A device for mixing multiple (N) pulse density modulated (PDM) bit streams of a bit rate, the device comprises an input logic, an error accumulation circuit, an error correction circuit and an adder of more than N bits; wherein the device is arranged to output an output PDM bit stream that represents a mixture of the multiple input PDM bit streams; wherein the output PDM bit stream comprises a plurality of output PDM bits, wherein a certain output PDM bit of a plurality of output PDM bits that form the output PDM bit stream is generated during a certain clock cycle; wherein the input logic is arranged to select, during each fraction of the certain clock cycle, a current bit of a selected PDM bit stream, wherein different PDM bit streams are selected during different fragments of the certain clock cycle; wherein the error accumulation circuit is arranged to store intermediate values during a first fraction till a penultimate fraction of the certain clock signal and to store a last value during a last fraction of the certain clock signal.

An apparatus for coding a signal by means of amplitude shift keying comprises a class E amplifier including a switching transistor, to whose gate is supplied a voltage having an operating frequency for operating the class E amplifier. For achieving an amplitude shift keying in the output signal of the class E amplifier, a circuit for switching the operating frequency of the voltage supplied to the gate of the switching transistor, or the resonance frequency of the class E amplifier, between a first value and a second value is provided and in order to switch a deviation degree between the operating frequency and the resonance frequency between a first value and a second value.

An electrical device not only controls train signals as trains advance, but also alters the voltage in the tracks leading up to the signals so that the trains will actually stop at a red signal, slow at an amber aspect and continue on at full speed when the signal is showing green. The electrical device of the present invention can change the “block signal” from “green” to “red”, thereby signaling the engineer behind the train to come to a stop. In addition, the electrical device can simultaneously change the voltage in the tracks to stop the approaching train at the red signal. Only when the forward train has cleared will the approaching train get a clear signal and voltage to resume its forward progress.

A USB interface to provide power delivery negotiated through a dedicated transmission channel includes a transmitter circuit including a digital-to-analog converter having an output coupled with an input of a transmission filter, a receiver circuit including an analog-to-digital converter having an input coupled with an output of a receiving filter, and a switching circuit configured in an operating mode of the USB interface to connect an output of the transmission filter and an input of the receiving filter to a connection node of the dedicated transmission channel.

Examples of adapters for transmitting signals are disclosed. In one example implementation according to aspects of the present disclosure, an adapter may include a first connector communicatively couplable to PCIe port of a computing system via a first plurality of pins and a second connecter communicatively couplable to an electronic device via a second plurality of pins. The first plurality of pins is communicatively coupled to the second plurality of pins. Additionally, signals of a first type are transmittable between the computing system and the electronic device via a first subset of the first and the second pluralities of pins and signals of a second type are transmittable between the computing system and the electronic device via a second subset of the first and the second pluralities of pins. The second subset of the first plurality of pins and the second plurality of pins conforms to the SFF 8639 standard.

A composition of matter comprising: a combination of a phytate and a plurality of microorganisms comprising a Trichoderma virens fungus, a Bacillus amyloliquefaciens bacterium, and one or a plurality of mycorrhizae fungi that is placed in the vicinity of a plant root in a manner that allows the microorganisms in the composition of matter to colonize said plant root; and a method for increasing plant yield comprising: placing a combination of a phytate and a plurality of microorganisms comprising a Trichoderma virens fungus, a Bacillus amyloliquefaciens bacterium, and one or a plurality of mycorrhizae fungi in the vicinity of a plant root in a manner that allows the microorganisms in the composition of matter to colonize said plant root.

An optical disk drive and a digital servo method for the optical disk drive includes controlling functions of the optical disk drive with a microprocessor. Low-pass filtered and gain adjusted versions of individual photodetector output signals resulting from an illumination of an optical disk are received. Versions of the individual photodetector output signals are digitized to produce digital signals. A focus control signal and/or a tracking control signal is determined through at least one servo algorithm executed by a digital signal processor based on a focus error and/or tracking error, respectively, determined from the digital signals. The digital signal processor is an integrated circuit structured and arranged for manipulation of digital signals in accordance with programmed commands, and in a manner that operates faster than the microprocessor.

A system is described, along with the related device and method, for transmission and/or reception of signals having electromagnetic modes with orbital angular momentum (OAM), wherein the device is adapted to receive, at its input, electromagnetic signals from at least one transmitter, and is configured to apply a discrete Fourier transform to the electromagnetic signals in order to generate the signals having electromagnetic modes with orbital angular momentum.

Methods and apparatus are described. A method, implemented in a decoder, includes receiving two or more signals from an encoder over two or more respective wires. At least one of the two or more signals includes at least one code that was recoded by the encoder. The decoder receives a recoding table. The recoding table provides a mapping indicating the recoding for each code that was recoded by the encoder in the received two or more signals. The decoder decodes the two or more received signals using the received recoding table.

Aspects of the subject disclosure may include, for example, an antenna structure having a feed point for coupling to a dielectric core of a cable that propagates electromagnetic waves without an electrical return path, and a dielectric antenna, substantially or entirely devoid of conductive external surfaces, coupled to the feed point, the dielectric antenna facilitating receipt, at the feed point, the electromagnetic waves for propagating the electromagnetic waves to an aperture of the dielectric antenna for radiating a wireless signal. Other embodiments are disclosed.

"Yesterday Was Everything" Misery Signals Documentary released. Jon did audio post production for the film.

The Bank of England maintained its key interest rate at a record low and refrained from unveiling additional quantitative easing, on Thursday, as the economic outlook remains uncertain due to the impact of the coronavirus, or Covid-19, pandemic. However, Governor Andrew Bailey kept the door open for further easing as the economy is set to contract the most in more than 300 years due to the lockdo

A lot of old members are back.

The post MISERY SIGNALS Begins Teasing New Material appeared first on Metal Injection.

High-frequency audio could be used to stealthily track netizens

Technical folks looking to improve web privacy haven't been able to decide whether sound beyond the range of human hearing poses enough of a privacy risk to merit restriction.…

Leaders of political revolutions never quit before the official battle begins, and say that they will vote for and support their enemies. When the moment arrived of walking all that endless talk of Bernie Sanders about fighting his political revolution, he caved out of self interest Continue reading →

Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.

Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

26 September 2019

Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from mice only under fasting conditions. Similarly, PLIN5 mitigated lipopolysaccharide- or palmitic acid-induced inflammatory responses in hepatocytes. During fasting, PLIN5 was also required for the induction of autophagy, which contributed to its anti-inflammatory effects. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Taken together, these data show that PLIN5 signals via SIRT1 to promote autophagy and prevent FA-induced inflammation as a means to maintain hepatocyte homeostasis during periods of fasting and FA mobilization.

If you've been keeping up to day with The BMJ - online on in print, you might have noticed that we've got a new type of article - NIHR Signals - and they are here to give busy clinicians a quick overview of practice changing research that has come out of the UK's National Institute for Health Research. Tara Lamont, director of the NIHR...

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children’s plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and -aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

Anatoli Juditsky, Arkadi Nemirovski.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 458--502.

Abstract:
We consider the problem of recovering linear image of unknown signal belonging to a given convex compact signal set from noisy observation of another linear image of the signal. We develop a simple generic efficiently computable non linear in observations “polyhedral” estimate along with computation-friendly techniques for its design and risk analysis. We demonstrate that under favorable circumstances the resulting estimate is provably near-optimal in the minimax sense, the “favorable circumstances” being less restrictive than the weakest known so far assumptions ensuring near-optimality of estimates which are linear in observations.

Sihai Dave Zhao, Yet Tien Nguyen.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 110--142.

Abstract:
It is frequently of interest to identify simultaneous signals, defined as features that exhibit statistical significance across each of several independent experiments. For example, genes that are consistently differentially expressed across experiments in different animal species can reveal evolutionarily conserved biological mechanisms. However, in some problems the test statistics corresponding to these features can have complicated or unknown null distributions. This paper proposes a novel nonparametric false discovery rate control procedure that can identify simultaneous signals even without knowing these null distributions. The method is shown, theoretically and in simulations, to asymptotically control the false discovery rate. It was also used to identify genes that were both differentially expressed and proximal to differentially accessible chromatin in the brains of mice exposed to a conspecific intruder. The proposed method is available in the R package github.com/sdzhao/ssa.

Kentaro Minami.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1508--1576.

Abstract:
We study the problem of estimating piecewise monotone vectors. This problem can be seen as a generalization of the isotonic regression that allows a small number of order-violating changepoints. We focus mainly on the performance of the nearly-isotonic regression proposed by Tibshirani et al. (2011). We derive risk bounds for the nearly-isotonic regression estimators that are adaptive to piecewise monotone signals. The estimator achieves a near minimax convergence rate over certain classes of piecewise monotone signals under a weak assumption. Furthermore, we present an algorithm that can be applied to the nearly-isotonic type estimators on general weighted graphs. The simulation results suggest that the nearly-isotonic regression performs as well as the ideal estimator that knows the true positions of changepoints.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.

SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

The leading drone vendor developed the system to address safety and privacy concerns. The US Federal Aviation Administration is also drafting a rule that'll require all consumer drones to offer 'remote identification,' or what's basically an electronic license plate.

Political observers see the fielding of Doval as the Prime Minister’s assertion on the issue of developments linked to changes in the citizenship law which have triggered protests across the country.

Weird blasts of radio waves from space called fast radio bursts have been baffling astronomers since they were discovered, but after finding one in our galaxy we may finally know what creates them

Andre J. Riveros, Anne S. Leonard, Wulfila Gronenberg, and Daniel R. Papaj

Similar to animal communication displays, flowers emit complex signals that attract pollinators. Signal complexity could lead to higher cognitive load, impairing performance, or might benefit pollinators by facilitating learning, memory and decision-making. Here, we evaluate learning and memory in foragers of the bumble bee Bombus impatiens trained to simple (unimodal) vs. complex signals (bimodal) under restrained conditions. Use of a proboscis extension response protocol enabled us to control the timing and duration of stimuli presented during absolute and differential learning tasks. Overall, we observed broad variation in the performance under the two conditions, with bees trained to compound bimodal signals learning and remembering as well as, better, or more poorly than bees trained to unimodal signals. Interestingly, the outcome of training was affected by the specific colour-odour combination. Among unimodal stimuli, the performance with odour stimuli was higher than with colour stimuli, suggesting that olfactory signals played a more significant role in the compound bimodal condition. This was supported by the fact that after 24 h, most bimodal-treatment bees responded to odour but not visual stimuli. We did not observe differences in latency of response, suggesting that signal composition affected decision accuracy, not speed. We conclude that restrained bumble bee workers exhibit broad variation of responses to bimodal stimuli and that components of the bimodal signal may not be used equivalently. The analysis of bee performance under restrained conditions enables accurately control the multimodal stimuli provided to individuals and to study the interaction of individual components within a compound.

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.

In our atmosphere, strange dense patches of charged air sometimes bounce radio waves around and disrupt radar – and now they have been spotted on Mars

We’ve spotted strange blasts of radio waves from space in a pattern that may be produced by a magnetised neutron star wobbling as it spins

Weird blasts of radio waves from space called fast radio bursts have been baffling astronomers since they were discovered, but after finding one in our galaxy we may finally know what creates them

The green-and-white banner from an Illinois high school recalls the first Earth Day 50 years ago

At the recent low of 12514 points, the Sensex has tested the 12800-12000-pts support zone and has since then attempted a corrective rally.

LifeSignals, based in Fremont, California, announced that it received the CE Mark for its LifeSignals ECG Remote Monitoring Patch. The patch, integrated with a remote monitoring platform, is designed as a continuous electrocardiography (ECG) and heart rate monitor. The ECG Remote Monitoring Patch is disposable and captures data for up to three days. The device […]

Chimeric antigen receptor T-cell therapies have shown remarkable efficacy in leukemia and lymphoma patients who relapsed or were refractory to several prior treatments, but many challenges remain in the cancer cell therapy field. Strategies that may improve upon first-generation therapies were presented during the American Association for Cancer Research virtual meeting with encouraging early activity, […]

The U.S. Justice Department released the following statement by department spokesman Brian Fallon in response to President Obama’s speech on U.S. signals intelligence.

Shares of Relmada Therapeutics Inc. (RLMD) have gained 19 percent so far this year and trade around $37.

Researchers have identified many of the gestures that dogs use to get humans to do their bidding.

And then they yell at cyclists for not following the rules.