functional roles
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2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Li Zhang ◽  
Yiming Zhang ◽  
Chengdi Wang ◽  
Ying Yang ◽  
Yinyun Ni ◽  
...  

AbstractLung adenocarcinoma (LUAD) and squamous carcinoma (LUSC) are two major subtypes of non-small cell lung cancer with distinct pathologic features and treatment paradigms. The heterogeneity can be attributed to genetic, transcriptional, and epigenetic parameters. Here, we established a multi-omics atlas, integrating 52 single-cell RNA sequencing and 2342 public bulk RNA sequencing. We investigated their differences in genetic amplification, cellular compositions, and expression modules. We revealed that LUAD and LUSC contained amplifications occurring selectively in subclusters of AT2 and basal cells, and had distinct cellular composition modules associated with poor survival of lung cancer. Malignant and stage-specific gene analyses further uncovered critical transcription factors and genes in tumor progression. Moreover, we identified subclusters with proliferating and differentiating properties in AT2 and basal cells. Overexpression assays of ten genes, including sub-cluster markers AQP5 and KPNA2, further indicated their functional roles, providing potential targets for early diagnosis and treatment in lung cancer.


2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Wei Song ◽  
Fei Fei ◽  
Fengchang Qiao ◽  
Zuyi Weng ◽  
Yuanxun Yang ◽  
...  

AbstractLong noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m6A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m6A modification by m6A-RNA sequencing and m6A-RIP assays. Decreased m6A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m6A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL.


2022 ◽  
Author(s):  
Alicia DeSantola ◽  
Ranjay Gulati ◽  
Pavel I. Zhelyazkov

We explore how the initial market positioning of entrepreneurial ventures shapes how they professionalize over time, focusing specifically on the development of functional roles. In contrast to existing literature, which presumes a uniform march toward professionalization as ventures scale and complete developmental milestones, we advance a contingent perspective, distinguishing between the development of external interface functions (marketing & sales and customer development) and internal process functions (accounting, human resources, and finance). Specifically, we argue that positioning in an unconventional market space raises demand for external engagement that focuses ventures’ attention and resources toward developing external interface roles. At the same time, such unconventional ventures are less apt to elaborate their internal process roles relative to more conventional peers. We test these predictions using a novel longitudinal data set on the internal organizations of 3,748 U.S.-based entrepreneurial ventures. In contrast to common assumptions of convergent professionalization, our theory and findings advance the perspective that ventures pursue divergent professionalization paths based on their initial market positioning as they scale up.


2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Christopher V.H.-H. Chen ◽  
Katherine Kearns ◽  
Lynn Eaton ◽  
Darren S. Hoffmann ◽  
Denise Leonard ◽  
...  

Our paper names the importance of communities of practice for ourselves as educational developers, inviting us to witness and name: the communities in which we belong; the important functions they engage; who they nurture and how; and what visible and hidden labor is undertaken to sustain these communities. We include narratives from educational developers who share examples of the functional roles and relational meanings from their membership in different communities of practice. Through these stories, we amplify the particularly important role these groups have played in our professional and personal lives during 2020. As these groups are fragile, we end with specific actions we can take to tend to our communities of practice, maintaining them so that they will provide us support and shelter into the future.


2022 ◽  
Author(s):  
Justin Galardi ◽  
Victoria N Bela ◽  
Nazish Jeffery ◽  
Xueyang He ◽  
Eliezra Glasser ◽  
...  

In the early stages of spliceosome assembly, the 3' splice site is recognized by sequential complexes of U2AF2 with SF1 followed by the SF3B1 subunit of the U2 small nuclear ribonucleoprotein particle. The U2AF2 - SF1 interface comprises a U2AF homology motif (UHM) of U2AF2 and a well-characterized U2AF ligand motif (ULM)/coiled coil region of SF1. However, the structure of the U2AF2 - SF3B1 interface and its importance for pre-mRNA splicing is unknown. To address this knowledge gap, we determined the crystal structure of the U2AF2 UHM bound to a SF3B1 ULM site at 1.8 Å resolution. The trajectory of the SF3B1 ULM across the U2AF2 UHM surface differed from prior UHM/ULM structures. This distinctive structure is expected to modulate the orientations of the full-length proteins. Using isothermal titration calorimetry, we established similar binding affinities of a minimal U2AF2 UHM - SF3B1 ULM complex and a nearly full-length U2AF2 protein binding the N-terminal SF3B1 region, with or without an auxiliary SF3B6 subunit. We showed that key residues at the U2AF2 UHM - SF3B1 ULM interface are required for high affinity association and co-immunoprecipitation of the splicing factors. Moreover, disrupting the U2AF2 - SF3B1 interface altered splicing of representative human transcripts. Further analysis of these transcripts and genome-wide data sets indicated that the subset of splice sites co-regulated by U2AF2 and SF3B1 are largely distinct from those co-regulated by U2AF2 and SF1. Altogether, these findings support distinct structural and functional roles for the sequential SF1 and SF3B1 complexes with U2AF2 during the pre-mRNA splicing process.


2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Dae Kwan Ko ◽  
Federica Brandizzi

AbstractAdverse environmental and pathophysiological situations can overwhelm the biosynthetic capacity of the endoplasmic reticulum (ER), igniting a potentially lethal condition known as ER stress. ER stress hampers growth and triggers a conserved cytoprotective signaling cascade, the unfolded protein response (UPR) for ER homeostasis. As ER stress subsides, growth is resumed. Despite the pivotal role of the UPR in growth restoration, the underlying mechanisms for growth resumption are yet unknown. To discover these, we undertook a genomics approach in the model plant species Arabidopsis thaliana and mined the gene reprogramming roles of the UPR modulators, basic leucine zipper28 (bZIP28) and bZIP60, in ER stress resolution. Through a network modeling and experimental validation, we identified key genes downstream of the UPR bZIP-transcription factors (bZIP-TFs), and demonstrated their functional roles. Our analyses have set up a critical pipeline for functional gene discovery in ER stress resolution with broad applicability across multicellular eukaryotes.


2022 ◽  
Vol 9 (1) ◽  
Author(s):  
Sunanda Sharma ◽  
Vera Meyer

Abstract Background Biological pigmentation is one of the most intriguing traits of many fungi. It holds significance to scientists, as a sign of biochemical metabolism and organism-environment interaction, and to artists, as the source of natural colors that capture the beauty of the microbial world. Furthermore, the functional roles and aesthetic appeal of biological pigmentation may be a path to inspiring human empathy for microorganisms, which is key to understanding and preserving microbial biodiversity. A project focused on cross-species empathy was initiated and conducted as part of an artist-in-residence program in 2021. The aim of this residency is to bridge the current divide between science and art through interdisciplinary practice focused on fungi. Results The residency resulted in multiple products that are designed for artistic and scientific audiences with the central theme of biological pigmentation in fungi and other microorganisms. The first product is a video artwork that focuses on Aspergillus niger as a model organism that produces melanin pigment in a biosynthetic process similar to that of humans. The growth and morphology of this commonplace organism are displayed through video, photo, animation, and time-lapse footage, inviting the viewer to examine the likenesses and overlaps between humans and fungi. The second product is The Living Color Database, an online compendium of biological colors for scientists, artists, and designers. It links organisms across the tree of life, focusing on fungi, bacteria, and archaea, and the colors they express through biological pigmentation. Each pigment is represented in terms of its chemistry, its related biosynthesis, and its color expressions according to different indices: HEX, RGB, and Pantone. It is available at color.bio. Conclusions As fungal biotechnology continues to mature into new application areas, it is as important as ever that there is human empathy for these organisms to promote the preservation and appreciation of fungal biodiversity. The products presented here provide paths for artists, scientists, and designers to understand microorganisms through the lens of color, promoting interspecies empathy through research, teaching, and practice.


Author(s):  
Stephan E. Lehnart ◽  
Xander H.T. Wehrens

Junctophilins (JPHs) comprise a family of structural proteins that connect the plasma membrane to intracellular organelles such as the endo/sarcoplasmic reticulum. Tethering of these membrane structures results in the formation of highly organized subcellular junctions that play important signaling roles in all excitable cell types. There are four JPH isoforms, expressed primarily in muscle and neuronal cell types. Each JPH protein consists of 6 'membrane occupation and recognition nexus' (MORN) motifs, a joining region connecting these to another set of 2 MORN motifs, a putative alpha-helical region, a divergent region exhibiting low homology between JPH isoforms, and a carboxy-terminal transmembrane region anchoring into the ER/SR membrane. JPH isoforms play essential roles in developing and maintaining subcellular membrane junctions. Conversely, inherited mutations in JPH2 cause hypertrophic or dilated cardiomyopathy, while trinucleotide expansions in the JPH3 gene cause Huntington Disease-Like 2. Loss of JPH1 protein levels can cause skeletal myopathy, while loss of cardiac JPH2 levels causes heart failure and atrial fibrillation, among other disease. This review will provide a comprehensive overview of the JPH gene family, phylogeny, and evolutionary analysis of JPH genes and other MORN domain proteins. JPH biogenesis, membrane tethering, and binding partners will be discussed, as well as functional roles of JPH isoforms in excitable cells. Finally, potential roles of JPH isoform deficits in human disease pathogenesis will be reviewed.


Author(s):  
Sterling B. Tebbett ◽  
Alexandre C. Siqueira ◽  
David R. Bellwood
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