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UFGI publication round-up week 2/26

Biochem J. 2018 Feb 28;475(4):813-825. doi: 10.1042/BCJ20170883.

A plastidial pantoate transporter with a potential role in pantothenate synthesis.

Author information

1
Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China.
2
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, U.S.A.
3
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
4
Max-Planck-Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
5
Horticultural Sciences Department, University of Florida, Gainesville, FL, U.S.A.
6
Microbiology and Cell Science Department, University of Florida, Gainesville, FL, U.S.A.
7
Mathematics and Computer Science Division, Argonne National Laboratory, Argonne, IL, U.S.A.
8
Computation Institute, The University of Chicago, Chicago, IL, U.S.A.
9
Horticultural Sciences Department, University of Florida, Gainesville, FL, U.S.A. adha@ufl.edu.

Abstract

The pantothenate (vitamin B5) synthesis pathway in plants is not fully defined because the subcellular site of its ketopantoate → pantoate reduction step is unclear. However, the pathway is known to be split between cytosol, mitochondria, and potentially plastids, and inferred to involve mitochondrial or plastidial transport of ketopantoate or pantoate. No proteins that mediate these transport steps have been identified. Comparative genomic and transcriptomic analyses identified Arabidopsis thaliana BASS1 (At1g78560) and its maize (Zea mays) ortholog as candidates for such a transport role. BASS1 proteins belong to the bile acid : sodium symporter family and share similarity with the Salmonella enterica PanS pantoate/ketopantoate transporter and with predicted bacterial transporters whose genes cluster on the chromosome with pantothenate synthesis genes. Furthermore, Arabidopsis BASS1 is co-expressed with genes related to metabolism of coenzyme A, the cofactor derived from pantothenate. Expression of Arabidopsis or maize BASS1 promoted the growth of a S. enterica panB panS mutant strain when pantoate, but not ketopantoate, was supplied, and increased the rate of [3H]pantoate uptake. Subcellular localization of green fluorescent protein fusions in Nicotiana tabacum BY-2 cells demonstrated that Arabidopsis BASS1 is targeted solely to the plastid inner envelope. Two independent Arabidopsis BASS1 knockout mutants accumulated pantoate ∼10-fold in leaves and had smaller seeds. Taken together, these data indicate that BASS1 is a physiologically significant plastidial pantoate transporter and that the pantoate reduction step in pantothenate biosynthesis could be at least partly localized in plastids.
 
 

Drug Saf. 2018 Mar;41(3):313-320. doi: 10.1007/s40264-017-0611-5.

Reported Adverse Events with Painkillers: Data Mining of the US Food and Drug Administration Adverse Events Reporting System.

Author information

1
Department of Epidemiology, University of Florida, 2004 Mowry Rd, PO Box 100231, GainesvilleFL, 32610, USA. jaemin@ufl.edu.
2
Department of Epidemiology, University of Florida, 2004 Mowry Rd, PO Box 100231, GainesvilleFL, 32610, USA.

Abstract

INTRODUCTION:

One-third of adults in the USA experience chronic pain and use a variety of painkillers, such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids. However, some serious adverse events (AEs), such as cardiovascular incidents, overdose, and death, have been found to be related to painkillers.

METHODS:

We used 2015 and 2016 AE reports from the US FDA’s Adverse Events Reporting System (FAERS) to conduct exploratory analysis on the demographics of those who reported painkiller-related AEs, examine the AEs most commonly associated with different types of painkillers, and identify potential safety signals. Summary descriptive statistics and proportional reporting ratios (PRRs) were performed.

RESULTS:

Out of over 2 million reports submitted to FAERS in 2015 and 2016, a total of 64,354 AE reports were associated with painkillers. Reports of opioid-associated AEs were more likely to be from males or younger patients (mean age 47.6 years). The highest numbers of AEs were reported for NSAID and opioid use, and the most commonly found AEs were related to drug ineffectiveness, administration issues, abuse, and overdose. Death was reported in 20.0% of the reports, and serious adverse reactions, including death, were reported in 67.0%; both adverse outcomes were highest among patients using opioids or combinations of painkillers and were associated with PRRs of 2.12 and 1.87, respectively.

CONCLUSIONS:

This study examined the AEs most commonly associated with varying classes of painkillers by mining the FAERS database. Our results and methods are relevant for future secondary analyses of big data and for understanding adverse outcomes related to painkillers.
 
 

Metabolites. 2018 Feb 28;8(1). pii: E19. doi: 10.3390/metabo8010019.

Carbonic Anhydrases: Role in pH Control and Cancer.

Author information

1
University of Florida, College of Medicine, Department of Biochemistry and Molecular Biology, P.O. Box 100245, GainesvilleFL 32610, USA. mammboge@ufl.edu.
2
University of Florida, College of Medicine, Department of Biochemistry and Molecular Biology, P.O. Box 100245, GainesvilleFL 32610, USA. brian.mahon@nih.gov.
3
University of Florida, College of Medicine, Department of Biochemistry and Molecular Biology, P.O. Box 100245, GainesvilleFL 32610, USA. rmckenna@ufl.edu.
4
University of Florida, College of Medicine, Department of Biochemistry and Molecular Biology, P.O. Box 100245, GainesvilleFL 32610, USA. sfrost@ufl.edu.

Abstract

The pH of the tumor microenvironment drives the metastatic phenotype and chemotherapeutic resistance of tumors. Understanding the mechanisms underlying this pH-dependent phenomenon will lead to improved drug delivery and allow the identification of new therapeutic targets. This includes an understanding of the role pH plays in primary tumor cells, and the regulatory factors that permit cancer cells to thrive. Over the last decade, carbonic anhydrases (CAs) have been shown to be important mediators of tumor cell pH by modulating the bicarbonate and proton concentrations for cell survival and proliferation. This has prompted an effort to inhibit specific CA isoforms, as an anti-cancer therapeutic strategy. Of the 12 active CA isoforms, two, CA IX and XII, have been considered anti-cancer targets. However, other CA isoforms also show similar activity and tissue distribution in cancers and have not been considered as therapeutic targets for cancer treatment. In this review, we consider all the CA isoforms and their possible role in tumors and their potential as targets for cancer therapy.
 
 

Oral Oncol. 2018 Mar;78:145-150. doi: 10.1016/j.oraloncology.2018.01.024. Epub 2018 Feb 20.

CD70 as a target for chimeric antigen receptor T cells in head and neck squamous cell carcinoma.

Author information

1
Department of Oral Biology, University of Florida, GainesvilleFL 32610, USA.
2
Department of Neurosurgery, University of Florida, GainesvilleFL 32610, USA; Fourth Section of the Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University (HMU), Harbin, China.
3
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, MD 20892, USA.
4
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, GainesvilleFL 32610, USA.
5
UF Health Cancer Center-Orlando Health, Orlando, FL 32806, USA.
6
Department of Molecular Genetics and Microbiology, University of Florida, GainesvilleFL 32610, USA. Electronic address: lchang@mgm.ufl.edu.
7
Department of Neurosurgery, University of Florida, GainesvilleFL 32610, USA. Electronic address: jianping.huang@neurosurgery.ufl.edu.
8
Department of Oral Biology, University of Florida, GainesvilleFL 32610, USA. Electronic address: echan@ufl.edu.

Abstract

OBJECTIVES:

In accordance with the Precision Medicine Initiative, new treatment strategies for head and neck squamous cell carcinoma (HNSCC) are needed to yield better therapeutic outcomes. The purpose of this study was to establish and validate chimeric antigen receptor (CAR)-T cells targets in HNSCC.

METHODS:

Putative CAR-T antigens were identified in The Cancer Genome Atlas database. To validate antigen suitability, quantitative RT-PCR, flow cytometry, and immunofluorescent staining were performed. A retroviral human CD70 CAR construct, using truncated CD27 conjugated with 4-1BB and CD3-zeta costimulatory molecules, was used to transduce activated human T cells to generate CD70 CAR-T cells. Cell-based cytotoxicity and cytokine ELISAs were used to measure efficacy of killing.

RESULTS:

Nine potential CAR-T targets (CD276, EGFR, MICA, MICB, MAGE-A4, FAP, EPCAM, CD70, B4GALNT1) were identified based on their high expression in tumors compared to flanking control tissues. CD70 was selected for further proof-of-principle analysis based on its differential expression in several tumor subtypes, and showed substantial heterogeneity in individual tumors analyzed. Cell surface CD70 protein and CD70 mRNA were detected from low to high levels in established HNSCC cancer cell lines. CD70 was highly expressed in 4 of 21 tumor biopsies (19%), and 3 of 4 specimens showed strong CD70 expression on the tumor cell surface. CD70-specific CAR-T cells were generated and further demonstrated to recognize and kill CD70-positive HNSCC cells efficiently, but not CD70-negative cancer cells.

CONCLUSION:

CD70-specific CAR-T cells specifically recognized and efficiently eliminated CD70-positive HNSCC cells. This study provides the basis for further investigation into CD70 and other CAR-T targets.
 
 

Mol Phylogenet Evol. 2018 Feb 26;123:88-100. doi: 10.1016/j.ympev.2018.02.016. [Epub ahead of print]

Pseudo-parallel patterns of disjunctions in an Arctic-alpine plant lineage.

Author information

1
Department of Biology, University of Florida, GainesvilleFL 32611, USA; Florida Museum of Natural History, University of Florida, GainesvilleFL 32611, USA. Electronic address: stubbsrl@ufl.edu.
2
Department of Biology, University of Florida, GainesvilleFL 32611, USA.
3
Key Laboratory of Biodiversity and Biogeography, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, PR China.
4
Department of Biology, University of Florida, GainesvilleFL 32611, USA; Florida Museum of Natural History, University of Florida, GainesvilleFL 32611, USA; Genetics Institute, University of Florida, GainesvilleFL 32608, USA.
5
Florida Museum of Natural History, University of Florida, GainesvilleFL 32611, USA.

Abstract

Disjunct distributions have intrigued biologists for centuries. Investigating these biogeographic patterns provides insight into speciation and biodiversity at multiple spatial and phylogenetic scales. Some disjunctions have been intensively studied, yet others have been largely overlooked and remain poorly understood. Among the lesser-known disjunction patterns is that between the mountain ranges of western North America. Flora and fauna endemic to the mountains of this region provide important systems for investigating causes and results of disjunctions, given the relatively recent geological formation of this area and the intense climatic fluctuations that have occurred since its formation. In Micranthes (Saxifragaceae), which has high rates of montane endemism, two species, M. bryophora and M. tolmiei, show this biogeographical pattern. By reconstructing a time-calibrated phylogeny based on 518 low-copy nuclear markers and including multiple populations of each species from the Coast Ranges, Cascades, Sierra Nevada, and Rocky Mountains, this study provides a biogeographical and temporal framework for the evolution of Micranthes in western North America. Strongly supported east-west differentiated clades are recovered for M. bryophora and M. tolmiei in both maximum likelihood and coalescent-based species tree reconstructions. Biogeographic analysis suggests different patterns of dispersal for both taxa and the dating analyses recovered contrasting ages for each clade. Due to both the different geographic patterns and the timing of the initial diversification of each taxon corresponding to different geologic and climatic events, the disjunction patterns shown for these taxa are suggested to be an example of biogeographical pseudocongruence.
 
 

Eur J Hum Genet. 2018 Feb 28. doi: 10.1038/s41431-018-0123-5. [Epub ahead of print]

Molecular-genetic characterization of common, noncoding UBASH3A variants associated with type 1 diabetes.

Ge Y1,2Concannon P3,4.

Author information

1
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, GainesvilleFL, USA.
2
Genetics Institute, University of Florida, GainesvilleFL, USA.
3
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, GainesvilleFL, USA. patcon@ufl.edu.
4
Genetics Institute, University of Florida, GainesvilleFL, USA. patcon@ufl.edu.

Abstract

Genome-wide association and fine-mapping studies have identified over 40 susceptibility regions for type 1 diabetes (T1D), a common autoimmune disease; however, most of the disease-associated variants are noncoding, and it remains a challenge to understand their biological contributions to T1D pathogenesis. One identified T1D risk locus is located at chromosome 21q22.3 where the most likely candidate gene is UBASH3A, a negative regulator of NF-κB signaling. Various noncoding variants in UBASH3A have been shown to be associated with T1D or other autoimmune diseases. Here we investigated four such SNPs-rs11203202, rs80054410, rs11203203, and rs1893592. We discovered a novel role for rs1893592 in T1D and showed that its minor allele protects against T1D. Our haplotype analysis identified three T1D-associated UBASH3A haplotypes, and revealed that risk for T1D is affected by additive effects of these four UBASH3A variants. In human primary CD4+ T cells, upon T-cell receptor stimulation, the minor allele of rs1893592 was associated with both a significant reduction in the overall mRNA levels of UBASH3A, and an increase in the proportion of a normally occurring, but low-abundant, UBASH3A transcript that retains intron-9 sequences and cannot produce full-length UBASH3A protein. This reduction in UBASH3A, as a consequence of the minor allele at rs1893592, resulted in increased secretion of IL-2, a key cytokine that is required for T-cell activation and function but is deficient in some T1D subjects. Our study provides new mechanistic insights into how rs1893592 affects T1D and autoimmunity, and how interactions between multiple T1D-associated, noncoding variants influence the disease risk.
 
 

Nat Commun. 2018 Feb 28;9(1):882. doi: 10.1038/s41467-018-03367-w.

Nanodroplet processing platform for deep and quantitative proteome profiling of 10-100 mammalian cells.

Author information

1
The Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, 99354, USA.
2
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA.
3
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, GainesvilleFL, 32611, USA.
4
The Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, 99354, USA. ryan.kelly@pnnl.gov.

Abstract

Nanoscale or single-cell technologies are critical for biomedical applications. However, current mass spectrometry (MS)-based proteomic approaches require samples comprising a minimum of thousands of cells to provide in-depth profiling. Here, we report the development of a nanoPOTS (nanodroplet processing in one pot for trace samples) platform for small cell population proteomics analysis. NanoPOTS enhances the efficiency and recovery of sample processing by downscaling processing volumes to <200 nL to minimize surface losses. When combined with ultrasensitive liquid chromatography-MS, nanoPOTS allows identification of ~1500 to ~3000 proteins from ~10 to ~140 cells, respectively. By incorporating the Match Between Runs algorithm of MaxQuant, >3000 proteins are consistently identified from as few as 10 cells. Furthermore, we demonstrate quantification of ~2400 proteins from single human pancreatic islet thin sections from type 1 diabetic and control donors, illustrating the application of nanoPOTS for spatially resolved proteome measurements from clinical tissues.
 
 

J Neurosci. 2018 Feb 28. pii: 0848-17. doi: 10.1523/JNEUROSCI.0848-17.2018. [Epub ahead of print]

Cell-specific deletion of PGC-1α from medium spiny neurons causes transcriptional alterations and age-related motor impairment.

Author information

1
Department of Neuroscience, Drug Discovery Division, Southern Research, Birmingham, AL 35294 and the Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, AL 35294.
2
Australian National University, Acton, ACT 2601, Australia.
3
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
4
Genetics Research Division, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
5
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
6
Department of Neurology, University of Florida, Gainesville, Florida 32610, USA.
7
Biochemistry & Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
8
Department of Neuroscience, Drug Discovery Division, Southern Research, Birmingham, AL 35294 and the Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, AL 35294 rcowell@southernresearch.org.

Abstract

Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1α (PGC-1α) is associated with neurodegeneration in diseases such as Huntington Disease (HD). Polymorphisms in the PGC-1α gene modify HD progression, and PGC-1α expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1α nor the contribution of PGC-1α deficiency to motor dysfunction is known. We identified novel PGC-1α-dependent transcripts involved in RNA processing, signal transduction and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-1α specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1α deletion caused reductions in previously identified neuronal and metabolic PGC-1α-dependent genes, without causing striatal vacuolizations. Interestingly, these mice exhibited a hypoactivity with age, similar to several HD animal models. However, these newly identified PGC-1α-dependent genes were upregulated with disease severity and age in knockin HD mouse models independent of changes in PGC-1α transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1α is necessary for MSN transcriptional homeostasis and function with age and that, while PGC-1α loss in MSNs does not replicate an HD-like phenocopy, its downstream genes are altered in a repeat-length and age-dependent fashion. Understanding the additive effects of PGC-1α gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD.SIGNIFICANCE STATEMENTReductions in PGC-1α-mediated transcription have been implicated in the pathogenesis of Huntington Disease (HD). We show that while PGC-1α-dependent transcription is necessary to maintain MSN function with age, its loss is insufficient to cause striatal atrophy in mice. We also highlight a set of genes that can serve as proxies for PGC-1α functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1α-dependent genes are upregulated in a dose and age-dependent fashion in HD mouse models, contrary to what would be predicted from a loss-of-function etiological mechanism. However, given this role for PGC-1α in MSN transcriptional homeostasis, it is important to consider how genetic variation in PGC-1α could contribute to mutant-huntingtin-induced cell death and disease progression.
 
 

BMC Genet. 2018 Feb 27;19(1):14. doi: 10.1186/s12863-018-0600-4.

Whole-genome scan reveals significant non-additive effects for sire conception rate in Holstein cattle.

Author information

1
Department of Animal Sciences, University of Florida, 2250 Shealy Drive, GainesvilleFL, 32611, USA.
2
Polo de Desarrollo Universitario, Universidad de la República, Tacuarembó, Uruguay.
3
Department of Animal Sciences, University of Florida, 2250 Shealy Drive, GainesvilleFL, 32611, USA. fpenagaricano@ufl.edu.
4
University of Florida Genetics Institute, University of Florida, GainesvilleFL, 32610, USA. fpenagaricano@ufl.edu.

Abstract

BACKGROUND:

Service sire has a considerable impact on reproductive success in dairy cattle. Most gene mapping studies for bull fertility have focused on additive effects, while non-additive effects have been largely ignored. The main goal of this study was to assess the relevance of non-additive effects on Sire Conception Rate (SCR) in Holstein dairy cattle. The analysis included 7.5 k Holstein bulls with both SCR records and 57.8 k single nucleotide polymorphism (SNP) markers spanning the entire genome.

RESULTS:

The importance of non-additive effects was evaluated using an efficient two-step mixed model-based approach. Four genomic regions located on chromosomes BTA8, BTA9, BTA13 and BTA17 showed marked dominance and/or recessive effects. Most of these regions harbor genes, such as ADAM28, DNAJA1, TBC1D20, SPO11, PIWIL3 and TMEM119, that are directly implicated in testis development, male germ line maintenance, and sperm maturation.

CONCLUSIONS:

This study provides further evidence for the relevance of non-additive effects in fitness-related traits, such as male fertility. In addition, these findings may point out new strategies for improving service sire fertility in dairy cattle via marker-assisted selection.
 
 

Nat Plants. 2018 Mar;4(3):134-135. doi: 10.1038/s41477-018-0114-0.

One effector at a time.

Author information

1
Department of Plant Pathology, University of Florida, GainesvilleFL, USA. ffwhite@ufl.edu.
2
Department of Plant Pathology, University of Florida, GainesvilleFL, USA.

 
 
NOTE: These abstracts were retrieved from the U.S. National Library of Medicine website managed in collaboration with the U.S. National Library of Medicine

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