SARS-CoV-2 infection causes dopaminergic neuron senescence

COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.</p

SARS-CoV-2 infection causes dopaminergic neuron senescence

COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.</p

Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis

The aim of our study is to disclose the role and underlying molecular mechanisms of circular RNA ubiquitin protein ligase E3 component n-recognin 4 (circ-UBR4) in atherosclerosis (AS). Our data showed that circ-UBR4 expression was upregulated in AS patients and oxidized low-density lipoprotein (ox-LDL)-induced vascular smooth muscle cells (VSMCs) compared with healthy volunteer and untreated VSMCs. In addition, ox-LDL stimulated proliferation, migration, and inflammation but decreased apoptosis in VSMCs, which were overturned by the inhibition of circ-UBR4. miR-515-5p was sponged by circ-UBR4, and its inhibitor reversed the inhibitory effect of circ-UBR4 knockdown on proliferation, migration, and inflammation in ox-LDL-induced VSMCs. Insulin-like growth factor2 (IGF2) was a functional target of miR-515-5p, and overexpression of IGF2 reversed the suppressive effect of miR-515-5p on ox-LDL-stimulated VSMCs proliferation, migration, and inflammation. Collectively, circ-UBR4 knockdown decreased proliferation, migration, and inflammation but stimulated apoptosis in ox-LDL-induced VSMCs by targeting the miR-515-5p/IGF2 axis

A transgenic zebrafish for in vivo visualization of cilia

Cilia are organelles for cellular signalling and motility. Mutations affecting ciliary function are also associated with cilia-related disorders (ciliopathies). The identification of cilia markers is critical for studying their function at the cellular level. Due to the lack of a conserved, short ciliary localization motif, the full-length ARL13b or 5HT6 proteins are normally used for cilia labelling. Overexpression of these genes, however, can affect the function of cilia, leading to artefacts in cilia studies. Here, we show that Nephrocystin-3 (Nphp3) is highly conserved among vertebrates and demonstrate that the N-terminal truncated peptide of zebrafish Nphp3 can be used as a gratuitous cilia-specific marker. To visualize the dynamics of cilia in vivo, we generated a stable transgenic zebrafish Tg (β-actin: nphp3N-mCherry)sx1001. The cilia in multiple cell types are efficiently labelled by the encoded fusion protein from embryonic stages to adulthood, without any developmental and physiological defects. We show that the line allows live imaging of ciliary dynamics and trafficking of cilia proteins, such as Kif7 and Smo, key regulators of the Hedgehog signalling pathway. Thus, we have generated an effective new tool for in vivo cilia studies that will help shed further light on the roles of these important organelles

Hexafluoroquinoxaline Based Polymer for Nonfullerene Solar Cells Reaching 9.4% Efficiency

Through introducing six fluorine atoms onto quinoxaline (Qx), a new electron acceptor unit-hexafluoroquinoxaline (HFQx) is first synthesized. On the basis of this unit, we synthesize a new donor–acceptor (D–A) copolymer (HFQx-T), which is composed of a benzodithiophene (BDT) derivative donor block and an HFQx accepting block. The strong electron-withdrawing properties of fluorine atoms increase significantly the open-circuit voltage (<i>V</i>_oc) by tuning the highest occupied molecular orbital (HOMO) energy level. In addition, fluorine atoms enhance the absorption coefficient of the conjugated copolymer and change the film morphology, which implies an increase of the short-circuit current density (<i>J</i>_sc) and fill factor (FF). Indeed, the HFQx-T:ITIC blended film achieves an impressive power conversion efficiency (PCE) of 9.4% with large short-current density (<i>J</i>_sc) of 15.60 mA/cm², high <i>V</i>_oc of 0.92 V, and FF of 65% via two step annealing (thermal annealing (TA) and solvent vapor annealing (SVA) treatments). The excellent results obtained show that the new copolymer HFQx-T synthesized could be a promising candidate for organic photovoltaics

A Medium Bandgap D–A Copolymer Based on 4‑Alkyl-3,5-difluorophenyl Substituted Quinoxaline Unit for High Performance Solar Cells

Development of high-performance donor–acceptor (D–A) copolymers has been indicated as a promising strategy to improve the power conversion efficiencies (PCEs) of organic solar cells (OSCs). In this work, a new medium bandgap conjugated D–A copolymer, HFAQx-T, based on 4,8-bis­(5-(2-ethylhexyl)­thiophen-2-yl)­benzo­[1,2-<i>b</i>:4,5-<i>b</i>′]­dithiophene (BDT-T) as donor unit, 4-alkyl-3,5-difluorophenyl substituted quinoxaline (HFAQx) as the acceptor unit, and thiophene as the spacer, was designed and synthesized. HFAQx-T is a well-compatible donor polymer; OSCs based on HFAQx-T exhibit excellent performance in both fullerene and fullerene-free based devices. The optimized conventional single junction bulk heterojunction (BHJ) OSCs of HFAQx-T:PC₇₁BM showed a PCE of 9.2%, with an open circut voltage (<i>V</i>_oc) of 0.9 V, a short circuit current (<i>J</i>_sc) of 14.0 mA cm^–2, and a fill factor (FF) of 0.74. Also, when blended with 3,9-bis­(2-methylene-(3-(1,1-dicyano­methylene)­indanone)-5,5,11,11-tetrakis­(4-hexylphenyl)­dithieno­[2,3-<i>d</i>:2′,3′-<i>d</i>′]-<i>s</i>-indaceno­[1,2-<i>b</i>:5,6-<i>b</i>′]-dithiophene (ITIC), the HFAQx-T-based device exhibited a PCE of 9.6%. HFAQx-T is among a few D–A copolymers that can deliver >9% efficiency in both fullerene and fullerene-free solar cells. This work demonstrates that the 4-alkyl-3,5-difluorophenyl substituted quinoxaline (Qx) is a promising electron-accepting building block in constructing ideal D–A copolymers for OSCs

Thieno[3,2‑<i>b</i>]pyrrolo-Fused Pentacyclic Benzotriazole-Based Acceptor for Efficient Organic Photovoltaics

A novel nonfullerene small molecular acceptor (BZIC) based on a ladder-type thieno­[3,2-<i>b</i>]­pyrrolo-fused pentacyclic benzotriazole core (dithieno­[3,2-<i>b</i>]­pyrrolobenzotriazole, BZTP) and end-capped with 1,1-dicyanomethylene-3-indanone (INCN) has been first reported in this work. Through introducing multifused benzotriazole and INCN, BZIC could maintain a high-lying lowest unoccupied molecular orbital (LUMO) energy level of −3.88 eV. Moreover, BZIC shows a low optical bandgap of 1.45 eV with broad and efficient absorption band from 600 to 850 nm due to increased π–π interactions by the covalently locking thiophene and benzotriazole units. A power conversion efficiency of 6.30% is delivered using BZIC as nonfullerene acceptor and our recently synthesized hexafluoroquinoxaline-based polymer HFQx-T as donor. This is the first time to synthesize mutifused benzotriazole-based molecules as nonfullerene electron acceptor up to date. The preliminary results demonstrate that the mutifused benzotriazole derivatives hold great potential for efficient photovoltaics