An Unusual Combination of Neurological Manifestations and Sudden Vision Loss in a Child with Familial Hyperphosphatemic Tumoral Calcinosis

Hyperphosphatemia in the absence of renal failure is an unusual occurrence, particularly in children, but is a common primary feature of familial hyperphosphatemic tumor calcinosis. We report a child with hyperphosphatemia who presented with multiple episodes of neurologic dysfunction involving lower motor neuron facial nerve palsy along with sequential visual loss. He also had an episode of stroke. There was an extensive metastatic calcification of soft tissue and vasculature. Hyperphosphatemia with normal serum alkaline phosphatase, calcium, parathyroid hormone, and renal function was noted. He was managed with hemodialysis and sevelamer (3 months) without much success in reducing serum phosphate level, requiring continuous ambulatory peritoneal dialysis (3 years). Intact fibroblast growth factor 23 (FGF23) was undetectable, with C-terminal FGF23 fragments significantly elevated (2575 RU/ml, normal A (p.N162K) mutation in FGF23 exon 3, confirming the diagnoses of primary FGF23 deficiency, the first case to be reported from India

Physical Controls on Carbonate Intraclasts: Modern Flat Pebbles From Great Salt Lake, Utah

In carbonate‐forming environments, authigenic minerals can cement surface sediments into centimeter‐sized intraclasts that are later reworked into “flat‐pebble” or “edgewise” conglomerates. Flat‐pebble conglomerates comprise only a small portion of facies in modern marine environments but are common in ancient strata, implying that seafloor cements were more widespread in the past. Flat‐pebble conglomerates nearly disappeared after the Ordovician radiation, yet it is unclear if this decline was due to changing seawater chemistry or if increased infaunalization and bioturbation simply worked to break down nascent clasts. We discovered a process analog that produces flat‐pebble conglomerates around the Great Salt Lake, Utah, USA, and studied these facies using field observations, wave models, satellite imagery, petrography, and microanalytic chemical data. Clasts were sourced from wave‐rippled grainstone that cemented in situ in offshore environments. Lake floor cements formed under aragonite saturation states that are lower than modern marine settings, suggesting that physical processes are at least as important as chemical ones. Results from our wave models showed that coarse sediments near the field site experience quiescent periods of up to 6 months between suspension events, allowing isopachous cements to form. Using a simple mathematical framework, we show that the main difference between Great Salt Lake and modern, low‐energy marine settings is that the latter has enough bioturbating organisms to break up clasts. Observations from Great Salt Lake demonstrate how geologic trends in flat‐pebble abundance could largely reflect changes in total infaunal biomass and ecology without requiring regional‐to‐global changes in seawater chemistry

Physical Controls on Carbonate Intraclasts: Modern Flat Pebbles From Great Salt Lake, Utah

In carbonate‐forming environments, authigenic minerals can cement surface sediments into centimeter‐sized intraclasts that are later reworked into “flat‐pebble” or “edgewise” conglomerates. Flat‐pebble conglomerates comprise only a small portion of facies in modern marine environments but are common in ancient strata, implying that seafloor cements were more widespread in the past. Flat‐pebble conglomerates nearly disappeared after the Ordovician radiation, yet it is unclear if this decline was due to changing seawater chemistry or if increased infaunalization and bioturbation simply worked to break down nascent clasts. We discovered a process analog that produces flat‐pebble conglomerates around the Great Salt Lake, Utah, USA, and studied these facies using field observations, wave models, satellite imagery, petrography, and microanalytic chemical data. Clasts were sourced from wave‐rippled grainstone that cemented in situ in offshore environments. Lake floor cements formed under aragonite saturation states that are lower than modern marine settings, suggesting that physical processes are at least as important as chemical ones. Results from our wave models showed that coarse sediments near the field site experience quiescent periods of up to 6 months between suspension events, allowing isopachous cements to form. Using a simple mathematical framework, we show that the main difference between Great Salt Lake and modern, low‐energy marine settings is that the latter has enough bioturbating organisms to break up clasts. Observations from Great Salt Lake demonstrate how geologic trends in flat‐pebble abundance could largely reflect changes in total infaunal biomass and ecology without requiring regional‐to‐global changes in seawater chemistry

Genomewide Association Study for Determinants of HIV-1 Acquisition and Viral Set Point in HIV-1 Serodiscordant Couples with Quantified Virus Exposure

Host genetic factors may be important determinants of HIV-1 sexual acquisition. We performed a genome-wide association study (GWAS) for host genetic variants modifying HIV-1 acquisition and viral control in the context of a cohort of African HIV-1 serodiscordant heterosexual couples. To minimize misclassification of HIV-1 risk, we quantified HIV-1 exposure, using data including plasma HIV-1 concentrations, gender, and condom use.We matched couples without HIV-1 seroconversion to those with seroconversion by quantified HIV-1 exposure risk. Logistic regression of single nucleotide polymorphisms (SNPs) for 798 samples from 496 HIV-1 infected and 302 HIV-1 exposed, uninfected individuals was performed to identify factors associated with HIV-1 acquisition. In addition, a linear regression analysis was performed using SNP data from a subset (n = 403) of HIV-1 infected individuals to identify factors predicting plasma HIV-1 concentrations.After correcting for multiple comparisons, no SNPs were significantly associated with HIV-1 infection status or plasma HIV-1 concentrations.This GWAS controlling for HIV-1 exposure did not identify common host genotypes influencing HIV-1 acquisition. Alternative strategies, such as large-scale sequencing to identify low frequency variation, should be considered for identifying novel host genetic predictors of HIV-1 acquisition

Multifunctionality of Prostatic Acid Phosphatase in Prostate Cancer Pathogenesis

The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP can also occur with the wildtype PAcP signal sequence. Clinical specimens from patients with prostate cancer demonstrate that one form, termed PLPAcP, correlates with early prostate cancer. These findings confirm the analytical power of this method, implicate PLPAcP in prostate cancer pathogenesis, and suggest novel anticancer therapeutic strategies

Biochemical and biophysical characterization of cell-free synthesized Rift Valley fever virus nucleoprotein capsids enables in vitro screening to identify novel antivirals

Cell fractionation indicates that the compounds access the nucleus. The most potent compounds were exposed to HEK cells at a concentration of 1 ΟM for 24 h, after which the nucleus was separated from the cytoplasm. The concentration of these two blue compounds could be observed by the relative higher intensity in the nucleus compared to that in the cytoplasm. (PDF 3721 kb

Active Ooid Growth Driven By Sediment Transport in a High-Energy Shoal, Little Ambergris Cay, Turks and Caicos Islands

Ooids are a common component of carbonate successions of all ages and present significant potential as paleoenvironmental proxies, if the mechanisms that control their formation and growth can be understood quantitatively. There are a number of hypotheses about the controls on ooid growth, each offering different ideas on where and how ooids accrete and what role, if any, sediment transport and abrasion might play. These hypotheses have not been well tested in the field, largely due to the inherent challenges of tracking individual grains over long timescales. This study presents a detailed field test of ooid-growth hypotheses on Little Ambergris Cay in the Turks and Caicos Islands, British Overseas Territories. This field site is characterized by westward net sediment transport from waves driven by persistent easterly trade winds. This configuration makes it possible to track changes in ooid properties along their transport path as a proxy for changes in time. Ooid size, shape, and radiocarbon age were compared along this path to determine in which environments ooids are growing or abrading. Ooid surface textures, petrographic fabrics, stable-isotope compositions (δ^(13)C, δ^(18)O, and δ^(34)S), lipid geochemistry, and genetic data were compared to characterize mechanisms of precipitation and degradation and to determine the relative contributions of abiotic (e.g., abiotic precipitation, physical abrasion) and biologically influenced processes (e.g., biologically mediated precipitation, fabric destruction through microbial microboring and micritization) to grain size and character. A convergence of evidence shows that active ooid growth occurs along the transport path in a high-energy shoal environment characterized by frequent suspended-load transport: median ooid size increases by more than 100 μm and bulk radiocarbon ages decrease by 360 yr westward along the ∼ 20 km length of the shoal crest. Lipid and 16S rRNA data highlight a spatial disconnect between the environments with the most extensive biofilm colonization and environments with active ooid growth. Stable-isotope compositions are indistinguishable among samples, and are consistent with abiotic precipitation of aragonite from seawater. Westward increases in ooid sphericity and the abundance of well-polished ooids illustrate that ooids experience subequal amounts of growth and abrasion—in favor of net growth—as they are transported along the shoal crest. Overall, these results demonstrate that, in the Ambergris system, the mechanism of ooid growth is dominantly abiotic and the loci of ooid growth is determined by both carbonate saturation and sediment transport mode. Microbes play a largely destructive, rather than constructive, role in ooid size and fabric