Faculty Bibliography

Our recent studies demonstrate that the focal adhesion protein Kindlin-2 is critical for chondrogenesis and early skeletal development. Here, we show that deleting Kindlin-2 from osteoblasts using the 2.3-kb mouse Col1a1-Cre transgene minimally impacts bone mass in mice, but deleting Kindlin-2 using the 10-kb mouse Dmp1-Cre transgene, which targets osteocytes and mature osteoblasts, results in striking osteopenia in mice. Kindlin-2 loss reduces the osteoblastic population but increases the osteoclastic and adipocytic populations in the bone microenvironment. Kindlin-2 loss upregulates sclerostin in osteocytes, downregulates β-catenin in osteoblasts, and inhibits osteoblast formation and differentiation in vitro and in vivo. Upregulation of β-catenin in the mutant cells reverses the osteopenia induced by Kindlin-2 deficiency. Kindlin-2 loss additionally increases the expression of RANKL in osteocytes and increases osteoclast formation and bone resorption. Kindlin-2 deletion in osteocytes promotes osteoclast formation in osteocyte/bone marrow monocyte cocultures, which is significantly blocked by an anti-RANKL-neutralizing antibody. Finally, Kindlin-2 loss increases osteocyte apoptosis and impairs osteocyte spreading and dendrite formation. Thus, we demonstrate an important role of Kindlin-2 in the regulation of bone homeostasis and provide a potential target for the treatment of metabolic bone diseases.

Clinical value and utility of checkpoint inhibitors, a drug class targeting adaptive immune suppression pathways (PD-1, PDL-1, and CTLA-4), is growing rapidly and maintains status of a landmark achievement in oncology. Their efficacy has transformed life expectancy in multiple deadly cancer types (melanoma, lung cancer, renal/urothelial carcinoma, certain colorectal cancers, lymphomas, etc.). Despite significant clinical development efforts, therapeutic indication of approved checkpoint inhibitors are not as wide as the oncology community and patients would like them to be, potentially bringing into question their universal efficacy across tumor histologies. With the main goal of expanding immunotherapy applications, identifying of biomarkers to accurately predict therapeutic response and treatment related side-effects are a paramount need in the field. Specificities surrounding checkpoint inhibitors in clinic, such as unexpected tumor response patterns (pseudo- and hyper-progression), late responders, as well as specific immune mediated toxicities, complicate the management of patients. They stem from the complexities and dynamics of the tumor/host immune interactions, as well as baseline tumor biology. Search for clinically effective biomarkers therefore calls for a holistic approach, rather than implementation of a single analyte. The goal is to achieve dynamic and comprehensive acquisition, analyses and interpretation of immunological and biologic information about the tumor and the immune system, and to compute these parameters into an actionable, maximally predictive value at the individual patient level. Limitation delaying swift incorporation of validated immuno-oncology biomarkers span from standardized biospecimens acquisition and processing, selection of proficient biomarker discovery and validation methods, to establishing multidisciplinary consortiums and data sharing platforms. Multi-disciplinary efforts have already yielded some approved (PDL-1 and MSI-status) and other advanced tests (TMB, neoantigen pattern, and TIL infiltration rate). Importantly, clinical trial taskforces now recognize the imperative of the biomarker-driven trial design and execution, to enable translating biomarker discoveries into the clinical setting. This will ensure we utilize the "conspiracy" between the peripheral and intra-tumoral dynamic markers in shaping responses to checkpoint blockade, for the ultimate patient benefit.

Purpose:This cross-sectional study aimed to describe personal growth and to analyze its associated factors among patients with chronic obstructive pulmonary disease (COPD) in China. Patients and Methods:A total of 364 Chinese COPD hospitalized patients were included in the study between November 2016 and April 2018. Participants provided demographic information and completed the Growth Through Uncertainty Scale (GTUS), the Multidimensional Scale of Perceived Social Support (MSPSS), and the modified Medical Research Council dyspnoea scale (mMRC). Results:< 0.001), explaining 42.7% of the variance. Conclusion:COPD patients tend to report a moderate level of personal growth in China. Educational level, average monthly income, social support, and breathlessness were significant factors associated with personal growth. Medical workers should be aware of the level of personal growth among COPD patients and make tailored interventions to facilitate COPD patients' personal growth, such as increasing social support and decrease breathlessness.

Telomerase plays a key role in the immortalization of cancer cells by maintaining telomeres length. Using single-molecule imaging of telomerase RNA molecules in cancer cells, we recently reported novel insights into the role of Cajal bodies in telomerase biogenesis and the regulation of telomerase recruitment to telomeres.

The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction¹. A unique GPCR that is known to require heterodimerization for function^2-6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands^7,8, while GABAB2 couples with G proteins^9-14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail¹⁵. Although the VFT heterodimer structure has been resolved¹⁶, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor at atomic resolution, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.
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The zona pellucida (ZP) is an extracellular matrix (ECM) that surrounds all mammalian oocytes, eggs, and embryos and plays vital roles during oogenesis, fertilization, and preimplantation development. The mouse and human ZP is composed of three or four unique proteins, respectively, called ZP1-4, that are synthesized, processed, and secreted by oocytes during their growth phase. All ZP proteins have a zona pellucida domain (ZPD) that consists of ≈270 amino acids and has 8 conserved Cys residues present as four intramolecular disulfides. Secreted ZP proteins assemble into long fibrils around growing oocytes with ZP2-ZP3 dimers located periodically along the fibrils. The fibrils are cross-linked by ZP1 to form a thick, transparent ECM to which sperm must first bind and then penetrate during fertilization of eggs. Inactivation of mouse ZP1, ZP2, or ZP3 by gene targeting affects both ZP formation around oocytes and fertility. Female mice with eggs that lack a ZP due to inactivation of either ZP2 or ZP3 are completely infertile, whereas inactivation of ZP1 results in construction of an abnormal ZP and reduced fertility. Results of a large number of studies of infertile female patients strongly suggest that gene sequence variations (GSV) in human ZP1, ZP2, or ZP3 due to point, missense, or frameshift mutations have similar deleterious effects on ZP formation and female fertility. These findings are discussed in light of our current knowledge of ZP protein synthesis, processing, secretion, and assembly.

Background/UNASSIGNED:Cartilage defects account for substantial economic and humanistic burdens and pose a significant clinical problem. The efficacy of clinical approaches to cartilage repair is often inadequate, in part, owing to the restricted proliferative capacity of chondrocytes. Molecules have the capacity to promote the differentiation of multipotent mesenchymal stem cells into chondrocytes and may also gain the ability to repair the damaged cartilage. Objective/UNASSIGNED:This study aimed to investigate the role of Atsttrin (progranulin-derived engineered protein) in cartilage repair as well as the signaling pathway involved. Methods/UNASSIGNED:. Real-time polymerase chain reaction and Western blot analysis were used to monitor the effect of Atsttrin on the transcriptional and protein levels, respectively, of key anabolic and catabolic signaling molecules. Results/UNASSIGNED:In addition, Atsttrin-mediated cartilage repair occurred primarily through tumor necrosis factor receptor 2-initiated Akt signaling and downstream JunB transcription factor. Conclusion/UNASSIGNED:Atsttrin might serve as a promising therapeutic modality for cartilage regeneration.