Publications by authors named "Hongyi Zhou"

95 Publications

Propofol Ameliorates ox-LDL-Induced Endothelial Damage Through Enhancing Autophagy via PI3K/Akt/m-TOR Pathway: A Novel Therapeutic Strategy in Atherosclerosis.

Front Mol Biosci 2021 25;8:695336. Epub 2021 Jun 25.

The First School of Clinical Medicine, Lanzhou University, Lanzhou, China.

Atherosclerosis (AS) represents a common age-associated disease, which may be accelerated by oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell injury. This study aimed to investigate the effects of Propofol on ox-LDL-induced endothelial damage and the underlying molecular mechanisms. Human umbilical vein endothelial cells (HUVECs) were exposed to ox-LDL to induce endothelial damage. HUVECs were pretreated with 0, 5, 25 and 100°μM Propofol, followed by exposure to 100°μg/ml ox-LDL for 24°h. Cell viability was assessed by cell counting kit-8 (CCK-8) assay. The expression of autophagy- and apoptosis-related proteins was detected via western blot. Autophagosome was investigated under a transmission electron microscope. After co-treatment with autophagy inhibitor Bafilomycin A1 or si-Beclin-1, cell apoptosis was detected by flow cytometry. Furthermore, under cotreatment with PI3K activator 740Y-P, PI3K/Akt/m-TOR pathway- and autophagy-related proteins were examined by western blot. With a concentration-dependent manner, Propofol promoted the viability of HUVECs exposed to ox-LDL, and increased LC3-II/I ratio and Beclin-1 expression, and decreased P62 expression. The formation of autophagosome was enhanced by Propofol. Furthermore, Propofol treatment elevated Bcl-2/Bax ratio and lowered Caspase-3 expression. Bafilomycin A1 or si-Beclin-1 distinctly ameliorated the inhibitory effects of Propofol on apoptosis in ox-LDL-exposed HUVECs. Moreover, Propofol lowered the activation of PI3K/Akt/m-TOR pathway in HUVECs under exposure to ox-LDL. However, its inhibitory effects were weakened by 740Y-P. Collectively, this study revealed that Propofol could ameliorate ox-LDL-induced endothelial damage through enhancing autophagy via PI3K/Akt/m-TOR pathway, which might offer a novel therapeutic strategy in AS.
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http://dx.doi.org/10.3389/fmolb.2021.695336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267008PMC
June 2021

Knockdown of MCM8 inhibits development and progression of bladder cancer in vitro and in vivo.

Cancer Cell Int 2021 Apr 30;21(1):242. Epub 2021 Apr 30.

Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Rd, Wuxi, 214023, China.

Background: Bladder cancer is a frequently diagnosed urinary system tumor, whose mortality remains rising. Minichromosome maintenance eight homologous recombination repair factor (MCM8), a newly discovered MCM family member, has been shown to be required for DNA replication. Unfortunately, little is known concerning the roles of MCM8 in bladder cancer.

Methods: The present study, we aimed at probing into the impacts and detailed mechanisms of MCM8 in bladder cancer progression. In this study, MCM8 expression level was detected through immunohistochemistry staining (IHC), qRT-PCR and Western blot assay. Silenced MCM8 cell models were constructed by lentivirus transfection. In vitro, the cell proliferation was evaluated by the MTT assay. The wound-healing assay and the transwell assay were utilized to assess the cell migration. Also, the cell apoptosis and the cell cycle were determined by flow cytometry. Moreover, the Human Apoptosis Antibody Array assay was performed to analyze the alterations of apoptosis-related proteins. The in vivo experiments were conducted to verify the effects of MCM8 knockdown on the tumor growth of bladder cancer.

Results: The results demonstrated that compared with normal adjacent tissues, MCM8 expression in bladder cancer tissues was strongly up-regulated. The up-regulation of MCM8 expression in bladder cancer may be a valuable independent prognostic indicator. Of note, MCM8 inhibition modulated the malignant phenotypes of bladder cancer cells. In terms of mechanism, it was validated that MCM8 knockdown made Akt, P-Akt, CCND1 and CDK6 levels down-regulated, as well as MAPK9 up-regulated.

Conclusions: Taken together, our study demonstrated an important role of MCM8 in bladder cancer and created a rationale for the therapeutic potential of MCM8 inhibition in human bladder cancer therapy.
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http://dx.doi.org/10.1186/s12935-021-01948-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086360PMC
April 2021

Effect of Static Magnetic Field on M7 Based on Transcriptome Analysis.

J Fungi (Basel) 2021 Mar 30;7(4). Epub 2021 Mar 30.

Hubei International Scientific and Technological Cooperation Base of Traditional Fermented Foods, Huazhong Agricultural University, Wuhan 430070, China.

The effects of a static magnetic field (SMF) on M7 ( M7) cultured on potato dextrose agar (PDA) plates under SMF treatment at different intensities (5, 10, and 30 mT) were investigated in this paper. The results revealed that, compared with the control (CK, no SMF treatment), the SMF at all tested intensities did not significantly influence the morphological characteristics of M7, while the intracellular and extracellular pigments (MPs) and extracellular citrinin (CIT) of M7 were increased at 10 and 30 mT SMF but there was no impact on the MPs and CIT at 5 mT SMF. The transcriptome data of M7 cultured at 30 mT SMF on PDA for 3 and 7 d showed that the SMF could increase the transcriptional levels of some relative genes with the primary metabolism, including the carbohydrate metabolism, amino acid metabolism, and lipid metabolism, especially in the early growing period (3 d). SMF could also affect the transcriptional levels of the related genes to the biosynthetic pathways of MPs, CIT, and ergosterol, and improve the transcription of the relative genes in the mitogen-activated protein kinase (MAPK) signaling pathway of M7. These findings provide insights into a comprehensive understanding of the effects of SMF on filamentous fungi.
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http://dx.doi.org/10.3390/jof7040256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066190PMC
March 2021

FRAGSITE: A Fragment-Based Approach for Virtual Ligand Screening.

J Chem Inf Model 2021 04 16;61(4):2074-2089. Epub 2021 Mar 16.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Drive, NW, Atlanta, Georgia 30332-2000, United States.

To reduce time and cost, virtual ligand screening (VLS) often precedes experimental ligand screening in modern drug discovery. Traditionally, high-resolution structure-based docking approaches rely on experimental structures, while ligand-based approaches need known binders to the target protein and only explore their nearby chemical space. In contrast, our structure-based FINDSITE approach takes advantage of predicted, low-resolution structures and information from ligands that bind distantly related proteins whose binding sites are similar to the target protein. Using a boosted tree regression machine learning framework, we significantly improved FINDSITE by integrating ligand fragment scores as encoded by molecular fingerprints with the global ligand similarity scores of FINDSITE. The new approach, FRAGSITE, exploits our observation that ligand fragments, e.g., rings, tend to interact with stereochemically conserved protein subpockets that also occur in evolutionarily unrelated proteins. FRAGSITE was benchmarked on the 102 protein DUD-E set, where any template protein whose sequence identify >30% to the target was excluded. Within the top 100 ranked molecules, FRAGSITE improves VLS precision and recall by 14.3 and 18.5%, respectively, relative to FINDSITE. Moreover, the mean top 1% enrichment factor increases from 25.2 to 30.2. On average, both outperform state-of-the-art deep learning-based methods such as AtomNet. On the more challenging unbiased set LIT-PCBA, FRAGSITE also shows better performance than ligand similarity-based and docking approaches such as two-dimensional ECFP4 and Surflex-Dock v.3066. On a subset of 23 targets from DEKOIS 2.0, FRAGSITE shows much better performance than the boosted tree regression-based, vScreenML scoring function. Experimental testing of FRAGSITE's predictions shows that it has more hits and covers a more diverse region of chemical space than FINDSITE. For the two proteins that were experimentally tested, DHFR, a well-studied protein that catalyzes the conversion of dihydrofolate to tetrahydrofolate, and the kinase ACVR1, FRAGSITE identified new small-molecule nanomolar binders. Interestingly, one new binder of DHFR is a kinase inhibitor predicted to bind in a new subpocket. For ACVR1, FRAGSITE identified new molecules that have diverse scaffolds and estimated nanomolar to micromolar affinities. Thus, FRAGSITE shows significant improvement over prior state-of-the-art ligand virtual screening approaches. A web server is freely available for academic users at http:/sites.gatech.edu/cssb/FRAGSITE.
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http://dx.doi.org/10.1021/acs.jcim.0c01160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243409PMC
April 2021

TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes.

Cell Death Differ 2021 Jul 19;28(7):2045-2059. Epub 2021 Jan 19.

Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.

The Hippo signaling effector, TEAD1 plays an essential role in cardiovascular development. However, a role for TEAD1 in postmitotic cardiomyocytes (CMs) remains incompletely understood. Herein we reported that TEAD1 is required for postmitotic CM survival. We found that adult mice with ubiquitous or CM-specific loss of Tead1 present with a rapid lethality due to an acute-onset dilated cardiomyopathy. Surprisingly, deletion of Tead1 activated the necroptotic pathway and induced massive cardiomyocyte necroptosis, but not apoptosis. In contrast to apoptosis, necroptosis is a pro-inflammatory form of cell death and consistent with this, dramatically higher levels of markers of activated macrophages and pro-inflammatory cytokines were observed in the hearts of Tead1 knockout mice. Blocking necroptosis by administration of necrostatin-1 rescued Tead1 deletion-induced heart failure. Mechanistically, genome-wide transcriptome and ChIP-seq analysis revealed that in adult hearts, Tead1 directly activates a large set of nuclear DNA-encoded mitochondrial genes required for assembly of the electron transfer complex and the production of ATP. Loss of Tead1 expression in adult CMs increased mitochondrial reactive oxygen species, disrupted the structure of mitochondria, reduced complex I-IV driven oxygen consumption and ATP levels, resulting in the activation of necroptosis. This study identifies an unexpected paradigm in which TEAD1 is essential for postmitotic CM survival by maintaining the expression of nuclear DNA-encoded mitochondrial genes required for ATP synthesis.
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http://dx.doi.org/10.1038/s41418-020-00732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257617PMC
July 2021

The Magnetic Receptor of M7: Gene Clone and Its Heterologous Expression in .

Front Microbiol 2020 19;11:1112. Epub 2020 Jun 19.

Hubei International Scientific and Technological Cooperation Base of Traditional Fermented Foods, Huazhong Agricultural University, Wuhan, China.

It is well known that many organisms can perceive the magnetic field (MF), including the geomagnetic field, but how to feel MF is unclear. Recently, a study has claimed that a biological compass, namely a complex of the magnetic receptor (MagR) and blue light (BL) receptor (cryptochrome), has been found in , , and , which may bring some new ideas to explore the mechanism of biomagnetism. spp. are edible filamentous fungi that can produce abundant beneficial secondary metabolites and have been used to produce food colorants for nearly 2000 years in the world, especially in China, Japan, and Korea. In this work, we firstly treated M7 by BL (500 lux,465-467 nm), MF (5, 10, 30 mT), and the combination of MF and BL (MF-BL), respectively. The results revealed that, compared with the control (CK, neither BL nor MF), the MF alone had no effect on the growth and morphological characteristics of M7, but BL made the colonial diameters only 66.7% of CK's and inhibited the formation of cleistothecia. Under MF-BL, the colony diameters were still 66.7% of CK's, but the colonial growth and cleistothecia production inhibited by BL were partially restored. Then, we have found that the gene widely exists in the genomes of animals, plants, and microorganisms, and we have also discovered a gene in the M7 genome, hereinafter referred to . Finally, the full-length cDNA of was successfully cloned and expressed in BL21 (DE3), and the Mr-MagR protein was purified by a Ni-NTA column and identified by Western blot. These results have laid a foundation for further investigation on the relationship between Mr-MagR and BL receptor(s) that might exist in M7. According to a literature search, it is the first time to report in filamentous fungi.
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http://dx.doi.org/10.3389/fmicb.2020.01112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318567PMC
June 2020

Differential kinase activity of ACVR1 G328V and R206H mutations with implications to possible TβRI cross-talk in diffuse intrinsic pontine glioma.

Sci Rep 2020 04 9;10(1):6140. Epub 2020 Apr 9.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Drive, NW, Atlanta, Georgia, 30332, United States.

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer whose median survival time is under one year. The possible roles of the two most common DIPG associated cytoplasmic ACVR1 receptor kinase domain mutants, G328V and R206H, are reexamined in the context of new biochemical results regarding their intrinsic relative ATPase activities. At 37 °C, the G328V mutant displays a 1.8-fold increase in intrinsic kinase activity over wild-type, whereas the R206H mutant shows similar activity. The higher G328V mutant intrinsic kinase activity is consistent with the statistically significant longer overall survival times of DIPG patients harboring ACVR1 G328V tumors. Based on the potential cross-talk between ACVR1 and TβRI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated the inhibition effects of several TβRI inhibitors on ACVR1 wild-type and G328V mutant patient tumor derived DIPG cell lines at 20-50 µM doses. SU-DIPG-IV cells harboring the histone H3.1K27M and activating ACVR1 G328V mutations appeared to be less susceptible to TβRI inhibition than SF8628 cells harboring the H3.3K27M mutation and wild-type ACVR1. Thus, inhibition of hidden oncogenic signaling pathways in DIPG such as TβRI that are not limited to ACVR1 itself may provide alternative entry points for DIPG therapeutics.
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http://dx.doi.org/10.1038/s41598-020-63061-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145857PMC
April 2020

Berardinelli-Seip congenital lipodystrophy 2/SEIPIN determines brown adipose tissue maintenance and thermogenic programing.

Mol Metab 2020 06 4;36:100971. Epub 2020 Mar 4.

Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA. Electronic address:

Objective: Understanding the mechanisms that control brown adipose tissue (BAT) mass and functionality is crucial for our understanding of how the disruption of energy homeostasis leads to obesity. Bernerdinali Seip Congenital Lipodystrophy (BSCL) type 2 (BSCL2, a.k.a. SEIPIN), a lipodystrophy-associated protein, has been shown to not be required for brown adipogenesis, but it has been shown to be essential for perinatal BAT development. However, its role in mature BAT maintenance and thermogenic programing remains poorly understood.

Methods: We subjected Bscl2 and Bscl2 (BKO) mice with a brown adipose-specific loss of BSCL2 through UCP1 promoter-driven Cre to environmental, pharmacological and diet interventions to challenge BAT functionality and reprogramming. We carried out physiological, molecular and transcriptomic analyses of BAT.

Results: The deletion of BSCL2 in mature brown adipocytes increased sympathetic nervous system-independent cAMP/protein kinase A (PKA) signaling in BAT. Such activation reduced BAT triglyceride content and mass and was sufficient to reduce plasma triglyceride, but not enough to combat thermoneutral and high fat diet-induced obesity. Surprisingly, BKO mice displayed an impaired response to acute and chronic cold challenges despite cAMP/PKA activation. When subjected to chronic cold exposure or the administration of a β3-adrenergic agonist, CL 316,243, BKO mice failed to induce BAT recruitment and underwent dramatic brown adipocyte loss. Transcriptomic analysis revealed pathological BAT remodeling with inflammation and fibrosis, which was further exacerbated by a chronic thermogenic challenge in BKO mice. Mechanistically, we found abnormal mitochondrial shapes and function in BAT of BKO mice housed at 21 °C; as well as mitochondrial DNA depletion and necroptotic-mediated brown adipocyte death after chronic thermogenic insult.

Conclusion: BSCL2-mediated lipid catabolism within BAT is crucial for mature brown adipocyte function and survival both during times of activation and quiescence. BSCL2 is an important regulator of mature brown adipocyte mitochondrial metabolism, necroptosis and thus adaptive thermogenesis.
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http://dx.doi.org/10.1016/j.molmet.2020.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136632PMC
June 2020

MEDICASCY: A Machine Learning Approach for Predicting Small-Molecule Drug Side Effects, Indications, Efficacy, and Modes of Action.

Mol Pharm 2020 05 13;17(5):1558-1574. Epub 2020 Apr 13.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Drive, N.W., Atlanta, Georgia 30332, United States.

To improve the drug discovery yield, a method which is implemented at the beginning of drug discovery that accurately predicts drug side effects, indications, efficacy, and mode of action based solely on the input of the drug's chemical structure is needed. In contrast, extant predictive methods do not comprehensively address these aspects of drug discovery and rely on features derived from extensive, often unavailable experimental information for novel molecules. To address these issues, we developed MEDICASCY, a multilabel-based boosted random forest machine learning method that only requires the small molecule's chemical structure for the drug side effect, indication, efficacy, and probable mode of action target predictions; however, it has comparable or even significantly better performance than existing approaches requiring far more information. In retrospective benchmarking on high confidence predictions, MEDICASCY shows about 78% precision and recall for predicting at least one severe side effect and 72% precision drug efficacy. Experimental validation of MEDICASCY's efficacy predictions on novel molecules shows close to 80% precision for the inhibition of growth in ovarian, breast, and prostate cancer cell lines. Thus, MEDICASCY should improve the success rate for new drug approval. A web service for academic users is available at http://pwp.gatech.edu/cssb/MEDICASCY.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b01248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319183PMC
May 2020

Antimalarial Peptide and Polyketide Natural Products from the Fijian Marine Cyanobacterium .

Mar Drugs 2020 03 18;18(3). Epub 2020 Mar 18.

School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA.

A new cyclic peptide, kakeromamide B (), and previously described cytotoxic cyanobacterial natural products ulongamide A (), lyngbyabellin A (), 18-lyngbyaloside C (), and lyngbyaloside () were identified from an antimalarial extract of the Fijian marine cyanobacterium . Compounds and exhibited moderate activity against blood-stages with EC values of 0.89 and 0.99 µM, respectively, whereas was more potent with an EC value of 0.15 nM, respectively. Compounds , , and displayed moderate liver-stage antimalarial activity against liver schizonts with EC values of 1.1, 0.71, and 0.45 µM, respectively. The threading-based computational method FINDSITE predicted the binding of and to potentially druggable proteins of , prompting formulation of hypotheses about possible mechanisms of action. Kakeromamide B () was predicted to bind to several actin-like proteins and a sortilin protein suggesting possible interference with parasite invasion of host cells. When 1 was tested in a mammalian actin polymerization assay, it stimulated actin polymerization in a dose-dependent manner, suggesting that 1 does, in fact, interact with actin.
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http://dx.doi.org/10.3390/md18030167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142784PMC
March 2020

On the possible origin of protein homochirality, structure, and biochemical function.

Proc Natl Acad Sci U S A 2019 Dec 10. Epub 2019 Dec 10.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332.

Living systems have chiral molecules, e.g., native proteins that almost entirely contain L-amino acids. How protein homochirality emerged from a background of equal numbers of L and D amino acids is among many questions about life's origin. The origin of homochirality and its implications are explored in computer simulations examining the stability and structural and functional properties of an artificial library of compact proteins containing 1:1 (termed demi-chiral), 3:1, and 1:3 ratios of D:L and purely L or D amino acids generated without functional selection. Demi-chiral proteins have shorter secondary structures and fewer internal hydrogen bonds and are less stable than homochiral proteins. Selection for hydrogen bonding yields a preponderance of L or D amino acids. Demi-chiral proteins have native global folds, including similarity to early ribosomal proteins, similar small molecule ligand binding pocket geometries, and many constellations of L-chiral amino acids with a 1.0-Å RMSD to native enzyme active sites. For a representative subset containing 550 active site geometries matching 457 (2) 4-digit (3-digit) enzyme classification (E.C.) numbers, native active site amino acids were generated at random for 472 of 550 cases. This increases to 548 of 550 cases when similar residues are allowed. The most frequently generated sequences correspond to ancient enzymatic functions, e.g., glycolysis, replication, and nucleotide biosynthesis. Surprisingly, even without selection, demi-chiral proteins possess the requisite marginal biochemical function and structure of modern proteins, but were thermodynamically less stable. If demi-chiral proteins were present, they could engage in early metabolism, which created the feedback loop for transcription and cell formation.
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http://dx.doi.org/10.1073/pnas.1908241116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936705PMC
December 2019

Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency.

Nat Med 2019 11 21;25(11):1684-1690. Epub 2019 Oct 21.

Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.

Dysregulation of the mammalian target of rapamycin (mTOR) signaling, which is mediated by two structurally and functionally distinct complexes, mTORC1 and mTORC2, has been implicated in several neurological disorders. Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability. It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (for example, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis. Using molecular genetics, we unexpectedly found that genetic deletion of mTORC2 (but not mTORC1) activity prolonged lifespan, suppressed seizures, rescued ASD-like behaviors and long-term memory, and normalized metabolic changes in the brain of mice lacking Pten. In a more therapeutically oriented approach, we found that administration of an antisense oligonucleotide (ASO) targeting mTORC2's defining component Rictor specifically inhibits mTORC2 activity and reverses the behavioral and neurophysiological abnormalities in adolescent Pten-deficient mice. Collectively, our findings indicate that mTORC2 is the major driver underlying the neuropathophysiology associated with Pten-deficiency, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where mTOR signaling is dysregulated.
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http://dx.doi.org/10.1038/s41591-019-0608-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082835PMC
November 2019

Quantum Coherence Witness with Untrusted Measurement Devices.

Phys Rev Lett 2019 Aug;123(9):090502

Hefei National Laboratory for Physical Sciences at Microscale and Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China.

Coherence is a fundamental resource in quantum information processing, which can be certified by a coherence witness. Due to the imperfection of measurement devices, a conventional coherence witness may lead to fallacious results. We show that the conventional witness could mistake an incoherent state as a state with coherence due to the inaccurate settings of measurement bases. In order to make the witness result reliable, we propose a measurement-device-independent coherence witness scheme without any assumptions on the measurement settings. We introduce the decoy-state method to significantly increase the capability of recognizing states with coherence. Furthermore, we experimentally demonstrate the scheme in a time-bin encoding optical system.
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http://dx.doi.org/10.1103/PhysRevLett.123.090502DOI Listing
August 2019

Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy.

JCI Insight 2019 06 11;5. Epub 2019 Jun 11.

Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.

Mutations in BSCL2 gene underlie human type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease. Global Bscl2-/- mice recapitulate human BSCL2 lipodystrophy and develop insulin resistance and hypertrophic cardiomyopathy. The pathological mechanisms underlying the development of lipodystrophy and cardiomyopathy in BSCL2 are controversial. Here we report that Bscl2-/- mice develop cardiac hypertrophy due to increased basal IGF1 receptor (IGF1R)-mediated PI3K/AKT signaling. Bscl2-/- hearts exhibited increased adipose triglyceride lipase (ATGL) protein stability and expression causing drastic reduction of glycerolipids. Excessive fatty acid oxidation was overt in Bscl2-/- hearts, partially attributing to the hyperacetylation of cardiac mitochondrial proteins. Intriguingly, pharmacological inhibition or genetic inactivation of ATGL could rescue adipocyte differentiation and lipodystrophy in Bscl2-/- cells and mice. Restoring a small portion of fat mass by ATGL partial deletion in Bscl2-/- mice not only reversed the systemic insulin resistance, but also ameliorated cardiac protein hyperacetylation, normalized cardiac substrate metabolism and improved contractile function. Collectively, our study uncovers novel pathways underlying lipodystrophy-induced cardiac hypertrophy and metabolic remodeling and pinpoints ATGL as a downstream target of BSCL2 in regulating the development of lipodystrophy and its associated cardiomyopathy.
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http://dx.doi.org/10.1172/jci.insight.129781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675548PMC
June 2019

DESTINI: A deep-learning approach to contact-driven protein structure prediction.

Sci Rep 2019 03 5;9(1):3514. Epub 2019 Mar 5.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA.

The amino acid sequence of a protein encodes the blueprint of its native structure. To predict the corresponding structural fold from the protein's sequence is one of most challenging problems in computational biology. In this work, we introduce DESTINI (deep structural inference for proteins), a novel computational approach that combines a deep-learning algorithm for protein residue/residue contact prediction with template-based structural modelling. For the first time, the significantly improved predictive ability is demonstrated in the large-scale tertiary structure prediction of over 1,200 single-domain proteins. DESTINI successfully predicts the tertiary structure of four times the number of "hard" targets (those with poor quality templates) that were previously intractable, viz, a "glass-ceiling" for previous template-based approaches, and also improves model quality for "easy" targets (those with good quality templates). The significantly better performance by DESTINI is largely due to the incorporation of better contact prediction into template modelling. To understand why deep-learning accomplishes more accurate contact prediction, systematic clustering reveals that deep-learning predicts coherent, native-like contact patterns compared to co-evolutionary analysis. Taken together, this work presents a promising strategy towards solving the protein structure prediction problem.
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http://dx.doi.org/10.1038/s41598-019-40314-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401133PMC
March 2019

The crystal structure of a tetrahydrofolate-bound dihydrofolate reductase reveals the origin of slow product release.

Commun Biol 2018 12;1:226. Epub 2018 Dec 12.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Drive, NW, Atlanta, GA 30332 USA.

Dihydrofolate reductase (DHFR) catalyzes the stereospecific reduction of 7,8-dihydrofolate (FH2) to (6s)-5,6,7,8-tetrahydrofolate (FH4) via hydride transfer from NADPH. The consensus DHFR mechanism involves conformational changes between closed and occluded states occurring during the rate-limiting product release step. Although the Protein Data Bank (PDB) contains over 250 DHFR structures, the FH4 complex structure responsible for rate-limiting product release is unknown. We report to our knowledge the first crystal structure of an . DHFR:FH4 complex at 1.03 Å resolution showing distinct stabilizing interactions absent in FH2 or related (6R)-5,10-dideaza-FH4 complexes. We discover the time course of decay of the co-purified endogenous FH4 during crystal growth, with conversion from FH4 to FH2 occurring in 2-3 days. We also determine another occluded complex structure of DHFR with a slow-onset nanomolar inhibitor that contrasts with the methotrexate complex, suggesting a plausible strategy for designing DHFR antibiotics by targeting FH4 product conformations.
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http://dx.doi.org/10.1038/s42003-018-0236-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290769PMC
December 2018

Novel metabolic disorders in skeletal muscle of Lipodystrophic Bscl2/Seipin deficient mice.

Mol Cell Endocrinol 2019 02 4;482:1-10. Epub 2018 Dec 4.

Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. Electronic address:

Bscl2 mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatosteatosis, muscular hypertrophy, and insulin resistance. Metabolic defects in Bscl2 mice with regard to glucose and lipid metabolism in skeletal muscle have never been investigated. Here, we identified Bscl2 mice displayed reduced intramyocellular triglyceride (IMTG) content but increased glycogen storage predominantly in oxidative type I soleus muscle (SM). These changes were associated with increased incomplete fatty acid oxidation and glycogen synthesis. Interestingly, SM in Bscl2 mice demonstrated a fasting duration induced insulin sensitivity which was further confirmed by hyperinsulinemic-euglycemic clamp in SM of overnight fasted Bscl2 mice but reversed by raising circulating NEFA levels through intralipid infusion. Furthermore, mice with skeletal muscle-specific inactivation of BSCL2 manifested no changes in muscle deposition of lipids and glycogen, suggesting BSCL2 does not play a cell-autonomous role in muscle lipid and glucose homeostasis. Our study uncovers a novel link between muscle metabolic defects and insulin resistance, and underscores an important role of circulating NEFA in regulating oxidative muscle insulin signaling in BSCL2 lipodystrophy.
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http://dx.doi.org/10.1016/j.mce.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340772PMC
February 2019

Obesity-associated family with sequence similarity 13, member A (FAM13A) is dispensable for adipose development and insulin sensitivity.

Int J Obes (Lond) 2019 06 9;43(6):1269-1280. Epub 2018 Oct 9.

Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.

Background: Obesity and its associated morbidities represent the major and most rapidly expanding world-wide health epidemic. Recent genome-wide association studies (GWAS) reveal that single nucleotide polymorphism (SNP) variant in the Family with Sequence Similarity 13, Member A (FAM13A) gene is strongly associated with waist-hip ratio (WHR) with adjustment for body mass index (BMI) (WHRadjBMI). However, the function of FAM13A in adipose development and obesity remains largely uncharacterized.

Methods: The expression of FAM13A in adipose tissue depots were investigated using lean, genetic obese and high fat diet-induced obese (DIO) animal models and during adipocyte differentiation. Stromal vascular cells (SVCs) or 3T3-L1 cells with gain and loss of function of FAM13A were used to determine the involvement of FAM13A in regulating adipocyte differentiation. Adipose development and metabolic homeostasis in Fam13a mice were characterized under normal chow and high fat diet feeding.

Results: Murine FAM13A expression was nutritionally regulated and dramatically reduced in epididymal and subcutaneous fat in genetic and diet-induced obesity. Its expression was enriched in mature adipocytes and significantly upregulated during murine and human adipogenesis potentially through a peroxisome proliferator-activated receptor-gamma (PPARγ)-dependent mechanism. However, Fam13a mice only exhibited a tendency of higher adiposity and were not protected from DIO and insulin resistance. While Fam13a SVCs maintained normal adipogenesis, overexpression of FAM13A in 3T3-L1 preadipocytes downregulated β-catenin signaling and rendered preadipocytes more susceptible to apoptosis. Moreover, FAM13A overexpression largely blocked adipogenesis induced by a standard hormone cocktail, but adipogenesis can be partially rescued by the addition of PPARγ agonist pioglitazone at an early stage of differentiation.

Conclusions: Our results suggest that FAM13A is dispensable for adipose development and insulin sensitivity. Yet the expression of FAM13A needs to be tightly controlled in adipose precursor cells for their proper survival and downstream adipogenesis. These data provide novel insights into the link between FAM13A and obesity.
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http://dx.doi.org/10.1038/s41366-018-0222-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456441PMC
June 2019

FINDSITE: A New Approach for Virtual Ligand Screening of Proteins and Virtual Target Screening of Biomolecules.

J Chem Inf Model 2018 11 16;58(11):2343-2354. Epub 2018 Oct 16.

Center for the Study of Systems Biology, School of Biological Sciences , Georgia Institute of Technology , 950 Atlantic Drive, NW , Atlanta , Georgia 30332-2000 , United States.

Computational approaches for predicting protein-ligand interactions can facilitate drug lead discovery and drug target determination. We have previously developed a threading/structural-based approach, FINDSITE, for the virtual ligand screening of proteins that has been extensively experimentally validated. Even when low resolution predicted protein structures are employed, FINDSITE has the advantage of being faster and more accurate than traditional high-resolution structure-based docking methods. It also overcomes the limitations of traditional QSAR methods that require a known set of seed ligands that bind to the given protein target. Here, we further improve FINDSITE by enhancing its template ligand selection from the PDB/DrugBank/ChEMBL libraries of known protein-ligand interactions by (1) parsing the template proteins and their corresponding binding ligands in the DrugBank and ChEMBL libraries into domains so that the ligands with falsely matched domains to the targets will not be selected as template ligands; (2) applying various thresholds to filter out falsely matched template structures in the structure comparison process and thus their corresponding ligands for template ligand selection. With a sequence identity cutoff of 30% of target to templates and modeled target structures, FINDSITE is shown to significantly improve upon FINDSITE on the DUD-E benchmark set by increasing the 1% enrichment factor from 16.7 to 22.1, with a p-value of 4.3 × 10 by the Student t-test. With an 80% sequence identity cutoff of target to templates for the DUD-E set and modeled target structures, FINDSITE, having a 1% ROC enrichment factor of 52.39, also outperforms state-of-the-art methods that employ machine learning such as a deep convolutional neural network, CNN, with an enrichment of 29.65. Thus, FINDSITE represents a significant improvement in the state-of-the-art. The FINDSITE web service is freely available for academic users at http://pwp.gatech.edu/cssb/FINDSITE-COMB-2 .
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http://dx.doi.org/10.1021/acs.jcim.8b00309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437778PMC
November 2018

Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs.

Med Res Rev 2019 03 7;39(2):684-705. Epub 2018 Sep 7.

Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, Georgia.

Escherichia coli Dihydrofolate reductase is an important enzyme that is essential for the survival of the Gram-negative microorganism. Inhibitors designed against this enzyme have demonstrated application as antibiotics. However, either because of poor bioavailability of the small-molecules resulting from their inability to cross the double membrane in Gram-negative bacteria or because the microorganism develops resistance to the antibiotics by mutating the DHFR target, discovery of new antibiotics against the enzyme is mandatory to overcome drug-resistance. This review summarizes the field of DHFR inhibition with special focus on recent efforts to effectively interface computational and experimental efforts to discover novel classes of inhibitors that target allosteric and active-sites in drug-resistant variants of EcDHFR.
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http://dx.doi.org/10.1002/med.21538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370515PMC
March 2019

ENTPRISE-X: Predicting disease-associated frameshift and nonsense mutations.

PLoS One 2018 3;13(5):e0196849. Epub 2018 May 3.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

To exploit the plethora of information provided by Next Generation Sequencing, the identification of the genetic mutations responsible for disease in general or cancer in particular, among the thousands of neutral germline or somatic variations is a crucial task. Genome-wide association studies for the detection of disease-associated genes or cancer drivers can only identify common variations or driver genes in a cohort of patients. Thus, they cannot discover unique disease-associated mutations or cancer driver genes on a personal basis. Moreover, even when there are such common variations, their significance is unknown. Here, we extend the machine learning based approach ENTPRISE developed for predicting the disease association of missense mutations to frameshift and nonsense mutations. The new approach, ENTPRISE-X, is shown to outperform the state-of-the-art methods VEST-indel and DDIG-in for predicting the disease association of germline frameshift mutations in terms of balanced measure Matthew's correlation coefficient, MCC, with a MCC of 0.586 for ENTPRISE-X, versus 0.412 by VEST-indel and 0.321 by DDIG-in, respectively. Large scale testing on the ExAC dataset shows ENTPRISE-X has a much lower fraction of 16% of variations classified as disease causing, as compared to VEST-indel's 26% and DDIG-in's 65% of predictions as being disease-associated. A web server for ENTPRISE-X is freely available for academic users at http://cssb2.biology.gatech.edu/entprise-x.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196849PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933770PMC
August 2018

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling.

Proc Natl Acad Sci U S A 2018 04 9;115(17):E4101-E4110. Epub 2018 Apr 9.

Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.
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http://dx.doi.org/10.1073/pnas.1719309115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924905PMC
April 2018

Local spatial obesity analysis and estimation using online social network sensors.

J Biomed Inform 2018 07 15;83:54-62. Epub 2018 Mar 15.

Shaanxi Key Laboratory of Network Computing and Security, Xi'an University of Technology, 710048, China.

Recently, the online social networks (OSNs) have received considerable attentions as a revolutionary platform to offer users massive social interaction among users that enables users to be more involved in their own healthcare. The OSNs have also promoted increasing interests in the generation of analytical, data models in health informatics. This paper aims at developing an obesity identification, analysis, and estimation model, in which each individual user is regarded as an online social network 'sensor' that can provide valuable health information. The OSN-based obesity analytic model requires each sensor node in an OSN to provide associated features, including dietary habit, physical activity, integral/incidental emotions, and self-consciousness. Based on the detailed measurements on the correlation of obesity and proposed features, the OSN obesity analytic model is able to estimate the obesity rate in certain urban areas and the experimental results demonstrate a high success estimation rate. The measurements and estimation experimental findings created by the proposed obesity analytic model show that the online social networks could be used in analyzing the local spatial obesity problems effectively.
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http://dx.doi.org/10.1016/j.jbi.2018.03.010DOI Listing
July 2018

Repurposed FDA-approved drugs targeting genes influencing aging can extend lifespan and healthspan in rotifers.

Biogerontology 2018 04 16;19(2):145-157. Epub 2018 Jan 16.

School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332-0230, USA.

Pharmaceutical interventions can slow aging in animals, and have advantages because their dose can be tightly regulated and the timing of the intervention can be closely controlled. They also may complement environmental interventions like caloric restriction by acting additively. A fertile source for therapies slowing aging is FDA approved drugs whose safety has been investigated. Because drugs bind to several protein targets, they cause multiple effects, many of which have not been characterized. It is possible that some of the side effects of drugs prescribed for one therapy may have benefits in retarding aging. We used computationally guided drug screening for prioritizing drug targets to produce a short list of candidate compounds for in vivo testing. We applied the virtual ligand screening approach FINDSITE for screening potential anti-aging protein targets against FDA approved drugs listed in DrugBank. A short list of 31 promising compounds was screened using a multi-tiered approach with rotifers as an animal model of aging. Primary and secondary survival screens and cohort life table experiments identified four drugs capable of extending rotifer lifespan by 8-42%. Exposures to 1 µM erythromycin, 5 µM carglumic acid, 3 µM capecitabine, and 1 µM ivermectin, extended rotifer lifespan without significant effect on reproduction. Some drugs also extended healthspan, as estimated by mitochondria activity and mobility (swimming speed). Our most promising result is that rotifer lifespan was extended by 7-8.9% even when treatment was started in middle age.
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http://dx.doi.org/10.1007/s10522-018-9745-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834582PMC
April 2018

Why Is There a Glass Ceiling for Threading Based Protein Structure Prediction Methods?

J Phys Chem B 2017 04 26;121(15):3546-3554. Epub 2016 Oct 26.

Center for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology , 950 Atlantic Drive Northwest, Atlanta, Georgia 30318, United States.

Despite their different implementations, comparison of the best threading approaches to the prediction of evolutionary distant protein structures reveals that they tend to succeed or fail on the same protein targets. This is true despite the fact that the structural template library has good templates for all cases. Thus, a key question is why are certain protein structures threadable while others are not. Comparison with threading results on a set of artificial sequences selected for stability further argues that the failure of threading is due to the nature of the protein structures themselves. Using a new contact map based alignment algorithm, we demonstrate that certain folds are highly degenerate in that they can have very similar coarse grained fractions of native contacts aligned and yet differ significantly from the native structure. For threadable proteins, this is not the case. Thus, contemporary threading approaches appear to have reached a plateau, and new approaches to structure prediction are required.
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http://dx.doi.org/10.1021/acs.jpcb.6b09517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398921PMC
April 2017

Novel small molecule binders of human N-glycanase 1, a key player in the endoplasmic reticulum associated degradation pathway.

Bioorg Med Chem 2016 10 13;24(19):4750-4758. Epub 2016 Aug 13.

Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 950, Atlantic Drive, Atlanta, GA 30332, United States. Electronic address:

Peptide:N-glycanase (NGLY1) is an enzyme responsible for cleaving oligosaccharide moieties from misfolded glycoproteins to enable their proper degradation. Deletion and truncation mutations in this gene are responsible for an inherited disorder of the endoplasmic reticulum-associated degradation pathway. However, the literature is unclear whether the disorder is a result of mutations leading to loss-of-function, loss of substrate specificity, loss of protein stability or a combination of these factors. In this communication, without burdening ourselves with the mechanistic underpinning of disease causation because of mutations on the NGLY1 protein, we demonstrate the successful application of virtual ligand screening (VLS) combined with experimental high-throughput validation to the discovery of novel small-molecules that show binding to the transglutaminase domain of NGLY1. Attempts at recombinant expression and purification of six different constructs led to successful expression of five, with three constructs purified to homogeneity. Most mutant variants failed to purify possibly because of misfolding and the resultant exposure of surface hydrophobicity that led to protein aggregation. For the purified constructs, our threading/structure-based VLS algorithm, FINDSITE(comb), was employed to predict ligands that may bind to the protein. Then, the predictions were assessed by high-throughput differential scanning fluorimetry. This led to the identification of nine different ligands that bind to the protein of interest and provide clues to the nature of pharmacophore that facilitates binding. This is the first study that has identified novel ligands that bind to the NGLY1 protein as a possible starting point in the discovery of ligands with potential therapeutic applications in the treatment of the disorder caused by NGLY1 mutants.
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http://dx.doi.org/10.1016/j.bmc.2016.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015769PMC
October 2016

Repurposing FDA-approved drugs for anti-aging therapies.

Biogerontology 2016 11 2;17(5-6):907-920. Epub 2016 Aug 2.

School of Biology, Georgia Institute of Technology, Atlanta, GA, 30332-0230, USA.

There is great interest in drugs that are capable of modulating multiple aging pathways, thereby delaying the onset and progression of aging. Effective strategies for drug development include the repurposing of existing drugs already approved by the FDA for human therapy. FDA approved drugs have known mechanisms of action and have been thoroughly screened for safety. Although there has been extensive scientific activity in repurposing drugs for disease therapy, there has been little testing of these drugs for their effects on aging. The pool of FDA approved drugs therefore represents a large reservoir of drug candidates with substantial potential for anti-aging therapy. In this paper we employ FINDSITE, a powerful ligand homology modeling program, to identify binding partners for proteins produced by temperature sensing genes that have been implicated in aging. This list of drugs with potential to modulate aging rates was then tested experimentally for lifespan and healthspan extension using a small invertebrate model. Three protein targets of the rotifer Brachionus manjavacas corresponding to products of the transient receptor potential gene 7, ribosomal protein S6 polypeptide 2 gene, or forkhead box C gene, were screened against a compound library consisting of DrugBank drugs including 1347 FDA approved, non-nutraceutical molecules. Twenty nine drugs ranked in the top 1 % for binding to each target were subsequently included in our experimental analysis. Continuous exposure of rotifers to 1 µM naproxen significantly extended rotifer mean lifespan by 14 %. We used three endpoints to estimate rotifer health: swimming speed (mobility proxy), reproduction (overall vitality), and mitochondria activity (cellular senescence proxy). The natural decline in swimming speed with aging was more gradual when rotifers were exposed to three drugs, so that on day 6, mean swimming speed of females was 1.19 mm/s for naproxen (P = 0.038), 1.20 for fludarabine (P = 0.040), 1.35 for hydralazine (P = 0.038), as compared to 0.88 mm/s in the control. The average reproduction of control females in the second half of their reproductive lifespan was 1.08 per day. In contrast, females treated with 1 µM naproxen produced 1.4 offspring per day (P = 0.027) and females treated with 10 µM fludarabine or 1 µM hydralazine produced 1.72 (P = <0.001) and 1.66 (P = 0.001) offspring per day, respectively. Mitochondrial activity naturally declines with rotifer aging, but B. manjavacas treated with 1 µM hydralazine or 10 µM fludarabine retained 49 % (P = 0.038) and 89 % (P = 0.002) greater mitochondria activity, respectively, than untreated controls. Our results demonstrate that coupling computation to experimentation can quickly identify new drug candidates with anti-aging potential. Screening drugs for anti-aging effects using a rotifer bioassay is a powerful first step in identifying compounds worthy of follow-up in vertebrate models. Even if lifespan extension is not observed, certain drugs could improve healthspan, slowing age-dependent losses in mobility and vitality.
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http://dx.doi.org/10.1007/s10522-016-9660-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065615PMC
November 2016

Note: Fully integrated 3.2 Gbps quantum random number generator with real-time extraction.

Rev Sci Instrum 2016 Jul;87(7):076102

Hefei National Laboratory for Physical Sciences at the Microscale and Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China.

We present a real-time and fully integrated quantum random number generator (QRNG) by measuring laser phase fluctuations. The QRNG scheme based on laser phase fluctuations is featured for its capability of generating ultra-high-speed random numbers. However, the speed bottleneck of a practical QRNG lies on the limited speed of randomness extraction. To close the gap between the fast randomness generation and the slow post-processing, we propose a pipeline extraction algorithm based on Toeplitz matrix hashing and implement it in a high-speed field-programmable gate array. Further, all the QRNG components are integrated into a module, including a compact and actively stabilized interferometer, high-speed data acquisition, and real-time data post-processing and transmission. The final generation rate of the QRNG module with real-time extraction can reach 3.2 Gbps.
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http://dx.doi.org/10.1063/1.4958663DOI Listing
July 2016

A knowledge-based approach for predicting gene-disease associations.

Bioinformatics 2016 09 9;32(18):2831-8. Epub 2016 Jun 9.

School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA.

Motivation: Recent advances of next-generation sequence technologies have made it possible to rapidly and inexpensively identify gene variations. Knowing the disease association of these gene variations is important for early intervention to treat deadly diseases and provide possible targets to cure these diseases. Genome-wide association studies (GWAS) have identified many individual genes associated with common diseases. To exploit the large amount of data obtained from GWAS studies and leverage our understanding of common as well as rare diseases, we have developed a knowledge-based approach to predict gene-disease associations. We first derive gene-gene mutual information by utilizing the cooccurrence of genes in known gene-disease association data. Subsequently, the mutual information is combined with known protein-protein interaction networks by a boosted tree regression method.

Results: The method called Know-GENE is compared with the method of random walking on the heterogeneous network using the same input data. For a set of 960 diseases, using the same training data in testing in 3-fold cross-validation, the average recall rate within the top ranked 100 genes by Know-GENE is 65.0% compared with 37.9% by the state of the art random walking on heterogeneous network. This significant improvement is mostly due to the inclusion of knowledge-based mutual information.

Availability And Implementation: Predictions for genes associated with the 960 diseases are available at http://cssb2.biology.gatech.edu/knowgene

Contact: : [email protected]
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http://dx.doi.org/10.1093/bioinformatics/btw358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018378PMC
September 2016

Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function.

Mol Cell Biol 2016 08 14;36(15):2027-38. Epub 2016 Jul 14.

Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA

Brown adipose tissue (BAT) plays a unique role in regulating whole-body energy homeostasis by dissipating energy through thermogenic uncoupling. Berardinelli-Seip congenital lipodystrophy (BSCL) type 2 (BSCL2; also known as seipin) is a lipodystrophy-associated endoplasmic reticulum membrane protein essential for white adipocyte differentiation. Whether BSCL2 directly participates in brown adipocyte differentiation, development, and function, however, is unknown. We show that BSCL2 expression is increased during brown adipocyte differentiation. Its deletion does not impair the classic brown adipogenic program but rather induces premature activation of differentiating brown adipocytes through cyclic AMP (cAMP)/protein kinase A (PKA)-mediated lipolysis and fatty acid and glucose oxidation, as well as uncoupling. cAMP/PKA signaling is physiologically activated during neonatal BAT development in wild-type mice and greatly potentiated in mice with genetic deletion of Bscl2 in brown progenitor cells, leading to reduced BAT mass and lipid content during neonatal brown fat formation. However, prolonged overactivation of cAMP/PKA signaling during BAT development ultimately causes apoptosis of brown adipocytes through inflammation, resulting in BAT atrophy and increased overall adiposity in adult mice. These findings reveal a key cell-autonomous role for BSCL2 in controlling BAT mass/activity and provide novel insights into therapeutic strategies targeting cAMP/PKA signaling to regulate brown adipocyte function, viability, and metabolic homeostasis.
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http://dx.doi.org/10.1128/MCB.01120-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946430PMC
August 2016
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