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MicroRNA-142 Is Critical for the Homeostasis and Function of Type 1 Innate Lymphoid Cells
No full textNatural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142−/− mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-β (TGF-β) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection
Bayesian Neural Networks for Cellular Image Classification and Uncertainty Analysis
No full textOver the last decades, deep learning models have rapidly gained popularity for their ability to
achieve state-of-the-art performances in different inference settings. Deep neural networks
have been applied to an increasing number of problems spanning different domains of
application. Novel applications define a new set of requirements that transcend accurate
predictions and depend on uncertainty measures. The aims of this study are to implement
Bayesian neural networks and use the corresponding uncertainty estimates to perform predictions
and dataset analysis. We identify two main advantages in modeling the predictive
uncertainty of deep neural networks performing classification tasks. The first is the possibility
to discard highly uncertain predictions to be able to guarantee a higher accuracy of
the remaining predictions. The second is the identification of unfamiliar patterns in the data
that correspond to outliers in the model representation of the training data distribution. Such
outliers can be further characterized as either corrupted observations or data belonging to
different domains. Both advantages are well demonstrated with the benchmark datasets.
Furthermore we apply the Bayesian approach to a biomedical imaging dataset where cancer
cells are treated with diverse drugs, and show how one can increase classification accuracy
and identify noise in the ground truth labels with uncertainty analysis
Development of a biochemical and biophysical suite for integral membrane protein targets: A review
No full textThe generation of integral membrane proteins (IMPs) in heterologous systems and their characterization remains a major challenge in biomedical research. Significant efforts have been invested both in academia and in the pharmaceutical industry to establish technologies for the expression, isolation and characterization of IMPs. Here we summarize some of the key aspects, which are important to support structure-based drug design (SBDD) in drug discovery projects. We furthermore include timeline estimates and an overview of the target selection and biophysical screening approaches
Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction.
No full textThe treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties
SHP2 inhibition overcomes RTK-mediated pathway re-activation in KRAS mutant tumors treated with MEK inhibitors
No full textFGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with MEK inhibitor trametinib in several KRAS mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTKs) are also feedback activated in this context. Herein, we profile a large panel of KRAS mutant cancer cell lines for the contribution of RTKs to the feedback activation of phospho-MEK following MEK inhibition, using a SHP2 inhibitor (SHP099) that blocks RAS activation mediated by multiple RTKs. We find that RTK-driven feedback activation widely exists in KRAS mutant cancer cells, to a less extent in those harboring the G13D variant, and involves several RTKs including EGFR, FGFR, and MET. We further demonstrate this pathway feedback activation is mediated through mutant KRAS, at least for the G12C, G12D and G12V variants, and wild-type KRAS can also contribute significantly to the feedback activation. Finally, SHP099 and MEK inhibitors exhibit combination benefits inhibiting KRAS mutant cancer cell proliferation in vitro and in vivo. These findings provide a rationale for exploration of combining SHP2 and MAPK pathway inhibitors for treating KRAS mutant cancers in the clinic
Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors
No full textThis phase I study aimed to determine tolerability and preliminary efficacy of single-agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28-day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose-limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all-grade treatment-suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression-free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors
UTS2B defines a novel enteroendocrine cell population and regulates GLP-1 secretion through SSTR5 in male mice.
No full textThe gut-pancreas axis plays a key role in the regulation of glucose homeostasis and may be therapeutically exploited to treat not only type II diabetes, but also hypoglycemia and hyperinsulinemia. We identify a novel enteroendocrine cell type expressing the peptide hormone urotensin 2B (UTS2B). UTS2B inhibits glucagon like peptide-1 (GLP-1) secretion in mouse intestinal crypts and organoids, not by signaling through its cognate receptor UTS2R but through the activation of the somatostatin receptor 5 (SSTR5). Circulating UTS2B concentrations in mice are physiologically regulated during starvation, further linking this peptide hormone to metabolism. Furthermore, administration of UTS2B to starved mice demonstrates that it is capable of regulating blood glucose and plasma concentrations of GLP-1 and insulin in vivo. Altogether, our results identify a novel cellular source of UTS2B in the gut, which acts in a paracrine manner to regulate GLP-1 secretion through SSTR5.These findings uncover a fine-tuning mechanism mediated by a ligand-receptor pair in the regulation of gut hormone secretion, which can be potentially exploited to correct metabolic unbalance caused by over-activation of the gut-pancreas axis
Organopolymer with dual chromophores and fast charge-transfer properties for sustainable photocatalysis
No full textPhotocatalytic polymers offer an alternative to prevailing organometallics and nanomaterials, and they may benefit from polymer-mediated catalytic and material enhancements. MPC-1, a polymer photoredox catalyst reported herein, exhibits enhanced catalytic activity arising from charge transfer states (CTSs) between its two chromophores. Oligomeric and polymeric MPC-1 preparations both promote efficient hydrodehalogenation of α-halocarbonyl compounds while exhibiting different solubility properties. The polymer is readily recovered by filtration. MPC-1-coated vessels enable batch and flow photocatalysis, even with opaque reaction mixtures, via “backside irradiation.” Ultrafast transient absorption spectroscopy indicates a fast charge-transfer process within 20 ps of photoexcitation. Time-resolved photoluminescence measurements reveal an approximate 10 ns lifetime for bright valence states. Ultrafast measurements suggest a long CTS lifetime. Empirical catalytic activities of small-molecule models of MPC-1 subunits support the CTS hypothesis. Density functional theory (DFT) and time-dependent DFT calculations are in good agreement with experimental spectra, spectral peak assignment, and proposed underlying energetics
PGC-1α regulates mitochondrial-sarcoplasmic reticulum (SR)-mediated calcium exchange, SR stress and cell death to mitigate skeletal muscle aging
No full textAge-related impairment of muscle function severely affects the health of a growing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor α (ERRα)-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1α. As a result, PGC-1α prevents tubular aggregate formation and apoptosis of fibers in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1α in muscle cells. Accordingly, mice with muscle-specific gain- and loss-of-function of PGC-1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1α on muscle function and overall health span in aging