Tumor-released RNA may mediate intercellular communication and serve as biomarkers. Here we develop a protocol enabling quantitative, minimally biased analysis of extracellular RNAs (exRNAs) ...associated with microvesicles, exosomes (collectively called EVs), and ribonucleoproteins (RNPs). The exRNA complexes isolated from patient-derived glioma stem-like cultures exhibit distinct compositions, with microvesicles most closely reflecting cellular transcriptome. exRNA is enriched in small ncRNAs, such as miRNAs in exosomes, and precisely processed tRNA and Y RNA fragments in EVs and exRNPs. EV-enclosed mRNAs are mostly fragmented, and UTRs enriched; nevertheless, some full-length mRNAs are present. Overall, there is less than one copy of non-rRNA per EV. Our results suggest that massive EV/exRNA uptake would be required to ensure functional impact of transferred RNA on brain recipient cells and predict the most impactful miRNAs in such conditions. This study also provides a catalog of diverse exRNAs useful for biomarker discovery and validates its feasibility on cerebrospinal fluid.
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also ...associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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•Type 2 cytokines directly activate both mouse and human sensory neurons•IL-4 enhances neuronal responsiveness to multiple pruritogens•Sensory neuron-specific deletion of IL-4Rα or JAK1 reduces chronic itch•Clinical studies demonstrate that JAK inhibitors relieve chronic itch
Type 2 cytokines directly stimulate itch-sensory neurons, and blocking this pathway is effective in a proof-of-concept study in patients with recalcitrant chronic itch.
While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game ...changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3
T cells.
To compare insulin glargine 300 units/mL (Gla-300) versus insulin degludec 100 units/mL (IDeg-100) in this first head-to-head randomized controlled trial.
BRIGHT (NCT02738151) was a multicenter, ...open-label, active-controlled, two-arm, parallel-group, 24-week, noninferiority study in insulin-naive patients with uncontrolled type 2 diabetes. Participants were randomized 1:1 to evening dosing with Gla-300 (
= 466) or IDeg-100 (
= 463), titrated to fasting self-monitored plasma glucose of 80-100 mg/dL. The primary end point was HbA
change from baseline to week 24. Safety end points included incidence and event rates of hypoglycemia.
At week 24, HbA
improved similarly from baseline values of 8.7% (72 mmol/mol) in the Gla-300 group and 8.6% (70 mmol/mol) in the IDeg-100 group to 7.0% (53 mmol/mol)-least squares mean difference -0.05% (95% CI -0.15 to 0.05) (-0.6 mmol/mol -1.7 to 0.6)-demonstrating noninferiority of Gla-300 versus IDeg-100 (
< 0.0001). Hypoglycemia incidence and event rates over 24 weeks were comparable with both insulins, whereas during the active titration period (0-12 weeks) the incidence and rate of anytime (24-h) confirmed hypoglycemia (≤70 and <54 mg/dL) were lower with Gla-300. Both insulins were properly titrated and exhibited no specific safety concerns.
Gla-300 and IDeg-100 provided similar glycemic control improvements with relatively low hypoglycemia risk. Hypoglycemia incidence and rates were comparable with both insulins during the full study period but lower in favor of Gla-300 during the titration period. The choice between these longer-acting basal insulins may be determined by factors such as access and cost, alongside clinical considerations.
In patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to bortezomib, melphalan, and prednisone increased progression-free ...survival and the response rate at the cost of an increase in infections.
Modern-day CMOS-based computation technology is reaching its fundamental limitations. The emerging field of magnonics, which utilizes spin waves for data transport and processing, proposes a ...promising path to overcome these limitations. Different devices have been demonstrated recently on the macro- and microscale, but the feasibility of the magnonics approach essentially relies on the scalability of the structure feature size down to the extent of a few 10 nm, which are typical sizes for the established CMOS technology. Here, we present a study of propagating spin-wave packets in individual yttrium iron garnet (YIG) conduits with lateral dimensions down to 50 nm. Space and time-resolved microfocused Brillouin-light-scattering (BLS) spectroscopy is used to characterize the YIG nanostructures and measure the spin-wave decay length and group velocity directly. The revealed magnon transport at the scale comparable to the scale of CMOS proves the general feasibility of magnon-based data processing.
S-adenosylmethionine (SAM) is an essential metabolite that acts as a cofactor for most methylation events in the cell. The N6-methyladenosine (m6A) methyltransferase METTL16 controls SAM homeostasis ...by regulating the abundance of SAM synthetase MAT2A mRNA in response to changing intracellular SAM levels. Here we present crystal structures of METTL16 in complex with MAT2A RNA hairpins to uncover critical molecular mechanisms underlying the regulated activity of METTL16. The METTL16-RNA complex structures reveal atomic details of RNA substrates that drive productive methylation by METTL16. In addition, we identify a polypeptide loop in METTL16 near the SAM binding site with an autoregulatory role. We show that mutations that enhance or repress METTL16 activity in vitro correlate with changes in MAT2A mRNA levels in cells. Thus, we demonstrate the structural basis for the specific activity of METTL16 and further suggest the molecular mechanisms by which METTL16 efficiency is tuned to regulate SAM homeostasis.
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•METTL16 recognizes substrate RNA sequence and structure for methylation•Methylation activity of METTL16 can be modulated by the substrate RNA conformation•METTL16 is autoregulated through its SAM binding pocket•Mutations in the catalytic domain of METTL16 regulate MAT2A mRNA levels in cells
Doxtader et al. determine crystal structures of the N6-methyladenosine methyltransferase METTL16 in complex with RNA substrates. METTL16 can be regulated by the conformation of the RNA substrate and by an autoregulatory loop near the SAM binding pocket. Modulating the catalytic activity of METTL16 changes MAT2A mRNA levels in cells.
Studying the complex web of interactions in biological communities requires large multifactorial experiments with sufficient statistical power. Automation tools reduce the time and labor associated ...with setup, data collection, and analysis in experiments that untangle these webs. We developed tools for high-throughput experimentation (HTE) in duckweeds, small aquatic plants that are amenable to autonomous experimental preparation and image-based phenotyping. We showcase the abilities of our HTE system in a study with 6,000 experimental units grown across 2,000 treatments. These automated tools facilitated the collection and analysis of time-resolved growth data, which revealed finer dynamics of plant-microbe interactions across environmental gradients. Altogether, our HTE system can run experiments with up to 11,520 experimental units and can be adapted for other small organisms.
Hybrid materials displaying multistage security behavior, where a single material shows both wavelength‐ and temperature‐dependent luminescence properties, are reported. The materials consist of ...mixed‐lanthanide β‐diketonate complexes grafted into the pores of a nanosized 2,2′‐bipyridine‐5,5′‐dicarboxylate‐acid MOF. A very specific choice of lanthanides and their ratios, as well as β‐diketonate ligand, is crucial for obtaining the desired properties. The wavelength‐dependent luminescence properties of the materials are very well matched with the excitation wavelengths of a standard UV lamp, and a clearly visible change in luminescence is observed in a narrow temperature range (slightly below and above room temperature), proving them to be excellent materials for use in anti‐counterfeit technologies, which would be almost impossible to mimic.
Hybrid lanthanide/metal–organic‐framework materials for application in multistage security technologies are proposed. These materials show both wavelength‐ and temperature‐dependent luminescence properties. They exhibit “chameleon” behavior by changing their emission color in response to changes in the environment. For this application, the combination of Tb3+/Sm3+ is superior to that of Tb3+/Eu3+, which is most often investigated for temperature‐dependent luminescence.
Soil is the largest organic carbon (C) pool of terrestrial ecosystems, and C loss from soil accounts for a large proportion of land‐atmosphere C exchange. Therefore, a small change in soil organic C ...(SOC) can affect atmospheric carbon dioxide (CO2) concentration and climate change. In the past decades, a wide variety of studies have been conducted to quantify global SOC stocks and soil C exchange with the atmosphere through site measurements, inventories, and empirical/process‐based modeling. However, these estimates are highly uncertain, and identifying major driving forces controlling soil C dynamics remains a key research challenge. This study has compiled century‐long (1901–2010) estimates of SOC storage and heterotrophic respiration (Rh) from 10 terrestrial biosphere models (TBMs) in the Multi‐scale Synthesis and Terrestrial Model Intercomparison Project and two observation‐based data sets. The 10 TBM ensemble shows that global SOC estimate ranges from 425 to 2111 Pg C (1 Pg = 1015 g) with a median value of 1158 Pg C in 2010. The models estimate a broad range of Rh from 35 to 69 Pg C yr−1 with a median value of 51 Pg C yr−1 during 2001–2010. The largest uncertainty in SOC stocks exists in the 40–65°N latitude whereas the largest cross‐model divergence in Rh are in the tropics. The modeled SOC change during 1901–2010 ranges from −70 Pg C to 86 Pg C, but in some models the SOC change has a different sign from the change of total C stock, implying very different contribution of vegetation and soil pools in determining the terrestrial C budget among models. The model ensemble‐estimated mean residence time of SOC shows a reduction of 3.4 years over the past century, which accelerate C cycling through the land biosphere. All the models agreed that climate and land use changes decreased SOC stocks, while elevated atmospheric CO2 and nitrogen deposition over intact ecosystems increased SOC stocks—even though the responses varied significantly among models. Model representations of temperature and moisture sensitivity, nutrient limitation, and land use partially explain the divergent estimates of global SOC stocks and soil C fluxes in this study. In addition, a major source of systematic error in model estimations relates to nonmodeled SOC storage in wetlands and peatlands, as well as to old C storage in deep soil layers.
Key Points
Simulated historical (1901–2010) SOC dynamics vary largely among models
Ten TBMs agree that climate and land use change have reduced SOC stocks
Rising CO2 and N deposition are prone to increase SOC with varying magnitudes
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