Evaluating Sedimentary Geochemical Lake-Level Tracers in Walker Lake, Nevada, Over the Last 200 Years

Walker Lake, a hydrologically closed, saline, alkaline lake located along the western margin of the Great Basin of western United States, has experienced a 77% reduction in volume and commitment drop in lake level as a result of anthropogenic perturbations and climatic fluctuations over the last century. The history of lake-level change in Walker Lake has been recorded instrumentally since 1860. A high-resolution multi-proxy sediment core record from Walker Lake has been generated through analysis of total inorganic carbon (TIC), total organic carbon (TOC), and oxygen and carbon isotope ratios (δ18O and δ13 C) of both downcore bulk TIC and ostracods over the last 200 yr. This allows us to examine how these sediment indices respond to actual changes in this lake’s hydrologic balance at interannual to decadal timescales. In Walker Lake sediments, changes in %TIC, %TOC, and δ13C and δ18O of TIC and ostracods are all associated to varying degrees with changes in the lake’s hydrologic balance, with δ18O of the TIC fraction (δ18OTIC) being the most highly correlated and the most effective hydrologic indicator in this closed-basin lake. The δ18OTIC record from Walker Lake nearly parallels the instrumental lake-level record back to 1860. However, comparison with sporadic lake-water δ18O and dissolved inorganic carbon δ13C (δ13CDIC) results spanning the last several decades suggests that the isotopic values of downcore carbonate sediments may not be readily translated into absolute or even relative values of corresponding lake-water δ18O and δ13CDIC. Changes in the lake’s hydrologic balance usually lead to changes in isotopic composition of lake waters and downcore sediments, but not all the variations in downcore isotopic composition are necessarily caused by hydrologic changes

Late Holocene Lake-Level Fluctuations in Walker Lake, Nevada, USA

alker Lake, a hydrologically closed, saline, and alkaline lake, is situated along the western margin of the Great Basin in Nevada of the western United States. Analyses of the magnetic susceptibility (χ), total inorganic carbon (TIC), and oxygen isotopic composition (δ18O) of carbonate sediments including ostracode shells (Limnocythere ceriotuberosa) from Walker Lake allow us to extend the sediment record of lake-level fluctuations back to 2700 years B.P. There are approximately five major stages over the course of the late Holocene hydrologic evolution in Walker Lake: an early lowstand (\u3e 2400 years B.P.), a lake-filling period (∼ 2400 to ∼ 1000 years B.P.), a lake-level lowering period during the Medieval Warm Period (MWP) (∼ 1000 to ∼ 600 years B.P.), a relatively wet period (∼ 600 to ∼ 100 years B.P.), and the anthropogenically induced lake-level lowering period (\u3c 100 years B.P.). The most pronounced lowstand of Walker Lake occurred at ∼ 2400 years B.P., as indicated by the relatively high values of δ18O. This is generally in agreement with the previous lower resolution paleoclimate results from Walker Lake, but contrasts with the sediment records from adjacent Pyramid Lake and Siesta Lake. The pronounced lowstand suggests that the Walker River that fills Walker Lake may have partially diverted into the Carson Sink through the Adrian paleochannel between 2700 to 1400 years B.P

Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of \u3ci\u3eFOXP1\u3c/i\u3e

Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G\u3eA (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation that does not result in cytoplasmic or nuclear aggregation of the protein but maintains normal nuclear localization

Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing developmen

Newborn screening for Pompe disease in Illinois: Experience with 684,290 infants

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing

Molecular basis of FIR-mediated c-myc transcriptional control

The far upstream element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR), which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment, showing that the tandem RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system precisely regulates c-myc transcription and suggest that a small change in FBP-FIR affinity leads to a substantial effect on c-Myc concentration.MRC Grant-in-aid U11757455

A Comparison of Components of Written Expression Abilities in Learning Disabled and Non-Learning Disabled Students at Three Grade Levels

Although written language plays a critical role in academic success, little empirical evidence exists on the normal development of processes involved in producing written products. Even less is known about the writing performance of LD children. This study empirically compared the written products of LD and normal students at three grade levels on The Test of Written Language. Results showed that LD subjects scored significantly lower than normal subjects on most written expression abilities, especially in the mechanical tasks of spelling, punctuation, and word usage.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Orientation of the central domains of KSRP and its implications for the interaction with the RNA targets

KSRP is a multi-domain RNA-binding protein that recruits the exosome-containing mRNA degradation complex to mRNAs coding for cellular proliferation and inflammatory response factors. The selectivity of this mRNA degradation mechanism relies on KSRP recognition of AU-rich elements in the mRNA 3′UTR, that is mediated by KSRP’s KH domains. Our structural analysis shows that the inter-domain linker orients the two central KH domains of KSRP—and their RNA-binding surfaces—creating a two-domain unit. We also show that this inter-domain arrangement is important to the interaction with KSRP’s RNA targets

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targetedpanel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations