Evolution of a Restriction Factor by Domestication of a Yeast Retrotransposon.

Transposable elements drive genome evolution in all branches of life. Transposable element insertions are often deleterious to their hosts and necessitate evolution of control mechanisms to limit their spread. The long terminal repeat retrotransposon Ty1 prime (Ty1'), a subfamily of the Ty1 family, is present in many Saccharomyces cerevisiae strains, but little is known about what controls its copy number. Here, we provide evidence that a novel gene from an exapted Ty1' sequence, domesticated restriction of Ty1' relic 2 (DRT2), encodes a restriction factor that inhibits Ty1' movement. DRT2 arose through domestication of a Ty1' GAG gene and contains the C-terminal domain of capsid, which in the related Ty1 canonical subfamily functions as a self-encoded restriction factor. Bioinformatic analysis reveals the widespread nature of DRT2, its evolutionary history, and pronounced structural variation at the Ty1' relic 2 locus. Ty1' retromobility analyses demonstrate DRT2 restriction factor functionality, and northern blot and RNA-seq analysis indicate that DRT2 is transcribed in multiple strains. Velocity cosedimentation profiles indicate an association between Drt2 and Ty1' virus-like particles or assembly complexes. Chimeric Ty1' elements containing DRT2 retain retromobility, suggesting an ancestral role of productive Gag C-terminal domain of capsid functionality is present in the sequence. Unlike Ty1 canonical, Ty1' retromobility increases with copy number, suggesting that C-terminal domain of capsid-based restriction is not limited to the Ty1 canonical subfamily self-encoded restriction factor and drove the endogenization of DRT2. The discovery of an exapted Ty1' restriction factor provides insight into the evolution of the Ty1 family, evolutionary hot-spots, and host-transposable element interactions.

In Situ Formation of Iodide Precursor for Perovskite Quantum Dots with Application in Efficient Solar Cells.

Perovskite quantum dots (PQDs) become a kind of competitive material for fabricating high-performance solar cells due to their solution processability and outstanding optoelectronic properties. However, the current synthesis method of PQDs is mostly based on the binary-precursor method, which results in a large deviation of the I/Pb input ratio in the reaction system from the stoichiometric ratio of PQDs. Herein, a ternary-precursor method with an iodide source self-filling ability is reported for the synthesis of the CsPbI3 PQDs with high optoelectronic properties. Systematically experimental characterizations and theoretical calculations are conducted to fundamentally understand the effects of the I/Pb input molar ratio on the crystallographic and optoelectronic properties of PQDs. The results reveal that increasing the I/Pb input molar ratio can obtain ideal cubic structure PQDs with iodine-rich surfaces, which can significantly reduce the surface defects of PQDs and realize high orientation of PQD solids, facilitating charge carrier transport in the PQD solids with diminished nonradiative recombination. Consequently, the PQD solar cells exhibit an impressive efficiency of 15.16%, which is largely improved compared with that of 12.83% for the control solar cell. This work provides a feasible strategy for synthesizing high-quality PQDs for high-performance optoelectronic devices.

Longitudinal mass loads of phthalate esters in sewage sludge and their association with public health and social measures for COVID-19 control in Beijing.

This study examines the concentrations and population-normalized mass loads (PNML) of five phthalate esters (PAEs) and four metabolites (mPAEs) in 390 sewage sludge samples collected from two municipal wastewater treatment plants in Beijing between July 2020 and June 2023, amidst the COVID-19 pandemic. Through GC/MS analysis, the compounds were simultaneously quantified, with peak concentrations in 2020. Bis(2-ethylhexyl) phthalate (DEHP) and mono(2-ethyl-5-oxohexyl) phthalate emerged as predominant PAE and mPAE congeners with concentrations of 78.7 µg/g dw and 259 µg/g dw, respectively. DEHP and monobenzyl phthalate had the highest median PNML among PAEs and mPAEs, respectively, at 128 µg/inhabitant/day and 798 µg/inhabitant/day. Linear regression models revealed a positive association between PNML of PAEs and five public health and social measures aimed at mitigating the COVID-19 pandemic. This research contributes to the expanding body of literature by emphasizing the role of wastewater-based epidemiology as a vital tool for monitoring community-level exposure to environmental contaminants.

Plastome evolution and phylogenomics of Impatiens (Balsaminaceae).

MAIN CONCLUSION: This study reported seven new plastomes from Impatiens and observed three highly variable regions for phylogeny and DNA barcoding, which resolved the relationships among sections of subgenus Impatiens. Impatiens L. (Balsaminaceae, Ericales) is one of the largest and most diverse genera of angiosperms, widely known for its taxonomic difficulty. In this study, we reevaluated the infrageneric relationships within the genus Impatiens, using complete plastome sequence data. Seven complete plastomes of Impatiens (representing 6 species) were newly sequenced and characterized along with 20 previously published plastomes of other Impatiens species, plus 2 plastomes of outgroups (Hydrocera triflora, Balsaminaceae; Marcgravia coriacea, Marcgraviaceae). The total size of these 29 plastomes ranged from 151,538 bp to 152,917 bp, except 2 samples of Impatiens morsei, which exhibited a shorter length and lost some genes encoding NADH dehydrogenase subunits. Moreover, the number of simple sequence repeats (SSRs) ranged from 51 to 113, and the number of long repeats from 17 to 26. In addition, three highly variable regions were identified (trnG-GCC (The previous one), ndhF-rpl32-trnL-UGA-ccsA, and ycf1). Our phylogenomic analysis based on 80 plastome-derived protein-coding genes strongly supported the monophyly of Impatiens and its two subgenera (Clavicarpa and Impatiens), and fully resolved relationships among the six (out of seven) sampled sections of subgenus Impatiens. Overall, the plastome DNA markers and phylogenetic results reported in this study will facilitate future identification, taxonomic and DNA barcoding studies in Impatiens as well as evolutionary studies in Balsaminaceae.

Electrically driven supersymmetric semiconductor laser arrays with single-lobe far-field patterns.

Semiconductor laser arrays based on the third-order supersymmetric (SUSY) transformation are proposed to increase the mode discrimination between fundamental supermode and high-order supermodes. The distance between the edge waveguide of the main array and that of the superpartners is optimized. Then, the electric field distributions of different modes are also calculated, which show that, except for the fundamental supermode, the high-order supermodes penetrate deeper into the superpartner arrays, which accounts for the increased loss of high-order supermodes. The fabricated third-order SUSY laser array can emit light with a single-lobe far-field pattern under an injection current of 70 mA, which is a promising candidate for optical couplings between lasers and optical elements.

Cell pyroptosis in picornavirus and its potential for treating viral infection.

Cell pyroptosis has received increased attention due to the associations between innate immunity and disease, and it has become a major focal point recently due to in-depth studies of cancer. With increased research on pyroptosis, scientists have discovered that it has an essential role in viral infections, especially in the occurrence and development of some picornavirus infections. Many picornaviruses, including Coxsackievirus, a71 enterovirus, human rhinovirus, encephalomyocarditis virus, and foot-and-mouth disease virus induce pyroptosis to varying degrees. This review summarized the mechanisms by which these viruses induce cell pyroptosis, which can be an effective defense against pathogen infection. However, excessive inflammasome activation or pyroptosis also can damage the host's health or aggravate disease progression. Careful approaches that acknowledge this dual effect will aid in the exploration of picornavirus infections and the mechanisms that produce the inflammatory response. This information will promote the development of drugs that can inhibit cell pyroptosis and provide new avenues for future clinical treatment.

Different phases in non-Hermitian topological semiconductor stripe laser arrays.

As a novel branch of topology, non-Hermitian topological systems have been extensively studied in theory and experiments recently. Topological parity-time (PT)-symmetric semiconductor stripe laser arrays based on the Su-Schreiffer-Heeger model are proposed. The degree of non-Hermicity can be tuned by altering the length of the cavities, and PT symmetry can be realized by patterned electrode. Three laser arrays working in different non-Hermitian phases are analyzed and fabricated. With the increasing degree of non-Hermicity, the peaks of output intensities move from the edge to the bulk. The proposed semiconductor stripe laser array can function as an active, flexible, and feasible platform to investigate and explore non-Hermitian topology for further developments in this field.

Single-chip hybrid integrated silicon photonics transmitter based on passive alignment.

A single-chip hybrid integrated silicon photonics transmitter based on passive alignment flip-chip bonding technology has been demonstrated. The transmitter is developed by the hybrid integration of a C-band slotted laser with 1 mm cavity length and a Mach-Zehnder modulator with 2 mm long phase shifter. A 3 dB bandwidth of the small signal response is 16.35 GHz at 5.99 VPP superimposed with a reverse bias voltage of 2.43 V. A 25 Gbps data transmission experiment of the hybrid integrated transmitter is performed at 25°C.

High-brightness and high-efficiency diode laser module based on double wavelength division multiplexing external cavities.

In this Letter, a new, to the best of our knowledge, external cavity structure based on double wavelength division multiplexing external cavities is proposed and demonstrated. The electro-optical conversion efficiency is improved and the brightness of the spectral beam combining diode lasers is enhanced. One wavelength division multiplexing external cavity is placed on the rear-side of the laser emitters to provide the strong optical feedback for wavelength locking and the other wavelength division multiplexing external cavity is placed on the front-side of laser emitters to combine three emitter beams to one beam. A maximum output power of up to 7.5 W is obtained and the brightness of the laser diode is 100 MW cm-2 sr-1 with an electro-optical conversion efficiency of 46.5%. Compared with a standard cavity for spectral beam combining, the use of double wavelength division multiplexing external cavities results in an electro-optical conversion efficiency improvement of 6.5%. The whole structure provides a new technology to achieve high-brightness and high electro-optical conversion efficiency for a laser diode source.

Electrically injected supersymmetric semiconductor lasers with narrow vertical divergence angle.

Electrically injected supersymmetric (SUSY) semiconductor lasers are proposed and fabricated. Two successive SUSY transformations are applied to the main array arranged along the direction of epitaxial growth, which can remove the propagation constants of the fundamental mode and the leaky mode of the main array from the superpartner while keeping those of other high-order modes. The SUSY laser possesses an excellent mode discrimination and favors the lasing of the fundamental mode. The fabricated SUSY laser can emit light with a single-lobe vertical far-field pattern with the full width at half maximum of 16.87° under an injection current of 1.4 A.

Discovery of novel Quinazoline-based KRAS G12C inhibitors as potential anticancer agents.

A series of novel quinazoline analogs were designed and synthesized based on ARS-1620 and LLK-10 (a KRAS inhibitor reported by us recently) as KRAS G12C inhibitors with a 5-nitrofuran-2-carboxylic acid warhead. Most of the newly synthesized compounds exhibited antiproliferative activities similar to or better than ARS-1620 and LLK-10. Among them, compound KS-19 showed the highest activity (IC50 = 460 âˆ¼ 870 nM) and reasonable selectivity (3 to 27-fold) for inhibiting the proliferation of KRAS G12C-mutated cells (NCI-H358 and NCI-H23) over other KRAS mutant (e.g. G13D, G12D, G12S, G12V, WT) cancer cells. ITC, KRAS-GTP pull-down assay and western blot analysis demonstrated that KS-19 could bind to KRAS G12C protein with high affinity (KD = 97 nM), thus decreasing the active form of KRAS G12C (KRAS G12C-GTP) and phosphorylated Erk, and leading to NCI-H358 tumor cell apoptosis. In addition, KS-19 was able to suppress the formation of NCI-H358 and NCI-H23 tumor colonies in a dose-dependent manner. Moreover, in vivo efficacy studies indicated that KS-19 (40 mg/kg) was effective in suppressing tumor growth in nude mice bearing NCI-H358 tumor xenografts with a TGI (tumor growth inhibition) of 47 %, comparable to that of ARS-1620 (50 %). Lastly, KS-19 possessed a benign toxicity profile without causing bone marrow suppression and any obvious morphological abnormalities in major organs of mice. Collectively, these results suggest that KS-19 represents a novel inhibitor of KRAS G12C worthy of further investigation as a potential anticancer agent.

Discovery of ARS-1620 analogs as KRas G12C inhibitors with high in vivo antitumor activity.

KRas is the most frequently mutated protein of the three Ras isoforms in various cancer types. KRas mutations (i.e. G12C) are present in approximately 30% of human cancers. Based on our previously reported KRas G12C inhibitor LLK-10, we designed a series of quinazoline analogues with a trifluoromethacrylic acid warhead as covalent inhibitor of KRas G12C. The pharmacological activities of these compounds were assessed against a panel of KRas G12C mutated cancer cells (i.e. H358 and H23). Among them, K20 showed that highest antiproliferative potency with an average IC50 of 1.16 µM, clearly better than that of the lead LLK-10 (average IC50 = 2.32 µM), and comparable to that of ARS-1620 (average IC50 = 1.32 µM, a known KRas G12C inhibitor). K20 also exhibited better selectivity index (SI = 5 âˆ¼ 23) than LLK-10 (SI = 1.5-3) for inhibiting the growth of KRas G12C mutated cancer cells (i.e. H358 and H23) over other KRas (e.g. G13D, G12S, G12D, G12V) mutated cancer cells. Utilizing a KRAS-GTP pull-down assay, it was demonstrated that K20 decreased the active form of KRAS (KRAS-GTP) in NCI-H358 cells. In addition, K20 reduced the level of phosphorylated Erk and caused cancer cell apoptosis. Further, K20 could inhibit the formation of H358 or H23 tumor colonies. Moreover, K20 displayed significant tumor-suppressing effects in NCI-H358 xenograft-bearing nude mice with a TGI (tumor growth inhibition) of 41%, comparable to that of ARS-1620 (47%). Lastly, K20 exhibited benign toxicity profiles without causing bone marrow suppression and any other apparent toxicity to major organs of mice. Collectively, these results indicate that K20 is a KRas G12C inhibitor deserving further investigation.

Discovery of novel 2-aryl-4-bis-amide imidazoles (ABAI) as anti-inflammatory agents for the treatment of inflammatory bowel diseases (IBD).

A series of 2-Aryl-4-Bis-amide Imidazoles (ABAI-1 to 30) were designed as anti-inflammatory agents. These compounds were synthesized and evaluated for the in vitro anti-inflammatory activities (inhibition of NO production and release of inflammatory cytokines). Several compounds effectively inhibited NO production in lipopolysaccharide (LPS) induced RAW264.7 cells. Among them, ABAI-30 exhibited the highest NO-inhibitory effect (inhibition rate of 87% at 20 µM). The anti-inflammatory mechanism of ABAI-30 was examined and found to be inhibiting the TLR4-pp65 and NLRP3-caspase-1 signaling pathway, thus leading to the downregulation of IL6, IL-1ß and TNFα at both transcriptional and translational levels. Importantly, ABAI-30 demonstrated high in vivo anti-inflammatory efficacy in a dextran sulfate sodium (DSS)-induced colitis mouse model without causing obvious toxicity. Collectively, our study provides a potent anti-inflammatory agent, which deserves further investigation as a novel therapeutic candidate for treating inflammatory bowel diseases.

Outer Membrane Vesicles Derived from Salmonella enterica Serotype Typhimurium Can Deliver Shigella flexneri 2a O-Polysaccharide Antigen To Prevent Shigella flexneri 2a Infection in Mice.

Shigellosis has become a serious threat to health in many developing countries due to the severe diarrhea it causes. Shigella flexneri 2a is the principal species responsible for this endemic disease. Despite multiple attempts to design a vaccine against shigellosis, no effective vaccine has been developed yet. Lipopolysaccharide (LPS) is both an essential virulence factor and an antigen protective against Shigella, due to its outer domain, termed O-polysaccharide antigen. In the present study, S. flexneri 2a O-polysaccharide antigen was innovatively biosynthesized in Salmonella and attached to core-lipid A via the ligase WaaL, with purified outer membrane vesicles (OMVs) utilized as vaccine vectors. Here, we identified the expression of the heterologous O-antigen and have described the isolation, characterization, and immune protection efficiency of the OMV vaccine. Furthermore, the results of animal experiments indicated that immunization of mice with the OMV vaccine induced significant specific anti-Shigella LPS antibodies in the serum, with similar trends in IgA levels from vaginal secretions and fluid from bronchopulmonary lavage, both intranasally and intraperitoneally. The OMV vaccine derived from both routes of administration provided significant protection against virulent S. flexneri 2a infection, as judged by a serum bactericidal assay, opsonization assay, and challenge test. This vaccination strategy represents a novel and improved approach to control shigellosis by the combination of Salmonella glycosyl carrier lipid bioconjugation with OMVs. IMPORTANCEShigella, the cause of shigellosis or bacillary dysentery, is a major public health concern, especially for children in developing countries. An effective vaccine would control the spread of the disease to some extent. However, no licensed vaccine against Shigella infection in humans has so far been developed. The Shigella O-antigen polysaccharide is effective in stimulating the production of protective antibodies and so could represent a vaccine antigen candidate. In addition, bacterial outer membrane vesicles (OMVs) have been used as antigen delivery platforms due to their nanoscale properties and ease of antigen delivery to trigger an immune response. Therefore, the present study provides a new strategy for vaccine design, combining a glycoconjugated vaccine with OMVs. The design concept of this strategy is the expression of Shigella O-antigen via the LPS synthesis pathway in recombinant Salmonella, from which the OMV vaccine is then isolated. Based on these findings, we believe that the novel vaccine design strategy in which polysaccharide antigens are delivered via bacterial OMVs will be effective for the development and clinical application of an effective Shigella vaccine.

Approaches to tuning the exceptional point of PT-symmetric double ridge stripe lasers.

Electrically injected Parity-time (PT)-symmetric double ridge stripe semiconductor lasers lasing at 980 nm range are designed and measured. The spontaneous PT-symmetric breaking point or exceptional point (EP) of the laser is tuned below or above the lasing threshold by means of varying the coupling constant or the mirror loss. The linewidth of the optical spectrum of the PT-symmetric laser is narrowed, compared with that of traditional single ridge (SR) laser and double ridge (DR) laser. Furthermore, the far field pattern of the PT-symmetric laser with EP below the lasing threshold is compared with that of the PT-symmetric laser with EP above the lasing threshold experimentally. It is found that when the laser start to lase, the former is single-lobed while the latter is double-lobed. when the current continues to increase, the former develops into double lobe directly while the latter first develops into single lobe and then double lobe again.

Discovery of novel quinazoline-based covalent inhibitors of KRAS G12C with various cysteine-targeting warheads as potential anticancer agents.

A series of novel quinazoline analogs with a variety of cysteine-targeting warheads (electrophiles) were designed and synthesized based on ARS-1620 as covalent KRAS G12C inhibitors. Among them, compounds LLK10 and LLK14 exhibited similar or better antiproliferative activity than ARS-1620. LLK10 was used for subsequent biological studies due to the higher selectivity towards KRAS G12C-mutated cells than LLK14. LLK10 maintained the mechanism of action by forming a covalent bond with KRAS G12C protein, thus decreasing the level of phosphorylated Mek and Erk, and leading to tumor cell apoptosis. In addition, LLK10 was able to suppress the formation of H358 tumor colonies. Molecular modeling study indicated that LLK10 binds with high affinity to the SWII binding site in KRAS G12C and overlaps well with ARS-1620. The high binding affinity of LLK10 was further confirmed by the isothermal titration calorimetry (ITC) assay in which LLK10 exhibited a KD of 115 nM for binding to KRAS G12C. These results suggest that the novel covalent inhibitors of KRAS G12C with different warheads deserve further investigation as potential anticancer agents.

Discovery of KRas G12C-IN-3 and Pomalidomide-based PROTACs as degraders of endogenous KRAS G12C with potent anticancer activity.

A series of KRAS G12C-targeting PROTACs (PROteolysis TArgeting Chimeras) were designed and synthesized based on KRas G12C-IN-3 (a KRAS G12C inhibitor) and pomalidomide as degraders of KRAS G12C with a molecular weight of < 900. Among them, compound KP-14 (m.w. = 852.16; tPSA = 174.53) showed the highest KRAS G12C-degrading capability in NCI-H358 cancer cells (DC50≈1.25 µM). KP-14 bound to KRAS G12C through the acrylamide warhead and recruited the E3 ligase CRBN, causing rapid and sustained KRAS G12C degradation which led to suppression of MAPK signaling pathway in NCI-H358 cells. In addition, KP-14 selectively induced the degradation of KRAS G12C but not other KRAS isoforms such as G13D via PROTAC mechanism. Furthermore, KP-14 exhibited potent antiproliferative activity against NCI-H358 cancer cells and was able to suppress the formation of NCI-H358 tumor colonies. Collectively, this work suggests that KP-14 may serve as a tool compound for exploring the degradation of KRAS G12C by PROTAC strategy and deserve further investigation as a potential anticancer agent.

Dual Passivation of CsPbI3 Perovskite Nanocrystals with Amino Acid Ligands for Efficient Quantum Dot Solar Cells.

Inorganic CsPbI3 perovskite quantum dot (PQD) receives increasing attention for the application in the new generation solar cells, but the defects on the surface of PQDs significantly affect the photovoltaic performance and stability of solar cells. Herein, the amino acids are used as dual-passivation ligands to passivate the surface defects of CsPbI3 PQDs using a facile single-step ligand exchange strategy. The PQD surface properties are investigated in depth by combining experimental studies and theoretical calculation approaches. The PQD solid films with amino acids as dual-passivation ligands on the PQD surface are thoroughly characterized using extensive techniques, which reveal that the glycine ligand can significantly improve defect passivation of PQDs and therefore diminish charge carrier recombination in the PQD solid. The power conversion efficiency (PCE) of the glycine-based PQD solar cell (PQDSC) is improved by 16.9% compared with that of the traditional PQDSC fabricated with Pb(NO3 )2 treating the PQD surface, owning to improved charge carrier extraction. Theoretical calculations are carried out to comprehensively understand the thermodynamic feasibility and favorable charge density distribution on the PQD surface with a dual-passivation ligand.

Identification of four hub genes as promising biomarkers to evaluate the prognosis of ovarian cancer in silico.

BACKGROUND: Ovarian cancer (OvCa) is one of the most fatal cancers among females in the world. With growing numbers of individuals diagnosed with OvCa ending in deaths, it is urgent to further explore the potential mechanisms of OvCa oncogenesis and development and related biomarkers. METHODS: The gene expression profiles of GSE49997 were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was applied to explore the most potent gene modules associated with the overall survival (OS) and progression-free survival (PFS) events of OvCa patients, and the prognostic values of these genes were exhibited and validated based on data from training and validation sets. Next, protein-protein interaction (PPI) networks were built by GeneMANIA. Besides, enrichment analysis was conducted using DAVID website. RESULTS: According to the WGCNA analysis, a total of eight modules were identified and four hub genes (MM > 0.90) in the blue module were reserved for next analysis. Kaplan-Meier analysis exhibited that these four hub genes were significantly associated with worse OS and PFS in the patient cohort from GSE49997. Moreover, we validated the short-term (4-years) and long-term prognostic values based on the GSE9891 data, respectively. Last, PPI networks analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed several potential mechanisms of four hub genes and their co-operators participating in OvCa progression. CONCLUSION: Four hub genes (COL6A3, CRISPLD2, FBN1 and SERPINF1) were identified to be associated with the prognosis in OvCa, which might be used as monitoring biomarkers to evaluate survival time of OvCa patients.

A comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism.

Cytochrome P450 2E1 (CYP2E1) plays a vital role in drug-induced hepatotoxicity and cancers (e.g. lung and bladder cancer), since it is responsible for metabolizing a number of medications and environmental toxins to reactive intermediate metabolites. CYP2E1 was recently found to be the highest expressed CYP enzyme in human livers using a proteomics approach, and CYP2E1-related toxicity is strongly associated with its protein level that shows significant inter-individual variability related to ethnicity, age, and sex. Furthermore, the expression of CYP2E1 demonstrates regulation by extensive genetic polymorphism, endogenous hormones, cytokines, xenobiotics, and varying pathological states. Over the past decade, the knowledge of pharmacology, toxicology, and biology about CYP2E1 has grown remarkably, but the research progress has yet to be summarized. This study presents a timely systematic review on CYP2E1's xenobiotic metabolism, genetic polymorphism, and inhibitors, with the focus on their clinical relevance for the efficacy and toxicity of various CYP2E1 substrates. Moreover, several knowledge gaps have been identified towards fully understanding the potential interactions among different CYP2E1 substrates in clinical settings. Through in-depth analyses of these knowns and unknowns, we expect this review will aid in future drug development and improve management of CYP2E1 related clinical toxicity.