Ash1L ameliorates psoriasis via limiting neuronal activity-dependent release of miR-let-7b.

BACKGROUND AND PURPOSE: Psoriasis is a common autoimmune skin disease that significantly diminishes patients' quality of life. Interactions between primary afferents of the somatosensory system and the cutaneous immune system mediate the pathogenesis of psoriasis. This study aims to elucidate the molecular mechanisms of how primary sensory neurons regulate psoriasis formation. EXPERIMENTAL APPROACH: Skin and total RNA were extracted from wild-type (WT) and ASH1-like histone lysine methyltransferase (Ash1l+/- ) mice in both naive and imiquimod (IMQ)-induced psoriasis models. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence-activated cell sorting (FACS) were then performed. Microfluidic chamber coculture was used to investigate the interaction between somatosensory neurons and bone marrow dendritic cells (BMDCs) ex vivo. Whole-cell patch clamp recordings were used to evaluate neuronal excitability after Ash1L haploinsufficiency in primary sensory neurons. KEY RESULTS: The haploinsufficiency of ASH1L, a histone methyltransferase, in primary sensory neurons causes both neurite hyperinnervation and increased neuronal excitability, which promote miR-let-7b release from primary afferents in the skin in a neuronal activity-dependent manner. With a 'GUUGUGU' core sequence, miR-let-7b functions as an endogenous ligand of toll-like receptor 7 (TLR7) and stimulates the activation of dermal dendritic cells (DCs) and interleukin (IL)-23/IL-17 axis, ultimately exacerbating the symptoms of psoriasis. Thus, by limiting miR-let-7b release from primary afferents, ASH1L prevents dermal DC activation and ameliorates psoriasis. CONCLUSION AND IMPLICATIONS: Somatosensory neuron ASH1L modulates the cutaneous immune system by limiting neuronal activity-dependent release of miR-let-7b, which can directly activate dermal DCs via TLR7 and ultimately lead to aggravated psoriatic lesion.

Characterization of Instrument Transformers under Realistic Conditions: Impact of Single and Combined Influence Quantities on Their Wideband Behavior.

Instrument transformers (ITs) play a key role in electrical power systems, facilitating the accurate monitoring and measurement of electrical quantities. They are essential for measurement, protection, and metering in transmission and distribution grids and accurately reducing the grid voltage and current for low-voltage input instrumentation. With the increase in renewable energy sources, electronic converters, and electric vehicles connected to power grids, ITs now face challenging distorted conditions that differ from the nominal ones. The study presented in this paper is a collaborative work between national metrology institutes and universities that analyzes IT performance in measuring distorted voltages and currents in medium-voltage grids under realistic conditions. Both current and voltage measuring transformers are examined, considering influence quantities like the temperature, mechanical vibration, burden, adjacent phases, and proximity effects. The study provides detailed insights into measurement setups and procedures, and it quantifies potential errors arising from IT behavior in measuring distorted signals in the presence of the various considered influence quantities and their combinations. The main findings reveal that the temperature has the most evident impact on the inductive voltage transformer performance, as well as the burden, causing significant changes in ratio error and phase displacement at the lower temperatures. As for low-power ITs, establishing a priori the effects of adjacent phases and proximity on the frequency responses of low-power ITs is a complex matter, because of their different characteristics and construction solutions.

Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance.

Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures ("tolerant"), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah-/- AMs were less responsive to LPS stimulation and less phagocytic than were Aoah+/+ AMs. Upon innate stimulation in the airways, Aoah-/- mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah-/- mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized ("tolerized") AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah-/- AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah-/- AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung.

How Instrument Transformers Influence Power Quality Measurements: A Proposal of Accuracy Verification Tests.

The integration of renewable energy sources on a large scale in the electrical energy distribution systems, as well as the widespread of non-linear loads, has led to a significant increase in power quality (PQ) disturbances. For this reason, PQ monitoring is also becoming a key task in medium voltage (MV) grids. The measurement of PQ at MV levels can only be performed using instrument transformers (ITs) to scale down the level of voltage and current to levels suitable for the input stage of PQ instruments. However, no international standards currently require the verification of the errors introduced by ITs in the measurement of PQ phenomena. Moreover, this issue is only partially addressed in the scientific literature, where papers dealing with specific and limited aspects of the problem can be found. For this reason, this paper aims to comprehensively assess the issue, proposing IT accuracy verification tests for different PQ parameters. First, a set of PQ phenomena relevant for IT testing is chosen, as well as the associated ranges of variation, based on a review of the enforced standards and the scientific literature. For each selected PQ phenomenon, possible performance indices and test waveforms are proposed. Finally, the proposed procedure is validated by applying it to the characterization of two different types of commercial voltage transformers.

Precise Amplitude and Phase Determination Using Resampling Algorithms for Calibrating Sampled Value Instruments.

Sampling-based calibration systems for calibrating "Sampled Value" (SV)-based instruments for substation automation require synchronised and time-aligned sampling processes. As the signal frequency of the power grid is always asynchronous to the standardised sampling frequencies according to IEC 61869-9, the sampled waveforms of the calibration system and of the SV-based device under test can be resampled to be synchronised and to allow better accuracy in the following measurements based on the Discrete Fourier Transform (DFT) of the resampled waveforms. The paper presents simulations and results for different resampling algorithms. A modified sinc interpolation method with a finite impulse response (FIR) is presented. The deviation of the results for the root mean square (RMS) and phase angle is in the order of 10-8 V/V (or rad) for normalised frequencies of up to 20% of the sampling frequency. No practical degradation in the presence of noise and harmonics could be observed. In addition, laboratory experiments demonstrate the realization of the proposed resampling process in the future SV-based calibration systems for SV-based instrumentation.