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HCFC1, a global transcriptional regulator, has been shown to associate with MMACHCexpression. Pathogenic variants in HCFC1cause X-linked combined methylmalonic acidemia and hyperhomocysteinemia, CblX type (MIM# 309541). Recent studies showed that certain variants in HCFC1are associated with X-linked intellectual disability with mild or absent metabolic abnormalities. Here, we report five subjects (three males, two females) from the same family with a novel predicted loss of function HCFC1variant. All five patients exhibit developmental delay or intellectual disability/learning difficulty and some dysmorphic features; findings were milder in the female as compared to male subjects. Biochemical studies in all patients did not show methylmalonic acidemia or hyperhomocysteinemia but revealed elevated vitamin B12 levels. Trio exome sequencing of the proband and his parents revealed a maternally inherited novel variant in HCFC1designated as c.1781_1803 + 3del26insCA (NM_005334). Targeted testing confirmed the presence of the same variant in two half-siblings and maternal great uncle. In silico analysis showed that the variant is expected to reduce the quality of the splice donor site in intron 10 and causes abnormal splicing. Sequencing of proband’s cDNA revealed exon 10 skipping. Further molecular studies in the two manifesting females revealed moderate and high skewing of X inactivation. Our results support previous observation that HCFC1variants located outside the Kelch domain exhibit dissociation of the clinical and biochemical phenotype and cause milder or no metabolic changes. We also show that this novel variant can be associated with a phenotype in females, although with milder severity, but further studies are needed to understand the role of skewed X inactivation among females in this rare disorder. Our work expands the genotypes and phenotypes associated with HCFC1-related disorder.

The advanced radiographic capability (ARC) laser system, part of the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory, is a short-pulse laser capability integrated into the NIF. The ARC is designed to provide adjustable pulse lengths of ∼1−38ps in four independent beamlets, each with energies up to 1 kJ (depending on pulse duration). A detailed model of the ARC lasers has been developed that predicts the time- and space-resolved focal spots on target for each shot. Measurements made to characterize static and dynamic wavefront characteristics of the ARC are important inputs to the code. Modeling has been validated with measurements of the time-integrated focal spot at the target chamber center (TCC) at low power, and the space-integrated pulse duration at high power, using currently available diagnostics. These simulations indicate that each of the four ARC beamlets achieves a peak intensity on target of up to a few 10^18W/cm^2.

We report on the design, performance, and qualification of the injection laser system designed to deliver joule-level chirped pulse beamlets arranged in dual rectangular beam formats into two main laser amplifier beamlines of the National Ignition Facility. The system is designed to meet the requirements of the Advanced Radiographic Capability upgrade with features that deliver performance, adjustability, and long-term reliability.

Inherited bone marrow failure syndromes (IBMFS) are a rare, heterogenous group of syndromes that are characterized by cytopenias, bone marrow hypocellularity, and in many cases an increased risk of transformation to myeloid malignancy. Presentation with severe pancytopenias at birth is reported but occurs very rarely, and more often neonatal pancytopenia is attributed to congenital and acquired infections or other acquired causes. We present the case of a preterm neonate with pancytopenia from birth and bone marrow failure of no known infectious, other acquired, or genetic etiology. Antenatal findings were notable for non-immune hydrops fetalis at 30 weeks of gestation prompting delivery. The initial laboratory evaluation revealed a normocytic, reticulocytopenic, severe anemia; leukopenia with an absolute neutrophil count of 500; and severe thrombocytopenia. Viral testing, including parvovirus, rubella, herpes simplex virus, cytomegalovirus, adenovirus, and enterovirus, was negative. Additional testing, including a chromosomal microarray, mitochondrial genome sequencing, chromosome stress testing, neonatal alloimmune thrombocytopenia panel, and telomere length analysis, was non-diagnostic. Bone marrow biopsy showed a remarkably hypoplastic marrow without evidence of dysplasia or cytogenetic abnormalities. The proband underwent matched unrelated donor hematopoietic stem cell transplant, and died approximately one month later from post-transplantation complications including hepatic veno-occlusive disease, thrombotic microangiopathy, CNS and pulmonary hemorrhages, pseudomonal sepsis, and multi-organ dysfunction. Autopsy was significant for microscopic pancreatic atrophy with lipomatous hypertrophy and osteopenia.

Dominant mutations in coding regions of the surfactant protein-C gene, SFTPC, cause respiratory distress syndrome (RDS) in infants. However, the contribution of variants in noncoding regions of SFTPC to pulmonary phenotypes is unknown. By using a case-control group of infants =34 weeks gestation (n = 538), we used complete resequencing of SFTPC and its promoter, genotyping, and logistic regression to identify 80 single nucleotide polymorphisms (SNPs). Three promoter SNPs were statistically associated with neonatal RDS among European descent infants. To assess the transcriptional effects of these three promoter SNPs, we selectively mutated the SFTPC promoter and performed transient transfection using MLE-15 cells and a firefly luciferase reporter vector. Each promoter SNP decreased SFTPC transcription. The combination of two variants in high linkage dysequilibrium also decreased SFTPC transcription. In silico evaluation of transcription factor binding demonstrated that the rare allele at g.-1167 disrupts a SOX (SRY-related high mobility group box) consensus motif and introduces a GATA-1 site, at g.-2385 removes a MZF-1 (myeloid zinc finger) binding site, and at g.-1647 removes a potential methylation site. This combined statistical, in vitro, and in silico approach suggests that reduced SFTPC transcription contributes to the genetic risk for neonatal RDS in developmentally susceptible infants.

Laser-induced growth of optical damage can limit component lifetime and, therefore, increase operating costs of large-aperture fusion-class laser systems. While far-infrared (IR) lasers have been used previously to treat laser damage on fused silica optics and render it benign, little is known about the effectiveness of less-absorbing mid-IR lasers for this purpose. In this study, we quantitatively compare the effectiveness and efficiency of mid-IR (4.6?μm) versus far-IR (10.6?μm) lasers in mitigating damage growth on fused silica surfaces. The nonlinear volumetric heating due to mid-IR laser absorption is analyzed by solving the heat equation numerically, taking into account the temperature-dependent absorption coefficient α(T) at λ=4.6?μm, while far-IR laser heating is well described by a linear analytic approximation to the laser-driven temperature rise. In both cases, the predicted results agree well with surface temperature measurements based on IR radiometry, as well as subsurface fictive temperature measurements based on confocal Raman microscopy. Damage mitigation efficiency is assessed using a figure of merit (FOM) relating the crack healing depth to laser power required, under minimally ablative conditions. Based on our FOM, we show that, for cracks up to at least 500?μm in depth, mitigation with a 4.6?μm mid-IR laser is more efficient than mitigation with a 10.6?μm far-IR laser. This conclusion is corroborated by direct application of each laser system to the mitigation of pulsed laser-induced damage possessing fractures up to 225?μm in depth.

The prevalence of the common mutations in the surfactant protein-B (121ins2), surfactant protein-C (I73T), and ATP-binding cassette member A3 (E292V) genes in population-based or case-control cohorts of newborn respiratory distress syndrome (RDS) is unknown. We determined the frequencies of these mutations in ethnically diverse population and disease-based cohorts using restriction enzyme analysis (121ins2 and E292V) and a 5′ nuclease assay (I73T) in DNA samples from population-based cohorts in Missouri, Norway, South Korea, and South Africa, and from a case–control cohort of newborns with and without RDS (n420). We resequenced the ATP-binding cassette member A3 gene (ABCA3) in E292V carriers and computationally inferred ABCA3haplotypes. The population-based frequencies of 121ins2, E292V, and I73T were rare (<0.4%). E292V was present in 3.8% of newborns with RDS, a 10-fold greater prevalence than in the Missouri cohort (p< 0.001). We did not identify other loss of function mutations in ABCA3among patients with E292V that would account for their RDS. E292V occurred on a unique haplotype that was derived from a recombination of two common ABCA3haplotypes. E292V was over-represented in newborns with RDS suggesting that E292V or its unique haplotype impart increased genetic risk for RDS.

Completely penetrant mutations in the surfactant protein B gene (SFTPB) and >75% reduction of SFTPB expression disrupt pulmonary surfactant function and cause neonatal respiratory distress syndrome. To inform studies of genetic regulation of SFTPB expression, we created a catalogue of SFTPB variants by comprehensive resequencing from an unselected, population-based cohort (n = 1,116). We found an excess of low-frequency variation [81 SNPs and five small insertion/deletions (in/dels)]. Despite its small genomic size (9.7 kb), SFTPB was characterized by weak linkage disequilibrium (LD) and high haplotype diversity. Using the HapMap Yoruban and European populations, we identified a recombination hot spot that spans SFTPB, was not detectable in our focused resequencing data, and accounts for weak LD. Using homology-based software tools, we discovered no definitively damaging exonic variants. We conclude that excess low-frequency variation, intragenic recombination and lack of common disruptive exonic variants favor complete resequencing as the optimal approach for genetic association studies to identify regulatory SFTPB variants that cause neonatal respiratory distress syndrome in genetically diverse populations.

The National Ignition Facility (NIF) is the world's largest laser system. It contains a 192 beam neodymium glass laser that is designed to deliver 1.8 MJ at 500 TW at 351 nm in order to achieve energy gain (ignition) in a deuterium-tritium nuclear fusion target. To meet this goal, laser design criteria include the ability to generate pulses of up to 1.8 MJ total energy, with peak power of 500 TW and temporal pulse shapes spanning 2 orders of magnitude at the third harmonic (351 nm or 3ω) of the laser wavelength. The focal-spot fluence distribution of these pulses is carefully controlled, through a combination of special optics in the 1ω (1053 nm) portion of the laser (continuous phase plates), smoothing by spectral dispersion, and the overlapping of multiple beams with orthogonal polarization (polarization smoothing). We report performance qualification tests of the first eight beams of the NIF laser. Measurements are reported at both 1ω and 3ω, both with and without focal-spot conditioning. When scaled to full 192 beam operation, these results demonstrate, to the best of our knowledge for the first time, that the NIF will meet its laser performance design criteria, and that the NIF can simultaneously meet the temporal pulse shaping, focal-spot conditioning, and peak power requirements for two candidate indirect drive ignition designs.

Efficient frequency doubling and tripling are critical to the successful operation of inertial confinement fusion laser systems such as the National Ignition Facility currently being constructed at the Lawrence Livermore National Laboratory and the Omega laser at the Laboratory for Laser Energetics. High-frequency conversion efficiency is strongly dependent on attainment of the phase-matching condition. In an ideal converter crystal, one can obtain the phase-matching condition throughout by angle tuning or temperature tuning of the crystal as a whole. In real crystals, imperfections in the crystal structure prohibit the attainment of phase matching at all locations in the crystal. We have modeled frequency doubling and tripling with a quantitative measure of this departure from phase matching in real crystals. This measure is obtained from interferometry of KDP and KD*P crystals at two orthogonal light polarizations.

We discuss the design and fabrication of 80-cm-diameter random phase plates for target-plane beam smoothing on the Nova laser. Random phase plates have been used in a variety of inertial confinement fusion target experiments, such as studying direct-drive hydrodynamic stability and producing spatially smooth x-ray backlighting sources. These phase plates were produced by using a novel sol-gel dip-coating technique developed by us. The sol-gel phase plates have a high optical damage threshold at the second- and third-harmonic wavelengths of the Nd:glass laser and have excellent optical performance.

High-powered glass-laser systems with multiple beams, frequency-conversion capabilities, and pulse-shaping flexibility have made numerous contributions to the understanding of inertial confinement fusion and related laser-plasma interactions. The Nova laser at Lawrence Livermore National Laboratory is the largest such laser facility. We have made improvements to the Nova amplifier system that permit increased power and energy output. We summarize the nonlinear effects that now limit Nova’s performance and discuss power and energy produced at 1.05-, 0.53-, and 0.35-μm wavelengths, including the results with pulses temporally shaped to improve inertial confinement fusion target performance.

We have constructed an optical parametric oscillator to generate 75-ps near-transform-limited pulses with wavelengths tunable about 1.053 μm for use in pump–probe studies of self-focusing. The singly resonant oscillator uses a Brewster-cut LiB_3O_5 crystal that is oriented for type-II phase matching and synchronously pumped by the amplified and frequency-tripled pulse trains from a mode-locked and Q-switched Nd:YLF laser. An intracavity Pockels cell is used to switch out single 0.5–MW pulses at rates of 1 to 10 Hz. The design, construction, and performance of the oscillator are discussed. Measured performance is compared with design predictions and with detailed numerical simulations.

To provide high-energy, high-power beams at short wavelengths for inertial-confinement fusion experiments, we routinely convert the 1.05-μm output of the Nova, Nd:phosphate-glass, laser system to its second- or third-harmonic wavelength. We describe the design and performance of the 3 × 3 arrays of potassium dihydrogen phosphate crystal plates used for type-II–type-II phase-matched harmonic conversion of the Nova 0.74-m diameter beams. We also describe an alternate type-I–type-II phase-matching configuration that improves third-harmonic conversion efficiency. These arrays provide conversion of a Nova beam of up to 75% to the second harmonic and of up to 70% to the third harmonic.