Abstract
The silica cell wall of diatoms, a widespread group of unicellular microalgae, is an exquisite example for the ability of organisms to finely sculpt minerals under strict biological control. ...The prevailing paradigm for diatom silicification is that this is invariably an intracellular process, occurring inside specialized silica deposition vesicles that are responsible for silica precipitation and morphogenesis. Here, we study the formation of long silicified extensions that characterize many diatom species. We use cryo-electron tomography to image silica formation in situ, in 3D, and at a nanometer-scale resolution. Remarkably, our data suggest that, contradictory to the ruling paradigm, these intricate structures form outside the cytoplasm. In addition, the formation of these silica extensions is halted at low silicon concentrations that still support the formation of other cell wall elements, further alluding to a different silicification mechanism. The identification of this unconventional strategy expands the suite of mechanisms that diatoms use for silicification.
Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. We developed an immunodeficient mouse model to test the tumorigenic ...potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. We show that a minority population of CD44⁺ cancer cells, which typically comprise <10% of the cells in a HNSCC tumor, but not the CD44⁻ cancer cells, gave rise to new tumors in vivo. Immunohistochemistry revealed that the CD44⁺ cancer cells have a primitive cellular morphology and costain with the basal cell marker Cytokeratin 5/14, whereas the CD44⁻ cancer cells resemble differentiated squamous epithelium and express the differentiation marker Involucrin. The tumors that arose from purified CD44⁺ cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate. Furthermore, the tumorigenic CD44⁺ cells differentially express the BMI1 gene, at both the RNA and protein levels. By immunohistochemical analysis, the CD44⁺ cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. Taken together, these data demonstrate that cells within the CD44⁺ population of human HNSCC possess the unique properties of cancer stem cells in functional assays for cancer stem cell self-renewal and differentiation and form unique histological microdomains that may aid in cancer diagnosis.
Model fit assessment is a central component of evaluating confirmatory factor analysis models and the validity of psychological assessments. Fit indices remain popular and researchers often judge fit ...with fixed cutoffs derived by Hu and Bentler (1999). Despite their overwhelming popularity, methodological studies have cautioned against fixed cutoffs, noting that the meaning of fit indices varies based on a complex interaction of model characteristics like factor reliability, number of items, and number of factors. Criticism of fixed cutoffs stems primarily from the fact that they were derived from one specific confirmatory factor analysis model and lack generalizability. To address this, we propose a simulation-based method called dynamic fit index cutoffs such that derivation of cutoffs is adaptively tailored to the specific model and data characteristics being evaluated. Unlike previously proposed simulation-based techniques, our method removes existing barriers to implementation by providing an open-source, Web based Shiny software application that automates the entire process so that users neither need to manually write any software code nor be knowledgeable about foundations of Monte Carlo simulation. Additionally, we extend fit index cutoff derivations to include sets of cutoffs for multiple levels of misspecification. In doing so, fit indices can more closely resemble their originally intended purpose as effect sizes quantifying misfit rather than improperly functioning as ad hoc hypothesis tests. We also provide an approach specifically designed for the nuances of 1-factor models, which have received surprisingly little attention in the literature despite frequent substantive interests in unidimensionality.
Translational AbstractEvaluating confirmatory factor model fit through the lens of "approximate fit" has enjoyed widespread - though not universal - adoption in empirical studies and is valued for its goal to assess whether the model may be practically useful, even if fit is not exact. An obstacle with approximate fit is that there is ambiguity regarding what is considered "practically useful". Hu and Bentler (1999) addressed this issue with an expansive study to provide guidelines for values indicating that a model demonstrates reasonable approximate fit. Though their suggestions remain widely used today and are engrained in the literature, their suggested cutoffs have unfortunately been shown to vary widely depending on context. That is, values that indicate great fit in one context may indicate poor fit in another. The inherent problem is that the Hu and Bentler cutoffs are fixed values, so they arbitrarily benefit some models and arbitrarily punish others. Previous literature has suggested custom simulation methods that take the logic of Hu and Bentler's approach and apply it to the individual model being evaluated. In this way, researchers can obtain values indicative of good approximate fit in their specific circumstances to avoid fixed cutoffs. Though a clever solution, such an approach has seen little uptake presumably because many researchers are not well-versed in conducting simulations. This paper addresses the issue by providing a method and software application that builds and executes a Hu-and- Bentler-style simulation from model output. In this way, researchers can benefit from modern computational resources without a deep programming background.
NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral ...defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus.
NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-β-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection.
In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the ...prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as ISRCTN64455289.
•Directly-coupled renewable energy powered reverse osmosis membrane system.•Produced acceptable quality water with constant solar irradiance (SI) 400–1200Wm−2.•Under fluctuating SI conditions, ...periods of high SI compensated for times of low SI.•Naturally-induced backwash that can disrupt concentration polarisation layer.•Short off-periods and high available power improve performance after shutdown.
Fluctuations in solar irradiance were varied in frequency and magnitude to investigate the performance of a directly-connected solar energy powered reverse osmosis (RO) membrane system. Typically, the system produced acceptable quality water with constant solar irradiances ranging from 400 to 1200Wm−2. Low average motor powers were encountered during fluctuations, however, in many cases, good performance was still realised, even at solar irradiance values that were equivalent to <400Wm−2. This counter-intuitive result arises from the effect of averaging the motor power, with periods of high solar irradiance compensating for the under-performance at times when the system was off. Overall, even though the permeate flux was often low when operating under fluctuating conditions, the RO system continued to deliver satisfactory quality water and at a low specific energy consumption (SEC). Temporal studies revealed that a disruption of the concentration polarisation layer occurs via a naturally induced backwash for steps in the solar irradiance as low as 100Wm−2. This suggests that a renewable energy powered RO filtration system could benefit from being operated from a fluctuating energy source. Furthermore, the operating conditions during the first couple of minutes after a system shutdown event is shown to be very important, with: (i) shorter off-periods resulting in good performance being achieved quicker, and (ii) short-term power availability dramatically improving system performance. These findings indicate that a renewable energy powered RO system can operate well from a fluctuating energy source, in particular when additional power – for example, via supercapacitor energy buffering – is available to boost the system after a shut-down period.
Background
In some breast and gynaecologic cancer centres in Germany, patients participate in their own case discussion in multidisciplinary tumour conferences (MTCs), where treatment recommendations ...are discussed and finalized. However, the extent to which patients in MTCs are involved in decision‐making on treatment recommendations remains largely unexplored. Hence, this study investigates how recommendations are communicated to patients and the extent to which the interactions with patients in MTCs are in line with shared decision‐making (SDM).
Methods
In this observational study, we audio‐recorded MTCs with patient participation in three breast and gynaecologic cancer centres in Germany. We qualitatively analysed the data with regard to content and linguistic aspects.
Results
We analysed 82 case discussions. Recommendations made during MTCs were regarding (i) treatment options, (ii) treatment initiation, (iii) next (treatment) steps and (iv) whether a treatment method should be initiated at all. The decision about recommendations depended in part on patients' preferences or further course/further outcomes. Although the purpose of MTCs is to provide recommendations, some recommendations were framed as the final decision. The majority of the decision‐making conversation could be characterized as option talk (78%), during which patients were mostly proposed only one (treatment) option.
Conclusions
This study establishes limited SDM in MTCs with patient participation. By indicating choices and thereby creating awareness of choices among patients, MTCs with patient participation could be used to foster SDM implementation.
Patient or Public Contribution
Two representatives of a large self‐help organization for patients with breast cancer assisted the research project, particularly, in discussing the results.
Histone deacetylase (HDAC) inhibitors have enormous therapeutic potential as effective epigenetic regulators, and now with the focus on the selective HDAC6 inhibitor in ongoing clinical trials, more ...advantages over other non-selective pan-HDAC inhibitors are foreseeable. As it is of paramount importance to understand the complex regulatory web of mutual interactions involving epigenetic machinery and non-coding genome in regulating gene expression, herein, we investigated the intriguing interactions between HDAC6-induced lncRNA (LINC00152) and its possible sponge miRNA (hsa-miR-499a-5p) in multiple myeloma.
This analysis aims at evaluating the impact of multidisciplinary tumor boards on clinical outcome of multiple tumor entities, the effect of the specific number of multidisciplinary tumor boards and ...potential differences between the tumor entities.
By a matched-pair analysis we compared the response to treatment, overall survival, relapse or disease free survival and progression free survival of patients whose cases were discussed in a tumor board meeting with patients whose cases were not. It was performed with patients registered in the cancer registry of the University of Bonn and diagnosed between 2010 and 2016. After the matching process with a pool of 7262 patients a total of 454 patients with 66 different tumor types were included in this study.
First, patients with three or more multidisciplinary tumor board meetings in their history show a significantly better overall survival than patients with no tumor board meeting. Second, response to treatment, relapse free survival and time to progression were not found to be significantly different. Third, there was no significant difference for a specific tumor entity.
This study revealed a positive impact of a higher number of multidisciplinary tumor boards on the clinical outcome. Also, our analysis hints towards a positive effect of multidisciplinary tumor boards on overall survival.
Glioblastoma multiforme (GBM) is probably the only tumor in which a unique epigenetic alteration, namely methylation of the MGMT gene, possesses direct clinical relevance. Now with the emergence of ...aberrant N6 methyladenosine (m6A) modifications (the most common epigenetic modification of mRNA, closely linked to the autophagy process) in cancer, the epi-transcriptomic landscape of GBM pathobiology has been expanded. Considering this, herein, we systematically analyzed m6A regulators, assessed their correlation with autophagy-related genes (ATG), and established a long non-coding RNAs (lncRNA)-dependent prognostic signature (m6A-autophagy-lncRNAs) for GBM. Our analysis identified a novel signature of five long non-coding RNAs (lncRNAs: ITGA6-AS1, AC124248.1, NFYC-AS1, AC025171.1, and AC005229.3) associated with survival of GBM patients, and four among them clearly showed cancer-associated potential. We further validated and confirmed the altered expression of two lncRNAs (AC124248.1, AC005229.3) in GBM associated clinical samples using RT-PCR. Concerning the prognostic ability, the obtained signature determined high-/low-risk groups in GBM patients and showed sensitivity to anticancer drugs. Collectively, the m6A-autophagy-lncRNAs signature presented in the study is clinically relevant and is the first attempt to systematically predict the potential interaction between the three key determinants (m6A, autophagy, lncRNA) in cancer, particularly in GBM.
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