Pan-genome analysis of 33 genetically diverse rice accessions reveals hidden genomic variations.

Structural variations (SVs) and gene copy number variations (gCNVs) have contributed to crop evolution, domestication, and improvement. Here, we assembled 31 high-quality genomes of genetically diverse rice accessions. Coupling with two existing assemblies, we developed pan-genome-scale genomic resources including a graph-based genome, providing access to rice genomic variations. Specifically, we discovered 171,072 SVs and 25,549 gCNVs and used an Oryza glaberrima assembly to infer the derived states of SVs in the Oryza sativa population. Our analyses of SV formation mechanisms, impacts on gene expression, and distributions among subpopulations illustrate the utility of these resources for understanding how SVs and gCNVs shaped rice environmental adaptation and domestication. Our graph-based genome enabled genome-wide association study (GWAS)-based identification of phenotype-associated genetic variations undetectable when using only SNPs and a single reference assembly. Our work provides rich population-scale resources paired with easy-to-access tools to facilitate rice breeding as well as plant functional genomics and evolutionary biology research.

Different ER-plasma membrane tethers play opposing roles in autophagy of the cortical ER.

The endoplasmic reticulum (ER) undergoes degradation by selective macroautophagy (ER-phagy) in response to starvation or the accumulation of misfolded proteins within its lumen. In yeast, actin assembly at sites of contact between the cortical ER (cER) and endocytic pits acts to displace elements of the ER from their association with the plasma membrane (PM) so they can interact with the autophagosome assembly machinery near the vacuole. A collection of proteins tether the cER to the PM. Of these, Scs2/22 and Ist2 are required for cER-phagy, most likely through their roles in lipid transport, while deletion of the tricalbins, TCB1/2/3, bypasses those requirements. An artificial ER-PM tether blocks cER-phagy in both the wild type (WT) and a strain lacking endogenous tethers, supporting the importance of cER displacement from the PM. Scs2 and Ist2 can be cross-linked to the selective cER-phagy receptor, Atg40. The COPII cargo adaptor subunit, Lst1, associates with Atg40 and is required for cER-phagy. This requirement is also bypassed by deletion of the ER-PM tethers, suggesting a role for Lst1 prior to the displacement of the cER from the PM during cER-phagy. Although pexophagy and mitophagy also require actin assembly, deletion of ER-PM tethers does not bypass those requirements. We propose that within the context of rapamycin-induced cER-phagy, Scs2/22, Ist2, and Lst1 promote the local displacement of an element of the cER from the cortex, while Tcb1/2/3 act in opposition, anchoring the cER to the plasma membrane.

Electric-Field Control of Perpendicularly Magnetized Ferrimagnetic Order and Giant Magnetoresistance in Multiferroic Heterostructures.

Electrical control of magnetism is highly desirable for energy-efficient spintronic applications. Realizing electric-field-driven perpendicular magnetization switching has been a long-standing goal, which, however, remains a major challenge. Here, electric-field control of perpendicularly magnetized ferrimagnetic order via strain-mediated magnetoelectric coupling is reported. We show that the gate voltages isothermally toggle the dominant magnetic sublattice of the compensated ferrimagnet FeTb at room temperature, showing high reversibility and good endurance under ambient conditions. By implementing this strategy in FeTb/Pt/Co spin valves with giant magnetoresistance (GMR), we demonstrate that the distinct high and low resistance states can be selectively controlled by the gate voltages with assisting magnetic fields. Our results provide a promising route to use ferrimagnets for developing electric-field-controlled, low-power memory and logic devices.

The global nitrogen regulator GlnR is a direct transcriptional repressor of the key gluconeogenic gene pckA in actinomycetes.

In most actinomycetes, GlnR governs both nitrogen and non-nitrogen metabolisms (e.g., carbon, phosphate, and secondary metabolisms). Although GlnR has been recognized as a global regulator, its regulatory role in central carbon metabolism [e.g., glycolysis, gluconeogenesis, and the tricarboxylic acid (TCA) cycle] is largely unknown. In this study, we characterized GlnR as a direct transcriptional repressor of the pckA gene that encodes phosphoenolpyruvate carboxykinase, catalyzing the conversion of the TCA cycle intermediate oxaloacetate to phosphoenolpyruvate, a key step in gluconeogenesis. Through the transcriptomic and quantitative real-time PCR analyses, we first showed that the pckA transcription was upregulated in the glnR null mutant of Amycolatopsis mediterranei. Next, we proved that the pckA gene was essential for A. mediterranei gluconeogenesis when the TCA cycle intermediate was used as a sole carbon source. Furthermore, with the employment of the electrophoretic mobility shift assay and DNase I footprinting assay, we revealed that GlnR was able to specifically bind to the pckA promoter region from both A. mediterranei and two other representative actinomycetes (Streptomyces coelicolor and Mycobacterium smegmatis). Therefore, our data suggest that GlnR may repress pckA transcription in actinomycetes, which highlights the global regulatory role of GlnR in both nitrogen and central carbon metabolisms in response to environmental nutrient stresses. IMPORTANCE: The GlnR regulator of actinomycetes controls nitrogen metabolism genes and many other genes involved in carbon, phosphate, and secondary metabolisms. Currently, the known GlnR-regulated genes in carbon metabolism are involved in the transport of carbon sources, the assimilation of short-chain fatty acid, and the 2-methylcitrate cycle, although little is known about the relationship between GlnR and the TCA cycle and gluconeogenesis. Here, based on the biochemical and genetic results, we identified GlnR as a direct transcriptional repressor of pckA, the gene that encodes phosphoenolpyruvate carboxykinase, a key enzyme for gluconeogenesis, thus highlighting that GlnR plays a central and complex role for dynamic orchestration of cellular carbon, nitrogen, and phosphate fluxes and bioactive secondary metabolites in actinomycetes to adapt to changing surroundings.

Dysregulation of mitochondrial dynamics and mitophagy are involved in High-fat diet-induced steroidogenesis inhibition.

Male obesity is a pandemic health issue and can disrupt testicular steroidogenesis. Here, we explored the mechanism by which High-fat diet (HFD)-induced steroidogenic inhibition. As expected, HFD induced lipid droplet accumulation and reduced the expression of StAR, P450scc, and 3ß-HSD, three steroidogenic enzymes, in mouse testes. Palmitic acid (PA), a saturated fatty acid is usually used to trigger lipotoxicity in vitro, induced greater accumulation of lipid droplets and the downregulation of steroidogenic enzymes in TM3 cells. Mechanistically, both HFD and PA disturbed mitochondrial fusion/fission dynamics, and then induced mitochondrial dysfunction and mitophagy inhibition in mouse Leydig cells. Additionally, mitochondrial fusion promoter M1 attenuated PA-induced imbalance of mitochondrial dynamics, mitophagy inhibition, mitochondrial reactive oxygen species (ROS) production and mitochondrial dysfunction in TM3 cells. Mitofusin 2 (MFN2) knock-down further aggravated PA-induced imbalance of mitochondrial dynamics, mitochondrial ROS production and mitochondrial dysfunction in TM3 cells. Importantly, M1 rescued PA-induced downregulation of steroidogenic enzymes, whereas MFN2 knock-down further aggravated PA-induced downregulation of steroidogenic enzymes in TM3 cells. Overall, our results provide laboratory evidence that mitochondrial dysfunction and mitophagy inhibition caused by dysregulation of mitochondrial fusion may be involved in HFD-induced steroidogenesis inhibition in mouse Leydig cells.

High-Entropy Design for 2D Halide Perovskite.

Hybrid halide perovskites are good candidates for a range of functional materials such as optical electronic and photovoltaic devices due to their tunable band gaps, long carrier diffusion lengths, and solution processability. However, the instability in moisture/air, the toxicity of lead, and rigorous reaction setup or complex postprocessing have long been the bottlenecks for practical application. Herein, we present a simultaneous configurational entropy design at A-sites, B-sites, and X-sites in the typical (CHA)2PbBr4 two-dimensional (2D) hybrid perovskite. Our results demonstrate that the high-entropy effect favors the stabilization of the hybrid perovskite phase and facilitates a simple crystallization process without precise control of the cooling rate to prepare regular crystals. Moreover, high-entropy 2D perovskite crystals exhibit tunable energy band gaps, broadband emission, and a long carrier lifetime. Meanwhile, the high-entropy composition almost maintains the initial crystal structure in deionized water for 18 h while the original (CHA)2PbBr4 crystal mostly decomposes, suggesting obviously improved humidity stability. This work offers a facile approach to synthesize humidity-stable hybrid perovskites under mild conditions, accelerating relevant preparation of optoelectronics and light-emitting devices and facilitating the ultimate commercialization of halide perovskite.

3D-Printed Hydrogels with High-Strength and Anisotropy Mediated by Chain Rigidity.

Extrusion-based 3D printing is a facile technology to construct complex structures of hydrogels, especially for tough hydrogels that have shown demonstrated potential in load-bearing materials and tissue engineering. However, 3D-printed hydrogels often possess mechanical properties that do not guarantee their usage in tissue-mimicking, load-bearing components, and motion sensors. This study proposes a novel strategy to construct high-strength and anisotropic Fe3+ cross-linked poly(acrylamide-co-acrylic acid)/sodium alginate double network hydrogels. The semi-flexible sodium alginate chains act as a "conformation regulator" to promote the formation of strong intermolecular interactions between polymer chains and lock the more extended conformation exerted by the pre-stretch, enabling the construction of 3D-printed hydrogel structures with high orientation. The equilibrated anisotropic hydrogel filaments with a water content of 50-60 wt.% exhibit outstanding mechanical properties (tensile strength: 9-44 MPa; elongation at break: 120-668%; Young's modulus: 7-62 MPa; toughness: 26-52 MJ m- 3). 3D-printed anisotropic hydrogel structures with high mechanical performance show demonstrated potential as loading-bearing structures and electrodes of flexible triboelectric nanogenerators for versatile human motion sensing.

The LCG1-OsBP5/OsEBP89-Wx module regulates the grain chalkiness and taste quality in rice.

It is well known that the overall quality of japonica/geng rice is superior to that of indica/xian rice varieties. However, the molecular mechanisms underlying the quality disparities between these two subspecies of rice are still largely unknown. In this study, we have pinpointed a gene homologous to SLR1, termed LCG1, exhibiting significant expression during early caryopsis development and playing a specific role in regulating rice chalkiness and taste by affecting the accumulation of grain storage components, starch granule structure and chain length distribution of amylopectin. LCG1 physically interacts with OsBP5 and indirectly influences the expression of the amylose synthesis gene Waxy (Wx) by hindering the transcriptional activity of the OsBP5/OsEBP89 complex. Notably, sequence variations in the promoter region of LCG1 result in enhanced transcription in japonica rice accessions. This leads to elevated LCG1 expression in CSSL-LCG1Nip, thereby enhancing rice quality. Our research elucidates the molecular mechanism underlying the impact of the LCG1-OsBP5/OsEBP89-Wx regulatory pathway on rice chalkiness and taste quality, offering new genetic resources for improving the indica rice quality.

PFC/M1 activation and excitability: a longitudinal cohort study on fatigue symptoms in healthcare workers post-COVID-19.

BACKGROUND: Fatigue is one of the most common neurological symptoms reported post coronavirus disease 2019 (COVID-19) infection. In order to establish effective early intervention strategies, more emphasis should be placed on the correlation between fatigue and cortical neurophysiological changes, especially in healthcare workers, who are at a heightened risk of COVID-19 infection. METHODS: A prospective cohort study was conducted involving 29 COVID-19 medical workers and 24 healthy controls. The assessment included fatigue, sleep and health quality, psychological status, and physical capacity. Functional near-infrared spectroscopy (fNIRS) was employed to detect activation of brain regions. Bilateral primary motor cortex (M1) excitabilities were measured using single- and paired-pulse transcranial magnetic stimulation. Outcomes were assessed at 1, 3, and 6 months into the disease course. RESULTS: At 1-month post-COVID-19 infection, 37.9% of patients experienced severe fatigue symptoms, dropping to 10.3% at 3 months. Interestingly, the remarkable decreased activation/excitability of bilateral prefrontal lobe (PFC) and M1 were closely linked to fatigue symptoms after COVID-19. Notably, greater increase in M1 region excitability correlated with more significant fatigue improvement. Re-infected patients exhibited lower levels of brain activation and excitability compared to single-infection patients. CONCLUSIONS: Both single infection and reinfection of COVID-19 lead to decreased activation and excitability of the PFC and M1. The degree of excitability improvement in the M1 region correlates with a greater recovery in fatigue. Based on these findings, targeted interventions to enhance and regulate the excitability of M1 may represent a novel strategy for COVID-19 early rehabilitation. TRIAL REGISTRATION: The Ethics Review Committee of Xijing Hospital, No. KY20232051-F-1; www.chictr.org.cn , ChiCTR2300068444.

C-TERMINAL DOMAIN PHOSPHATASE-LIKE 3 contributes to GA-mediated growth and flowering by interaction with DELLA proteins.

Gibberellic acid (GA) plays a central role in many plant developmental processes and is crucial for crop improvement. DELLA proteins, the core suppressors in the GA signaling pathway, are degraded by GA via the 26S proteasomal pathway to release the GA response. However, little is known about the phosphorylation-mediated regulation of DELLA proteins. In this study, we combined GA response assays with protein-protein interaction analysis to infer the connection between Arabidopsis thaliana DELLAs and the C-TERMINAL DOMAIN PHOSPHATASE-LIKE 3 (CPL3), a phosphatase involved in the dephosphorylation of RNA polymerase II. We show that CPL3 directly interacts with DELLA proteins and promotes DELLA protein stability by inhibiting its degradation by the 26S proteasome. Consequently, CPL3 negatively modulates multiple GA-mediated processes of plant development, including hypocotyl elongation, flowering time, and anthocyanin accumulation. Taken together, our findings demonstrate that CPL3 serves as a novel regulator that could improve DELLA stability and thereby participate in GA signaling transduction.

Analysis of 12 kinds of cytokines in seminal plasma by flow cytometry and their correlations with routine semen parameters.

OBJECTIVE: To investigate the levels of 12 kinds of cytokines in seminal plasma and their correlations with routine semen parameters. METHODS: The remaining seminal plasma samples of 134 patients undergoing routine semen examination were collected for detecting cytokines. The parameters for sperm concentration, percentage of progressively motile sperm (PR), and motility were analyzed by a computer-assisted sperm analysis (CASA) system. According to the results of sperm concentration, PR and motility, 134 patients were divided into the normal routine semen parameters group, oligoasthenospermia group and azoospermia group. The levels of 12 kinds of cytokines in seminal plasma, including interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17, interferin (IFN)-α, IFN-γ, and tumor necrosis factor (TNF)-α, were detected by flow cytometry. Two seminal plasma samples were detected for 10 times, respectively, to calculate the coefficients of variation (CV) of each cytokine. The linear range of each cytokine was measured using the standard, and the correlation coefficient (r) was calculated. RESULTS: The r2 of 12 kinds of cytokines detected by flow cytometry were all greater than 0.99. The reproducibility of 2 seminal plasma samples showed that the CVs of all cytokines were lower than 15 % except for TNF-α in sample 1 (15.15 %). Seminal plasma IL-6 levels were negatively correlated with semen volume (P < 0.01). Seminal plasma IL-5 levels were positively correlated with sperm concentration (P < 0.01). Seminal plasma IL-8 levels were negatively correlated with sperm motility (P < 0.01). Seminal plasma IL-8, IL-17 and IL-12P70 levels were negatively correlated with sperm PR (P < 0.05). In addition to the significant negative correlation between IL-5 and IL-17 (P < 0.05), there was a significant positive correlation between the majority of other cytokines. The levels of seminal plasma IL-17 and IL-12P70 in the oligoasthenospermia group and IL-1ß and IL-12P70 in the azoospermia group were significantly higher than those in the normal routine semen parameters group (P ≤ 0.05), while the levels of IL-10 in the azoospermia group were significantly lower than that in the normal routine semen parameters group (P < 0.05). CONCLUSION: There are certain correlations between seminal plasma cytokines and routine semen parameters and strong correlations between different seminal plasma cytokines, suggesting that the imbalance between seminal plasma cytokines may affect sperm quality. However, it still needs to be further confirmed by large samples and multi-center clinical studies and related basic researches.

Clinicopathological and survival analysis for patients with uterine sarcoma treated following surgery for presumed benign disease.

OBJECTIVES: To investigate the clinicopathological characteristics and prognosis of patients with uterine sarcoma treated following surgery for presumed benign disease. METHODS: We identified all patients with uterine sarcoma found incidentally after primary surgery for presumed benign disease who presented to our institution and received re-exploration for completion surgery from January 1, 2004 to January 1, 2021. We analyzed the clinicopathological characteristics and prognosis. RESULTS: Overall, 95 patients were included in our study. For the initial surgery, myomectomy was performed in 50 (52.6%, 50/95) patients, hysterectomy was performed in 45 (47.4%, 45/95) patients. All patients were re-explored to complete the staging operation. The median time to the staging surgery was 40 days (range 15-90 days). There were 29 patients (30.5%, 29/95) had remnant sarcomas, with 17 patients (17/95, 17.9%) on the remaining uterus, 9 patients (9/95, 9.5%) had disseminated diseases, and 4 patients (4/95, 4.2%) had positive lymph nodes. About 40 patients (42.1%) received adjuvant chemotherapy, 55.2% (16/29) and 36.4% (24/66) patients with/without remnant diseases received adjuvant chemotherapy, respectively (P = 0.087). The median follow-up duration was 76.7 months (IQR: 34.8-118.1 months). And 17 patients (17.9%) had recurrence following re-exploration surgery. 5-year progression-free survival (PFS) and 5-year overall survival (OS) for the entire cohort was 81.7% and 92.1%, respectively. Patients with remnant sarcomas had a tendency towards a worse 5-year PFS and 5-year OS, compared with those without (5-year PFS: 75.6% vs. 84.5%, P = 0.224; 5-year OS: 85.5% vs. 95.1%, P = 0.217). Patients with disseminated diseases had a worse 5-year OS (62.5% vs. 95.1%, P = 0.007) and non-significantly worse 5-year PFS (64.8% vs. 83.4%, P = 0.153) compared with those without. CONCLUSIONS: Patients with uterine sarcoma treated following surgery for presumed benign disease have a favorable survival. Patients with disseminated diseases had a worse 5-year OS compared with those without. Surgical re-exploration may be valuable for removing remnant sarcomas and disseminated diseases.

A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR-mediated inhibition of osteoclastogenesis.

Calcium modulates bone cell recruitment, differentiation, and function by binding to the calcium-sensing receptor (CaSR). However, the function of CaSR induced by high extracellular calcium (Ca2+ e ) in the regulation of osteoclast formation in rheumatoid arthritis (RA) remains unknown. Here, we used TNFα-transgenic (TNFTG ) RA mice and their wildtype (WT) littermates fed a normal or a rescue diet (high calcium, high phosphorus, and high lactose diet, termed rescue diet) to compare their joint bone phenotypes. In comparison to TNFTG mice fed the normal diet, articular bone volume and cartilage area are increased, whereas inflamed area, eroded surface, TRAP+ surface, and osteoclast-related genes expression are decreased in TNFTG mice fed the rescue diet. Besides, TNFTG mice fed the rescue diet were found to exhibit more CaSR+ area and less NFATc1+ /TRAP+ area. Furthermore, at normal Ca2+ e concentrations, osteoclast precursors (OCPs) from TNFTG mice formed more osteoclasts than OCPs from WT mice, but the number of osteoclasts gradually decreased when the Ca2+ e concentration increased. Meanwhile, the expression of CaSR increased responding to a high level of Ca2+ e , whereas the expression of NF-κB/NFATc1 signaling molecules decreased. At last, the knockdown of CaSR blocked the inhibition of osteoclast differentiation attributed to high Ca2+ e . Taken together, our findings indicate that high Ca2+ e inhibits osteoclast differentiation in RA mice partially through the CaSR/NF-κB/NFATc1 pathway.

Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species-mediated activation of placental GCN2/eIF2α pathway.

Epidemiological studies suggest that fetal growth restriction (FGR) caused by gestational cholestasis is associated with elevated serum cholic acid (CA). Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown-rump length, and increased the incidence of FGR in a dose-dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down-regulating the protein but not the mRNA level of placental 11ß-Hydroxysteroid dehydrogenase-2 (11ß-HSD2). Additionally, CA activated placental GCN2/eIF2α pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA-induced down-regulation of 11ß-HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA-induced placental barrier dysfunction by inhibiting activation of GCN2/eIF2α pathway and subsequent down-regulation of 11ß-HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA-induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS-mediated placental GCN2/eIF2α activation. This study provides valuable insight for understanding the mechanism of cholestasis-induced placental dysfunction and subsequent FGR.

Accelerated Wound Healing by Electrospun Multifunctional Fibers with Self-Powered Performance.

Wound healing has been a persistent clinical challenge for a long time. Electrical stimulation is an effective therapy with the potential to accelerate wound healing. In this work, the self-powered electrospun nanofiber membranes (triples) were constructed as multifunctional wound dressings with electrical stimulation and biochemical capabilities. Triple was composed of a hydrolyzable inner layer with antiseptic and hemostatic chitosan, a hydrophilic core layer loaded with conductive AgNWs, and a hydrophobic outer layer fabricated by self-powered PVDF. Triple exhibited presentable wettability and acceptable moisture permeability. Electrical performance tests indicated that triple can transmit electrical signals formed by the piezoelectric effect to the wound. High antibacterial activities were observed for triple against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, with inhibition rates of 96.52, 98.63, and 97.26%, respectively. In vitro cell assays demonstrated that triple cells showed satisfactory proliferation and mobility. A whole blood clotting test showed that triple can enhance hemostasis. The innovative self-powered multifunctional fibers presented in this work offer a promising approach to addressing complications and expediting the promotion of chronic wound healing.

Correlation of bilateral M1 hand area excitability and overall functional recovery after spinal cord injury: protocol for a prospective cohort study.

BACKGROUND: After spinal cord injury (SCI), a large number of survivors suffer from severe motor dysfunction (MD). Although the injury site is in the spinal cord, excitability significantly decreases in the primary motor cortex (M1), especially in the lower extremity (LE) area. Unfortunately, M1 LE area-targeted repetitive transcranial magnetic stimulation (rTMS) has not achieved significant motor improvement in individuals with SCI. A recent study reported that the M1 hand area in individuals with SCl contains a compositional code (the movement-coding component of neural activity) that links matching movements from the upper extremities (UE) and the LE. However, the correlation between bilateral M1 hand area excitability and overall functional recovery is unknown. OBJECTIVE: To clarify the changes in the excitability of the bilateral M1 hand area after SCI and its correlation with motor recovery, we aim to specify the therapeutic parameters of rTMS for SCI motor rehabilitation. METHODS: This study is a 12-month prospective cohort study. The neurophysiological and overall functional status of the participants will be assessed. The primary outcomes included single-pulse and paired-pulse TMS. The second outcome included functional near-infrared spectroscopy (fNIRS) measurements. Overall functional status included total motor score, modified Ashworth scale score, ASIA Impairment Scale grade, spinal cord independence measure and modified Barthel index. The data will be recorded for individuals with SCI at disease durations of 1 month, 2 months, 4 months, 6 months and 12 months. The matched healthy controls will be measured during the same period of time after recruitment. DISCUSSION: The present study is the first to analyze the role of bilateral M1 hand area excitability changes in the evaluation and prediction of overall functional recovery (including motor function and activities of daily living) after SCI, which will further expand the traditional theory of the predominant role of M1, optimize the current rTMS treatment, and explore the brain-computer interface design for individuals with SCI. TRIAL REGISTRATION NUMBER: ChiCTR2300068831.

Silver(I) Complexes with Mefenamic Acid and Nitrogen Heterocyclic Ligands: Synthesis, Characterization, and Biological Evaluation.

Four Ag(I) complexes with mefenamato and nitrogen heterocyclic ligands, [Ag(2-apy)(mef)]2 (1), [Ag(3-apy)(mef)] (2), [Ag2(tmpyz)(mef)2] (3), and {[Ag(4,4'-bipy)(mef)]2(CH3CN)1.5(H2O)2}n (4), (mef = mefenamato, 2-apy = 2-aminopyridine, 3-apy = 3-aminopyridine, tmpyz = 2,3,5,6-tetramethylpyrazine, 4,4'-bipy = 4,4'-bipyridine), were synthesized and characterized. The interactions of these complexes with BSA were investigated by fluorescence spectroscopy, which indicated that these complexes quench the fluorescence of BSA by a static mechanism. The fluorescence data also indicated that the complexes showed good affinity for BSA, and one binding site on BSA was suitable for the complexes. The in vitro cytotoxicity of the four complexes against human cancer cell lines (MCF-7, HepG-2, A549, and MDA-MB-468) and one normal cell line (HTR-8) was evaluated by the MTT assay. Complex 1 displayed high cytotoxic activity against A549 cells. Further studies revealed that complex 1 could enhance the intracellular levels of ROS (reactive oxygen species) in A549 cells, cause cell cycle arrest in the G0/G1 phase, and induce apoptosis in A549 cells in a dose-dependent manner.

Bithieno[3,4-c]pyrrole-4,6-dione-Based Wide-Bandgap Donor Polymers for Efficient Polymer Solar Cells.

The polymer solar cells (PSCs) have garnered substantial interest owing to their lightweight, cost-effectiveness, and flexibility, making them ideal for large-scale roll-to-roll manufacturing. In this study, two wide-bandgap (WBG) donor polymers, PFBiTPD and PClBiTPD, utilizing bithieno[3,4-c]pyrrole-4,6-dione (BiTPD) as the electron-accepting unit and fluorinated/chlorinated benzo[1,2-b:4,5-b']dithiophene (BDT) as the electron-donating moiety are designed and synthesized. The polymers demonstrated large optical bandgaps (exceeding 1.80 eV) and are blended with ITIC-4F to form the active layers in PSCs. The PFBiTPD-based devices showed a well-dispersed fibrillar network, facilitating efficient charge generation and transport. Thus, these devices attained a power conversion efficiency (PCE) of 8.60%, featuring a fill factor (FF) of 62.89%, an open-circuit voltage (Voc) of 0.88 V and a short-circuit current density (Jsc) of 15.54 mA cm-2. In contrast, PClBiTPD-based devices displayed lower performance due to less favorable morphology. The study underscores the importance of polymer design and morphology control in optimizing the photovoltaic performance of PSCs.

Clinical follow-up investigation on thickness changes in the peripapillary retinal nerve fibre layer of patients with Leber hereditary optic neuropathy.

BACKGROUND: To investigate the peripapillary retinal nerve fibre layer (RNFL) thickness changes and analyse factors associated with visual recovery of G11778A Leber hereditary optic neuropathy (LHON) patients. METHODS: Patients diagnosed with G11778A LHON between July 2017 and December 2020 in Tongji hospital were included in this follow-up study. Patients were grouped according to disease duration. Variations in the RNFL thickness in each quadrant at different disease stages were characterised using optical coherence tomography. According to the absence or presence of significant visual acuity improvements, LHON patients of disease duration ≥ 6 months were divided into two groups. A bivariate logistic regression model was constructed to analyse the potential factors associated with spontaneous visual recovery. RESULTS: This study included 56 G11778A LHON patients (112 eyes) and 25 healthy controls (50 eyes), with a mean follow-up of 5.25 ± 1.42 months. All quadrants and mean RNFL thicknesses of LHON patients first increased and then decreased, except for the temporal RNFL. As the disease progressed, RNFL thinning slowed; however, gradual RNFL thinning occurred. Logistic regression revealed that baseline best corrected visual acuity was related to spontaneous visual recovery of LHON patients with disease duration ≥ 6 months. CONCLUSION: The pattern of RNFL involvement could be helpful in the differential diagnosis of LHON and other optic neuropathies. LHON patients with better vision are more likely to experience some degree of spontaneous visual acuity recovery after the subacute phase.

Base excision repair system targeting DNA adducts of trioxacarcin/LL-D49194 antibiotics for self-resistance.

Two families of DNA glycosylases (YtkR2/AlkD, AlkZ/YcaQ) have been found to remove bulky and crosslinking DNA adducts produced by bacterial natural products. Whether DNA glycosylases eliminate other types of damage formed by structurally diverse antibiotics is unknown. Here, we identify four DNA glycosylases-TxnU2, TxnU4, LldU1 and LldU5-important for biosynthesis of the aromatic polyketide antibiotics trioxacarcin A (TXNA) and LL-D49194 (LLD), and show that the enzymes provide self-resistance to the producing strains by excising the intercalated guanine adducts of TXNA and LLD. These enzymes are highly specific for TXNA/LLD-DNA lesions and have no activity toward other, less stable alkylguanines as previously described for YtkR2/AlkD and AlkZ/YcaQ. Similarly, TXNA-DNA adducts are not excised by other alkylpurine DNA glycosylases. TxnU4 and LldU1 possess unique active site motifs that provide an explanation for their tight substrate specificity. Moreover, we show that abasic (AP) sites generated from TxnU4 excision of intercalated TXNA-DNA adducts are incised by AP endonuclease less efficiently than those formed by 7mG excision. This work characterizes a distinct class of DNA glycosylase acting on intercalated DNA adducts and furthers our understanding of specific DNA repair self-resistance activities within antibiotic producers of structurally diverse, highly functionalized DNA damaging agents.