About the Authors: Daniel Lin Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ...ORCID logo http://orcid.org/0000-0001-6398-4789 Ramez Kouzy Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0002-1521-0495 Joseph Abi Jaoude Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0002-2283-4765 Sonal S. Noticewala Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America Andrea Y. Delgado Medrano Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0003-0813-3492 Ann H. Klopp Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America Cullen M. Taniguchi * E-mail: ctaniguchi@mdanderson.org (CMT); lcolbert@mdanderson.org (LEC) Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0002-8052-3316 Lauren E. Colbert * E-mail: ctaniguchi@mdanderson.org (CMT); lcolbert@mdanderson.org (LEC) Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0001-5806-4339 Introduction Human papillomavirus (HPV) infections account for over 600,000 new cancer cases every year 1. Factors unique to the individual mucosal sites such as epithelial surface integrity, mucosal secretions, immune regulation, and the local microbiota likely play a role in HPV persistence and progression to cancer 2–4. Insights into the potential influence of the microbiome on viral persistence, immune response, host-mucosal environment, and cancer treatments for HPV-related cancers are just beginning to emerge. All of these bacterial, mucosal, and immune complications related to BV can result in an increased susceptibility to HPV infection and the development of high-grade intraepithelial lesions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a
pathway to invasive ...neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single-cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC.
Single-cell RNA sequencing was performed through droplet-based sequencing on 5,403 cells from 2 low-grade IPMNs (LGD-IPMNs), 2 high-grade IPMNs (HGD-IPMN), and 2 PDACs (all surgically resected).
Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. Although HGD-IPMNs expressed many core signaling pathways described in PDAC, LGD-IPMNs harbored subsets of single cells with a transcriptomic profile that overlapped with invasive cancer. Notably, a proinflammatory immune component was readily seen in low-grade IPMNs, composed of cytotoxic T cells, activated T-helper cells, and dendritic cells, which was progressively depleted during neoplastic progression, accompanied by infiltration of myeloid-derived suppressor cells. Finally, stromal myofibroblast populations were heterogeneous and acquired a previously described tumor-promoting and immune-evading phenotype during invasive carcinogenesis.
This study demonstrates the ability to perform high-resolution profiling of the transcriptomic changes that occur during multistep progression of cystic PDAC precursors to cancer. Notably, single-cell analysis provides an unparalleled insight into both the epithelial and microenvironmental heterogeneities that accompany early cancer pathogenesis and might be a useful substrate to identify targets for cancer interception.
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C4 plants supply concentrated CO2 to bundle sheath (BS) cells, improving photosynthetic efficiency by suppressing photorespiration. Mesophyll chloroplasts in C4 plants are redistributed toward the ...sides of the BS cells (aggregative movement) in response to environmental stresses under light. Although this chloroplast movement is common in C4 plants, the significance and mechanisms underlying the aggregative movement remain unknown.
Under environmental stresses, such as drought and salt, CO2 uptake from the atmosphere is suppressed by closing stomata to prevent water loss. We hypothesized that CO2 limitation may induce the chloroplast aggregative movement. In this study, the mesophyll chloroplast arrangement in a leaf of finger millet, an NAD‐malic enzyme type C4 plant, was examined under different CO2 concentrations and light conditions.
CO2 limitation around the leaves promoted the aggregative movement, but the aggregative movement was not suppressed, even at the higher CO2 concentration than in the atmosphere, under high intensity blue light. In addition, mesophyll chloroplasts did not change their arrangement under darkness or red light.
From these results, it can be concluded that CO2 limitation is not a direct inducer of the aggregative movement but would be a promoting factor of the movement under high intensity blue light.
CO2 limitation would be a promoting factor for the aggregative movement of mesophyll chloroplasts to the bundle sheath cell side in C4 plant.
Dopamine in prefrontal cortices is implicated in cognitive and emotional functions, and the dysfunction of prefrontal dopamine has been associated with cognitive and emotional deficits in mental ...illnesses. These findings have led to clinical trials of dopamine-targeting drugs and brain imaging of dopamine receptors in patients with mental illnesses. Rodent studies have suggested that dopaminergic pathway projecting to the medial prefrontal cortex (mPFC) suppresses stress susceptibility. Although various types of mPFC neurons express several dopamine receptor subtypes, previous studies neither isolated a role of dopamine receptor subtype nor identified the site of its action in mPFC. Using social defeat stress (SDS) in mice, here we identified a role of dopamine D1 receptor subtype in mPFC excitatory neurons in suppressing stress susceptibility. Repeated social defeat stress (R-SDS) reduces the expression of D1 receptor subtype in mPFC of mice susceptible to R-SDS. Knockdown of D1 receptor subtype in whole neuronal populations or excitatory neurons in mPFC facilitates the induction of social avoidance by SDS. Single social defeat stress (S-SDS) induces D1 receptor-mediated extracellular signal-regulated kinase phosphorylation and c-Fos expression in mPFC neurons. Whereas R-SDS reduces dendritic lengths of mPFC layer II/III pyramidal neurons, S-SDS increases arborization and spines of apical dendrites of these neurons in a D1 receptor-dependent manner. Collectively, our findings show that D1 receptor subtype and related signaling in mPFC excitatory neurons mediate acute stress-induced dendritic growth of these neurons and contribute to suppression of stress susceptibility. Therefore, we propose that D1 receptor-mediated dendritic growth in mPFC excitatory neurons suppresses stress susceptibility.
The topology of pure Bi is controversial because of its very small (∼10 meV) band gap. Here we perform high-resolution angle-resolved photoelectron spectroscopy measurements systematically on 14-202 ...bilayer Bi films. Using high-quality films, we succeed in observing quantized bulk bands with energy separations down to ∼10 meV. Detailed analyses on the phase shift of the confined wave functions precisely determine the surface and bulk electronic structures, which unambiguously show nontrivial topology. The present results not only prove the fundamental property of Bi but also introduce a capability of the quantum-confinement approach.
Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. With molecular subtypes of PDAC gaining relevance in the context of therapeutic ...stratification, the ability to characterize heterogeneity of cancer-specific gene expression patterns is of great interest. In addition, understanding patterns of immune evasion within PDAC is of importance as novel immunotherapeutic strategies are developed.
Single-cell RNA sequencing (scRNA-seq) is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes.
Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches.
Our analysis demonstrates that the use of
biopsies from patients with PDAC paired with scRNA-seq may facilitate therapeutic prediction from limited biopsy samples.
Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), ...frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1α, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1α suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1α expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1α exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1α expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1α recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1α expression as a therapeutic modality for the treatment of ccRCC.
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•PGC-1α suppression reprograms mitochondrial metabolism in ccRCC•PGC-1α repression is HIF dependent and requires induction of the HIF target gene Dec1•PGC-1α expression induces oxidative stress and suppresses ccRCC tumor growth•Low PGC-1α expression is a marker of poor prognosis in ccRCC
LaGory et al. show that PGC-1α expression is suppressed in ccRCC in a HIF-α- and Dec1-dependent manner. Rescued expression of PGC-1α restores mitochondrial function, induces oxidative stress, and suppresses tumor growth. In patients, low expression of PGC-1α is associated with poor overall survival and advanced-stage metastatic disease.
The three-dimensional topological semimetals represent a new quantum state of matter. Distinct from the surface state in the topological insulators that exhibits linear dispersion in two-dimensional ...momentum plane, the three-dimensional semimetals host bulk band dispersions linearly along all directions. In addition to the gapless points in the bulk, the three-dimensional Weyl/Dirac semimetals are also characterized by "topologically protected" surface state with Fermi arcs on their surface. While Cd3As2 is proposed to be a viable candidate of a Dirac semimetal, more investigations are necessary to pin down its nature. In particular, the topological surface state, the hallmark of the three-dimensional semimetal, has not been observed in Cd3As2. Here we report the electronic structure of Cd3As2 investigated by angle-resolved photoemission measurements on the (112) crystal surface and detailed band structure calculations. The measured Fermi surface and band structure show a good agreement with the band structure calculations with two bulk Dirac-like bands approaching the Fermi level and forming Dirac points near the Brillouin zone center. Moreover, the topological surface state with a linear dispersion approaching the Fermi level is identified for the first time. These results provide experimental indications on the nature of topologically non-trivial three-dimensional Dirac cones in Cd3As2.
In the hole-doped cuprates, a small number of carriers suppresses antiferromagnetism and induces superconductivity. In the electron-doped cuprates, on the other hand, superconductivity appears only ...in a narrow window of high-doped Ce concentration after reduction annealing, and strong antiferromagnetic correlation persists in the superconducting phase. Recently, Pr(1.3-x)La0.7Ce(x)CuO4 (PLCCO) bulk single crystals annealed by a protect annealing method showed a high critical temperature of around 27 K for small Ce content down to 0.05. Here, by angle-resolved photoemission spectroscopy measurements of PLCCO crystals, we observed a sharp quasi-particle peak on the entire Fermi surface without signature of an antiferromagnetic pseudogap unlike all the previous work, indicating a dramatic reduction of antiferromagnetic correlation length and/or of magnetic moments. The superconducting state was found to extend over a wide electron concentration range. The present results fundamentally challenge the long-standing picture on the electronic structure in the electron-doped regime.
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