00 ±0.87), color (1.27 ±0.65; 1.29 ±0.69), and texture (1.36 ±0.50; 1.53 ±0.62) did not show significant differences. Conclusions: The current study suggests that the pink esthetic score is not significantly different between single posterior implants impressed with immediate and delayed implant workflows