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Furthermore, by using a nearby graphene electronic sensor in a ferroelectric field transistor geometry, we quantify the ferroelectric built-in interlayer potential, in good agreement with first-principles calculations. The new semiconducting ferroelectric properties of these four new TMDs opens up the possibility of studying the interplay between ferroelectricity and their rich electric and optical properties2-5.Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.Immune-checkpoint inhibitors (ICIs) have transformed patient care in oncology but are associated with a unique spectrum of organ-specific inflammatory toxicities known as immune-related adverse events (irAEs). Given the expanding use of ICIs, an increasing number of patients with cancer experience irAEs, including severe irAEs. Proper diagnosis and management of irAEs are important to optimize the quality of life and long-term outcomes of patients receiving ICIs; however, owing to the substantial heterogeneity within irAEs, and despite multicentre initiatives, performing clinical studies of these toxicities with a sufficient cohort size is challenging. Pioneering studies from the past few years have demonstrated that aggregate clinical data, real-world data (such as data on pharmacovigilance or from electronic health records) and multi-omics data are alternative tools well suited to investigating the underlying mechanisms and clinical presentations of irAEs. In this Perspective, we summarize the advantages and shortcomings of different sources of 'big data' for the study of irAEs and highlight progress made using such data to identify biomarkers of irAE risk, evaluate associations between irAEs and therapeutic efficacy, and characterize the effects of demographic and anthropometric factors on irAE risk. Harnessing big data will accelerate research on irAEs and provide key insights that will improve the clinical management of patients receiving ICIs.Machine learning-based models of protein fitness typically learn from either unlabeled, evolutionarily related sequences or variant sequences with experimentally measured labels. For regimes where only limited experimental data are available, recent work has suggested methods for combining both sources of information. Toward that goal, we propose a simple combination approach that is competitive with, and on average outperforms more sophisticated methods. Our approach uses ridge regression on site-specific amino acid features combined with one probability density feature from modeling the evolutionary data. Within this approach, we find that a variational autoencoder-based probability density model showed the best overall performance, although any evolutionary density model can be used. Moreover, our analysis highlights the importance of systematic evaluations and sufficient baselines.Over the past two decades, compelling evidence has emerged indicating that immune mechanisms can contribute to the pathogenesis of major depressive disorder (MDD) and that drugs with primary immune targets can improve depressive symptoms. Patients with MDD are heterogeneous with respect to symptoms, treatment responses and biological correlates. Defining a narrower patient group based on biology could increase the treatment response rates in certain subgroups a major advance in clinical psychiatry. For example, patients with MDD and elevated pro-inflammatory biomarkers are less likely to respond to conventional antidepressant drugs, but novel immune-based therapeutics could potentially address their unmet clinical needs. This article outlines a framework for developing drugs targeting a novel patient subtype within MDD and reviews the current state of neuroimmune drug development for mood disorders. We discuss evidence for a causal role of immune mechanisms in the pathogenesis of depression, together with targets under investigation in randomized controlled trials, biomarker evidence elucidating the link to neural mechanisms, biological and phenotypic patient selection strategies, and the unmet clinical need among patients with MDD.The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity.Integral membrane proteins isolated from cellular environment often lose activity and native conformation required for functional analyses and structural studies. Even in their native state, they lack sufficient surfaces to form crystal contacts. Furthermore, most of them are too small for cryogenic electron microscopy detection and too big for solution NMR. To overcome these difficulties, we recently developed a strategy to stabilize the folded state of membrane proteins by restraining their two termini with a self-assembling protein coupler. The termini-restrained membrane proteins from distinct functional families retain their activities and show increased stability and yield. This strategy enables their structure determination at near-atomic resolution by facilitating the entire pipeline from crystallization, crystal identification, diffraction enhancement and phase determination, to electron density improvement. Furthermore, stabilization of membrane proteins enables their biochemical and biophysical characterization. Here we present the protocol of membrane protein engineering (2 weeks), quality assessment (1-2 weeks), protein production (1-6 weeks), crystallization (1-2 weeks), diffraction improvement (1-3 months) and crystallographic data analysis (1 week). This protocol is intended not only for structural biologists, but also for biochemists, biophysicists and pharmaceutical scientists whose research focuses on membrane proteins.The efficient transfection of functional proteins into cells can serve as a means for regulating cellular processes toward solving fundamental challenges in biology and medicine. However, the use of proteins as effective intracellular agents is hindered by their low cellular uptake and susceptibility to degradation. Over the past 15 years, our group has been developing spherical nucleic acids (SNAs), nanoparticles functionalized with a dense radially oriented shell of nucleic acids. These structures actively enter cells and have opened new frontiers in chemical sensing, biodiagnostics and therapeutics. Recently, we have shown that proteins can be used as structurally precise and homogeneous nanoparticle cores in SNAs. The resultant protein SNAs (ProSNAs) allow previously cell-impermeable proteins to actively enter cells, exhibit high degrees of stability and activity both in cell culture and in vivo, and show enhanced pharmacokinetics. Consequently, these modular structures constitute a plug-and-play platform in which the protein core and nucleic acid shell can be independently varied to achieve a desired function. Here, we describe the synthesis of ProSNAs through the chemical modification of solvent-accessible surface residues (3-5 d). We also discuss design considerations, strategies for characterization, and applications of ProSNAs in cellular transfection, biological sensing and functional enzyme delivery in vivo.Macrophages derived from human induced pluripotent stem cells (iPSCs) have the potential to enable the development of cell-based therapies for numerous disease conditions. We here provide a detailed protocol for the mass production of iPSC-derived macrophages (iPSC-Mac) in scalable suspension culture on an orbital shaker or in stirred-tank bioreactors (STBRs). This strategy is straightforward, robust and characterized by the differentiation of primed iPSC aggregates into 'myeloid-cell-forming-complex' intermediates by means of a minimal cytokine cocktail. In contrast to the 'batch-like differentiation approaches' established for other iPSC-derived lineages, myeloid-cell-forming-complex-intermediates are stably maintained in suspension culture and continuously generate functional and highly pure iPSC-Mac. Employing a culture volume of 120 ml in the STBR platform, ~1-4 × 107 iPSC-Mac can be harvested at weekly intervals for several months. The STBR technology allows for real-time monitoring of crucial process parameters such as biomass, pH, dissolved oxygen, and nutrition levels; the system also promotes systematic process development, optimization and linear upscaling. The process duration, from the expansion of iPSC until the first iPSC-Mac harvest, is 28 d. Successful application of the protocol requires expertise in pluripotent stem cell culture, differentiation and analytical methods, such as flow cytometry. Fundamental know-how in biotechnology is also advantageous to run the process in the STBR platform. The continuous, scalable production of well-defined iPSC-Mac populations is highly relevant to various fields, ranging from developmental biology, immunology and cell therapies to industrial applications for drug safety and discovery.The treat-to-target (T2T) concept has improved outcomes for patients with diabetes, hypertension and rheumatoid arthritis. This therapeutic strategy involves choosing a well-defined, relevant target, taking therapeutic steps, evaluating whether the target has been achieved, and taking action if it has not. The T2T principle has been embraced by systemic lupus erythematosus (SLE) experts, but measurable and achievable outcomes, and therapeutic options, are needed to make this approach possible in practice. Considerable evidence has been generated regarding meaningful 'state' outcomes for SLE. Low disease activity has been defined and studied, and the most aspirational goal, remission, has been defined by the Definition of Remission in SLE task force. By contrast, current therapeutic options in SLE are limited, and more effective and safer therapies are urgently needed. Fortunately, clinical trial activity in SLE has been unprecedented, and encouraging results have been seen for novel therapies, including biologic and small-molecule agents.