Emerging nonfullerene acceptors (NFAs) with crystalline domains enable high-performance bulk heterojunction (BHJ) solar cells. Thermal annealing is known to enhance the BHJ photoactive layer ...morphology and performance. However, the microscopic mechanism of annealing-induced performance enhancement is poorly understood in emerging NFAs, especially regarding competing factors. Here, optimized thermal annealing of model system PBDB-TF:Y6 (Y6 = 2,2′-((2Z,2′Z)-((12,13-bis(2-ethylhexyl)-3,9-diundecyl-12,13-dihydro-1,2,5thiadiazolo3,4-ethieno2″,3′’:4′,5′thieno2′,3′:4,5pyrrolo3,2-gthieno2′,3′:4,5-thieno3,2-bindole-2,10-diyl)bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile) decreases the open circuit voltage (V OC) but increases the short circuit current (J SC) and fill factor (FF) such that the resulting power conversion efficiency (PCE) increases from 14 to 15% in the ambient environment. Here we systematically investigate these thermal annealing effects through in-depth characterizations of carrier mobility, film morphology, charge photogeneration, and recombination using SCLC, GIXRD, AFM, XPS, NEXAFS, R-SoXS, TEM, STEM, fs/ns TA spectroscopy, 2DES, and impedance spectroscopy. Surprisingly, thermal annealing does not alter the film crystallinity, R-SoXS characteristic size scale, relative average phase purity, or TEM-imaged phase separation but rather facilitates Y6 migration to the BHJ film top surface, changes the PBDB-TF/Y6 vertical phase separation and intermixing, and reduces the bottom surface roughness. While these morphology changes increase bimolecular recombination (BR) and lower the free charge (FC) yield, they also increase the average electron and hole mobility by at least 2-fold. Importantly, the increased μh dominates and underlies the increased FF and PCE. Single-crystal X-ray diffraction reveals that Y6 molecules cofacially pack via their end groups/cores, with the shortest π–π distance as close as 3.34 Å, clarifying out-of-plane π-face-on molecular orientation in the nanocrystalline BHJ domains. DFT analysis of Y6 crystals reveals hole/electron reorganization energies of as low as 160/150 meV, large intermolecular electronic coupling integrals of 12.1–37.9 meV rationalizing the 3D electron transport, and relatively high μe of 10–4 cm2 V–1 s–1. Taken together, this work clarifies the richness of thermal annealing effects in high-efficiency NFA solar cells and tasks for future materials design.
The DNA sequencing technologies in use today produce either highly accurate short reads or less-accurate long reads. We report the optimization of circular consensus sequencing (CCS) to improve the ...accuracy of single-molecule real-time (SMRT) sequencing (PacBio) and generate highly accurate (99.8%) long high-fidelity (HiFi) reads with an average length of 13.5 kilobases (kb). We applied our approach to sequence the well-characterized human HG002/NA24385 genome and obtained precision and recall rates of at least 99.91% for single-nucleotide variants (SNVs), 95.98% for insertions and deletions <50 bp (indels) and 95.99% for structural variants. Our CCS method matches or exceeds the ability of short-read sequencing to detect small variants and structural variants. We estimate that 2,434 discordances are correctable mistakes in the 'genome in a bottle' (GIAB) benchmark set. Nearly all (99.64%) variants can be phased into haplotypes, further improving variant detection. De novo genome assembly using CCS reads alone produced a contiguous and accurate genome with a contig N50 of >15 megabases (Mb) and concordance of 99.997%, substantially outperforming assembly with less-accurate long reads.
Using a simple copper(i) catalyst has allowed a high yielding sulfonylative-Suzuki-Miyaura cross-coupling reaction to be developed. The process provides a single step route to diaryl sulfones from ...the direct combination of aryl boronic acids, sulfur dioxide and aryl iodides, and represents the first sulfonylative variant of a classic cross-coupling reaction. Sulfur dioxide is delivered from the surrogate reagent, DABSO. Variation of the reaction conditions allowed interruption of the sulfonylative-Suzuki coupling, resulting in the formation of a presumed Cu-sulfinate intermediate. These sulfinates could be trapped as their sodium salts and treated with electrophiles to allow access to arylalkyl sulfones, β-hydroxyl sulfones, sulfonamides and sulfonyl fluorides.
Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial ...fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future.
Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration. Most knowledge on astrocyte biology is based on studies of mouse models and the similarities ...and differences between human and mouse astrocytes are insufficiently characterized, presenting a barrier in translational research. Based on analyses of acutely purified astrocytes, serum-free cultures of primary astrocytes, and xenografted chimeric mice, we find extensive conservation in astrocytic gene expression between human and mouse samples. However, the genes involved in defense response and metabolism show species-specific differences. Human astrocytes exhibit greater susceptibility to oxidative stress than mouse astrocytes, due to differences in mitochondrial physiology and detoxification pathways. In addition, we find that mouse but not human astrocytes activate a molecular program for neural repair under hypoxia, whereas human but not mouse astrocytes activate the antigen presentation pathway under inflammatory conditions. Here, we show species-dependent properties of astrocytes, which can be informative for improving translation from mouse models to humans.
Recent resting-state fMRI studies have shown that the apparent functional connectivity (FC) between brain regions may undergo changes on time-scales of seconds to minutes, the basis and importance of ...which are largely unknown. Here, we examine the electrophysiological correlates of within-scan FC variations during a condition of eyes-closed rest. A sliding window analysis of simultaneous EEG–fMRI data was performed to examine whether temporal variations in coupling between three major networks (default mode; DMN, dorsal attention; DAN, and salience network; SN) are associated with temporal variations in mental state, as assessed from the amplitude of alpha and theta oscillations in the EEG. In our dataset, alpha power showed a significant inverse relationship with the strength of connectivity between DMN and DAN. In addition, alpha power covaried with the spatial extent of anticorrelation between DMN and DAN, with higher alpha power associated with larger anticorrelation extent. Results suggest an electrical signature of the time-varying FC between the DAN and DMN, potentially reflecting neural and state-dependent variations.
► We examined correlations between time-varying BOLD fMRI connectivity and EEG power. ► Connectivity between two major networks was inversely correlated with alpha power. ► EEG power also correlated with spatial anticorrelation extent between these networks.
People with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it ...is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10
). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.
Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In ...this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.
•The Janus kinase (JAK)1/2 inhibitor ruxolitinib induced responses in more than half of patients with steroid-refractory aGVHD by day 28.•Ruxolitinib was well tolerated, and the safety profile was consistent with expectations for ruxolitinib and this patient population.
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Retinal ganglion cells (RGCs) are the sole output neurons that transmit visual information from the retina to the brain. Diverse insults and pathological states cause degeneration of RGC somas and ...axons leading to irreversible vision loss. A fundamental question is whether manipulation of a key regulator of RGC survival can protect RGCs from diverse insults and pathological states, and ultimately preserve vision. Here, we report that CaMKII-CREB signaling is compromised after excitotoxic injury to RGC somas or optic nerve injury to RGC axons, and reactivation of this pathway robustly protects RGCs from both injuries. CaMKII activity also promotes RGC survival in the normal retina. Further, reactivation of CaMKII protects RGCs in two glaucoma models where RGCs degenerate from elevated intraocular pressure or genetic deficiency. Last, CaMKII reactivation protects long-distance RGC axon projections in vivo and preserves visual function, from the retina to the visual cortex, and visually guided behavior.
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•Excitotoxic and axonal injuries lead to loss of CaMKII activity in RGCs•Reactivation of CaMKII protects RGCs in multiple injury/disease models•CREB acts downstream of CaMKII in protecting RGCs•Reactivation of CaMKII protects visual pathway and preserves functional vision
CaMKII-CREB signaling plays a major role in maintenance of retinal ganglion cells (RGCs), and reactivation of CaMKII activity via AAV gene therapy in injury and disease models in mice protects RGCs and preserves visual function and visually guided behavior.
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