We present the vibrational properties and phonon dispersion for quasi-2D hybrid organic–inorganic perovskites (BA)2CsPb2I7, (HA)2CsPb2I7, (BA)2(MA)Pb2I7, and (HA)2(MA)Pb2I7 calculated from first ...principles. Given the highly complex nature of these compounds, we first perform careful benchmarking and convergence testing to identify suitable parameters to describe their structural features and vibrational properties. We find that the inclusion of van der Waals corrections on top of generalized gradient approximation (GGA) exchange-correlation functionals provides the best agreement for the equilibrium structure relative to experimental data. We also investigate the impact of the molecular orientation on the equilibrium structure of these layered perovskite systems. Our results suggest ground state ferroelectric alignment of molecular dipoles in the out-of-plane direction is unlikely and support the assignment of the centrosymmetric space group for the low-temperature phase of (HA)2(MA)Pb2I7. Finally, we compute vibrational properties under the harmonic approximation. We find that stringent energy cut-offs are required to obtain well-converged phonon properties, and once converged, the harmonic approximation can capture key physics for such a large, hybrid inorganic–organic system with vastly different atom types, masses, and interatomic interactions. We discuss the obtained phonon modes and dispersion behavior in the context of known properties for bulk 3D perovskites and ligand molecular crystals. While many vibrational properties are inherited from the parent systems, we also observe unique coupled vibrations that cannot be associated with vibrations of the pure constituent perovskite and ligand subphases. Energy dispersion of the low energy phonon branches primarily occurs in the in-plane direction and within the perovskite subphase and arises from bending and breathing modes of the equatorial Pb–I network within the perovskite octahedral plane. The analysis herein provides the foundation for future investigations on this class of materials, such as exciton–phonon coupling, phase transitions, and general temperature-dependent properties.
Radiologic screening of high-risk adults reduces lung-cancer-related mortality
; however, a small minority of eligible individuals undergo such screening in the United States
. The availability of ...blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)
, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.
Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in ...cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Purpose
Stigma is a major factor causing delayed help-seeking and poor treatment adherence in patients with psychotic disorders. Previous research has mostly focused on chronic samples and the impact ...of culturally-relevant variables on both patients’ and their caregivers’ stigmatization is understudied. This study aimed to examine the relationships between various forms of stigma, “face concern”, and clinical characteristics in a group of Chinese first-episode psychosis (FEP) patients and their caregivers.
Methods
Forty-four Hong Kong Chinese aged 15–54 years presenting with FEP to psychiatric services and their caregivers were recruited. Assessments on self-stigma, affiliate stigma, perceived public stigma, “face concern”, symptom severity and subjective quality of life (QoL) were conducted.
Results
Self-stigma of FEP patients was correlated with perceived public stigma, “face concern”, insight and psychological health of QoL. Multiple regression analysis revealed that perceived public stigma and “face concern” independently predicted self-stigma. Mediation analysis further suggested that “face concern” partially mediated the relationship between perceived public stigma and self-stigma. Caregivers’ affiliate stigma was significantly associated with higher levels of stress, and symptoms of depression and anxiety. Affiliate stigma did not correlate with perceived public stigma and “face concern”.
Conclusion
Our results indicate a critical role of perceived public stigma and fear of losing face in determining self-stigma in Chinese patients with FEP. Caregivers with greater degree of affiliate stigma experience increased stress and emotional distress. Our findings highlight the importance to examine culturally specific factors that may contribute to the development of self-stigma in first-episode populations of different ethnicities.
Democracies are postulated upon the ability to carry out fair elections, free from any form of interference or manipulation. Social media have been reportedly used to distort public opinion nearing ...election events in the United States and beyond. With over 240 million election-related tweets recorded between 20 June and 9 September 2020, in this study we chart the landscape of social media manipulation in the context of the upcoming 3 November 2020 U.S. presidential election. We focus on characterizing two salient dimensions of social media manipulation, namely (i) automation (e.g., the prevalence of bots), and (ii) distortion (e.g., manipulation of narratives, injection of conspiracies or rumors). Despite being outnumbered by several orders of magnitude, just a few thousands of bots generated spikes of conversations around real-world political events in all comparable with the volume of activity of humans. We discover that bots also exacerbate the consumption of content produced by users with their same political views, worsening the issue of political echo chambers. Furthermore, coordinated efforts carried out by Russia, China and other countries are hereby characterized. Finally, we draw a clear connection between bots, hyper-partisan media outlets, and conspiracy groups, suggesting the presence of systematic efforts to distort political narratives and propagate disinformation. Our findings may have impactful implications, shedding light on different forms of social media manipulation that may, altogether, ultimately pose a risk to the integrity of the election.
Mitochondria have an essential role in powering cells by generating ATP following the metabolism of pyruvate derived from glycolysis. They are also the major source of generating reactive oxygen ...species (ROS), which have regulatory roles in cell death and proliferation. Mutations in mitochondrial DNA (mtDNA) and dysregulation of mitochondrial metabolism have been frequently described in human tumors. Although the role of oxidative stress as the consequence of mtDNA mutations and/or altered mitochondrial functions has been demonstrated in carciongenesis, a causative role of mitochondria in tumor progression has only been demonstrated recently. Specifically, the subject of this mini-review focuses on the role of mitochondria in promoting cancer metastasis. Cancer relapse and the subsequent spreading of cancer cells to distal sites are leading causes of morbidity and mortality in cancer patients. Despite its clinical importance, the underlying mechanisms of metastasis remain to be elucidated. Recently, it was demonstrated that mitochondrial oxidative stress could actively promote tumor progression and increase the metastatic potential of cancer cells. The purpose of this mini-review is to summarize current investigations of the roles of mitochondria in cancer metastasis. Future development of diagnostic and therapeutic strategies for patients with advanced cancer will benefit from the new knowledge of mitochondrial metabolism in epithelial cancer cells and the tumor stroma.
Although transcriptional regulation of stem cell pluripotency and differentiation has been extensively studied, only a small number of studies have addressed the roles for posttranslational ...modifications in these processes. A key mechanism of posttranslational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Here, using shotgun proteomics, we map the ubiquitinated protein landscape during embryonic stem cell (ESC) differentiation and induced pluripotency. Moreover, using UPS-targeted RNAi screens, we identify additional regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme Psmd14 and the E3 ligase Fbxw7, and characterize their importance in ESC pluripotency and cellular reprogramming. This global characterization of the UPS as a key regulator of stem cell pluripotency opens the way for future studies that focus on specific UPS enzymes or ubiquitinated substrates.
► Shotgun proteomics characterizes the ubiquitin landscape in ESCs and iPSCs ► RNAi screens of ubiquitin-proteasome system members find pluripotency regulators ► Psmd14 deubiquitinase activity is required for maintaining pluripotency ► c-Myc stabilization by Fbxw7 inhibits differentiation and enhances reprogramming
The ubiquitin-proteasome system plays a widespread role in pluripotency and reprogramming.
Endosomal trafficking has emerged as a defective biological pathway in Alzheimer's disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the ...identity of the CSF proteins that accumulate in the setting of defects in AD's endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-to-human studies suggest that retromer-dependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD's trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.
Abstract
Biased sex ratios are commonly found in nature and were also observed in this study on pelagic ostracods in both the Arctic and Southern Oceans. Because changes in sex ratio may occur in ...response to environmental perturbations, studying this aspect in polar regions as they continue to warm is of ecological importance. Here, a robust spatiotemporal dataset of historical and contemporary sex data was compiled to explore variation in ostracod sex ratio with respect to species, depth, region, season and ontogeny. Global ostracod populations in both the Arctic and Antarctic demonstrated a stable female bias of ~ 60–70% over all tested factors. This female bias was even higher when only the premature A-1 stage was considered, regardless of the factor. The widespread stability in stage-specific sex ratio and its subtle changes, especially in the interannual context, show that marine Ostracoda has the potential to be a model organism for more comprehensive sex ratio research, but deeper investigation into their ecology and reproduction is necessary.