Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses.

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.

Stabilization and operation of a Kerr-cat qubit.

Quantum superpositions of macroscopically distinct classical states-so-called Schrödinger cat states-are a resource for quantum metrology, quantum communication and quantum computation. In particular, the superpositions of two opposite-phase coherent states in an oscillator encode a qubit protected against phase-flip errors1,2. However, several challenges have to be overcome for this concept to become a practical way to encode and manipulate error-protected quantum information. The protection must be maintained by stabilizing these highly excited states and, at the same time, the system has to be compatible with fast gates on the encoded qubit and a quantum non-demolition readout of the encoded information. Here we experimentally demonstrate a method for the generation and stabilization of Schrödinger cat states based on the interplay between Kerr nonlinearity and single-mode squeezing1,3 in a superconducting microwave resonator4. We show an increase in the transverse relaxation time of the stabilized, error-protected qubit of more than one order of magnitude compared with the single-photon Fock-state encoding. We perform all single-qubit gate operations on timescales more than sixty times faster than the shortest coherence time and demonstrate single-shot readout of the protected qubit under stabilization. Our results showcase the combination of fast quantum control and robustness against errors, which is intrinsic to stabilized macroscopic states, as well as the potential of of these states as resources in quantum information processing5-8.

Quantum error correction of a qubit encoded in grid states of an oscillator.

The accuracy of logical operations on quantum bits (qubits) must be improved for quantum computers to outperform classical ones in useful tasks. One method to achieve this is quantum error correction (QEC), which prevents noise in the underlying system from causing logical errors. This approach derives from the reasonable assumption that noise is local, that is, it does not act in a coordinated way on different parts of the physical system. Therefore, if a logical qubit is encoded non-locally, we can-for a limited time-detect and correct noise-induced evolution before it corrupts the encoded information1. In 2001, Gottesman, Kitaev and Preskill (GKP) proposed a hardware-efficient instance of such a non-local qubit: a superposition of position eigenstates that forms grid states of a single oscillator2. However, the implementation of measurements that reveal this noise-induced evolution of the oscillator while preserving the encoded information3-7 has proved to be experimentally challenging, and the only realization reported so far relied on post-selection8,9, which is incompatible with QEC. Here we experimentally prepare square and hexagonal GKP code states through a feedback protocol that incorporates non-destructive measurements that are implemented with a superconducting microwave cavity having the role of the oscillator. We demonstrate QEC of an encoded qubit with suppression of all logical errors, in quantitative agreement with a theoretical estimate based on the measured imperfections of the experiment. Our protocol is applicable to other continuous-variable systems and, in contrast to previous implementations of QEC10-14, can mitigate all logical errors generated by a wide variety of noise processes and facilitate fault-tolerant quantum computation.

To catch and reverse a quantum jump mid-flight.

In quantum physics, measurements can fundamentally yield discrete and random results. Emblematic of this feature is Bohr's 1913 proposal of quantum jumps between two discrete energy levels of an atom1. Experimentally, quantum jumps were first observed in an atomic ion driven by a weak deterministic force while under strong continuous energy measurement2-4. The times at which the discontinuous jump transitions occur are reputed to be fundamentally unpredictable. Despite the non-deterministic character of quantum physics, is it possible to know if a quantum jump is about to occur? Here we answer this question affirmatively: we experimentally demonstrate that the jump from the ground state to an excited state of a superconducting artificial three-level atom can be tracked as it follows a predictable 'flight', by monitoring the population of an auxiliary energy level coupled to the ground state. The experimental results demonstrate that the evolution of each completed jump is continuous, coherent and deterministic. We exploit these features, using real-time monitoring and feedback, to catch and reverse quantum jumps mid-flight-thus deterministically preventing their completion. Our findings, which agree with theoretical predictions essentially without adjustable parameters, support the modern quantum trajectory theory5-9 and should provide new ground for the exploration of real-time intervention techniques in the control of quantum systems, such as the early detection of error syndromes in quantum error correction.

The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response.

The induction of type I interferons by the bacterial secondary messengers cyclic di-GMP (c-di-GMP) or cyclic di-AMP (c-di-AMP) is dependent on a signaling axis that involves the adaptor STING, the kinase TBK1 and the transcription factor IRF3. Here we identified the heliase DDX41 as a pattern-recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP. Knockdown of DDX41 via short hairpin RNA in mouse or human cells inhibited the induction of genes encoding molecules involved in the innate immune response and resulted in defective activation of STING, TBK1 and IRF3 in response to c-di-GMP or c-di-AMP. Our results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by DDX41, which forms a complex with STING to signal to TBK1-IRF3 and activate the interferon response.

Horizontal transfer of miR-383 sensitise cells to cisplatin by targeting VEGFA-Akt signalling loop.

BACKGROUND: Cellular resistance to cisplatin has been one of the major obstacles in the success of combination therapy for many types of cancers. Emerging evidences suggest that exosomes released by drug resistant tumour cells play significant role in conferring resistance to drug sensitive cells by means of horizontal transfer of genetic materials such as miRNAs. Though exosomal miRNAs have been reported to confer drug resistance, the exact underlying mechanisms are still unclear. METHODS AND RESULTS: In the present study, mature miRNAs secreted differentially by cisplatin resistant and cisplatin sensitive HepG2 cells were profiled and the effect of most significantly lowered miRNA in conferring cisplatin resistance when horizontally transferred, was analysed. we report miR-383 to be present at the lowest levels among the differentially abundant miRNAs expressed in exosomes secreted by cisplatin resistant cells compared to that that of cisplatin sensitive cells. We therefore, checked the effect of ectopic expression of miR-383 in altering cisplatin sensitivity of Hela cells. Drug sensitivity assay and apoptotic assays revealed that miR-383 could sensitise cells to cisplatin by targeting VEGF and its downstream Akt mediated pathway. CONCLUSION: Results presented here provide evidence for the important role of miR-383 in regulating cisplatin sensitivity by modulating VEGF signalling loop upon horizontal transfer across different cell types.

An Asymmetric Coumarin-Anthracene Conjugate as Efficient Fullerene-Free Acceptor for Organic Solar Cells.

Asymmetric wide-band gap fullerene-free acceptors (FFAs) play a crucial role in organic solar cells (OSCs). Here, we designed and synthesized a simple asymmetric coumarin-anthracene conjugate named CA-CN with optical band gap of 2.1 eV in a single-step condensation reaction. Single crystal X-ray structure analysis confirms various multiple intermolecular non-covalent interactions. The molecular orbital energy levels of CA-CN estimated from cyclic voltammetry were found to be suitable for its use as an acceptor for OSCs. Binary OSCs fabricated using CA-CN as acceptor and PTB7-Th as the donor achieve a power conversion efficiency (PCE) of 11.13 %. We further demonstrate that the insertion of 20 wt % of CA-CN as a third component in ternary OSCs with PTB7-Th : DICTF as the host material achieved an impressive PCE of 14.91 %, an improvement of ~43 % compared to the PTB7-Th : DICTF binary device (10.38 %). Importantly, the ternary blend enhances the absorption coverage from 400 to 800 nm and improves the morphology of the active layer. The findings highlight the efficacy of an asymmetric design approach for FFAs, which paves the way for developing high-efficiency OSCs at low cost.

Unveiling the impact of Ni2+/Y3+ co-substitution on the structural, dielectric, and impedance properties of multiferroic spinel ferrite for hydroelectric cell application.

Substitution with rare earth (RE3+) and transition (X = Cu, Ni, Mn, Zn, etc.) metals can distort the spinel ferrite structure and create defects, which can be exploited in multifarious applications. In this study, yttrium and nickel co-substituted cobalt ferrites [Co1-xNixFe1.85Y0.15O4], (0.0 ≤ x ≤ 0.15) were synthesized by a modified sol-gel reaction route. The X-ray diffraction (XRD) patterns confirmed the single phase and highly crystalline nature of the prepared samples. Field emission scanning electron microscopy with energy dispersive X-ray (FESEM-EDX) spectroscopy confirmed the morphology of the prepared samples sintered at 800 °C and showed the grain sizes of the particles decreased with the addition of nickel ions. The simultaneous co-existence of saturation magnetization and ferroelectricity at room temperature confirmed the multiferroic nature of the co-substituted cobalt ferrites. The dielectric and impedance studies confirmed the Maxwell-Wagner polarization phenomenon and the enhanced values with Y-Ni co-substitution. The maximum saturation ferroelectric polarization was attained around 6.142 µC cm-2 for yttrium-substituted cobalt ferrite and then decreased with the increase in the substitution % of nickel. The maximum value of saturation magnetization (Ms = 99.50 emu g-1) was obtained with the highest substitution % of nickel of x = 0.15 in yttrium-substituted cobalt ferrite (YCFO) nanoferrites, which was also confirmed from the vibrating sample magnitude (VSM) studies at room temperature. The improvements in the structural, morphological, electrical, and multiferroic properties in the co-substituted cobalt ferrites were found to correlated to the substitution of the bigger cationic Y3+ ions compared to the Fe3+ ions, while the small substitution of Ni2+ ions lead to changes in the lattice parameters, porosity, and conduction behavior. These significant enhancements in co-substituted cobalt ferrites can be exploited for hydroelectric cell applications.

Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation.

Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which ROS is a required upstream mediator of Nlrp3 inflammasome activation. Here we have identified the oxazolidinone antibiotic linezolid as a Nlrp3 agonist that activates the Nlrp3 inflammasome independently of ROS. The pathways for ROS-dependent and ROS-independent Nlrp3 activation converged upon mitochondrial dysfunction and specifically the mitochondrial lipid cardiolipin. Cardiolipin bound to Nlrp3 directly and interference with cardiolipin synthesis specifically inhibited Nlrp3 inflammasome activation. Together these data suggest that mitochondria play a critical role in the activation of the Nlrp3 inflammasome through the direct binding of Nlrp3 to cardiolipin.

Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells.

Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation.

An unusual case of eosinophilia, myalgia and skin contractures: Shulman's disease revisited.

Shulman's disease (eosinophilic fasciitis) is a very rare autoimmune disorder with an unknown etiopathogenesis. During the initial period of disease, it usually causes limb and trunk edema followed by collagenous thickening of the subcutaneous fascia. Eosinophilia is a predominant laboratory finding during the initial phase of the disease and less prominent in the later phases. Patients may also present with arthritis, myositis, peripheral neuropathy, and rarely pleuropericarditis. Here, we are reporting a case of eosinophilic fasciitis presenting with vague constitutional symptoms, fever, and peripheral blood eosinophilia followed by rapidly evolving skin tightening with joint contractures and muscle stiffness, which misled the treating team toward Scleroderma and its overlap syndromes. The diagnosis was finally clinched by a full-thickness skin biopsy along with underlying fascia and muscle tissue from an effected area, with a gratifying treatment response to standard immune suppression.

Impact of digital boards on hand and neck muscle activity during online teaching process.

Academicians across the globe due to Covid 19 shifted to online teaching as a mainstream method by replacing the chalk and talk method. The main objective of this study is to find the impact of different sizes of digital boards used for online teaching on muscle activity and muscle fatigue, and then results are compared with conventional writing. Initially, a questionnaire survey is conducted among 100 college professors about the issue they faced while using online teaching methods. Experimental analysis are then conducted using electromyography sensor (sEMG) among ten college professors and their muscle activity on the dominant hand and neck while writing on two commercially available digital boards namely Type 1 (small writing area) and Type 2 (large writing area). Four muscles namely Flexor carpi radialis, Extensor carpi radialis, Biceps brachii, and Sternocleidomastoid (SCM) are chosen for the study. The results are then compared with muscle activity while writing on conventional A4 sheets. Normalized root mean square (RMS) is used to assess the muscle activity and the trend line of MPF value is utilized to assess the muscle fatigue. The results show that SCM muscle has more muscle activation compared to other selected muscles followed by flexor carpi radialis. Subjective analysis is carried out using the Borg scale, which has reported that Type 2 digital board having larger working area was preferred by the participants as it reduces muscle fatigue.

Quantum Microwave Radiometry with a Superconducting Qubit.

The interaction of photons and coherent quantum systems can be employed to detect electromagnetic radiation with remarkable sensitivity. We introduce a quantum radiometer based on the photon-induced dephasing process of a superconducting qubit for sensing microwave radiation at the subunit photon level. Using this radiometer, we demonstrate the radiative cooling of a 1 K microwave resonator and measure its mode temperature with an uncertainty ∼0.01 K. We thus develop a precise tool for studying the thermodynamics of quantum microwave circuits, which provides new solutions for calibrating hybrid quantum systems and detecting candidate particles for dark matter.

Real-Time Noninvasive Bioluminescence, Ultrasound and Photoacoustic Imaging in NFκB-RE-Luc Transgenic Mice Reveal Glia Maturation Factor-Mediated Immediate and Sustained Spatio-Temporal Activation of NFκB Signaling Post-Traumatic Brain Injury in a Gender-Specific Manner.

Neurotrauma especially traumatic brain injury (TBI) is the leading cause of death and disability worldwide. To improve upon the early diagnosis and develop precision-targeted therapies for TBI, it is critical to understand the underlying molecular mechanisms and signaling pathways. The transcription factor, nuclear factor kappa B (NFκB), which is ubiquitously expressed, plays a crucial role in the normal cell survival, proliferation, differentiation, function, as well as in disease states like neuroinflammation and neurodegeneration. Here, we hypothesized that real-time noninvasive bioluminescence molecular imaging allows rapid and precise monitoring of TBI-induced immediate and rapid spatio-temporal activation of NFκB signaling pathway in response to Glia maturation factor (GMF) upregulation which in turn leads to neuroinflammation and neurodegeneration post-TBI. To test and validate our hypothesis and to gain novel mechanistic insights, we subjected NFκB-RE-Luc transgenic male and female mice to TBI and performed real-time noninvasive bioluminescence imaging (BLI) as well as photoacoustic and ultrasound imaging (PAI). Our BLI data revealed that TBI leads to an immediate and sustained activation of NFκB signaling. Further, our BLI data suggest that especially in male NFκB-RE-Luc transgenic mice subjected to TBI, in addition to brain, there is widespread activation of NFκB signaling in multiple organs. However, in the case of the female NFκB-RE-Luc transgenic mice, TBI induces a very specific and localized activation of NFκB signaling in the brain. Further, our microRNA data suggest that TBI induces significant upregulation of mir-9-5p, mir-21a-5p, mir-34a-5p, mir-16-3p, as well as mir-155-5p within 24 h and these microRNAs can be successfully used as TBI-specific biomarkers. To the best of our knowledge, this is one of the first and unique study of its kind to report immediate and sustained activation of NFκB signaling post-TBI in a gender-specific manner by utilizing real-time non-invasive BLI and PAI in NFκB-RE-Luc transgenic mice. Our study will prove immensely beneficial to gain novel mechanistic insights underlying TBI, unravel novel therapeutic targets, as well as enable us to monitor in real-time the response to innovative TBI-specific precision-targeted gene and stem cell-based precision medicine.

Role of bronchoscopy and imaging in long-standing foreign body bronchus presenting as recurrent or non-resolving lower respiratory tract infection.

INTRODUCTION: A long-standing retained foreign body in the bronchus is unusual. In majority of cases, an adequate history is not obtained, the clinical picture is usually clouded by superadded pathological changes. CASE SERIES: We report three cases of long-standing foreign body in the airway who presented with recurrent lower respiratory tract infection. Examination of respiratory system revealed no significant abnormality. Chest radiograph was normal. CT scan of the chest was useful to indicate endobronchial opacity in the airway suggestive of a foreign body. The patients underwent rigid bronchoscopy under general anesthesia for successful removal of the foreign body. CONCLUSION: So the patients with non-resolving or recurrent lower respiratory symptoms in spite of medical treatment and without any obstructive findings must undergo diagnostic bronchoscopy evaluation and imaging.

Acute Coronary Syndrome From Green Snake Envenomation.

BACKGROUND: Snake bite is a grossly underreported public health issue in subtropical, tropical suburban, and rural areas of Africa and South Asia. In literature, ophitoxemia (snake bite envenomation) as a cause of acute coronary syndrome (ACS) is limited to very few case reports. Viper envenomation is the most common cause of ACS among snake bites. We report the first case of unstable angina caused by Colubridae snake bite (Ahaetullanasuta, commonly called green snakes) in a young man without comorbidities. CASE REPORT: A young healthy man had a green snake bite that was camouflaged in the green fodder. He was managed elsewhere with anti-snake serum. He developed acute chest pain and breathlessness on day 3 of his treatment. Electrocardiogram (ECG) showed biphasic T wave inversions suggestive of type A Wellens pattern in the anterior chest leads (V1-V4). He was treated for ACS medically outside and was referred to our institute for further management on the following day. ECG and cardiac enzymes were normal. The echocardiogram showed no regional wall motion abnormality. Computed tomography coronary angiography showed normal epicardial coronaries. He was discharged in stable condition and asymptomatic at 2 months follow-up. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ACS after a snake bite is not limited to venomous snakes. The diagnosis should be considered promptly even with a nonvenomous snake bite, especially in those with typical symptoms and ECG changes. The time interval between snake bite and development of ACS can be long and warrants prolonged medical supervision.

Proposal for Heralded Generation and Detection of Entangled Microwave-Optical-Photon Pairs.

Quantum state transfer between microwave and optical frequencies is essential for connecting superconducting quantum circuits to optical systems and extending microwave quantum networks over long distances. However, establishing such a quantum interface is extremely challenging because the standard direct quantum transduction requires both high coupling efficiency and small added noise. We propose an entanglement-based scheme-generating microwave-optical entanglement and using it to transfer quantum states via quantum teleportation-which can bypass the stringent requirements in direct quantum transduction and is robust against loss errors. In addition, we propose and analyze a counterintuitive design-suppress the added noise by placing the device at a higher temperature environment-which can improve both the device quality factor and power handling capability. We systematically analyze the generation and verification of entangled microwave-optical-photon pairs. The parameter for entanglement verification favors the regime of cooperativity mismatch and can tolerate certain thermal noises. Our scheme is feasible given the latest advances on electro-optomechanics, and can be generalized to various physical systems.

A role for glia maturation factor dependent activation of mast cells and microglia in MPTP induced dopamine loss and behavioural deficits in mice.

The molecular mechanism mediating degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) is not yet fully understood. Previously, we have shown the contribution of glia maturation factor (GMF), a proinflammatory protein in dopaminergic neurodegeneration mediated by activation of mast cells (MCs). In this study, methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal neurodegeneration and astro-glial activations were determined by western blot and immunofluorescence techniques in wild type (WT) mice, MC-deficient (MC-KO) mice and GMF-deficient (GMF-KO) mice, with or without MC reconstitution before MPTP administration. We show that GMF-KO in the MCs reduces the synergistic effects of MC and Calpain1 (calcium-activated cysteine protease enzyme)-dependent dopaminergic neuronal loss that reduces motor behavioral impairments in MPTP-treated mouse. Administration of MPTP increase in calpain-mediated proteolysis in nigral dopaminergic neurons further resulting in motor decline in mice. We found that MPTP administered WT mice exhibits oxidative stress due to significant increases in the levels of malondialdehyde, superoxide dismutase and reduction in the levels of reduced glutathione and glutathione peroxidase activity as compared with both MC-KO and GMF-KO mice. The number of TH-positive neurons in the ventral tegmental area, substantia nigra and the fibers in the striatum were significantly reduced while granulocyte macrophage colony-stimulating factor (GM-CSF), MC-Tryptase, GFAP, IBA1, Calpain1 and intracellular adhesion molecule 1 expression were significantly increased in WT mice. Similarly, tyrosine hydroxylase, dopamine transporters and vesicular monoamine transporters 2 proteins expression were significantly reduced in the SN of MPTP treated WT mice. The motor behavior as analyzed by rotarod and hang test was significantly reduced in WT mice as compared with both the MC-KO and GMF-KO mice. We conclude that GMF-dependent MC activation enhances the detrimental effect of astro-glial activation-mediated oxidative stress and neuroinflammation in the midbrain, and its inhibition may slowdown the progression of PD.

Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming.

The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1-dependent secretion of the proinflammatory cytokines IL-1ß and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.