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"Nicolas, G"
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Fundamental transport mechanisms, fabrication and potential applications of nanoporous atomically thin membranes
This Review examines the development of nanoporous atomically thin membranes, focusing on fundamental mechanisms of gas- and liquid-phase transport, membrane fabrication techniques, and advances towards practical applications.
Graphene and other two-dimensional materials offer a new approach to controlling mass transport at the nanoscale. These materials can sustain nanoscale pores in their rigid lattices and due to their minimum possible material thickness, high mechanical strength and chemical robustness, they could be used to address persistent challenges in membrane separations. Here we discuss theoretical and experimental developments in the emerging field of nanoporous atomically thin membranes, focusing on the fundamental mechanisms of gas- and liquid-phase transport, membrane fabrication techniques and advances towards practical application. We highlight potential functional characteristics of the membranes and discuss applications where they are expected to offer advantages. Finally, we outline the major scientific questions and technological challenges that need to be addressed to bridge the gap from theoretical simulations and proof-of-concept experiments to real-world applications.
Journal Article
High IRF8 expression correlates with CD8 T cell infiltration and is a predictive biomarker of therapy response in ER-negative breast cancer
Background
Characterization of breast cancer (BC) through the determination of conventional markers such as ER, PR, HER2, and Ki67 has been useful as a predictive and therapeutic tool. Also, assessment of tumor-infiltrating lymphocytes has been proposed as an important prognostic aspect to be considered in certain BC subtypes. However, there is still a need to identify additional biomarkers that could add precision in distinguishing therapeutic response of individual patients. To this end, we focused in the expression of interferon regulatory factor 8 (IRF8) in BC cells. IRF8 is a transcription factor which plays a well-determined role in myeloid cells and that seems to have multiple antitumoral roles: it has tumor suppressor functions; it acts downstream IFN/STAT1, required for the success of some therapeutic regimes, and its expression in neoplastic cells seems to depend on a cross talk between the immune contexture and the tumor cells.
The goal of the present study was to examine the relationship between IRF8 with the therapeutic response and the immune contexture in BC, since its clinical significance in this type of cancer has not been thoroughly addressed.
Methods
We identified the relationship between IRF8 expression and the clinical outcome of BC patients and validated IRF8 as predictive biomarker by using public databases and then performed in silico analysis. To correlate the expression of IRF8 with the immune infiltrate in BC samples, we performed quantitative multiplex immunohistochemistry.
Results
IRF8 expression can precisely predict the complete pathological response to monoclonal antibody therapy or to select combinations of chemotherapy such as FAC (fluorouracil, adriamycin, and cytoxan) in ER-negative BC subtypes. Analysis of immune cell infiltration indicates there is a strong correlation between activated and effector CD8
+
T cell infiltration and tumoral IRF8 expression.
Conclusions
We propose IRF8 expression as a potent biomarker not only for prognosis, but also for predicting therapy response in ER-negative BC phenotypes. Its expression in neoplastic cells also correlates with CD8
+
T cell activation and infiltration. Therefore, our results justify new efforts towards understanding mechanisms regulating IRF8 expression and how they can be therapeutically manipulated.
Journal Article
Electrosorption at metal surfaces from first principles
Electrosorption of solvated species at metal electrodes is a most fundamental class of processes in interfacial electrochemistry. Here, we use its sensitive dependence on the electric double layer to assess the performance of ab initio thermodynamics approaches increasingly used for the first-principles description of electrocatalysis. We show analytically that computational hydrogen electrode calculations at zero net-charge can be understood as a first-order approximation to a fully grand canonical approach. Notably, higher-order terms in the applied potential caused by the charging of the double layer include contributions from adsorbate-induced changes in the work function and in the interfacial capacitance. These contributions are essential to yield prominent electrochemical phenomena such as non-Nernstian shifts of electrosorption peaks and non-integer electrosorption valencies. We illustrate this by calculating peak shifts for H on Pt electrodes and electrosorption valencies of halide ions on Ag electrodes, obtaining qualitative agreement with experimental data already when considering only second order terms. The results demonstrate the agreement between classical electrochemistry concepts and a first-principles fully grand canonical description of electrified interfaces and shed new light on the widespread computational hydrogen electrode approach.
Journal Article
Specific post-translational modifications of soluble tau protein distinguishes Alzheimer’s disease and primary tauopathies
Tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The tau isoforms observed in
post mortem
human brain aggregates is used to classify tauopathies. However, distinguishing tauopathies
ante mortem
remains challenging, potentially due to differences between insoluble tau in aggregates and soluble tau in body fluids. Here, we demonstrated that tau isoforms differ between tauopathies in insoluble aggregates, but not in soluble brain extracts. We therefore characterized post-translational modifications of both the aggregated and the soluble tau protein obtained from
post mortem
human brain tissue of patients with Alzheimer’s disease, cortico-basal degeneration, Pick’s disease, and frontotemporal lobe degeneration. We found specific soluble signatures for each tauopathy and its specific aggregated tau isoforms: including ubiquitination on Lysine 369 for cortico-basal degeneration and acetylation on Lysine 311 for Pick’s disease. These findings provide potential targets for future development of fluid-based biomarker assays able to distinguish tauopathies in vivo.
Post-translational modifications on tau protein in the brain could distinguish primary tauopathies. Here, the authors assess insoluble and soluble tau extracted from
post
mortem
human tauopathy brains and show 4R/3R tau isoform ratio in aggregates is associated with specific modifications on soluble tau protein.
Journal Article
Development of a reverse transcription-loop-mediated isothermal amplification as a rapid early-detection method for novel SARS-CoV-2
The previous outbreaks of SARS-CoV and MERS-CoV have led researchers to study the role of diagnostics in impediment of further spread and transmission. With the recent emergence of the novel SARS-CoV-2, the availability of rapid, sensitive, and reliable diagnostic methods is essential for disease control. Hence, we have developed a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for the specific detection of SARS-CoV-2. The primer sets for RT-LAMP assay were designed to target the nucleocapsid gene of the viral RNA, and displayed a detection limit of 10
2
RNA copies close to that of qRT-PCR
.
Notably, the assay has exhibited a rapid detection span of 30 min combined with the colorimetric visualization. This test can detect specifically viral RNAs of the SARS-CoV-2 with no cross-reactivity to related coronaviruses, such as HCoV-229E, HCoV-NL63, HCoV-OC43, and MERS-CoV as well as human infectious influenza viruses (type B, H1N1pdm, H3N2, H5N1, H5N6, H5N8, and H7N9), and other respiratory disease-causing viruses (RSVA, RSVB, ADV, PIV, MPV, and HRV). Furthermore, the developed RT-LAMP assay has been evaluated using specimens collected from COVID-19 patients that exhibited high agreement to the qRT-PCR. Our RT-LAMP assay is simple to perform, less expensive, time-efficient, and can be used in clinical laboratories for preliminary detection of SARS-CoV-2 in suspected patients. In addition to the high sensitivity and specificity, this isothermal amplification conjugated with a single-tube colorimetric detection method may contribute to the public health responses and disease control, especially in the areas with limited laboratory capacities.
Journal Article
Active eosinophils regulate host defence and immune responses in colitis
In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils—elusive granulocytes that are implicated in a plethora of human pathologies
1
–
5
—are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4
+
T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.
Single-cell transcriptomic profiling and functional assays are used to identify subpopulations of eosinophils that are present in the mouse gastrointestinal tract and provide insight into the role of these cells in inflammatory bowel diseases in humans.
Journal Article
Convergence, transdisciplinarity, and team science: an interepistemic approach
The challenges facing the Intermountain West are characterized by extreme complexity and enormous consequences. They include climate change and associated ecological effects, such as catastrophic wildfire and drought. They are also inextricably linked to social inequities, including freshwater availability, land conversion, and access to basic human needs such as quality food, affordable energy, and access to healthcare. A meaningful response to these challenges requires new thinking. Convergent research is designed to foster new thinking by creating novel frameworks and conceptual models that drive innovation. Here, we share our approach to convergent research in the Transformation Network (TN), a National Science Foundation supported Sustainable Regional Systems Network. A key element of the TN’s design is an interepistemic and even interontological approach that builds across different knowledge systems throughout academia and among Native American and community partners. After first providing an overview of the development of the field of convergence research and its relationship to transdisciplinary research, we provide an outline of the TN’s approach, which draws from two schools of transdisciplinarity thought—the metaphysical approach of the Nicolescuian School and the more solution-focused Zürich School. We then explain how we operationalize our approach with systems thinking and systems dynamics modeling, as well as community engagement, diversity, equity, inclusion, and justice efforts, and continual learning with reflexive assessment and training practices. This includes an example where TN faculty and students partner with members of the Navajo Nation to support the independence of Native American communities in the San Juan River Watershed through the implementation of small-scale sustainable off-grid food-energy-water systems.
Journal Article