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Article ; Online: Quantitative Proteomics of the CDK9 Interactome Reveals a Function of the HSP90-CDC37-P-TEFb Complex for BETi-Induced HIV-1 Latency Reactivation.

Wang, Cong / Chen, Chunjing / Pan, Zhenrui / He, Yaohui / Zhang, Zhanming / Liu, Rongdiao / Xue, Yuhua / Zhou, Qiang / Gao, Xiang

Journal of proteome research

2023 Volume 22, Issue 9, Page(s) 2880–2889

Abstract: ... in controlling the dynamic equilibrium of the P-TEFb complex during BETi-induced reactivation of HIV-1 latency ... functions in oncogenesis, inflammation, and HIV-1 transcription. The formation of the Brd4-P-TEFb (CDK9 ... reactivation and expression of many oncogenes. To further investigate the mechanism of the Brd4-P-TEFb complex ...

Abstract	Brd4 has been intensively investigated as a promising drug target because of its implicated functions in oncogenesis, inflammation, and HIV-1 transcription. The formation of the Brd4-P-TEFb (CDK9/Cyclin T1) complex and its regulation of transcriptional elongation are critical for HIV latency reactivation and expression of many oncogenes. To further investigate the mechanism of the Brd4-P-TEFb complex in controlling elongation, mass spectrometry-based quantitative proteomics of the CDK9 interactome was performed. Upon treatment with the selective BET bromodomain inhibitor JQ1, 352 proteins were successfully identified with high confidence as CDK9-interacting proteins. Among them, increased bindings of HSP90 and CDC37 to CDK9 were particularly striking, and our data suggest that the HSP90-CDC37-P-TEFb complex is involved in controlling the dynamic equilibrium of the P-TEFb complex during BETi-induced reactivation of HIV-1 latency. Furthermore, the HSP90-CDC37-P-TEFb complex directly regulates HIV-1 transcription and relies on recruitment by heat shock factor 1 (HSF1) for binding to the HIV-1 promoter. These results advance the understanding of HSP90-CDC37-P-TEFb in HIV-1 latency reversal and enlighten the development of potential strategies to eradicate HIV-1 using a combination of targeted drugs.
MeSH term(s)	Transcription Factors/genetics ; Transcription Factors/metabolism ; HIV-1/genetics ; Positive Transcriptional Elongation Factor B/genetics ; Positive Transcriptional Elongation Factor B/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Proteomics ; Molecular Chaperones/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Transcription, Genetic
Chemical Substances	Transcription Factors ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; Nuclear Proteins ; Molecular Chaperones ; HSP90 Heat-Shock Proteins
Language	English
Publishing date	2023-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.3c00162
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Article ; Online: Group peer mentoring to improve faculty connections and enhance mentoring networks.

Barr, Karen P / Deluca, Kerry / Dicianno, Brad E / Helkowski, Wendy M / Liu, Betty

The clinical teacher

2024 , Page(s) e13747

Abstract: Background: Difficulty finding mentors and forging connections in academic departments can be challenging and became even more so when the COVID-19 pandemic reduced opportunities for informal networking. Even as restrictions on in-person meetings eased, ...

Abstract	Background: Difficulty finding mentors and forging connections in academic departments can be challenging and became even more so when the COVID-19 pandemic reduced opportunities for informal networking. Even as restrictions on in-person meetings eased, many faculty preferred meetings to remain virtual. Because some of the most powerful predictors of faculty vitality are positive professional relationships and feelings of inclusion and belonging to an institution, attending to faculty needs in this area is important to mitigate undesired lingering consequences. Approach: We created structured peer mentoring groups for our department's physicians and psychologists that meet virtually. Groups span career stages, academic appointments and clinical interests. The purpose was to establish a deeper culture of mentoring, increase feelings of connection to a supportive community within the department, facilitate career planning and enhance the development of skills necessary in academic medicine such as teaching skills, scholarly productivity and personal wellness. Evaluation: A survey conducted after the first year of the programme was completed by 70% of eligible faculty (31/45). Ninety-six percent felt the programme had created an inclusive and appreciative culture, 86% met faculty members they had never met before and 79% sought mentoring advice from a colleague they would not usually have interacted with in that manner. All participants appreciated hearing their colleagues' perspectives on topics they do not typically discuss. Implications: Departmentally based group peer mentoring that spans career stages and interests can facilitate faculty connections and enhance a supportive culture of mentorship.
Language	English
Publishing date	2024-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2151518-9
ISSN	1743-498X ; 1743-4971
ISSN (online)	1743-498X
ISSN	1743-4971
DOI	10.1111/tct.13747
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Article ; Online: Evolving topological order in the postnatal visceral pleura.

Liu, Betty S / Ali, Ali B / Kwan, Stacey P / Pan, Jennifer M / Wagner, Willi L / Khalil, Hassan A / Chen, Zi / Ackermann, Maximilian / Mentzer, Steven J

Developmental dynamics : an official publication of the American Association of Anatomists

2024

Abstract: Background: Changes in epithelial cell shape reflects optimal cell packing and the minimization of surface free energy, but also cell-cell interactions, cell proliferation, and cytoskeletal rearrangements.: Results: Here, we studied the structure of ... ...

Abstract	Background: Changes in epithelial cell shape reflects optimal cell packing and the minimization of surface free energy, but also cell-cell interactions, cell proliferation, and cytoskeletal rearrangements. Results: Here, we studied the structure of the rat pleura in the first 15 days after birth. After pleural isolation and image segmentation, the analysis demonstrated a progression of epithelial order from postnatal day 1 (P1) to P15. The cells with the largest surface area and greatest shape variability were observed at P1. In contrast, the cells with the smallest surface area and most shape consistency were observed at P15. A comparison of polygonal cell geometries demonstrated progressive optimization with an increase in the number of hexagons (six-sided) as well as five-sided and seven-sided polygons. Analysis of the epithelial organization with Voronoi tessellations and graphlet motif frequencies demonstrated a developmental path strikingly distinct from mathematical and natural reference paths. Graph Theory analysis of cell connectivity demonstrated a progressive decrease in network heterogeneity and clustering coefficient from P1 to P15. Conclusions: We conclude that the rat pleura undergoes a striking change in pleural structure from P1 to P15. Further, a geometric and network-based approach can provide a quantitative characterization of these developmental changes.
Language	English
Publishing date	2024-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.688
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Article ; Online: RNASE2 Mediates Age-Associated B Cell Expansion Through Monocyte Derived IL-10 in Patients With Systemic Lupus Erythematosus.

Zhu, Yantong / Tang, Xiaojun / Xu, Yang / Wu, Si / Liu, Weilin / Geng, Linyu / Ma, Xiaolei / Tsao, Betty P / Feng, Xuebing / Sun, Lingyun

Frontiers in immunology

2022 Volume 13, Page(s) 752189

Abstract: Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies. Ribonuclease A family member 2 (RNase2) is known to have antiviral activity and immunomodulatory function. Although RNASE2 level has been reported to be ... ...

Abstract	Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies. Ribonuclease A family member 2 (RNase2) is known to have antiviral activity and immunomodulatory function. Although RNASE2 level has been reported to be elevated in SLE patients based on mRNA microarray detection, its pathologic mechanism remains unclear. Here, we confirmed that RNASE2 was highly expressed in PBMCs from SLE patients and associated with the proportion of CD11c
MeSH term(s)	B-Lymphocytes ; Eosinophil-Derived Neurotoxin ; Humans ; Interleukin-10/genetics ; Interleukin-10/metabolism ; Leukocytes, Mononuclear ; Lupus Erythematosus, Systemic ; Monocytes/metabolism
Chemical Substances	IL10 protein, human ; Interleukin-10 (130068-27-8) ; Eosinophil-Derived Neurotoxin (EC 3.1.-) ; RNASE2 protein, human (EC 3.1.27.5)
Language	English
Publishing date	2022-02-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.752189
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Article ; Online: Spatially controlled construction of assembloids using bioprinting.

Roth, Julien G / Brunel, Lucia G / Huang, Michelle S / Liu, Yueming / Cai, Betty / Sinha, Sauradeep / Yang, Fan / Pașca, Sergiu P / Shin, Sungchul / Heilshorn, Sarah C

Nature communications

2023 Volume 14, Issue 1, Page(s) 4346

Abstract: The biofabrication of three-dimensional (3D) tissues that recapitulate organ-specific architecture and function would benefit from temporal and spatial control of cell-cell interactions. Bioprinting, while potentially capable of achieving such control, ... ...

Abstract	The biofabrication of three-dimensional (3D) tissues that recapitulate organ-specific architecture and function would benefit from temporal and spatial control of cell-cell interactions. Bioprinting, while potentially capable of achieving such control, is poorly suited to organoids with conserved cytoarchitectures that are susceptible to plastic deformation. Here, we develop a platform, termed Spatially Patterned Organoid Transfer (SPOT), consisting of an iron-oxide nanoparticle laden hydrogel and magnetized 3D printer to enable the controlled lifting, transport, and deposition of organoids. We identify cellulose nanofibers as both an ideal biomaterial for encasing organoids with magnetic nanoparticles and a shear-thinning, self-healing support hydrogel for maintaining the spatial positioning of organoids to facilitate the generation of assembloids. We leverage SPOT to create precisely arranged assembloids composed of human pluripotent stem cell-derived neural organoids and patient-derived glioma organoids. In doing so, we demonstrate the potential for the SPOT platform to construct assembloids which recapitulate key developmental processes and disease etiologies.
MeSH term(s)	Humans ; Organoids ; Bioprinting/methods ; Hydrogels ; Pluripotent Stem Cells ; Biocompatible Materials
Chemical Substances	Hydrogels ; Biocompatible Materials
Language	English
Publishing date	2023-07-19
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40006-5
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Article ; Online: Mutant p53

Inflammation research : official journal of the European Histamine Research Society ... [et al.

2023 Volume 72, Issue 12, Page(s) 2199–2219

Abstract: Background: Rheumatoid arthritis (RA) is an autoimmune inflammation disease characterized by imbalance of immune homeostasis. p53 mutants are commonly described as the guardian of cancer cells by conferring them drug-resistance and immune evasion. ... ...

Abstract	Background: Rheumatoid arthritis (RA) is an autoimmune inflammation disease characterized by imbalance of immune homeostasis. p53 mutants are commonly described as the guardian of cancer cells by conferring them drug-resistance and immune evasion. Importantly, p53 mutations have also been identified in RA patients, and this prompts the investigation of its role in RA pathogenesis. Methods: The cytotoxicity of disease-modifying anti-rheumatic drugs (DMARDs) against p53 Results: Among p53 mutants, p53 Conclusions: This study unravels the role of p53
MeSH term(s)	Animals ; Humans ; Rats ; Arthritis, Experimental/drug therapy ; Arthritis, Experimental/genetics ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/genetics ; Cytokines/metabolism ; Immunity, Innate ; Interferon Regulatory Factor-3 ; Protein Serine-Threonine Kinases ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Cytokines ; Interferon Regulatory Factor-3 ; IRF3 protein, human ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; TBK1 protein, human (EC 2.7.11.1) ; Tumor Suppressor Protein p53 ; Tbk1 protein, rat (EC 2.7.11.1) ; Tp53 protein, rat
Language	English
Publishing date	2023-11-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1221794-3
ISSN	1420-908X ; 1023-3830
ISSN (online)	1420-908X
ISSN	1023-3830
DOI	10.1007/s00011-023-01809-w
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Article ; Online: Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy.

Coghi, Paolo / Ng, Jerome P L / Kadioglu, Onat / Law, Betty Yuen Kwan / Qiu, Alena Congling / Saeed, Mohamed E M / Chen, Xi / Ip, Chi Kio / Efferth, Thomas / Liu, Liang / Wong, Vincent Kam Wai

European journal of medicinal chemistry

2021 Volume 224, Page(s) 113676

Abstract: A series of eleven celastrol derivatives was designed, synthesized, and evaluated for their in vitro cytotoxic activities against six human cancer cell lines (A549, HepG2, HepAD38, PC3, DLD-1 Bax-Bak WT and DKO) and three human normal cells ( ... ...

Abstract	A series of eleven celastrol derivatives was designed, synthesized, and evaluated for their in vitro cytotoxic activities against six human cancer cell lines (A549, HepG2, HepAD38, PC3, DLD-1 Bax-Bak WT and DKO) and three human normal cells (LO
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Binding Sites ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Design ; Drug Resistance, Neoplasm/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Molecular Docking Simulation ; Pentacyclic Triterpenes/chemistry ; Pentacyclic Triterpenes/metabolism ; Pentacyclic Triterpenes/pharmacology ; Pentacyclic Triterpenes/therapeutic use ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Structure-Activity Relationship
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Antineoplastic Agents ; Pentacyclic Triterpenes ; Sarcoplasmic Reticulum Calcium-Transporting ATPases (EC 3.6.3.8) ; celastrol (L8GG98663L)
Language	English
Publishing date	2021-07-05
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2021.113676
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Article ; Online: Identifying the core concepts of pharmacology education: A global initiative.

White, Paul J / Guilding, Clare / Angelo, Tom / Kelly, John P / Gorman, Laurel / Tucker, Steven J / Fun, Ashleigh / Han, Jae / Chen, Guanliang / Samak, Yassmin / Babey, Anna-Marie / Caetano, Fabiana A / Sarangi, Sudhir Chandra / Koenig, Jennifer / Hao, Haiping / Goldfarb, Joseph / Karpa, Kelly / Vieira, Luciene / Restini, Carolina /

Cunningham, Margaret / Aronsson, Patrik / Kelly-Laubscher, Roisin / Hernandez, Mark / Rangachari, Patangi K / Mifsud, Janet / Mraiche, Fatima / Sabra, Ramzi / Piñeros, Octavio / Zhen, Xuechu / Kwanashie, Helen / Exintaris, Betty / Karunaratne, Nilushi / Ishii, Kuniaki / Liu, Yannee

British journal of pharmacology

2023 Volume 180, Issue 9, Page(s) 1197–1209

Abstract: Background and purpose: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks ... ...

Abstract	Background and purpose: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. Experimental approach: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. Key results: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. Conclusion and implications: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.
Language	English
Publishing date	2023-01-03
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.16000
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Article ; Online: Loss-of-function variants in

Annals of the rheumatic diseases

2022 Volume 81, Issue 12, Page(s) 1712–1721

Abstract: Objectives: Families that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to ... ...

Abstract	Objectives: Families that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus. Methods: Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional patients with SLE. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively. Results: The two familial ultra-rare, predicted loss-of-function (LOF) Conclusions: We identified two novel
MeSH term(s)	Animals ; Child ; Female ; Humans ; Male ; Mice ; Genetic Predisposition to Disease ; Homozygote ; Lupus Erythematosus, Systemic/genetics ; Spermine/blood ; Genetic Diseases, X-Linked/genetics ; Acetyltransferases/genetics
Chemical Substances	Spermine (2FZ7Y3VOQX) ; diamine N-acetyltransferase (EC 2.3.1.57) ; Acetyltransferases (EC 2.3.1.-)
Language	English
Publishing date	2022-08-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	7090-7
ISSN	1468-2060 ; 0003-4967
ISSN (online)	1468-2060
ISSN	0003-4967
DOI	10.1136/ard-2022-222795
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Article ; Online: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir Mini-Tabs Plus Ribavirin for Children Aged 3-11 Years with Hepatitis C Genotype 1a.

Rosenthal, Philip / Narkewicz, Michael R / Yao, Betty B / Jolley, Christopher D / Lobritto, Steven J / Wen, Jessica / Molleston, Jean P / Hsu, Evelyn K / Jonas, Maureen M / Zha, Jiuhong / Liu, Li / Leung, Daniel H

Advances in therapy

2020 Volume 37, Issue 7, Page(s) 3299–3310

Abstract: Introduction: To assess the safety, efficacy, and pharmacokinetics of mini-tablet formulations of ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) with or without ribavirin for 12 weeks in children infected with chronic hepatitis C ... ...

Abstract	Introduction: To assess the safety, efficacy, and pharmacokinetics of mini-tablet formulations of ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) with or without ribavirin for 12 weeks in children infected with chronic hepatitis C virus (HCV) genotype (GT) 1. Methods: This is an ongoing, open-label, Phase 2/3 study in children 3-11 years old infected with HCV GT1 who were HCV treatment-naïve and non-cirrhotic. Pediatric mini-tablet formulations of OBV, PTV, ritonavir, and DSV plus ribavirin oral solution were administered for 12 weeks based on body weight. Endpoints included SVR12, adverse events (AEs), and pharmacokinetic parameters. Results: Overall, 26 children received OBV, PTV, ritonavir, and DSV plus ribavirin; 14 were 3-8 years old and 12 were 9-11 years old; 35% were male; and all had chronic HCV GT1a infection. The SVR12 rate was 96% (25/26; 95% CI 81.1-99.3), with 1 child failing to achieve SVR12 due to non-adherence and treatment discontinuation. Treatment-emergent AEs of Grade ≥ 3 occurred in 3 children; 2 events in 1 child were considered serious; and none were considered treatment-related. No AEs led to discontinuation of study treatment. The most common AEs were headache (27%), fatigue (23%), pyrexia (19%), and vomiting (19%). Pharmacokinetic results showed mini-tablet formulations of OBV, PTV, DSV, and ritonavir drug exposures were comparable to the adult formulation. Conclusion: The mini-tablet combination of OBV, PTV, ritonavir, and DSV plus ribavirin to treat HCV GT1a infection for 12 weeks was highly effective and suitable in children 3-11 years of age. Trial registration: ClinicalTrials.gov identifier, NCT02486406.
MeSH term(s)	Anilides/therapeutic use ; Antiviral Agents/therapeutic use ; Carbamates/therapeutic use ; Child ; Child, Preschool ; Cyclopropanes/therapeutic use ; Cytochrome P-450 CYP3A Inhibitors/therapeutic use ; Drug Therapy, Combination ; Female ; Genotype ; Hepacivirus/drug effects ; Hepacivirus/genetics ; Hepatitis C, Chronic/drug therapy ; Humans ; Lactams, Macrocyclic/therapeutic use ; Male ; Proline/analogs & derivatives ; Proline/therapeutic use ; Ribavirin/therapeutic use ; Ritonavir/therapeutic use ; Sulfonamides/therapeutic use ; Tablets ; Uracil/analogs & derivatives ; Uracil/therapeutic use
Chemical Substances	Anilides ; Antiviral Agents ; Carbamates ; Cyclopropanes ; Cytochrome P-450 CYP3A Inhibitors ; Lactams, Macrocyclic ; Sulfonamides ; Tablets ; ombitasvir (2302768XJ8) ; Ribavirin (49717AWG6K) ; Uracil (56HH86ZVCT) ; Proline (9DLQ4CIU6V) ; dasabuvir (DE54EQW8T1) ; Ritonavir (O3J8G9O825) ; paritaprevir (OU2YM37K86)
Language	English
Publishing date	2020-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632651-1
ISSN	1865-8652 ; 0741-238X
ISSN (online)	1865-8652
ISSN	0741-238X
DOI	10.1007/s12325-020-01389-9
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