G Protein-Coupled Receptors: A Century of Research and Discovery.

GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and ß-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of ß-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.

Graphene-Based Artificial Dendrites for Bio-Inspired Learning in Spiking Neuromorphic Systems.

Analog neuromorphic computing systems emulate the parallelism and connectivity of the human brain, promising greater expressivity and energy efficiency compared to those of digital systems. Though many devices have emerged as candidates for artificial neurons and artificial synapses, there have been few device candidates for artificial dendrites. In this work, we report on biocompatible graphene-based artificial dendrites (GrADs) that can implement dendritic processing. By using a dual side-gate configuration, current applied through a Nafion membrane can be used to control device conductance across a trilayer graphene channel, showing spatiotemporal responses of leaky recurrent, alpha, and Gaussian dendritic potentials. The devices can be variably connected to enable higher-order neuronal responses, and we show through data-driven spiking neural network simulations that spiking activity is reduced by ≤15% without accuracy loss while low-frequency operation is stabilized. This positions the GrADs as strong candidates for energy efficient bio-interfaced spiking neural networks.

Magnetic tunnel junction random number generators applied to dynamically tuned probability trees driven by spin orbit torque.

Perpendicular magnetic tunnel junction (pMTJ)-based true-random number generators (RNGs) can consume orders of magnitude less energy per bit than CMOS pseudo-RNGs. Here, we numerically investigate with a macrospin Landau-Lifshitz-Gilbert equation solver the use of pMTJs driven by spin-orbit torque to directly sample numbers from arbitrary probability distributions with the help of a tunable probability tree. The tree operates by dynamically biasing sequences of pMTJ relaxation events, called 'coinflips', via an additional applied spin-transfer-torque current. Specifically, using a single, ideal pMTJ device we successfully draw integer samples on the interval [0, 255] from an exponential distribution based onp-value distribution analysis. In order to investigate device-to-device variations, the thermal stability of the pMTJs are varied based on manufactured device data. It is found that while repeatedly using a varied device inhibits ability to recover the probability distribution, the device variations average out when considering the entire set of devices as a 'bucket' to agnostically draw random numbers from. Further, it is noted that the device variations most significantly impact the highest level of the probability tree, with diminishing errors at lower levels. The devices are then used to draw both uniformly and exponentially distributed numbers for the Monte Carlo computation of a problem from particle transport, showing excellent data fit with the analytical solution. Finally, the devices are benchmarked against CMOS and memristor RNGs, showing faster bit generation and significantly lower energy use.

Ambient air pollutants and their effect on COVID-19 mortality in the United States of America.

OBJECTIVE: To examine the impact of four ambient air pollutants on the COVID-19 mortality rate in the United States of America. METHODS: Using publicly accessible data collected by the United States Census Bureau, Environmental Protection Agency, and other agencies, county-level mortality rates were regressed on concentration values of ground-level ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide. Four confounder variables were included in the regression analysis: median household income, rate of hospital beds, population density, and days since first confirmed case. RESULTS: Regression analysis showed that ground-level ozone is positively correlated with county-level mortality rates regardless of whether confounders are controlled for. Nitrogen dioxide is also shown to have a direct relationship with county-level mortality rates, except when all confounders are included in the analysis. CONCLUSIONS: High ground-level ozone and nitrogen dioxide concentrations contribute to a greater COVID-19 mortality rate. To limit further losses, it is important to reflect research findings in public policies. In the case of air pollution, environmental restrictions should be reinforced, and extra precautions should be taken as facilities start reopening.

OBJETIVO: Examinar el impacto de cuatro contaminantes del aire ambiental en la tasa de mortalidad por la COVID-19 en los Estados Unidos de América. MÉTODOS: Utilizando datos de acceso público recopilados por la Oficina del Censo de los Estados Unidos, la Agencia para la Protección del Medio Ambiente y otros organismos, se llevó a cabo análisis de regresión para evaluar la relación entre las concentraciones de ozono, dióxido de nitrógeno, monóxido de carbono y dióxido de azufre a nivel del suelo y las tasas de mortalidad a nivel de condado. En el análisis de regresión se incluyeron cuatro variables confusoras: la mediana de los ingresos familiares, la tasa de camas de hospital, la densidad de población y los días transcurridos desde el primer caso confirmado. RESULTADOS: El análisis de regresión mostró que el ozono a nivel del suelo se correlaciona de manera positiva con las tasas de mortalidad a nivel de condado, independientemente de si los factores de confusión están controlados. El dióxido de nitrógeno también tiene una relación directa con las tasas de mortalidad a nivel de condado, excepto cuando se incluyen todos los factores de confusión en el análisis. CONCLUSIONES: Las concentraciones elevadas de ozono y dióxido de nitrógeno a nivel del suelo contribuyen a una mayor tasa de mortalidad por COVID-19. Para limitar los daños, es importante que los resultados de investigación se reflejen en las políticas públicas. En el caso de la contaminación del aire ambiental, deben reforzarse las restricciones ambientales y deben tomarse precauciones adicionales cuando los establecimientos empiecen a reabrirse.

Long-Face Dentofacial Deformities: Occlusion and Facial Esthetic Surgical Outcomes.

PURPOSE: The purpose of this study was to document malocclusion and facial dysmorphology in a series of patients with long face (LF) and chronic obstructive nasal breathing before treatment and the outcomes after bimaxillary orthognathic, osseous genioplasty, and intranasal surgery. MATERIALS AND METHODS: A retrospective cohort study of patients with LF undergoing bimaxillary, chin, and intranasal (septoplasty and inferior turbinate reduction) surgery was implemented. Predictor variables were grouped into demographic, anatomic, operative, and longitudinal follow-up categories. Primary outcome variables were the initial postoperative occlusion achieved (T2; 5 weeks after surgery) and the occulsion maintained long-term (>2 years after surgery). Six key occlusion parameters were assessed: overjet, overbite, coincidence of dental midlines, canine Angle classification, and molar vertical and transverse positions. The second outcome variable was the facial esthetic results. Photographs in 6 views were analyzed to document 7 facial contour characteristics. RESULTS: Seventy-eight patients met the inclusion criteria. Average age at surgery was 24 years (range, 13 to 54 yr). The study included 53 female patients (68%). Findings confirmed that occlusion after initial surgical healing (T2) met the objectives for all parameters in 97% of patients (76 of 78). Most (68 of 78; 87%) maintained a favorable anterior and posterior occlusion for each parameter studied long-term (mean, 5 years 5 months). Facial contour deformities at presentation included prominent nose (63%), flat cheekbones (96%), flat midface (96%), weak chin (91%), obtuse neck-to-chin angle (56%), wide lip separation (95%), and excess maxillary dental show (99%). Correction of all pretreatment facial contour deformities was confirmed in 92% of patients after surgery. Long face patients with higher preoperative body mass index levels were more likely to have residual facial dysmorphology after surgery (P = .0009). CONCLUSION: Using orthognathic surgery techniques, patients with LF dentofacial deformity achieved the planned occlusion and most maintained the corrected occlusion long-term. In unoperated patients with LF, a "facial esthetic type" was identified. Orthognathic surgery proved effective in correcting associated facial dysmorphology in most patients.

A New n = 4 Layered Ruddlesden-Popper Phase K(2.5)Bi(2.5)Ti4O13 Showing Stoichiometric Hydration.

A new bismuth-containing layered perovskite of the Ruddlesden-Popper type, K(2.5)Bi(2.5)Ti4O13, has been prepared by solid-state synthesis. It has been shown to hydrate to form stoichiometric K(2.5)Bi(2.5)Ti4O13·H2O. Diffraction data show that the structure consists of a quadruple-stacked (n = 4) perovskite layer, with potassium ions occupying the rock salt layer and its next-nearest A site. The hydrated sample was shown to remove the offset between stacked perovskite layers relative to the dehydrated sample. Computational methods show that the hydrated phase consists of intact H2O molecules in a vertical "pillared" arrangement bridging across the interlayer space. Rotations of H2O molecules about the c axis were evident in molecular dynamic calculations, which increased in rotation angle with increasing temperature. In situ diffraction data for the dehydrated phase point to a broad structural phase transition from orthorhombic to tetragonal at ∼600 °C. The relative bismuth-rich composition in the perovskite block results in a higher transition temperature compared to related perovskite structures. Water makes a significant contribution to the dielectric constant, which disappears after dehydration.

Oxygenated Phosphine Fumigation for Control of Light Brown Apple Moth (Lepidoptera: Tortricidae) Eggs on Cut-Flowers.

Light brown apple moth, Epiphyas postvittana (Walker), eggs were subjected to oxygenated phosphine fumigation treatments under 70% oxygen on cut flowers to determine efficacy and safety. Five cut flower species: roses, lilies, tulips, gerbera daisy, and pompon chrysanthemums, were fumigated in separate groups with 2,500 ppm phosphine for 72 h at 5°C. Egg mortality and postharvest quality of cut flowers were determined after fumigation. Egg mortalities of 99.7-100% were achieved among the cut flower species. The treatment was safe to all cut flowers except gerbera daisy. A 96-h fumigation treatment with 2,200 ppm phosphine of eggs on chrysanthemums cut flowers also did not achieve complete control of light brown apple moth eggs. A simulation of fumigation in hermetically sealed fumigation chambers with gerbera daisy showed significant accumulations of carbon dioxide and ethylene by the end of 72-h sealing. However, oxygenated phosphine fumigations with carbon dioxide and ethylene absorbents did not reduce the injury to gerbera daisy, indicating that it is likely that phosphine may directly cause the injury to gerbera daisy cut flowers. The study demonstrated that oxygenated phosphine fumigation is effective against light brown apple moth eggs. However, it may not be able to achieve the probit9 quarantine level of control and the treatment was safe to most of the cut flower species.

Impact of Cu doping on the structure and electronic properties of LaCr(1-y)Cu(y)O3.

Oxides of the type LaCr(1-y)Cu(y)O3 have been prepared using solid-state methods and their crystal structures refined using synchrotron X-ray powder diffraction. The solubility limit of Cu was found to be around y = 0.2, and such oxides are orthorhombic in space group Pbnm. X-ray absorption spectroscopy measurements at the Cr and Cu L-edges demonstrated that the Cr remains trivalent upon Cu doping, with the Cu being present as Cu(III). The oxides are found to be antiferromagnets, and the Néel temperature, TN, decreases as the Cu content is increased. The crystal and magnetic structures of one example La(Cr0.85Cu0.15)O3 have been investigated between 3 and 350 K by neutron powder diffraction. The samples are semiconductors.

Synthesis and characterization of the crystal and magnetic structures and properties of the hydroxyfluorides Fe(OH)F and Co(OH)F.

The title compounds were synthesized by a hydrothermal route from a 1:1 molar ratio of lithium fluoride and transition-metal acetate in an excess of water. The crystal structures were determined using a combination of powder and/or single-crystal X-ray and neutron powder diffraction (NPD) measurements. The magnetic structure and properties of Co(OH)F were characterized by magnetic susceptibility and low-temperature NPD measurements. M(OH)F (M = Fe and Co) crystallizes with structures related to diaspore-type α-AlOOH, with the Pnma space group, Z = 4, a = 10.471(3) Å, b = 3.2059(10) Å, and c = 4.6977(14) Å and a = 10.2753(3) Å, b = 3.11813(7) Å, and c = 4.68437(14) Å for the iron and cobalt phases, respectively. The structures consist of double chains of edge-sharing M(F,O)6 octahedra running along the b axis. These infinite chains share corners and give rise to channels. The protons are located in the channels and form O-H···F bent hydrogen bonds. The magnetic susceptibility indicates an antiferromagnetic ordering at ∼40 K, and the NPD measurements at 3 K show that the ferromagnetic rutile-type chains with spins parallel to the short b axis are antiferromagnetically coupled to each other, similarly to the magnetic structure of goethite α-FeOOH.

Key role of bismuth in the magnetoelastic transitions of Ba3BiIr2O9 and Ba3BiRu2O9 as revealed by chemical doping.

The key role played by bismuth in an average intermediate oxidation state in the magnetoelastic spin-gap compounds Ba3BiRu2O9 and Ba3BiIr2O9 has been confirmed by systematically replacing bismuth with La(3+) and Ce(4+). Through a combination of powder diffraction (neutron and synchrotron), X-ray absorption spectroscopy, and magnetic properties measurements, we show that Ru/Ir cations in Ba3BiRu2O9 and Ba3BiIr2O9 have oxidation states between +4 and +4.5, suggesting that Bi cations exist in an unusual average oxidation state intermediate between the conventional +3 and +5 states (which is confirmed by the Bi L3-edge spectrum of Ba3BiRu2O9). Precise measurements of lattice parameters from synchrotron diffraction are consistent with the presence of intermediate oxidation state bismuth cations throughout the doping ranges. We find that relatively small amounts of doping (∼10 at%) on the bismuth site suppress and then completely eliminate the sharp structural and magnetic transitions observed in pure Ba3BiRu2O9 and Ba3BiIr2O9, strongly suggesting that the unstable electronic state of bismuth plays a critical role in the behavior of these materials.

Oxygenated phosphine fumigation for control of Epiphyas postvittana (Lepidoptera: Tortricidae) eggs on lettuce.

Light brown apple moth, Epiphyas postvittana (Walker), is a quarantined pest in most countries. Its establishment in California and potential spread to other parts of the state and beyond make it urgent to develop effective postharvest treatments to control the pest on fresh commodities. Fumigation with cylindered phosphine at low temperature has emerged to be a practical methyl bromide alternative treatment for postharvest pest control on fresh commodities. However, its use to control E. postvittana eggs on sensitive commodities such as lettuce is problematic. E. postvittana eggs are tolerant of phosphine and long phosphine treatment also injures lettuce. In the current study, E. postvittana eggs were subjected to oxygenated phosphine fumigations to develop an effective treatment at a low storage temperature of 2 degrees C. In addition, soda lime as a CO2 absorbent was tested to determine its effects in reducing and preventing injuries to lettuce associated with phosphine fumigations. Three-day fumigation with 1,000 ppm phosphine under 60% O2 achieved 100% mortality of E. postvittana eggs in small-scale laboratory tests. In the presence of the CO2 absorbent, a 3-d large-scale fumigation of lettuce with 1,700 ppm phosphine under 60% O2 resulted in a relative egg mortality of 99.96% without any negative effect on lettuce quality. The 3-d fumigation treatment without the CO2 absorbent, however, resulted in significant injuries to lettuce and consequential quality reductions. The study demonstrated that oxygenated phosphine fumigation has the potential to control E. postvittana eggs and the CO2 absorbent has the potential to prevent injuries and quality reductions of lettuce associated with long-term oxygenated phosphine fumigation.

The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt.

Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2-3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7-11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.

Anion disorder in lanthanoid zirconates Gd(2-x)Tb(x)Zr2O7.

The pyrochlore-defect fluorite order-disorder transition has been studied for a series of oxides of the type Gd(2-x)Tb(x)Zr2O7 by a combination of diffraction and spectroscopy techniques. Synchrotron X-ray diffraction data suggest an abrupt transition from the coexistence of pyrochlore and defect fluorite phases to a single defect fluorite phase with increasing Tb content. However neutron diffraction data, obtained at λ ≈ 0.497 Å for all Gd-containing samples to minimize absorption, not only provide evidence for independent ordering of the anion and cation sublattices but also suggest that the disorder transition across the pyrochlore-defect fluorite boundary of Ln2Zr2O7 is rather gradual. Such disorder was also evident in X-ray absorption measurements at the Zr L3-edge, which showed a gradual increase in the effective coordination number of the Zr from near 6-coordinate in the pyrochlore rich samples to near 7-coordinate in the Tb rich defect fluorites. These results indicate the presence of ordered domains throughout the defect fluorite region, and demonstrate the gradual nature of the order-disorder transition across the Gd(2-x)Tb(x)Zr2O7 series.

Synthesis and characterization of the crystal structure and magnetic properties of the hydroxyfluoride MnF(2-x)(OH)x (x ~ 0.8).

The new compound MnF(2-x)(OH)x (x ~ 0.8) was synthesized by a hydrothermal route from a 1 : 1 molar ratio of lithium fluoride and manganese acetate in an excess of water. The crystal structure was determined using the combination of single crystal X-ray and neutron powder diffraction measurements. The magnetic properties of the title compound were characterized by magnetic susceptibility and low-temperature neutron powder diffraction measurements. MnF(2-x)(OH)x (x ~ 0.8) crystallizes with orthorhombic symmetry, space group Pnn2 (no. 34), a = 4.7127(18), b = 5.203(2), c = 3.2439(13) Å, V = 79.54(5) Å(3) and Z = 2. The crystal structure is a distorted rutile-type with [Mn(F,O)4] infinite edge-sharing chains along the c-direction. The protons are located in the channels and form O-HF bent hydrogen bonds. The magnetic susceptibility measurements indicate an antiferromagnetic ordering at ~70 K and the neutron powder diffraction measurements at 3 K show that the ferromagnetic chains with spins parallel to the c-axis are antiferromagnetically coupled to each other, similarly to the magnetic structure of tetragonal rutile-type MnF2 with isoelectronic Mn(2+). MnF(2-x)(OH)x (x ~ 0.8) is expected to be of great interest as a positive electrode for Li cells if the protons could be exchanged for lithium.

Effects of phosphine fumigation on survivorship of Epiphyas postvittana (Lepidoptera: Tortricidae) eggs.

Light brown apple moth, Epiphyas postvittana (Walker), eggs were subjected to phosphine fumigations under normal atmospheric and elevated oxygen levels in laboratory-scale chamber experiments to compare their susceptibilities to the two different fumigation methods. In fumigations conducted under atmospheric oxygen at 5 and 10 degrees C, egg survivorship decreased with increase in phosphine concentration but then increased at a concentration of 3,000 ppm; this increase was significant at 10 degrees C. Based on egg survivorship data, phosphine fumigations conducted in a 60% oxygen atmosphere were significantly more effective than those conducted under atmospheric oxygen conditions. Oxygenated phosphine fumigations at 5 and 10 degrees C killed all 1,998 and 2,213 E. postvittana eggs treated, respectively, after 72 h of exposure. These results indicate the great potential of oxygenated phosphine fumigation for the control of E. postvittana eggs.

Loss of biased signaling at a G protein-coupled receptor in overexpressed systems.

G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and ß-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (AT1R), fails to activate G protein in physiologically relevant models. Despite this, SII and several derivatives induce cellular signaling outcomes through ß-arrestin-2-dependent mechanisms. However, studies reliant on exogenous AT1R overexpression indicate that SII is a partial agonist for G protein signaling and lacks ß-arrestin-exclusive functional specificity. We investigated this apparent discrepancy by profiling changes in functional specificity at increasing expression levels of AT1R using a stably integrated tetracycline-titratable expression system stimulated with AngII, SII, and four other AngII analogs displaying different signaling biases. Unbiased and G protein-biased ligands activated dose-dependent calcium responses at all tested receptor concentrations. In contrast, ß-arrestin-biased ligands induced dose-dependent calcium signaling only at higher AT1R overexpression levels. Using inhibitors of G proteins, we demonstrated that both Gi and Gq/11 mediated overexpression-dependent calcium signaling by ß-arrestin-biased ligands. Regarding ß-arrestin-mediated cellular events, the ß-arrestin-biased ligand TRV026 induced receptor internalization at low physiological receptor levels insufficient for it to initiate calcium signaling. In contrast, unbiased AngII exhibited no relative preference between these outcomes under such low receptor conditions. However, with high receptor overexpression, TRV026 lost its functional selectivity. These results suggest receptor overexpression misleadingly distorts the bias of AT1R ligands and highlight the risks of using overexpressed systems to infer the signaling bias of GPCR ligands in physiologically relevant contexts.

Allosteric modulator potentiates ß2AR agonist-promoted bronchoprotection in asthma models.

Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled ß2-adrenergic receptor (ß2AR) agonists (ß2-agonists) promote - with limited efficacy - bronchodilation in asthma. All ß2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a ß2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on ß2AR-mediated bronchoprotection. Consistent with our findings using human ß2ARs, Cmpd-6 allosterically potentiated ß2-agonist binding to guinea pig ß2ARs and downstream signaling of ß2ARs. In contrast, Cmpd-6 had no such effect on murine ß2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced ß2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated ß2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced ß2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of ß2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.

Preventive Effect of Arctium lappa Polysaccharides on Acute Lung Injury through Anti-Inflammatory and Antioxidant Activities.

The objective of this study was to investigate the preventive effects of polysaccharides extracted from the roots of Arctium lappa (ALP) against acute lung injury (ALI) models induced by lipopolysaccharide (LPS). The polysaccharides were extracted and characterized, and their anti-inflammatory and antioxidant capacities were assessed. The findings demonstrated that ALP could mitigate the infiltration of inflammatory cells and reduce alveolar collapse in LPS-induced ALI in mice. The expression levels of the pro-inflammatory factor TNF-α decreased, while the anti-inflammatory factor IL-10 increased. Furthermore, the administration of ALP improved the activities of lung antioxidant enzymes, including SOD, GSH, and CAT, and lowered MDA levels. These results suggest that ALP exhibits a preventive effect on ALI and has potential as an alternative treatment for lung injury.

The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling.

The elimination of synapses during circuit remodeling is critical for brain maturation; however, the molecular mechanisms directing synapse elimination and its timing remain elusive. We show that the transcriptional regulator DVE-1, which shares homology with special AT-rich sequence-binding (SATB) family members previously implicated in human neurodevelopmental disorders, directs the elimination of juvenile synaptic inputs onto remodeling C. elegans GABAergic neurons. Juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during the maturation of wild-type GABAergic neurons but persist into adulthood in dve-1 mutants, producing heightened motor connectivity. DVE-1 localization to GABAergic nuclei is required for synapse elimination, consistent with DVE-1 regulation of transcription. Pathway analysis of putative DVE-1 target genes, proteasome inhibitor, and genetic experiments implicate the ubiquitin-proteasome system in synapse elimination. Together, our findings define a previously unappreciated role for a SATB family member in directing synapse elimination during circuit remodeling, likely through transcriptional regulation of protein degradation processes.

Metaplastic and energy-efficient biocompatible graphene artificial synaptic transistors for enhanced accuracy neuromorphic computing.

CMOS-based computing systems that employ the von Neumann architecture are relatively limited when it comes to parallel data storage and processing. In contrast, the human brain is a living computational signal processing unit that operates with extreme parallelism and energy efficiency. Although numerous neuromorphic electronic devices have emerged in the last decade, most of them are rigid or contain materials that are toxic to biological systems. In this work, we report on biocompatible bilayer graphene-based artificial synaptic transistors (BLAST) capable of mimicking synaptic behavior. The BLAST devices leverage a dry ion-selective membrane, enabling long-term potentiation, with ~50 aJ/µm2 switching energy efficiency, at least an order of magnitude lower than previous reports on two-dimensional material-based artificial synapses. The devices show unique metaplasticity, a useful feature for generalizable deep neural networks, and we demonstrate that metaplastic BLASTs outperform ideal linear synapses in classic image classification tasks. With switching energy well below the 1 fJ energy estimated per biological synapse, the proposed devices are powerful candidates for bio-interfaced online learning, bridging the gap between artificial and biological neural networks.