Digital Commons Network^™

Single-Cell Sequencing Reveals The Landscape Of The Human Brain Metastatic Microenvironment, Qianqian Song, Jimmy Ruiz, Fei Xing, Hui-Wen Lo, Lou Craddock, Ashok K Pullikuth, Lance D Miller, Michael H Soike, Stacey S O'Neill, Kounosuke Watabe, Michael D Chan, Jing Su

Faculty, Staff and Student Publications

Brain metastases is the most common intracranial tumor and account for approximately 20% of all systematic cancer cases. It is a leading cause of death in advanced-stage cancer, resulting in a five-year overall survival rate below 10%. Therefore, there is a critical need to identify effective biomarkers that can support frequent surveillance and promote efficient drug guidance in brain metastasis. Recently, the remarkable breakthroughs in single-cell RNA-sequencing (scRNA-seq) technology have advanced our insights into the tumor microenvironment (TME) at single-cell resolution, which offers the potential to unravel the metastasis-related cellular crosstalk and provides the potential for improving therapeutic effects mediated …

Differential Effects Of Bariatric Surgery And Caloric Restriction On Hepatic One-Carbon And Fatty Acid Metabolism, Arnon Haran, Michael Bergel, Doron Kleiman, Liron Hefetz, Hadar Israeli, Sarah Weksler-Zangen, Bella Agranovich, Ifat Abramovich, Rachel Ben-Haroush Schyr, Eyal Gottlieb, Danny Ben-Zvi

Faculty, Staff and Student Publications

Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to

Gold Nanoparticles For Monitoring Of Mesenchymal Stem-Cell-Loaded Bioresorbable Polymeric Wraps For Arteriovenous Fistula Maturation, Allan John R Barcena, Joy Vanessa D Perez, Jossana A Damasco, Marvin R Bernardino, Erin Marie D San Valentin, Carleigh Klusman, Benjamin Martin, Andrea Cortes, Gino Martin Canlas, Huckie C Del Mundo, Francisco M Heralde, Rony Avritscher, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Student Publications

Mesenchymal stem cell (MSC)-seeded polymeric perivascular wraps have been shown to enhance arteriovenous fistula (AVF) maturation. However, the wraps' radiolucency makes their placement and integrity difficult to monitor. Through electrospinning, we infused gold nanoparticles (AuNPs) into polycaprolactone (PCL) wraps to improve their radiopacity and tested whether infusion affects the previously reported beneficial effects of the wraps on the AVF's outflow vein. Sprague Dawley rat MSCs were seeded on the surface of the wraps. We then compared the effects of five AVF treatments-no perivascular wrap (i.e., control), PCL wrap, PCL + MSC wrap, PCL-Au wrap, and PCL-Au + MSC wrap-on AVF …

Comparison Of Dna Vaccines With As03 As An Adjuvant And An Mrna Vaccine Against Sars-Cov-2, Praveen Neeli, Dafei Chai, Xu Wang, Navid Sobhani, George Udeani, Yong Li

Faculty, Staff and Students Publications

Emerging variants of SARS-CoV-2 call for frequent changes in vaccine antigens. Nucleic acid-based vaccination strategies are superior as the coding sequences can be easily altered with little impact on downstream production. mRNA vaccines, including variant-specific boosters, are approved for SARS-CoV-2. Here, we tested the efficacy of DNA vaccines against the SARS-CoV-2 Spike aided by the AddaS03 adjuvant using electroporation and compared their immunogenicity with an approved mRNA vaccine (mRNA-1273). DNA vaccination elicited robust humoral and cellular immune responses in C57BL/6 mice with Spike-specific antibody neutralization and T cells produced from 20 μg DNA vaccines similar to that from 0.5 μg …

Study Of Polytopic Membrane Protein Topological Organization As A Function Of Membrane Lipid Composition, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst

Faculty, Staff and Student Publications

Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show that K+ versus Na+ …

Measuring And Enhancing The Ionic Conductivity Of Chloroaluminate Electrolytes For Al-Ion Batteries, Anthony J Lucio, Iwan Sumarlan, Elena Bulmer, Igor Efimov, Stephen Viles, A Robert Hillman, Christopher J Zaleski, Karl S Ryder

Faculty, Staff and Student Publications

At the core of the aluminum (Al) ion battery is the liquid electrolyte, which governs the underlying chemistry. Optimizing the rheological properties of the electrolyte is critical to advance the state of the art. In the present work, the chloroaluminate electrolyte is made by reacting AlCl3 with a recently reported acetamidinium chloride (Acet-Cl) salt in an effort to make a more performant liquid electrolyte. Using AlCl3:Acet-Cl as a model electrolyte, we build on our previous work, which established a new method for extracting the ionic conductivity from fitting voltammetric data, and in this contribution, we validate the method across a …

A Novel Statistical Method For Decontaminating T-Cell Receptor Sequencing Data, Ruoxing Li, Mehmet Altan, Alexandre Reuben, Ruitao Lin, John V Heymach, Hai Tran, Runzhe Chen, Latasha Little, Shawna Hubert, Jianjun Zhang, Ziyi Li

Faculty, Staff and Student Publications

The T-cell receptor (TCR) repertoire is highly diverse among the population and plays an essential role in initiating multiple immune processes. TCR sequencing (TCR-seq) has been developed to profile the T cell repertoire. Similar to other high-throughput experiments, contamination can happen during several steps of TCR-seq, including sample collection, preparation and sequencing. Such contamination creates artifacts in the data, leading to inaccurate or even biased results. Most existing methods assume 'clean' TCR-seq data as the starting point with no ability to handle data contamination. Here, we develop a novel statistical model to systematically detect and remove contamination in TCR-seq data. …

Structures Of Channelrhodopsin Paralogs In Peptidiscs Explain Their Contrasting K+ And Na+ Selectivities, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst

Faculty, Staff and Student Publications

Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show …

Multi-Campaign Ship And Aircraft Observations Of Marine Cloud Condensation Nuclei And Droplet Concentrations, Kevin J Sanchez, David Painemal, Matthew D Brown, Ewan C Crosbie, Francesca Gallo, Johnathan W Hair, Chris A Hostetler, Carolyn E Jordan, Claire E Robinson, Amy Jo Scarino, Taylor J Shingler, Michael A Shook, Kenneth L Thornhill, Elizabeth B Wiggins, Edward L Winstead, Luke D Ziemba, Scott Chambers, Alastair Williams, Ruhi S Humphries, Melita D Keywood, Jason P Ward, Luke Cravigan, Ian M Mcrobert, Connor Flynn, Gourihar R Kulkarni, Lynn M Russell, Gregory C Roberts, Greg M Mcfarquhar, Athanasios Nenes, Sarah F Woods, Jeffery S Reid, Jennifer Small-Griswold, Sarah Brooks, Simon Kirschler, Christianne Voigt, Jian Wang, David J Delene, Patricia K Quinn, Richard H Moore

Faculty, Staff and Student Publications

In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to …

Genome-Wide Identification And Phenotypic Characterization Of Seizure-Associated Copy Number Variations In 741,075 Individuals, Ludovica Montanucci, David Lewis-Smith, Ryan L Collins, Lisa-Marie Niestroj, Shridhar Parthasarathy, Julie Xian, Shiva Ganesan, Marie Macnee, Tobias Brünger, Rhys H Thomas, Michael Talkowski, Epi25 Collaborative, Ingo Helbig, Costin Leu, Dennis Lal

Faculty, Staff and Student Publications

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, …

Dynamic Mapping Of Proteome Trafficking Within And Between Living Cells By Transitid, Wei Qin, Joleen S Cheah, Charles Xu, James Messing, Brian D Freibaum, Steven Boeynaems, J Paul Taylor, Namrata D Udeshi, Steven A Carr, Alice Y Ting

Faculty, Staff and Students Publications

The ability to map trafficking for thousands of endogenous proteins at once in living cells would reveal biology currently invisible to both microscopy and mass spectrometry. Here, we report TransitID, a method for unbiased mapping of endogenous proteome trafficking with nanometer spatial resolution in living cells. Two proximity labeling (PL) enzymes, TurboID and APEX, are targeted to source and destination compartments, and PL with each enzyme is performed in tandem via sequential addition of their small-molecule substrates. Mass spectrometry identifies the proteins tagged by both enzymes. Using TransitID, we mapped proteome trafficking between cytosol and mitochondria, cytosol and nucleus, and …

Early Non-Response As A Predictor Of Later Non-Response To Antipsychotics In Schizophrenia: A Randomized Trial, Yujun Long, Qiongqiong Wu, Ye Yang, Jingda Cai, Jingmei Xiao, Zhaoqian Liu, Yifeng Xu, Ying Chen, Manli Huang, Ruiguo Zhang, Xijia Xu, Jian Hu, Zhifen Liu, Fang Liu, Yingjun Zheng, Huaqing Meng, Zhimin Wang, Yanqing Tang, Xueqin Song, Yunchun Chen, Xueyi Wang, Tiebang Liu, Xiaoli Wu, Maosheng Fang, Chunling Wan, Jingping Zhao, Renrong Wu

Faculty, Staff and Student Publications

BACKGROUND: It remains a challenge to predict the long-term response to antipsychotics in patients with schizophrenia who do not respond at an early stage. This study aimed to investigate the optimal predictive cut-off value for early non-response that would better predict later non-response to antipsychotics in patients with schizophrenia.

METHODS: This multicenter, 8-week, open-label, randomized trial was conducted at 19 psychiatric centers throughout China. All enrolled participants were assigned to olanzapine, risperidone, amisulpride, or aripiprazole monotherapy for 8 weeks. The positive and negative syndrome scale (PANSS) was evaluated at baseline, week 2, week 4, and week 8. The main outcome …

Metastatic Infiltration Of Nervous Tissue And Periosteal Nerve Sprouting In Multiple Myeloma-Induced Bone Pain In Mice And Human, Marta Diaz-Delcastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with …

China Stroke Surveillance Report 2021, Wen-Jun Tu, Long-De Wang, Special Writing Group Of China Stroke Surveillance Report

Faculty, Staff and Student Publications

Since 2015, stroke has become the leading cause of death and disability in China, posing a significant threat to the health of its citizens as a major chronic non-communicable disease. According to the China Stroke High-risk Population Screening and Intervention Program, an estimated 17.8 million [95% confidence interval (CI) 17.6–18.0 million] adults in China had experienced a stroke in 2020, with 3.4 million (95% CI 3.3–3.5 million) experiencing their first-ever stroke and another 2.3 million (95% CI 2.2–2.4 million) dying as a result. Additionally, approximately 12.5% (95% CI 12.4–12.5%) of stroke survivors were left disabled, as defined by a modified …

Metastatic Infiltration Of Nervous Tissue And Periosteal Nerve Sprouting In Multiple Myeloma-Induced Bone Pain In Mice And Human, Marta Diaz-Delcastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with …

Proteomics Analysis Of Plasma From Middle-Aged Adults Identifies Protein Markers Of Dementia Risk In Later Life, Keenan A Walker, Jingsha Chen, Liu Shi, Yunju Yang, Myriam Fornage, Linda Zhou, Pascal Schlosser, Aditya Surapaneni, Morgan E Grams, Michael R Duggan, Zhongsheng Peng, Gabriela T Gomez, Adrienne Tin, Ron C Hoogeveen, Kevin J Sullivan, Peter Ganz, Joni V Lindbohm, Mika Kivimaki, Alejo J Nevado-Holgado, Noel Buckley, Rebecca F Gottesman, Thomas H Mosley, Eric Boerwinkle, Christie M Ballantyne, Josef Coresh

Faculty, Staff and Student Publications

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that …

Βii-Spectrin Is Required For Synaptic Positioning During Retinal Development, Debalina Goswami-Sewell, Caitlin Bagnetto, Cesiah C Gomez, Joseph T Anderson, Akash Maheshwari, Elizabeth Zuniga-Sanchez

Faculty, Staff and Students Publications

Neural circuit assembly is a multistep process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here, we uncovered a new role for the cytoskeletal protein βII-spectrin in properly positioning presynaptic and postsynaptic neurons to the developing synaptic layer. Loss of βII-spectrin …

Integrating Genetics And Metabolomics From Multi-Ethnic And Multi-Fluid Data Reveals Putative Mechanisms For Age-Related Macular Degeneration, Xikun Han, Ines Lains, Jun Li, Jinglun Li, Yiheng Chen, Bing Yu, Qibin Qi, Eric Boerwinkle, Robert Kaplan, Bharat Thyagarajan, Martha Daviglus, Charlotte E Joslin, Jianwen Cai, Marta Guasch-Ferré, Deirdre K Tobias, Eric Rimm, Alberto Ascherio, Karen Costenbader, Elizabeth Karlson, Lorelei Mucci, A Heather Eliassen, Oana Zeleznik, John Miller, Demetrios G Vavvas, Ivana K Kim, Rufino Silva, Joan Miller, Frank Hu, Walter Willett, Jessica Lasky-Su, Peter Kraft, J Brent Richards, Stuart Macgregor, Deeba Husain, Liming Liang

Faculty, Staff and Student Publications

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal …

Impact Of Mir196a-2 Genotypes On Colorectal Cancer Risk In Taiwan, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jen-Sheng Pei, Jian Gu, Chia-Wen Tsai, Da-Tian Bau, Wen-Shin Chang

Faculty, Staff and Student Publications

We aimed to investigate the association between genotypes for

Efficacy And Safety Of Elamipretide In Individuals With Primary Mitochondrial Myopathy: The Mmpower-3 Randomized Clinical Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce H Cohen, Gregory M Enns, Marni J Falk, Amy Goldstein, Gráinne Siobhan Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russell Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, David A Brown, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM.

METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints …

Timigp: Inferring Cell-Cell Interactions And Prognostic Associations In The Tumor Immune Microenvironment Through Gene Pairs, Chenyang Li, Baoyi Zhang, Evelien Schaafsma, Alexandre Reuben, Linghua Wang, Mary Jo Turk, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Determining the prognostic association of different immune cell types in the tumor microenvironment is critical for understanding cancer biology and developing new therapeutic strategies. However, this is challenging in certain cancer types, where the abundance of different immune subsets is highly correlated. In this study, we develop a computational method named TimiGP to overcome this challenge. Based on bulk gene expression and survival data, TimiGP infers cell-cell interactions that reveal the association between immune cell relative abundance and prognosis. As demonstrated in metastatic melanoma, TimiGP prioritizes immune cells critical in prognosis based on the identified cell-cell interactions. Highly consistent results …

Dual Antiplatelet Therapy: A Concise Review For Clinicians, Hafeez Ul Hassan Virk, Johao Escobar, Mario Rodriguez, Eric R Bates, Umair Khalid, Hani Jneid, Yochai Birnbaum, Glenn N Levine, Sidney C Smith, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Dual antiplatelet therapy (DAPT) combines two antiplatelet agents to decrease the risk of thrombotic complications associated with atherosclerotic cardiovascular diseases. Emerging data about the duration of DAPT is being published continuously. New approaches are trying to balance the time, benefits, and risks for patients taking DAPT for established cardiovascular diseases. Short-term dual DAPT of 3-6 months, or even 1 month in high-bleeding risk patients, is equivalent in terms of efficacy and effectiveness compared to long-term DAPT for patients who experienced percutaneous coronary intervention in an acute coronary syndrome setting. Prolonged DAPT beyond 12 months reduces stent thrombosis, major adverse cardiovascular …

A Polycistronic System For Multiplexed And Precalibrated Expression Of Multigene Pathways In Fungi, Qun Yue, Jie Meng, Yue Qiu, Miaomiao Yin, Liwen Zhang, Weiping Zhou, Zhiqiang An, Zihe Liu, Qipeng Yuan, Wentao Sun, Chun Li, Huimin Zhao, István Molnár, Yuquan Xu, Shuobo Shi

Faculty, Staff and Student Publications

Synthetic biology requires efficient systems that support the well-coordinated co-expression of multiple genes. Here, we discover a 9-bp nucleotide sequence that enables efficient polycistronic gene expression in yeasts and filamentous fungi. Coupling polycistronic expression to multiplexed, markerless, CRISPR/Cas9-based genome editing, we develop a strategy termed HACKing (Highly efficient and Accessible system by CracKing genes into the genome) for the assembly of multigene pathways. HACKing allows the expression level of each enzyme to be precalibrated by linking their translation to those of host proteins with predetermined abundances under the desired fermentation conditions. We validate HACKing by rapidly constructing highly efficient Saccharomyces …

Ancestry-Driven Metabolite Variation Provides Insights Into Disease States In Admixed Populations, Kaylia M Reynolds, Andrea R V R Horimoto, Bridget M Lin, Ying Zhang, Nuzulul Kurniansyah, Bing Yu, Eric Boerwinkle, Qibin Qi, Robert Kaplan, Martha Daviglus, Lifang Hou, Laura Y Zhou, Jianwen Cai, Saame Raza Shaikh, Tamar Sofer, Sharon R Browning, Nora Franceschini

Faculty, Staff and Student Publications

BACKGROUND: Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk.

METHODS: We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data.

RESULTS: By leveraging local ancestry, this …

The Checkpoint Inhibitor Pd-1h/Vista Controls Osteoclast-Mediated Multiple Myeloma Bone Disease, Jing Fu, Shirong Li, Huihui Ma, Jun Yang, Gabriel M Pagnotti, Lewis M Brown, Stephen J Weiss, Markus Y Mapara, Suzanne Lentzsch

Faculty, Staff and Student Publications

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone …

Anti-Mir-93-5p Therapy Prolongs Sepsis Survival By Restoring The Peripheral Immune Response, Mihnea P Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W Anderson, Spencer J Rothfuss, Robert Silasi, Ravi S Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Constantin Georgescu, Pinaki P Banerjee, Rafet Basar, Ziyi Li, David Horst, Catalin Vasilescu, Maria Teresa S Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai-Ching Yeung, George A Calin

Faculty, Staff and Student Publications

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and …

Anoctamin 4 Channel Currents Activate Glucose-Inhibited Neurons In The Mouse Ventromedial Hypothalamus During Hypoglycemia, Longlong Tu, Jonathan C Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A Scarcelli, Kristine M Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu

Faculty, Staff and Student Publications

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood …

Are The Post-Covid-19 Posttraumatic Stress Disorder (Ptsd) Symptoms Justified By The Effects Of Covid-19 On Brain Structure? A Systematic Review, Georgios D Kotzalidis, Ottavia Marianna Ferrara, Stella Margoni, Valentina Ieritano, Antonio Restaino, Evelina Bernardi, Alessia Fischetti, Antonello Catinari, Laura Monti, Daniela Pia Rosaria Chieffo, Alessio Simonetti, Gabriele Sani

Faculty, Staff and Students Publications

COVID-19 affects brain function, as deduced by the "brain fog" that is often encountered in COVID-19 patients and some cognitive impairment that is observed in many a patient in the post-COVID-19 period. Approximately one-third of patients, even when they have recovered from the acute somatic disease, continue to show posttraumatic stress disorder (PTSD) symptoms. We hypothesized that the persistent changes induced by COVID-19 on brain structure would overlap with those associated with PTSD. We performed a thorough PubMed search on 25 April 2023 using the following strategy: ((posttraumatic OR PTSD) AND COVID-19 AND (neuroimaging OR voxel OR VBM OR freesurfer …

Phase 1b Study Of Combined Selinexor And Eribulin For The Treatment Of Advanced Solid Tumors And Triple-Negative Breast Cancer, Blessie Elizabeth Nelson, Sadia Saleem, Senthil Damodaran, Neeta Somaiah, Sarina Piha-Paul, Julia Ann Moore, Bulent Yilmaz, Deby Ogbonna, Daniel D Karp, Ecaterina Dumbrava, Apostolia M Tsimberidou, David S Hong, Jordi Rodon Ahnert, Denái R Milton, Xiaofeng Zheng, Daniel J Booser, Nuhad K Ibrahim, Anthony P Conley, Priya Bhosale, Cristhiam M Rojas Hernandez, Debasish Tripathy, Aung Naing, Funda Meric-Bernstam

Faculty, Staff and Student Publications

BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.

METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.

RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), …

Five-Year Patient-Reported Outcomes In Nrg Oncology Rtog 0938, Evaluating Two Ultrahypofractionated Regimens For Prostate Cancer, Himanshu R Lukka, Snehal Deshmukh, Deborah W Bruner, Jean-Paul Bahary, Colleen A F Lawton, Jason A Efstathiou, Rajat J Kudchadker, Lee E Ponsky, Samantha A Seaward, Ian S Dayes, Darindra D Gopaul, Jeff M Michalski, Guila Delouya, Irving D Kaplan, Eric M Horwitz, Mack Roach, Felix Y Feng, Stephanie L Pugh, Howard M Sandler, Lisa A Kachnic

Faculty, Staff and Student Publications

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores.

METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions …