Halseybork7548

Hypomelanosis of Ito (HMI) is part of a neuroectodermal syndrome characterized by distinctive skin manifestations with or without multisystemic involvements. In our undiagnosed diseases program, we have encountered a 3-year-old girl presenting with characteristic skin hypopigmentation suggesting HMI and developmental delay. An exome and genome approach utilizing next-generation sequencing revealed a heterozygous de novo frameshift variant in the KIF13A gene, i.e., NM_022113.6 c.2357dupA, resulting in nonsense-mediated decay. The low mutant allelic ratio suggested that the mutation has occurred postzygotically leading to embryonic mosaicism. Functionally, K1F3A regulates cell membrane blebbing and migration of neural crest cells by controlling recycling of RHOB to the plasma membrane and is also involved in melanosome biogenesis. Importantly, hypopigmentation of the skin has been reported in chr 6p22.3-p23 microdeletion syndrome supporting the association of KIF13A haploinsufficiency with the novel neuroectodermal syndrome. With the increased availability of genome sequencing, we envisage more genetic causes of HMI will be identified in the future.Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs due to pyramidal tract dysfunction. REEP2 mutations have been identified as a cause of "pure" HSP, SPG72, with both autosomal dominant and autosomal recessive inheritance. We describe a rare Nepalese family with early-onset pure-type HSP harboring a heterozygous REEP2 missense mutation (c.119T>G, p.Met40Arg). This is only the second SPG72 family with autosomal dominant inheritance. The proband presented slow and spastic gait at age 2 years and the symptoms progressed slowly. The proband's father and uncle presented even milder symptoms of pure spastic paraplegia. Our study may provide an opportunity to further study the genotype-phenotype correlation of SPG72.Leukocyte immunoglobulin (Ig)-like receptors (LILRs) are encoded by members of a human multigene family, comprising 11 protein-coding genes and two pseudogenes. Among the LILRs, LILRB3 and LILRA6 show the highest homology with each other, along with high allelic and copy number variations. Therefore, it has been difficult to discriminate between them, both genetically and functionally, precluding disease association studies of LILRB3 and LILRA6. In this study, we carefully performed variant screening of LILRB3 and LILRA6 by cDNA cloning from Japanese individuals and identified four allelic lineages showing significantly high non-synonymous-to-synonymous ratios in pairwise comparisons. Furthermore, the extracellular domains of the LILRB3*JP6 and LILRA6*JP1 alleles were identical at the DNA level, suggesting that gene conversion-like events diversified LILRB3 and LILRA6. To determine the four allelic lineages from genomic DNA, we established a lineage typing method that accurately estimated the four allelic lineages in addition to specific common alleles from genomic DNA. Analysis of LILRA6 copy number variation revealed one, two, and three copies of LILRA6 in the Japanese-in-Tokyo (JPT) population. Flow cytometric analysis showed that an anti-LILRB3 antibody did not recognize the second most common lineage in the Japanese population, indicating significant amino acid differences across the allelic lineages. Taken together, our findings indicate that our lineage typing is useful for classifying the lineage-specific functions of LILRB3 and LILRA6, serving as the basis for disease association studies.

On August 5th, 2015, 3 million gallons of acid mine drainage was accidentally discharged from the Gold King Mine near Silverton, Colorado into Cement Creek which is a tributary to the Animas and San Juan Rivers. The government-initiated risk assessment only assessed a recreational scenario (i.e. hiker drinking from the river), failing to recognize the deep connection of the Diné (Navajo) with the San Juan River.

Utilizing a mixed-methods approach we determined the impacts of the 2015 Gold King Mine Spill (GKMS or Spill) on Diné activities. We developed a questionnaire to collect pre- and post-GKMS Diné activity frequency and duration. Navajo Nation Community Health Representatives administered the questionnaire to 63 Diné adults and 27 children living in three Navajo communities along the River.

Through analysis of the focus group transcripts we identified 43 unique activities between the Diné and San Juan River. There were significant reductions in the total number, frequency, and duration of livelihoos when responding to environmental disasters and conducting risk assessments among Indigenous communities.Osteoarthritis is characterized by structural alteration of joints. Fibrosis of the synovial tissue is often detected and considered one of the main causes of joint stiffness and pain. In our earlier proteomic study, increased levels of vitronectin (VTN) fragment (amino acids 381-397) were observed in the serum of osteoarthritis patients. In this work, the affinity of this fragment for integrins and its putative role in TGF-β1 activation were investigated. A competition study determined the interaction of VTN(381-397 a.a.) with αVβ6 integrin. Subsequently, the presence of αVβ6 integrin was substantiated on primary human fibroblast-like synoviocytes (FLSs) by western blot and flow cytometry. By immunohistochemistry, β6 was detected in synovial membranes, and its expression showed a correlation with tissue fibrosis. Moreover, β6 expression was increased under TGF-β1 stimulation; hence, a TGF-β bioassay was applied. We observed that αVβ6 could mediate TGF-β1 bioavailability and that VTN(381-397 a.a.) could prevent TGF-β1 activation by interacting with αVβ6 in human FLSs and increased α-SMA. Finally, we analyzed serum samples from healthy controls and patients with osteoarthritis and other rheumatic diseases by nano-LC/Chip MS-MS, confirming the increased expression of VTN(381-397 a.a.) in osteoarthritis as well as in lupus erythematosus and systemic sclerosis. These findings corroborate our previous observations concerning the overexpression of VTN(381-397 a.a.) in osteoarthritis but also in other rheumatic diseases. This fragment interacts with αVβ6 integrin, a receptor whose expression is increased in FLSs from the osteoarthritic synovial membrane and that can mediate the activation of the TGF-β1 precursor in human FLSs.Cyclophosphamide (CPA) dosing by body surface area (BSA, m2) has been questioned as a predictor for individual drug exposure. This study investigated phosphoramide mustard-hemoglobin (PAM-Hb, pmol g-1 Hb) as a biomarker of CPA exposure in 135 female breast cancer patients receiving CPA during three courses based on BSA 500 mg/m2 (C500 group, n = 67) or 600 mg/m2 (C600 group, n = 68). The inter-individual difference was calculated for both groups by dividing the highest through the lowest PAM-Hb value of each course. The inter-occasion difference was calculated in percentage for each individual by dividing their PAM-Hb value through the group mean per course, and subsequently dividing this ratio of the latter through the previous course. A multivariable linear regression (MLR) was performed to identify factors that explained the variation of PAM-Hb. During the three courses, the inter-individual difference changed from 3.5 to 2.1 and the inter-occasion difference ranged between 13.3% and 11.9% in the C500 group. In the C600 group, the inter-individual difference changed from 2.7 to 2.9 and the inter-occasion difference ranged between 14.1% and 11.7%. The MLR including BSA, age, GFR, and albumin explained 17.1% of the variation of PAM-Hb and was significantly better then the model including only BSA. These factors should be considered when calculating the first dose of CPA for breast cancer patients.The view that has genotypic sex determination and environmental sex determination as mutually exclusive states in fishes and reptiles has been contradicted by the discovery that chromosomal sex and environmental influences can co-exist within the same species, hinting at a continuum of intermediate states. Systems where genes and the environment interact to determine sex present the opportunity for sex reversal to occur, where the phenotypic sex is the opposite of that predicted by their sex chromosome complement. The skink Bassiana duperreyi has XX/XY sex chromosomes with sex reversal of the XX genotype to a male phenotype, in laboratory experiments, and in field nests, in response to exposure to cold incubation temperatures. Here we studied the frequency of sex reversal in adult populations of B. duperreyi in response to climatic variation, using elevation as a surrogate for environmental temperatures. We demonstrate sex reversal in the wild for the first time in adults of a reptile species with XX/XY sex determination. The highest frequency of sex reversal occurred at the highest coolest elevation location, Mt Ginini (18.46%) and decreased in frequency to zero with decreasing elevation. We model the impact of this under Fisher's frequency-dependent selection to show that, at the highest elevations, populations risk the loss of the Y chromosome and a transition to temperature-dependent sex determination. This study contributes to our understanding of the risks of extinction from climate change in species subject to sex reversal by temperature, and will provide focus for future research to test on-the-ground management strategies to mitigate the effects of climate in local populations.The Indian summer monsoon rainfall (ISMR) is vital for the livelihood of millions of people in the Indian region; droughts caused by monsoon failures often resulted in famines. Large volcanic eruptions have been linked with reductions in ISMR, but the responsible mechanisms remain unclear. Here, using 145-year (1871-2016) records of volcanic eruptions and ISMR, we show that ISMR deficits prevail for two years after moderate and large (VEI > 3) tropical volcanic eruptions; this is not the case for extra-tropical eruptions. Moreover, tropical volcanic eruptions strengthen El Niño and weaken La Niña conditions, further enhancing Indian droughts. Using climate-model simulations of the 2011 Nabro volcanic eruption, we show that eruption induced an El Niño like warming in the central Pacific for two consecutive years due to Kelvin wave dissipation triggered by the eruption. This El Niño like warming in the central Pacific led to a precipitation reduction in the Indian region. In addition, solar dimming caused by the volcanic plume in 2011 reduced Indian rainfall.Conventional microalgae oil extraction applies physicochemical destruction of dry cell biomass prior to transesterification process to produce fatty acid methyl esters (FAMEs). This report presents a simple and rapid direct transesterification (DT) method for FAMEs production and fatty acid profiling of microalgae using freshly harvested biomass. Results revealed that the FAMEs recovered from Chlorella vulgaris were 50.1 and 68.3 mg with conventional oil-extraction-transesterification (OET) and DT method, respectively. While for Messastrum gracile, the FAMEs recovered, were 49.9 and 76.3 mg, respectively with OET and DT methods. This demonstrated that the DT method increased FAMEs recovery by 36.4% and 53.0% from C. vulgaris and M. gracile, respectively, as compared to OET method. Nafamostat Additionally, the DT method recovered a significantly higher amount of palmitic (C160) and stearic (C180) acids from both species, which indicated the important role of these fatty acids in the membranes of cells and organelles. The DT method performed very well using a small volume (5 mL) of fresh biomass coupled with a shorter reaction time (~ 15 min), thus making real-time monitoring of FAMEs and fatty acid accumulation in microalgae culture feasible.