Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.

Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases. However, methods to dynamically regulate lysosomal function in living cells or animals are still lacking. Here, we constructed lysosome-localized optogenetic actuators, named lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2, to achieve optogenetic manipulation of lysosomes. These new actuators enable light-dependent control of lysosomal membrane potential, pH, hydrolase activity, degradation, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy through the mTOR pathway, promotes Aß clearance in an autophagy-dependent manner in cellular models, and alleviates Aß-induced paralysis in the Caenorhabditis elegans model of Alzheimer's disease. Our lysosomal optogenetic actuators supplement the optogenetic toolbox and provide a method to dynamically regulate lysosomal physiology and function in living cells and animals.

Glia-specific expression of neuropeptide receptor Lgr4 regulates development and adult physiology in Drosophila.

Similar to the human brain, Drosophila glia may well be divided into several subtypes that each carries out specific functions. Glial GPCRs play key roles in crosstalk between neurons and glia. Drosophila Lgr4 (dLgr4) is a human relaxin receptor homolog involved in angiogenesis, cardiovascular regulation, collagen remodeling, and wound healing. A recent study suggests that ilp7 might be the ligand for Lgr4 and regulates escape behavior of Drosophila larvae. Here we demonstrate that Drosophila Lgr4 expression in glial cells, not neurons, is necessary for early development, adult behavior, and lifespan. Reducing the Lgr4 level in glial cells disrupts Drosophila development, while knocking down other LGR family members in glia has no impact. Adult-specific knockdown of Lgr4 in glia but not neurons reduce locomotion, male reproductive success, and animal longevity. The investigation of how glial expression of Lgr4 contributes to this behavioral alteration will increase our understanding of how insulin signaling via glia selectively modulates neuronal activity and behavior.

Complex genome assembly based on long-read sequencing.

High-quality genome chromosome-scale sequences provide an important basis for genomics downstream analysis, especially the construction of haplotype-resolved and complete genomes, which plays a key role in genome annotation, mutation detection, evolutionary analysis, gene function research, comparative genomics and other aspects. However, genome-wide short-read sequencing is difficult to produce a complete genome in the face of a complex genome with high duplication and multiple heterozygosity. The emergence of long-read sequencing technology has greatly improved the integrity of complex genome assembly. We review a variety of computational methods for complex genome assembly and describe in detail the theories, innovations and shortcomings of collapsed, semi-collapsed and uncollapsed assemblers based on long reads. Among the three methods, uncollapsed assembly is the most correct and complete way to represent genomes. In addition, genome assembly is closely related to haplotype reconstruction, that is uncollapsed assembly realizes haplotype reconstruction, and haplotype reconstruction promotes uncollapsed assembly. We hope that gapless, telomere-to-telomere and accurate assembly of complex genomes can be truly routinely achieved using only a simple process or a single tool in the future.

Lysosomal cation channel TRPML1 suppression sensitizes acute myeloid leukemia cells to chemotherapeutics by inhibiting autophagy.

Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML.

Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease.

Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear. Here, we show that the apoptotic regulator Bcl-2 binds to and inhibits TMEM175 activity. Accordingly, Bcl-2 inhibitors activate the channel in a caspase-independent way. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases production of reactive oxygen species (ROS). ROS further activates TMEM175 and thus forms a positive feedback loop to augment apoptosis. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout (KO) of TMEM175 mitigated motor impairment and dopaminergic (DA) neuron loss, suggesting that TMEM175-mediated apoptosis plays an important role in Parkinson's disease (PD). Overall, our study reveals that TMEM175 is an important regulatory site in the apoptotic signaling pathway and a potential therapeutic target for Parkinson's disease (PD).

VThunter: a database for single-cell screening of virus target cells in the animal kingdom.

Viral infectious diseases are a devastating and continuing threat to human and animal health. Receptor binding is the key step for viral entry into host cells. Therefore, recognizing viral receptors is fundamental for understanding the potential tissue tropism or host range of these pathogens. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology has paved the way for studying the expression of viral receptors in different tissues of animal species at single-cell resolution, resulting in huge scRNA-seq datasets. However, effectively integrating or sharing these datasets among the research community is challenging, especially for laboratory scientists. In this study, we manually curated up-to-date datasets generated in animal scRNA-seq studies, analyzed them using a unified processing pipeline, and comprehensively annotated 107 viral receptors in 142 viruses and obtained accurate expression signatures in 2 100 962 cells from 47 animal species. Thus, the VThunter database provides a user-friendly interface for the research community to explore the expression signatures of viral receptors. VThunter offers an informative and convenient resource for scientists to better understand the interactions between viral receptors and animal viruses and to assess viral pathogenesis and transmission in species. Database URL: https://db.cngb.org/VThunter/.

Precisely Regulating Intermolecular Interactions and Molecular Packing of Nonfused-Ring Electron Acceptors via Halogen Transposition for High-Performance Organic Solar Cells.

The structure of molecular aggregates is crucial for charge transport and photovoltaic performance in organic solar cells (OSCs). Herein, the intermolecular interactions and aggregated structures of nonfused-ring electron acceptors (NFREAs) are precisely regulated through a halogen transposition strategy, resulting in a noteworthy transformation from a 2D-layered structure to a 3D-interconnected packing network. Based on the 3D electron transport pathway, the binary and ternary devices deliver outstanding power conversion efficiencies (PCEs) of 17.46% and 18.24%, respectively, marking the highest value for NFREA-based OSCs.

Comparative analysis of single cell lung atlas of bat, cat, tiger, and pangolin.

Horseshoe bats (Rhinolophus sinicus) might help maintain coronaviruses severely affecting human health, such as severe acute respiratory syndrome coronavirus (SARS-CoV). Bats may be more tolerant of viral infection than other mammals due to their unique immune system, but the exact mechanism remains to be fully explored. During the coronavirus disease 2019 (COVID-19) pandemic, multiple animal species were diseased by coronavirus infection, especially in the respiratory system. Herein, a comparative analysis with single nucleus transcriptomic data of the lungs across four species, including horseshoe bat, cat, tiger, and pangolin, were conducted. The distribution of entry factors for twenty-eight respiratory viruses was characterized for the four species. Our findings might increase our understanding of the immune background of horseshoe bats.

Endometrioid adenocarcinoma arising in adenomyosis in a patient with pelvic organ prolapse-case report.

BACKGROUND: Adenomyosis is a frequent finding in endometrial carcinoma patients. Endometrioid adenocarcinoma is the most common type of endometrial carcinoma; however, endometrioid adenocarcinoma arising from adenomyosis is extremely rare. CASE PRESENTATION: In this case report, we describe a 69-year-old woman who required surgical treatment for pelvic organ prolapse (POP). The patient had been postmenopausal for 20 years and had no abnormal bleeding after menopause. The patient underwent transvaginal hysterectomy, repair of anterior and posterior vaginal walls, ischium fascial fixation and repair of an old perineal laceration. Histological examination of surgical specimens revealed endometrioid adenocarcinoma of the uterus. Bilateral adnexectomy, pelvic lymphadenectomy and para-aortic lymphadenectomy were then performed. The postoperative histopathological diagnosis was stage IB endometrial cancer (endometrioid carcinoma G2). CONCLUSIONS: In summary, endometrioid adenocarcinoma arising from adenomyosis (EC-AIA) is a rare entity and the early diagnosis is difficult. Adequate preoperative assessment and enhanced inquiry of occult clinical symptoms of postmenopausal women before hysterectomy may contribute to the diagnosis of EC-AIA preoperatively.

[Risk Factors of Clopidogrel Resistance in the Elderly Patients with Atherosclerotic Cardiovascular Disease].

Objective To explore the risk factors of clopidogrel resistance (CR) in the elderly patients with atherosclerotic cardiovascular disease and to provide evidence for the antiplatelet therapy. Methods A total of 223 elderly patients (≥80 years old) with atherosclerotic cardiovascular disease treated in the Department of Geriatrics in the Peking University People's Hospital from January 18,2013 to November 30,2019 and meeting the inclusion criteria were enrolled in this study.The clinical data and laboratory test results were collected,including clinical disease,drug use,physical examination,complete blood cell analysis,biochemical indicators,and thromboelastogram (TEG).The rate of platelet inhibition induced by adenosine diphosphate was calculated according to the TEG.We assigned the patients into a CR group (n=84) and a control group (n=139) to analyze the incidence and influence factors of CR in the elderly patients with atherosclerotic cardiovascular disease. Results The incidence of CR was 37.7% in the elderly patients with atherosclerotic cardiovascular disease.The CR group had lower hemoglobin (t=3.533,P=0.001) and higher hypertension prevalence rate (χ2=6.581,P=0.006),proportion of multiple drugs (χ2=3.332,P=0.048),body mass index (BMI) (t=-2.181,P=0.030),total cholesterol (t=-2.264,P=0.025),triglycerides (Z=-2.937,P=0.003),low-density lipoprotein cholesterol (LDL-C) (t=-2.347,P=0.020),and proportion of women (χ2=5.562,P=0.014) than the control group.The results of multivariate Logistic regression showed that hemoglobin (OR=0.962,P<0.001),BMI (OR=1.154,P=0.003),and LDL-C (OR=1.688,P=0.018) were the factors influencing CR in the elderly patients with atherosclerotic cardiovascular disease. Conclusion Hemoglobin,BMI,and LDL-C may be independent factors associated with the occurrence of CR in the elderly patients with atherosclerotic cardiovascular disease.

Retina-Inspired Organic Photonic Synapses for Selective Detection of SWIR Light.

Photonic synapses with the dual function of optical signal detection and information processing can simulate human visual system. However, photonic synapses with selective detection of short-wavelength infrared (SWIR) light have never been reported, which can not only broaden the human vision region but also integrate neuromorphic computation and infrared optical communication. Here, organic photonic synapses based on a new donor-acceptor copolymer P1 are fabricated, which exhibit excellent synaptic characteristics with selective detection for SWIR and extremely low energy consumption (2.85 fJ). The working mechanism is rooted in energy level barriers and unbalanced charge transportation. Moreover, these photonic synapses demonstrate excellent performance in multi-signal logic editing, letter imaging and memory with noise reduction function. This contribution provides ideas of constructing selective-response synapses for artificial visual system and neuromorphic computing.

Achieving Record-Efficiency Organic Solar Cells upon Tuning the Conformation of Solid Additives.

Volatile solid additives (SADs) are considered as a simple yet effective approach to tune the film morphology for high-performance organic solar cells (OSCs). However, the structural effects of the SADs on the photovoltaic performance are still elusive. Herein, two volatilizable SADs were designed and synthesized. One is SAD1 with twisted conformation, while the other one is planar SAD2 with the S···O noncovalent intramolecular interactions (NIIs). The theoretical and experimental results revealed that the planar SAD2 with smaller space occupation can more easily insert between the Y6 molecules, which is beneficial to form a tighter intermolecular packing mode of Y6 after thermal treatment. As a result, the SAD2-treated OSCs exhibited less recombination loss, more balanced charge mobility, higher hole transfer rate, and more favorable morphology, resulting in a record power conversion efficiency (PCE) of 18.85% (certified PCE: 18.7%) for single-junction binary OSCs. The universality of this study shed light on understanding the conformation effects of SADs on photovoltaic performances of OSCs.

Toehold-controlled ligation and transcription for accurate COVID-19 genotyping.

The global pandemic of coronavirus disease 2019 (COVID-19) has significant impact on the entire human society. However, in the face of continually emerging more contagious SARS-CoV-2 variant, the risk to bog down into more severe crisis is around us anytime. Here, we introduce an isothermal, ultrasensitive method for identifying important SNV mutations of SARS-CoV-2. It is based on combined specificity of toehold-assisted linear probe ligation and in vitro transcription signal enlargement, TLT. A ready-to-use panel of TLT assay is developed including detection of 80 crucial SARS-CoV-2 SNVs, by which people could response to the next coming contagious virus variant more rapidly. These advanced point-of-care features make TLT one good approach for large scale population testing of special SARS-CoV-2 variants of interesting.

A New Noncovalently Fused-Ring Electron Acceptor Based on 3,7-Dialkyloxybenzo[1,2-b:4,5-b']dithiophene for Low-Cost and High-Performance Organic Solar Cells.

The innovation of high-performance fused-ring electron acceptors (FREAs) has carried the field of organic solar cells (OSCs) toward a new stage of development. However, due to high synthetic complexity and production costs, FREAs may not be the most promising candidates for future commercialization applications. To address these disadvantages of FREAs, a series of low-cost acceptors, named as noncovalently FREAs (NFREAs), is successfully constructed by employing the strategy of noncovalently conformational locks. Herein, a novel NFREA (BDTO-4F) based on 3,7-dialkyloxybenzo[1,2-b:4,5-b']dithiophene is synthesized and fully characterized. Benefiting from the complementary absorption of the donor and acceptor, balanced charge transport, and favorable film morphology, J52:BDTO-4F based OSCs afford a satisfied power conversion efficiency of 12.09%, much higher than PBDB-T:BDTO-4F-based devices (8.30%). It is worth mentioning that BDTO-4F possesses a higher figure-of-merit value of 55.65 in comparison with several representative FREAs based on a cost-efficiency evaluation. This work demonstrates the potential of the novel benzo[1,2-b:4,5-b″]dithiophene derivative for constructing low-cost and high-performance NFREAs, providing a valuable insight on the materials design.

Oligo replication advantage driven by GC content and Gibbs free energy.

Large scale DNA oligo pools are emerging as a novel material in a variety of advanced applications. However, GC content and length cause significant bias in amplification of oligos. We systematically explored the amplification of one oligo pool comprising of over ten thousand distinct strands with moderate GC content in the range of 35-65%. Uniqual amplification of oligos result to the increased Gini index of the oligo distribution while a few oligos greatly increased their proportion after 60 cycles of PCR. However, the significantly enriched oligos all have relatively high GC content. Further thermodynamic analysis demonstrated that a high value of both GC content and Gibbs free energy could improve the replication of specific oligos during biased amplification. Therefore, this double-G (GC content and Gibbs free energy) driven replication advantage can be used as a guiding principle for the sequence design for a variety of applications, particularly for data storage.

Mitochondria-targeted ratiometric fluorescent imaging of cysteine.

As an indispensable biothiol, cysteine (Cys) plays a critical part in cellular redox homeostasis, and pathological and physiological processes. One of the main sources of reactive oxygen species (ROS) in human cells is the substrate end of the respiratory chain in the mitochondrial inner membrane. Therefore, it is valuable to develop probes targeting mitochondria to detect Cys. In this work, we designed a novel fluorescent probe, 2-(2-(6-(acryloyloxy) naphthalen-2-yl) vinyl)-3-ethylbenzothiazol-3-ium (ANET). The naphthyl benzothiazole is the fluorophore group and the acrylate moiety is the Cys response site to avoid the interference of homocysteine (Hcy) and glutathione (GSH). ANET combines multiple strengths for detecting Cys: targeting mitochondria, ratiometric fluorescence, high selectivity, and a large Stokes shift. After ANET reacted with Cys, the fluorescence signals changed from green (λem = 525 nm) to orange red (λem = 595 nm), and the detection limit was calculated to be 74 nM through a linear relationship between ratiometric fluorescence F595/F525 and Cys concentration. The imaging of Cys was confirmed in HepG2 cells.

Electrochemical Synthesis of Large Area Two-Dimensional Metal-Organic Framework Films on Copper Anodes.

Owing to their excellent physical and electrical properties, metal-organic framework (MOF) materials with well-defined supramolecular structures have received extensive research attention. However, the fabrication of large-area two-dimensional (2D) MOF films is still a significant challenge. Herein, we propose a novel electrochemical (EC) synthesis method for the preparation of large-area Cu3 (HHTP)2 MOF film on single-crystal Cu (100) anode. The surface reaction was achieved via charge-induced molecular assembly. The synthesized MOF film exhibited a high crystalline quality with an electrical conductivity of approximately 0.087 S cm-1 , which was around 1000 times larger than the previously reported values for the same material prepared by the interface method. In addition, Cu2 (MTCP), Cu3 (BTPA)2 , and Cu3 (TPTC)2 MOF films were synthesized on Cu foil with the same strategy, which confirmed the universality of the proposed method. This controllable EC method can be effectively applied to the industrial-scale production of 2D MOF films on Cu foil.

High-Performance Noncovalently Fused-Ring Electron Acceptors for Organic Solar Cells Enabled by Noncovalent Intramolecular Interactions and End-Group Engineering.

Noncovalently fused-ring electron acceptors (NFREAs) have attracted much attention in recent years owing to their advantages of simple synthetic routes, high yields and low costs. However, the efficiencies of NFREAs based organic solar cells (OSCs) are still far behind those of fused-ring electron acceptors (FREAs). Herein, a series of NFREAs with S⋅⋅⋅O noncovalent intramolecular interactions were designed and synthesized with a two-step synthetic route. Upon introducing π-extended end-groups into the backbones, the electronic properties, charge transport, film morphology, and energy loss were precisely tuned by fine-tuning the degree of multi-fluorination. As a result, a record PCE of 14.53 % in labs and a certified PCE of 13.8 % for NFREAs based devices were obtained. This contribution demonstrated that combining the strategies of noncovalent conformational locks and π-extended end-group engineering is a simple and effective way to explore high-performance NFREAs.

Two-Dimensional Metal-Organic Framework Film for Realizing Optoelectronic Synaptic Plasticity.

2D metal-organic framework (MOF) film as the active layer show promising application prospects in various fields including sensors, catalysis, and electronic devices. However, exploring the application of 2D MOF film in the field of artificial synapses has not been implemented yet. In this work, we fabricated a novel 2D MOF film (Cu-THPP, THPP=5,10,15,20-Tetrakis(4-hydroxyphenyl)-21H,23H-porphine), and further used it as an active layer to explore the application in the simulation of human brain synapses. It shows excellent light-stimulated synaptic plasticity properties, and exhibits the foundation function of synapses such as long-term plasticity (LTP), short-term plasticity (STP), and the conversion of STP to LTP. Most critically, the MOF based artificial synaptic device exhibits an excellent stability in atmosphere. This work opens the door for the application of 2D MOF film in the simulation of human brain synapses.

Side-Chain Engineering for Enhancing the Molecular Rigidity and Photovoltaic Performance of Noncovalently Fused-Ring Electron Acceptors.

Side-chain engineering is an effective strategy to regulate the solubility and packing behavior of organic materials. Recently, a unique strategy, so-called terminal side-chain (T-SC) engineering, has attracted much attention in the field of organic solar cells (OSCs), but there is a lack of deep understanding of the mechanism. Herein, a new noncovalently fused-ring electron acceptor (NFREA) containing two T-SCs (NoCA-5) was designed and synthesized. Introduction of T-SCs can enhance molecular rigidity and intermolecular π-π stacking, which is confirmed by the smaller Stokes shift value, lower reorganization free energy, and shorter π-π stacking distance in comparison to NoCA-1. Hence, the NoCA-5-based device exhibits a record power conversion efficiency (PCE) of 14.82 % in labs and a certified PCE of 14.5 %, resulting from a high electron mobility, a short charge-extraction time, a small Urbach energy (Eu ), and a favorable phase separation.