SGLT2i improves kidney senescence by down-regulating the expression of LTBP2 in SAMP8 mice.

Senescent kidney can lead to the maladaptive repairment and predispose age-related kidney diseases. Here, we explore the renal anti-senescence effect of a known kind of drug, sodium-dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence-accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence-related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK-2) cells induced by H2 O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti-senescence role. Dapagliflozin down-regulate the LTBP2 expression in kidney tissues and HK-2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein-docking analysis implies there is salt-bridge formation between them; these all indicate the possibility of weak-interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2 O2 , dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non-diabetes environment; the mechanism may be through regulating the role of LTBP2.

Spatio-temporal expression patterns of glycine-rich beta proteins and cysteine-rich beta proteins in setae development of Gekko japonicus.

BACKGROUND: Setae on the pad lamellae of the Japanese gecko Gekko japonicus (Schlegel, 1836), a vital epidermal derivative, are primarily composed of cornified beta-proteins (CBPs) and play a pivotal role in adhesion and climbing. The amino acid composition of CBPs might be a determining factor influencing their functional properties. However, the molecular mechanisms governed by CBP genes with diverse amino acid compositions in setae development remain unexplored. RESULTS: Based on RNA-seq analyses, this study confirmed that all G. japonicus CBPs (GjCBPs) are involved in setae formation. Cysteine-rich CBPs encoding genes (ge-cprp-17 to ge-cprp-26) and glycine-rich CBPs encoding genes (ge-gprp-17 to ge-gprp-22) were haphazardly selected, with quantitative real-time PCR revealing their expression patterns in embryonic pad lamellae and dorsal epidermis. It is inferred that glycine-rich CBPs are integral to the formation of both dorsal scales and lamellar setae, cysteine-rich CBPs are primarily associated with setae development. Additionally, fluorescence in situ hybridization revealed spatiotemporal differences in the expression of a glycine-rich CBP encoding gene (ge-gprp-19) and a cysteine-rich CBP encoding gene (ge-cprp-17) during dorsal scales and/or lamellar development. CONCLUSIONS: All 66 CBPs are involved in the formation of setae. Glycine-rich CBPs hold a significant role in the development of dorsal scales and lamellar setae, whereas most cysteine-rich CBPs appear to be essential components of G. japonicus setae. Even GjCBPs with similar amino acid compositions may play diverse functions. The clear spatio-temporal expression differences between the glycine-rich and cysteine-rich CBP encoding genes during epidermal scale and/or setae formation were observed. Embryonic developmental stages 39 to 42 emerged as crucial phases for setae development. These findings lay the groundwork for deeper investigation into the function of GjCBPs in the development of G. japonicus setae.

Reversible Fusion-Fission MXene Fiber-Based Microelectrodes for Target-Specific Gram-Positive and Gram-Negative Bacterium Discrimination.

Inaccurate or cumbersome clinical pathogen diagnosis between Gram-positive bacteria (G+) and Gram-negative (G-) bacteria lead to delayed clinical therapeutic interventions. Microelectrode-based electrochemical sensors exhibit the significant advantages of rapid response and minimal sample consumption, but the loading capacity and discrimination precision are weak. Herein, we develop reversible fusion-fission MXene-based fiber microelectrodes for G+/G- bacteria analysis. During the fissuring process, the spatial utilization, loading capacity, sensitivity, and selectivity of microelectrodes were maximized, and polymyxin B and vancomycin were assembled for G+/G- identification. The surface-tension-driven reversible fusion facilitated its reusability. A deep learning model was further applied for the electrochemical impedance spectroscopy (EIS) identification in diverse ratio concentrations of G+ and G- of (1:100-100:1) with higher accuracy (>93%) and gave predictable detection results for unknown samples. Meanwhile, the as-proposed sensing platform reached higher sensitivity toward E. coli (24.3 CFU/mL) and S. aureus (37.2 CFU/mL) in 20 min. The as-proposed platform provides valuable insights for bacterium discrimination and quantification.

Climate match is key to predict range expansion of the world's worst invasive terrestrial vertebrates.

Understanding the determinants of the range expansion of invasive alien species is crucial for developing effective prevention and control strategies. Nevertheless, we still lack a global picture of the potential factors influencing the invaded range expansion across taxonomic groups, especially for the world's worst invaders with high ecological and economic impacts. Here, by extensively collecting data on 363 distributional ranges of 19 of world's worst invasive terrestrial vertebrates across 135 invaded administrative jurisdictions, we observed remarkable variations in the range expansion across species and taxonomic groups. After controlling for taxonomic and geographic pseudoreplicates, model averaging analyses based on generalized additive mixed-effect models showed that species in invaded regions having climates more similar to those of their native ranges tended to undergo a larger range expansion. In addition, as proxies of propagule pressure and human-assisted transportation, the number of introduction events and the road network density were also important predictors facilitating the range expansion. Further variance partitioning analyses validated the predominant role of climate match in explaining the range expansion. Our study demonstrated that regions with similar climates to their native ranges could still be prioritized to prevent the spread of invasive species under the sustained global change.

Circadian Rhythm Disturbance in Acute Ischemic Stroke Patients and Its Effect on Prognosis.

INTRODUCTION: Poststroke sleep disturbances are common and can affect stroke outcomes, but the clinical studies mainly focus on breathing-related sleep disorders, while the bidirectional impact of circadian rhythm dysfunction in ischemic stroke remains unknown. This study observed the characteristics of melatonin secretion in acute ischemic stroke patients and evaluated whether melatonin rhythm impacts the prognosis after stroke by assessing the neurological function, cognition, emotion, and quality of life 3 months after stroke. METHODS: Acute ischemic stroke patients were selected from the Department of Neurology Inpatients of the Second Hospital affiliated with Soochow University from October 2019 to July 2021. Healthy control subjects were recruited at the same time. Demographic and clinical data were collected, and relevant scale scores (including neurological function, cognition, emotion, and sleep) were assessed within 2 weeks of onset and followed up 3 months later. All participants collected salivary melatonin samples on the 4th day of hospitalization and dim light melatonin onset (DLMO) was calculated according to melatonin concentration. Stroke patients were then divided into three groups based on their DLMO values. RESULTS: A total of 74 stroke patients and 33 control subjects were included in this analysis. Compared with healthy controls, stroke patients exhibited a delayed melatonin rhythm during the acute phase of stroke (21:36 vs. 20:38, p = 0.004). Stroke patients were then divided into three groups, namely normal (n = 36), delayed (n = 28), or advanced DLMO (n = 10), based on their DLMO values. A χ2 test showed that there were significant differences in the rate of poor prognosis (p = 0.011) and depression tendency (p = 0.028) among the three groups. A further pairwise comparison revealed that stroke patients with delayed DLMO were more likely to experience poor short-term outcomes than normal DLMO group (p = 0.003). The average melatonin concentration of stroke patients at 5 time points was significantly lower than that of the control group (3.145 vs. 7.065 pg/mL, p < 0.001). Accordingly, we split stroke patients into three groups, namely low melatonin level (n = 14), normal melatonin level (n = 54), or high melatonin level (n = 6). Unfortunately, there were no great differences in the clinical characteristics, cognition, emotion, sleep quality, and short-term outcome among groups. CONCLUSIONS: This is a preliminary study, and our results indicate that changes in melatonin secretion phase of stroke patients may have effect on their short-term prognosis.

Aerobic Denitrification Promoting by Actinomycetes Coculture: Investigating Performance, Carbon Source Metabolic Characteristic, and Raw Water Restoration.

The coculture theory that promotes denitrification relies on effectively utilizing the resources of low-efficiency denitrification microbes. Here, the strains Streptomyces sp. PYX97 and Streptomyces sp. TSJ96 were isolated and showed lower denitrification capacity when cultured individually. However, the coculture of strains PYX97 and TSJ96 enhanced nitrogen removal (removed 96.40% of total nitrogen) and organic carbon reduction (removed 92.13% of dissolved organic carbon) under aerobic conditions. Nitrogen balance analysis indicated that coculturing enhanced the efficiency of nitrate converted into gaseous nitrogen reaching 70.42%. Meanwhile, the coculturing promoted the cell metabolism capacity and carbon source metabolic activity. The coculture strains PYX97 and TSJ96 thrived in conditions of C/N = 10, alkalescence, and 150 rpm shaking speed. The coculturing reduced total nitrogen and CODMn in the raw water treatment by 83.32 and 84.21%, respectively. During this treatment, the cell metabolic activity and cell density increased in the coculture strains PYX97 and TSJ96 reactor. Moreover, the coculture strains could utilize aromatic protein and soluble microbial products during aerobic denitrification processes in raw water treatment. This study suggests that coculturing inefficient actinomycete strains could be a promising approach for treating polluted water bodies.

Single substrate-functionalized molybdenum oxide nanozyme for specific colorimetric monitoring of xanthine oxidase activity.

Xanthine-functionalized molybdenum oxide nanodots (X-MoO3-x NDs) with peroxidase (POD)-like activity were developed for selective, sensitive, and facile colorimetric quantification of xanthine oxidase (XO). Xanthine functionalization can not only be favorable for the successful nanozyme preparation, but also for the specific recognition of XO as well as the simultaneous generation of hydrogen peroxide, which was subsequently transformed into hydroxyl radical to oxidize the chromogenic reagent based on the POD-like catalysis. Under the optimized conditions, the colorimetric biosensing platform was established for XO assay without addition of further substrates, showing good linearity relationship between absorbance difference (ΔA) and XO concentrations in the range 0.05-0.5 U/mL (R2 = 0.998) with a limit of detection (LOD) of 0.019 U/mL. The quantification of XO occurs in 25 min, which is superior to the previously reported and commercial XO assays. The proposed method has been successfully used in the assay of human serum samples, showing its high potential in the field of clinical monitoring.

Factors associated with risk analysis for asymptomatic left ventricular diastolic dysfunction in nondialysis patients with chronic kidney disease.

Heart failure (HF) constitutes a major determinant of outcome in chronic kidney disease (CKD) patients. The main pattern of HF in CKD patients is preserved ejection fraction (HFpEF), and left ventricular diastolic dysfunction (LVDD) is a frequent pathophysiological mechanism and specific preclinical manifestation of HFpEF. Therefore, exploring and intervention of the factors associated with risk for LVDD is of great importance in reducing the morbidity and mortality of cardiovascular disease (CVD) complications in CKD patients. We designed this retrospective cross-sectional study to collect clinical and echocardiographic data from 339 nondialysis CKD patients without obvious symptoms of HF to analyze the proportion of asymptomatic left ventricular diastolic dysfunction (ALVDD) and its related factors associated with risk by multivariate logistic regression analysis. Among the 339 nondialysis CKD patients, 92.04% had ALVDD. With the progression of CKD stage, the proportion of ALVDD gradually increased. The multivariate logistic regression analysis revealed that increased age (OR 1.237; 95% confidence interval (CI) 1.108-1.381, per year), diabetic nephropathy (DN) and hypertensive nephropathy (HTN) (OR 25.000; 95% CI 1.355-48.645, DN and HTN vs chronic interstitial nephritis), progression of CKD stage (OR 2.785; 95% CI 1.228-6.315, per stage), increased mean arterial pressure (OR 1.154; 95% CI 1.051-1.268, per mmHg), increased urinary protein (OR 2.825; 95% CI 1.484-5.405, per g/24 h), and low blood calcium (OR 0.072; 95% CI 0.006-0.859, per mmol/L) were factors associated with risk for ALVDD in nondialysis CKD patients after adjusting for other confounding factors. Therefore, dynamic monitoring of these factors associated with risk, timely diagnosis and treatment of ALVDD can delay the progression to symptomatic HF, which is of great importance for reducing CVD mortality, and improving the prognosis and quality of life in CKD patients.

Chemical-free vacuum ultraviolet irradiation as ultrafiltration membrane pretreatment technique: Performance, mechanisms and DBPs formation.

Membrane fouling induced by natural organic matter (NOM) has seriously affected the further extensive application of ultrafiltration (UF). Herein, a simple, green and robust vacuum ultraviolet (VUV) technology was adopted as pretreatment before UF and ultraviolet (UV) technology was used for comparison. The results showed that control effect of VUV pretreatment on membrane fouling was better than that of UV pretreatment, as evidenced by the increase of normalized flux from 0.27 to 0.38 and 0.73 after 30 min UV or VUV pretreatment, respectively. This is related to the fact that VUV pretreatment exhibited stronger NOM degradation ability than UV pretreatment owing to the formation of HO•. The steady-state concentration of HO• was calculated as 3.04 × 10-13 M and the cumulative exposure of HO• reached 5.52 × 10-10 M s after 30 min of VUV irradiation. And the second-order rate constant between NOM and HO• was determined as 1.36 × 104 L mg-1 s-1. Furthermore, fluorescence EEM could be applied to predict membrane fouling induced by humic-enriched water. Standard blocking and cake filtration were major fouling mechanisms. Moreover, extension of UV pretreatment time increased the disinfection by-products (DBPs) formation, the DBPs concentration was enhanced from 322.36 to 1187.80 µg/L after 210 min pretreatment. However, VUV pretreatment for 150 min reduced DBPs content to 282.57 µg/L, and DBPs content continued to decrease with the extension of pretreatment time, revealing that VUV pretreatment achieved effective control of DBPs. The variation trend of cytotoxicity and health risk of DBPs was similar to that of DBPs concentration. In summary, VUV pretreatment exhibited excellent effect on membrane fouling alleviation, NOM degradation and DBPs control under a certain pretreatment time.

Humidity-Controlled Molecular Assembly and Photoisomerization Behavior with a Bubble-Assisted Patterning Approach.

Precise control of molecular assembly is of great significance in the application of functional molecules. This work has systematically investigated the humidity effect in bubble-assisted molecular assembly. This work finds humidity is critical in the evolution of the soft confined space, leading to the formation of microscale liquid confined space under high humidity, and nanoscale liquid confined space under low humidity. It is also revealed that the differences in surface wettability and adhesion play the key role. Consequently, a flat pattern with thermodynamically favorable ordered structure and a sharp pattern with dynamically favorable disordered structure are achieved, which show different solid-state photoisomerization behaviors and photoresponsiveness. Interestingly, conductivity of sharp pattern with disordered structure is higher than that of flat pattern with layered ordered structure due to electronic transport mechanism of different spatial dimensions. This work opens a new way for manipulating the molecular self-assembly to control the morphology and function of molecular patterns.

Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation.

BACKGROUND: Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease in developed countries. Evidence of the benefits of resveratrol (RES) for the treatment of DKD is accumulating. However, comprehensive therapeutic targets and underlying mechanisms through which RES exerts its effects against DKD are limited. METHODS: Drug targets of RES were obtained from Drugbank and SwissTargetPrediction Databases. Disease targets of DKD were obtained from DisGeNET, Genecards, and Therapeutic Target Database. Therapeutic targets for RES against DKD were identified by intersecting the drug targets and disease targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were performed using the DAVID database and visualized by Cytoscape software. Molecular docking validation of the binding capacity between RES and targets was performed by UCSF Chimera software and SwissDock webserver. The high glucose (HG)-induced podocyte injury model, RT-qPCR, and western blot were used to verify the reliability of the effects of RES on target proteins. RESULTS: After the intersection of the 86 drug targets and 566 disease targets, 25 therapeutic targets for RES against DKD were obtained. And the target proteins were classified into 6 functional categories. A total of 11 cellular components terms and 27 diseases, and the top 20 enriched biological processes, molecular functions, and KEGG pathways potentially involved in the RES action against DKD were recorded. Molecular docking studies showed that RES had a strong binding affinity toward PPARA, ESR1, SLC2A1, SHBG, AR, AKR1B1, PPARG, IGF1R, RELA, PIK3CA, MMP9, AKT1, INSR, MMP2, TTR, and CYP2C9 domains. The HG-induced podocyte injury model was successfully constructed and validated by RT-qPCR and western blot. RES treatment was able to reverse the abnormal gene expression of PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR. CONCLUSIONS: RES may target PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR domains to act as a therapeutic agent for DKD. These findings comprehensively reveal the potential therapeutic targets for RES against DKD and provide theoretical bases for the clinical application of RES in the treatment of DKD.

Fluorenylidene-Cyclopentadithiophene Based Asymmetric Bistricyclic Aromatic Ene Compounds: Synthesis and Substituents Effects.

Low band gap materials have always been a focus of attention due to their potential applications in various fields. In this work, a series of asymmetric bistricyclic aromatic ene (BAE) compounds with fluorenylidene-cyclopentadithiophene (FYT) skeleton were facially synthesized, which were modified with different substituents (-OMe, -SMe). The FYT core exhibit twisted C=C bond with dihedral angles around 30°, and the introduction of -SMe group can provide additional S⋅⋅⋅S interaction between molecules, which is conducive to the charge transporting. The UV-Vis spectra, electrochemistry and photoelectron spectroscopy revealed that these compounds have relatively narrow band gaps, particularly, the -SMe modified compounds have slightly lower HOMO and Fermi energy levels than that of the -OMe modified compounds. Furthermore, PSCs devices were fabricated with the three compounds as HTMs, and FYT-DSDPA exhibit the best performance among them, revealing the fine-tuning band structure could influence properties of HTMs.

Exercise ameliorates skeletal muscle insulin resistance by modulating GRK4-mediated D1R expression.

Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed that dopamine D1-like receptor agonists, such as fenoldopam, could improve peripheral insulin sensitivity, while antipsychotics, which are dopamine receptor antagonists, increased susceptibility to Type 2 diabetes mellitus (T2DM). Meanwhile, exercise has been proved to stimulate dopamine receptors. However, whether the dopamine D1 receptor (D1R) is involved in exercise-mediated amelioration of IR remains unclear. We found that the D1-like receptor antagonist, SCH23390, reduced the effect of exercise on lowering blood glucose and insulin in insulin-resistant mice and inhibited the contraction-induced glucose uptake in C2C12 myotubes. Similarly, the opposite was true for the D1-like receptor agonist, fenoldopam. Furthermore, the expression of D1R was decreased in skeletal muscles from streptozotocin (STZ)- and high-fat intake-induced T2DM mice, accompanied by increased D1R phosphorylation, which was reversed by exercise. A screening study showed that G protein-coupled receptor kinase 4 (GRK4) may be the candidate kinase for the regulation of D1R function, because, in addition to the increased GRK4 expression in skeletal muscles of T2DM mice, GRK4 transgenic T2DM mice exhibited lower insulin sensitivity, accompanied by higher D1R phosphorylation than control mice, whereas the AAV9-shGRK4 mice were much more sensitive to insulin than AAV9-null mice. Mechanistically, the up-regulation of GRK4 expression caused by increased reactive oxygen species (ROS) in IR was ascribed to the enhanced expression of c-Myc, a transcriptional factor of GRK4. Taken together, the present study shows that exercise, via regulation of ROS/c-Myc/GRK4 pathway, ameliorates D1R dysfunction and improves insulin sensitivity.

Evolutionary characterization and pathogenicity of Getah virus from pigs in Guangdong Province of China.

Getah virus (GETV) is an emerging zoonotic virus that can infect humans and many mammals through mosquitoes. In this study, a novel pathogenic GETV strain, GDQY2022, was isolated from a pig farm in Guangdong Province, China. Sequence comparisons and phylogenetic analysis showed that GDQY2022 belongs to group III (GIII) and was most closely related to strain HeN202009-2, with 99.78% nucleotide sequence identity. Histopathological examination revealed significant pathological changes, such as widened alveolar septum in the lungs with mild congestion and hemorrhage. Differences in viral load between tissues were assessed by real-time RT-PCR, and significantly higher levels of GETV were found in abdominal lymph nodes and lungs of subclinically and clinically affected pigs (P < 0.01). This study provides valuable data for understanding the risk of GETV infection in the pig industry and a reliable basis for studying the pathogenic mechanisms and diagnostic surveillance of GETV.

Aerobic Denitrification Enhanced by Immobilized Slow-Released Iron/Activated Carbon Aquagel Treatment of Low C/N Micropolluted Water: Denitrification Performance, Denitrifying Bacterial Community Co-occurrence, and Implications.

The key limiting factors in the treatment of low C/N micropolluted water bodies are deficient essential electron donors for nitrogen removal processes. An iron/activated carbon aquagel (IACA) was synthesized as a slowly released inorganic electron donor to enhance aerobic denitrification performance in low C/N micropolluted water treatment. The denitrification efficiency in IACA reactors was enhanced by more than 56.72% and the highest of 94.12% was accomplished compared with those of the control reactors. Moreover, the CODMn removal efficiency improved by more than 34.32% in IACA reactors. The Illumina MiSeq sequencing consequence explained that the denitrifying bacteria with facultative denitrification, iron oxidation, and iron reduction function were located in the dominant species niches in the IACA reactors (e.g., Pseudomonas, Leptothrix, and Comamonas). The diversity and richness of the denitrifying bacterial communities were enhanced in the IACA reactors. Network analysis indicated that aerobic denitrifying bacterial consortia in IACA reactors presented a more complicated co-occurrence structure. The IACA reactors presented the potential for long-term denitrification operation. This study affords a pathway to utilize IACA, promoting aerobic denitrification during low C/N micropolluted water body treatment.

Temporal patterns of algae in different urban lakes and their correlations with environmental variables in Xi'an, China.

Urban lakes were critical in aquatic ecology environments, but how environmental factors affected the distribution and change characteristics of algal communities in urban lakes of Xi'an city was not clearly. Here, we investigated the algal community structure of six urban lakes in Xi'an and evaluated the effects of water quality parameters on algae. The results indicated that the significant differences on physicochemical parameters existed in different urban lakes. The maximum concentration of total phosphorus in urban lakes was (0.18 ± 0.01) mg/L and there was a phenomenon of phosphorus limitation. In addition, 51 genera of algae were identified and Chlorella sp. was the dominant algal species, which was affiliated with Chlorophyta. Network analysis elucidated that each lake had a unique algal community network and the positive correlation was dominant in the interaction between algae species, illustrating that mature microbial communities existed or occupied similar niches. Redundancy analysis illustrated that environmental factors explained 47.35% variance of algal species-water quality correlation collectively, indicating that water quality conditions had a significant influence on the temporal variations of algae. Structural equation model further verified that algal community structure was directly or indirectly regulated by different water quality conditions. Our study shows that temporal patterns of algal communities can reveal the dynamics and interactions of different urban ecosystem types, providing a theoretical basis for assessing eutrophication levels and for water quality management.

Volatile Dual-Solvent Assisted Intermediate Phase Regulation for Anti-Solvent-Free Perovskite Photovoltaics.

The unprecedented development of perovskite solar cells (PSCs) makes them one of the most promising candidates for terawatt-scale green energy production with low cost. However, the high boiling point solvents during the solution-processed film deposition cause anisotropic crystal growth and toxic solvent vapor during high-throughput manufacturing. Here, a dual-component green solvent consisting of isopropyl acetate and acetonitrile is proposed to form a volatile perovskite precursor, which can realize the high-quality perovskite thin film deposition by intermediate phase regulation. A room-temperature stable perovskite intermediate phase is constructed with the engagement of isopropyl acetate as co-solvent, which suppresses the exploding nucleation rate in volatile perovskite precursor, providing a fine grain growth rate and wide processing window in scalable film deposition. The corresponding PSCs fabricated by blade coating without anti-solvents or gas quenching achieve power conversion efficiency (PCE) of 16.37 % and 15.29 % for the areas of 14.08 cm2 and 37.83 cm2 , respectively.

Distinct mutational features across preinvasive and invasive subtypes identified through comprehensive profiling of surgically resected lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Reducing phase noise coupled by wavefront errors in optical telescopes for the space measurement of gravitational waves.

Space-based gravitational-wave observatories (SGOs) promise to measure pico-meter variations in gigameter separations of a triangular constellation. Telescopes play an essential role in transmitting and receiving laser beams measuring the constellation arms with the heterodyne laser interferometry. The wavefront aberrations of the telescopes are coupled with the unavoidable misalignments caused by jitters and pointing tilts and induce additional phase changes into the heterodyne signal. As a critical aspect of achieving the measuring stability of 1p m/H z, we analytically investigate the above process and determine that by properly controlling the relevant key aberrations in the design of the telescopes, the phase noise can be reduced exponentially, which makes the heterodyne signal insensitive to jitter and reduces the demand for wavefront quality. This method is validated whether the LISA Pathfinder (LPF) signal definition or the Average Phase (AP) signal definition is adopted, underpinning the guidance for the design and manufacturing of the optical telescope in SGOs.

Identification and mapping of genetic locus conferring resistance to multiple plant viruses in soybean.

KEY MESSAGE: A reliable locus confers broad-spectrum resistance to multiple plant viruses in soybean under field conditions. Soybean mosaic disease (SMD) can be caused by a variety of viruses, most of which have been largely overlooked in breeding programs. Effective mitigation of the adverse of SMD might result from breeding cultivars with broad-spectrum resistance. However, reports on broad-spectrum resistance to multiple virus have been limited. To catalog viral community members behind SMD, virus samples were collected from symptomatic field plots, and pathogenicity of component strains was assessed. Preliminary ELISA and PCR detection revealed that 39.58% and 66.67% of samples contained two or more virus strains, respectively. Only three soybean accessions were completely asymptomatic, while 42% exhibited moderate or severe susceptibility, indicating that co-infection of multiple virus remains a significant threat in current soybean production systems. Further, a RIL population consisting of 150 F7:9 strains derived from two soybean genotypes with contrasting reactions to virus infection was constructed and explored for significant markers and resistance genes. QTL analysis returned a reliable locus, named GmRmv, on chromosome 13. Significance of GmRmv in imparting resistance to SMD was further confirmed in NIL lines and delimited into a 157-kb interval that contains 17 annotated genes. Among these genes, three, Glyma.13G190000, Glyma.13G190300 and Glyma.13G190400, each contained LRR domains, as well as significant variation in coding sequences between resistant and susceptible parents. Hence, these three genes are considered strong candidate genes for explaining GmRmv significance. In summary, this research opens a new avenue for formulating strategies to breed soybean varieties with broad-spectrum resistance to multiple virus associated with SMD.