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Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop Type 2 diabetes.

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Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop Type 2 diabetes.

Elife. 2020 Aug 04;9:

Authors: Lai M, Al Rijjal D, Röst HL, Dai FF, Gunderson EP, Wheeler MB

Abstract
Approximately 35% of women with Gestational Diabetes (GDM) progress to Type2 Diabetes (T2D) within 10 years. However, links between GDM and T2D are not well understood. We used a well-characterised GDM prospective cohort of 1,035 women following up to 8 years postpartum. Lipidomics profiling covering >1000 lipids, was performed on fasting plasma samples from participants 6-9week postpartum (171 incident T2D vs. 179 controls). We discovered 311 lipids positively and 70 lipids negatively associated with T2D risk. The upregulation of glycerolipid metabolism involving triacylglycerol and diacylglycerol biosynthesis suggested activated lipid storage before diabetes onset. In contrast, decreased sphingomyelines, hexosylceramide and lactosylceramide indicated impaired sphingolipid metabolism. Additionally, a lipid signature was identified to effectively predict future diabetes risk. These findings demonstrate an underlying dyslipidemia during the early postpartum in those GDM women who progress to T2D and suggest endogenous lipogenesis may be a driving force for future diabetes onset.

PMID: 32748787 [PubMed - as supplied by publisher]



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Alternative splicing of coq-2 controls the level of rhodoquinone in animals.

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Alternative splicing of coq-2 controls the level of rhodoquinone in animals.

Elife. 2020 Aug 03;9:

Authors: Tan JH, Lautens M, Romanelli-Cedrez L, Wang J, Schertzberg MR, Reinl SR, Davis RE, Shepherd JN, Fraser AG, Salinas G

Abstract
Parasitic helminths use two benzoquinones as electron carriers in the electron transport chain. In normoxia they use ubiquinone (UQ), but in the anaerobic conditions inside the host, they require rhodoquinone (RQ) and greatly increase RQ levels. We previously showed the switch from UQ to RQ synthesis is driven by a change in substrates by the polyprenyltransferase COQ-2 (Del Borrello et al., 2019; Roberts Buceta et al., 2019) - how this substrate choice is made is unknown. Here, we show helminths make two coq-2 splice forms, coq-2a and coq-2e, and the coq-2e-specific exon is only found in species that make RQ. We show that in C. elegans COQ-2e is required for efficient RQ synthesis and for survival in cyanide. Crucially, parasites switch from COQ-2a to COQ-2e as they transition into anaerobic environments. We conclude helminths switch from UQ to RQ synthesis principally via changes in the alternative splicing of coq-2.

PMID: 32744503 [PubMed - as supplied by publisher]



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Education and the moderating roles of age, sex, ethnicity and apolipoprotein epsilon 4 on the risk of cognitive impairment.

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Education and the moderating roles of age, sex, ethnicity and apolipoprotein epsilon 4 on the risk of cognitive impairment.

Arch Gerontol Geriatr. 2020 Nov/Dec;91:104112

Authors: Makkar SR, Lipnicki DM, Crawford JD, Kochan NA, Castro-Costa E, Lima-Costa MF, Diniz BS, Brayne C, Stephan B, Matthews F, Llibre-Rodriguez JJ, Llibre-Guerra JJ, Valhuerdi-Cepero AJ, Lipton RB, Katz MJ, Zammit A, Ritchie K, Carles S, Carriere I, Scarmeas N, Yannakoulia M, Kosmidis M, Lam L, Fung A, Chan WC, Guaita A, Vaccaro R, Davin A, Kim KW, Han JW, Suh SW, Riedel-Heller SG, Roehr S, Pabst A, Ganguli M, Hughes TF, Jacobsen EP, Anstey KJ, Cherbuin N, Haan MN, Aiello AE, Dang K, Kumagai S, Narazaki K, Chen S, Ng TP, Gao Q, Nyunt MSZ, Meguro K, Yamaguchi S, Ishii H, Lobo A, Lobo Escolar E, De la Cámara C, Brodaty H, Trollor JN, Leung Y, Lo JW, Sachdev P, for Cohort Studies of Memory in an International Consortium (COSMIC)

Abstract
BACKGROUND: We examined how the relationship between education and latelife cognitive impairment (defined as a Mini Mental State Examination score below 24) is influenced by age, sex, ethnicity, and Apolipoprotein E epsilon 4 (APOE*4).
METHODS: Participants were 30,785 dementia-free individuals aged 55-103 years, from 18 longitudinal cohort studies, with an average follow-up ranging between 2 and 10 years. Pooled hazard ratios were obtained from multilevel parametric survival analyses predicting cognitive impairment (CI) from education and its interactions with baseline age, sex, APOE*4 and ethnicity. In separate models, education was treated as continuous (years) and categorical, with participants assigned to one of four education completion levels: Incomplete Elementary; Elementary; Middle; and High School.
RESULTS: Compared to Elementary, Middle (HR = 0.645, P = 0.004) and High School (HR = 0.472, P < 0.001) education were related to reduced CI risk. The decreased risk of CI associated with Middle education weakened with older baseline age (HR = 1.029, P = 0.056) and was stronger in women than men (HR = 1.309, P = 0.001). The association between High School and lowered CI risk, however, was not moderated by sex or baseline age, but was stronger in Asians than Whites (HR = 1.047, P = 0.044), and significant among Asian (HR = 0.34, P < 0.001) and Black (HR = 0.382, P = 0.016), but not White, APOE*4 carriers.
CONCLUSION: High School completion may reduce risk of CI associated with advancing age and APOE*4. The observed ethnoregional differences in this effect are potentially due to variations in social, economic, and political outcomes associated with educational attainment, in combination with neurobiological and genetic differences, and warrant further study.

PMID: 32738518 [PubMed - in process]



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Neutralizing Antibody and Soluble ACE2 Inhibition of a Replication-Competent VSV-SARS-CoV-2 and a Clinical Isolate of SARS-CoV-2.

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Neutralizing Antibody and Soluble ACE2 Inhibition of a Replication-Competent VSV-SARS-CoV-2 and a Clinical Isolate of SARS-CoV-2.

Cell Host Microbe. 2020 09 09;28(3):475-485.e5

Authors: Case JB, Rothlauf PW, Chen RE, Liu Z, Zhao H, Kim AS, Bloyet LM, Zeng Q, Tahan S, Droit L, Ilagan MXG, Tartell MA, Amarasinghe G, Henderson JP, Miersch S, Ustav M, Sidhu S, Virgin HW, Wang D, Ding S, Corti D, Theel ES, Fremont DH, Diamond MS, Whelan SPJ

Abstract
Antibody-based interventions against SARS-CoV-2 could limit morbidity, mortality, and possibly transmission. An anticipated correlate of such countermeasures is the level of neutralizing antibodies against the SARS-CoV-2 spike protein, which engages with host ACE2 receptor for entry. Using an infectious molecular clone of vesicular stomatitis virus (VSV) expressing eGFP as a marker of infection, we replaced the glycoprotein gene (G) with the spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and developed a high-throughput-imaging-based neutralization assay at biosafety level 2. We also developed a focus-reduction neutralization test with a clinical isolate of SARS-CoV-2 at biosafety level 3. Comparing the neutralizing activities of various antibodies and ACE2-Fc soluble decoy protein in both assays revealed a high degree of concordance. These assays will help define correlates of protection for antibody-based countermeasures and vaccines against SARS-CoV-2. Additionally, replication-competent VSV-eGFP-SARS-CoV-2 provides a tool for testing inhibitors of SARS-CoV-2 mediated entry under reduced biosafety containment.

PMID: 32735849 [PubMed - indexed for MEDLINE]



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Discovery of Protein-Protein Interaction Inhibitors by Integrating Protein Engineering and Chemical Screening Platforms.

Discovery of Protein-Protein Interaction Inhibitors by Integrating Protein Engineering and Chemical Screening Platforms.

Cell Chem Biol. 2020 Jul 27;:

Authors: Maculins T, Garcia-Pardo J, Skenderovic A, Gebel J, Putyrski M, Vorobyov A, Busse P, Varga G, Kuzikov M, Zaliani A, Rahighi S, Schaeffer V, Parnham MJ, Sidhu SS, Ernst A, Dötsch V, Akutsu M, Dikic I

Abstract
Protein-protein interactions (PPIs) govern intracellular life, and identification of PPI inhibitors is challenging. Roadblocks in assay development stemming from weak binding affinities of natural PPIs impede progress in this field. We postulated that enhancing binding affinity of natural PPIs via protein engineering will aid assay development and hit discovery. This proof-of-principle study targets PPI between linear ubiquitin chains and NEMO UBAN domain, which activates NF-κB signaling. Using phage display, we generated ubiquitin variants that bind to the functional UBAN epitope with high affinity, act as competitive inhibitors, and structurally maintain the existing PPI interface. When utilized in assay development, variants enable generation of robust cell-based assays for chemical screening. Top compounds identified using this approach directly bind to UBAN and dampen NF-κB signaling. This study illustrates advantages of integrating protein engineering and chemical screening in hit identification, a development that we anticipate will have wide application in drug discovery.

PMID: 32726587 [PubMed - as supplied by publisher]



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Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.

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Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.

Nat Med. 2020 08;26(8):1285-1294

Authors: Ayoub R, Ruddy RM, Cox E, Oyefiade A, Derkach D, Laughlin S, Ades-Aron B, Shirzadi Z, Fieremans E, MacIntosh BJ, de Medeiros CB, Skocic J, Bouffet E, Miller FD, Morshead CM, Mabbott DJ

Abstract
We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.

PMID: 32719487 [PubMed - indexed for MEDLINE]



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Electric field application in vivo regulates neural precursor cell behaviour in the adult mammalian forebrain.

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Electric field application in vivo regulates neural precursor cell behaviour in the adult mammalian forebrain.

eNeuro. 2020 Jul 27;:

Authors: Sefton E, Iwasa SN, Morrison T, Naguib HE, Popovic MR, Morshead CM

Abstract
Deep brain stimulation (DBS), which uses electrical stimulation, is a well-established neurosurgical technique used to treat neurological disorders. Despite its broad therapeutic use, the effects of electrical stimulation on brain cells is not fully understood. Here, we examine the effects of electrical stimulation on neural stem and progenitor cells (collectively neural precursor cells; NPCs) C57BLJ/6 mice found in the subventricular zone (SVZ) of the adult forebrain. Previous work has demonstrated that adult-derived NPCs are electro-sensitive and undergo rapid and directed migration in response to application of clinically relevant electric fields. We examine NPC proliferation kinetics and their differentiation profile following electric field application using in vitro and in vivo assays. In vitro direct current electrical stimulation of 250 mV/mm is sufficient to elicit a 2-fold increase in the neural stem cell pool and increases neurogenesis and oligogenesis. In vivo, asymmetric biphasic electrical stimulation similarly increases the size of the NPC pool and alters neurogenesis. These findings provide insight into the effects of electrical stimulation on NPCs and suggest its potential use as a regenerative approach to neural repair.Significance Statement Electrical stimulation promotes neural precursor cell migration. In this study we demonstrate that electrical stimulation in addition to cell migration can also expand the size of the NPC pool and enhance neurogenesis, both in vitro and in vivo Using electrical stimulation to activate neural stem cells could be a powerful tool to promote tissue repair.

PMID: 32719101 [PubMed - as supplied by publisher]



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Author Correction: Caenorhabditis elegans is a useful model for anthelmintic discovery.

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Author Correction: Caenorhabditis elegans is a useful model for anthelmintic discovery.

Nat Commun. 2020 Jul 24;11(1):3779

Authors: Burns AR, Luciani GM, Musso G, Bagg R, Yeo M, Zhang Y, Rajendran L, Glavin J, Hunter R, Redman E, Stasiuk S, Schertzberg M, McQuibban GA, Caffrey CR, Cutler SR, Tyers M, Giaever G, Nislow C, Fraser AG, MacRae CA, Gilleard J, Roy PJ

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 32709866 [PubMed - in process]



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Binding specificities of human RNA-binding proteins toward structured and linear RNA sequences.

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Binding specificities of human RNA-binding proteins toward structured and linear RNA sequences.

Genome Res. 2020 Jul 23;:

Authors: Jolma A, Zhang J, Mondragón E, Morgunova E, Kivioja T, Laverty KU, Yin Y, Zhu F, Bourenkov G, Morris Q, Hughes TR, Maher LJ, Taipale J

Abstract
RNA-binding proteins (RBPs) regulate RNA metabolism at multiple levels by affecting splicing of nascent transcripts, RNA folding, base modification, transport, localization, translation, and stability. Despite their central role in RNA function, the RNA-binding specificities of most RBPs remain unknown or incompletely defined. To address this, we have assembled a genome-scale collection of RBPs and their RNA-binding domains (RBDs) and assessed their specificities using high-throughput RNA-SELEX (HTR-SELEX). Approximately 70% of RBPs for which we obtained a motif bound to short linear sequences, whereas ∼30% preferred structured motifs folding into stem-loops. We also found that many RBPs can bind to multiple distinctly different motifs. Analysis of the matches of the motifs in human genomic sequences suggested novel roles for many RBPs. We found that three cytoplasmic proteins-ZC3H12A, ZC3H12B, and ZC3H12C-bound to motifs resembling the splice donor sequence, suggesting that these proteins are involved in degradation of cytoplasmic viral and/or unspliced transcripts. Structural analysis revealed that the RNA motif was not bound by the conventional C3H1 RNA-binding domain of ZC3H12B. Instead, the RNA motif was bound by the ZC3H12B's PilT N terminus (PIN) RNase domain, revealing a potential mechanism by which unconventional RBDs containing active sites or molecule-binding pockets could interact with short, structured RNA molecules. Our collection containing 145 high-resolution binding specificity models for 86 RBPs is the largest systematic resource for the analysis of human RBPs and will greatly facilitate future analysis of the various biological roles of this important class of proteins.

PMID: 32703884 [PubMed - as supplied by publisher]



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An optimized QF-binary expression system for use in zebrafish.

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An optimized QF-binary expression system for use in zebrafish.

Dev Biol. 2020 Jul 19;:

Authors: Burgess J, Burrows JT, Sadhak R, Chiang S, Weiss A, D'Amata C, Molinaro AM, Zhu S, Long M, Hu C, Krause HM, Pearson BJ

Abstract
The zebrafish model organism has been of exceptional utility for the study of vertebrate development and disease through the application of tissue-specific labelling and overexpression of genes carrying patient-derived mutations. However, there remains a need for a binary expression system that is both non-toxic and not silenced over animal generations by DNA methylation. The Q binary expression system derived from the fungus Neurospora crassa is ideal, because the consensus binding site for the QF transcription factor lacks CpG dinucleotides, precluding silencing by CpG-meditated methylation. To optimize this system for zebrafish, we systematically tested several variants of the QF transcription factor: QF full length; QF2, which lacks the middle domain; QF2w, which is an attenuated version of QF2; and chimeric QFGal4. We found that full length QF and QF2 were strongly toxic to zebrafish embryos, QF2w was mildly toxic, and QFGal4 was well tolerated, when injected as RNA or expressed ubiquitously from stable transgenes. In addition, QFGal4 robustly activated of a Tg(QUAS:GFPNLS) reporter transgene. To increase the utility of this system, we also modified the QF effector sequence termed QUAS, which consists of five copies of the QF binding site. Specifically, we decreased both the CpG dinucleotide content, as well as decreased the repetitiveness of QUAS, to reduce the risk of transgene silencing via CpG methylation. Moreover, these modifications to QUAS removed leaky QF-independent neural expression that we detected in the original QUAS sequence. To demonstrate the utility of our QF optimizations, we show how the Q-system can be used for lineage tracing using a Cre-dependent Tg(ubi:QFGal4-switch) transgene. We also demonstrate that QFGal4 can be used in transient injections to tag and label endogenous genes by knocking in QFGal4 into sox2 and ubiquitin C genes.

PMID: 32697972 [PubMed - as supplied by publisher]



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