Glutamine transporters as effective targets in digestive system malignant tumor treatment.

Glutamine is one of the most abundant non-essential amino acids in human plasma and plays a crucial role in many biological processes of the human body. Tumor cells take up a large amount of glutamine to meet their rapid proliferation requirements, which is supported by the upregulation of glutamine transporters. Targeted inhibition of glutamine transporters effectively inhibits cell growth and proliferation in tumors. Among all cancers, digestive system malignant tumors (DSMTs) have the highest incidence and mortality rates, and the current therapeutic strategies for DSMTs are mainly surgical resection and chemotherapy. Due to the relatively low survival rate and severe side effects associated with DSMTs treatment, new treatment strategies are urgently required. This article summarizes the glutamine transporters involved in DSMTs and describes their role in DSMTs. Additionally, glutamine transporter-target drugs are discussed, providing theoretical guidance for the further development of drugs DSMTs treatment.

Enhanced Emitting Dipole Orientation Based on Asymmetric Iridium(III) Complexes for Efficient Saturated-Blue Phosphorescent OLEDs.

Three novel asymmetric Ir(III) complexes have been rationally designed to optimize their emitting dipole orientations (EDO) and enhance light outcoupling in blue phosphorescent organic light-emitting diodes (OLEDs), thereby boosting their external quantum efficiency (EQE). Bulky electron-donating groups (EDGs), namely: carbazole (Cz), di-tert-butyl carbazole (tBuCz), and phenoxazine (Pxz) are incorporated into the tridentate dicarbene pincer chelate to induce high degree of packing anisotropy, simultaneously enhancing their photophysical properties. Angle-dependent photoluminescence (ADPL) measurements indicate increased horizontal transition dipole ratios of 0.89 and 0.90 for the Ir(III) complexes Cz-dfppy-CN and tBuCz-dfppy-CN, respectively. Analysis of the single crystal structure and density functional theory (DFT) calculation results revealed an inherent correlation between molecular aspect ratio and EDO. Utilizing the newly obtained emitters, the blue OLED devices demonstrated exceptional performance, achieving a maximum EQE of 30.7% at a Commission International de l'Eclairage (CIE) coordinate of (0.140, 0.148). Optical transfer matrix-based simulations confirmed a maximum outcoupling efficiency of 35% due to improved EDO. Finally, the tandem OLED and hyper-OLED devices exhibited a maximum EQE of 44.2% and 31.6%, respectively, together with good device stability. This rational molecular design provides straightforward guidelines to reach highly efficient and stable saturated blue emission.

Microscale Normal Compression Behaviors of Clay Aggregates: A Coarse-Grained Molecular Dynamics Study.

Given the limitations of micromechanical experiments and molecular dynamics simulations, the normal compression process of clay aggregates was simulated under different vertical pressures (P), numbers of particles, loading methods, and environments by a Gay-Berne potential model. On the basis of the variations of particle orientation and the distribution of stacks, the evolution of deformation and stresses was elucidated. The results showed that the effects of the pressure level and loading environment on the deformation were significant. In the range of 0.1-10 MPa, the changes in the void ratio were essentially the evolution of the distribution of stacks determined by attractive short-range van der Waals interactions. The deformation under constant pressure was larger than that under step loading. Because the interactions between clay particles were mainly controlled by mechanical force when in the range of 40-100 MPa, the void ratios under various loading conditions were consistent. It was also found that changes in three-dimensional stresses during compression were dependent on those of the distribution of stacks. In the vacuum environment, owing to the lateral movement of interlocked small stacks, the horizontal stress decreased. The lateral pressure coefficients (k) were greater in an atmospheric environment because the anisotropic particle orientation was relatively less obvious. In the range of 10-100 MPa, when the loading path became longer, k was similar in vacuum but became smaller in an atmosphere. If the initial loading pressure was increased, the number of large stacks sharply increased and the anisotropy was significant in a vacuum environment, which was less prone to lateral expansion. In contrast, more consistent particle arrangements were maintained in an atmosphere. This work will be conducive to explaining experimental observations of long-term ripening.

Posterior Wall Fragments in Acetabular Both-Column Fractures: Morphology, Type, and the Significance of its Projection.

OBJECTIVE: Most both-column acetabular fractures are combined with posterior wall fragments. However, the morphology of this posterior wall is varied, and how to fix this posterior wall remains a controversial topic. To investigate the morphological characteristics of posterior wall fragments of both-column acetabular fractures and select corresponding fixation methods. METHODS: Data from 352 patients with acetabular fractures admitted to the level one trauma centre in our hospital between January 2006 and December 2022 were collected. The morphology of posterior wall fragments was observed and analyzed in 83 cases of both-column acetabular fractures and classified according to the consistency of posterior wall morphology. A fracture map of the posterior wall was created on a normal template according to the three morphological types of posterior wall fragments. Finally, the high-incidence area of the posterior wall fracture was projected onto the iliac fossa and the medial side of the posterior column to guide the fixation of the posterior wall fragment using the anterior intrapelvic approach. RESULTS: Fractures were divided into four types: I, large posterior wall fragment which was high in the ilium bone (34 cases, 41.0%); II, posterior wall fragment in the acetabular parietal region (18 cases, 21.7%); III, posterior wall marginal fracture (10 cases, 12.0%); and IV, non-combined posterior wall fracture (21 cases, 25.3%). The most common morphologies of the posterior wall fragments of the first two types were mapped and projected onto the anterior iliac inner plate and medial side of the posterior column, where the corresponding area could be used to guide the insertion of the internal fixation. CONCLUSION: Both-column acetabular fractures combined with posterior wall fractures can be divided into four types according to the morphology of the posterior wall fragment. Understanding the corresponding three-dimensional morphology and projection position of different types of these fragments can help surgeons determine the position and orientation of internal fixation of posterior wall fractures.

PlantMine: A Machine-Learning Framework to Detect Core SNPs in Rice Genomics.

As a fundamental global staple crop, rice plays a pivotal role in human nutrition and agricultural production systems. However, its complex genetic architecture and extensive trait variability pose challenges for breeders and researchers in optimizing yield and quality. Particularly to expedite breeding methods like genomic selection, isolating core SNPs related to target traits from genome-wide data reduces irrelevant mutation noise, enhancing computational precision and efficiency. Thus, exploring efficient computational approaches to mine core SNPs is of great importance. This study introduces PlantMine, an innovative computational framework that integrates feature selection and machine learning techniques to effectively identify core SNPs critical for the improvement of rice traits. Utilizing the dataset from the 3000 Rice Genomes Project, we applied different algorithms for analysis. The findings underscore the effectiveness of combining feature selection with machine learning in accurately identifying core SNPs, offering a promising avenue to expedite rice breeding efforts and improve crop productivity and resilience to stress.

[Rapid determination of 15 N-nitrosamines in air-dried yak meat using one-step QuEChERS-gas chromatography-triple quadrupole mass spectrometry].

A method based on gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) coupled with one-step QuEChERS technique was developed for the simultaneous determination of 15 N-nitrosamines in air-dried yak meat. The hydration volume, extraction solvent, extracting salt, and cleaning material were optimized according to the characteristics of the N-nitrosamines and sample matrix. The optimized conditions were as follows: 10 mL of purified water for sample hydration, acetonitrile as the extraction solvent for the sample after hydration, 4.0 g of anhydrous MgSO4 and 1.0 g of NaCl as extracting salts, 500 mg of MgSO4+25 mg of C18+50 mg of PSA as cleaning materials. Favorable recoveries of the 15 N-nitrosamines were obtained when the extraction solution was incompletely dried. Thus, the final extract was dried to below 0.5 mL under a mild nitrogen stream and then redissolved to 0.5 mL with acetonitrile. After filtration, 200 µL of the sample was transferred to an autosampler vial for GC-MS/MS analysis. The 15 N-nitrosamines were determined using GC-MS/MS on a DB-HeavyWAX column (30 m×0.25 mm×0.25 µm) with an electron impact ion source in multiple-reaction monitoring (MRM) mode, and quantified using an external standard method. Under the optimized experimental conditions, the results showed that the calibration curves exhibited good linearities for the 15 N-nitrosamines, with correlation coefficients (r2) greater than 0.9990. The limits of detection (LODs) and the limits of quantification (LOQs) ranged from 0.05 to 0.20 µg/kg and from 0.10 to 0.50 µg/kg, respectively. At spiked levels of 1LOQ, 2LOQ, and 10LOQ, the average recoveries were 79.4%-102.1%, 80.6%-109.5%, and 83.0%-110.6%, respectively, and the relative standard deviations were in the range of 0.8%-16.0%. The low matrix effects of the 15 N-nitrosamines indicated the high sensitivity of the proposed method. The method was applied to detect representative commercial air-dried yak meat samples obtained using different processing techniques. Seven N-nitrosamines, including N-nitrosodimethylamine, N-nitrosodiisobutylamine, N-nitrosodibutylamine, N-methyl-N-phenylnitrous amide, N-ethyl-N-nitrosoaniline, N-nitrosopyrrolidine, and N-nitrosodiphenylamine were detected in all samples. The average contents of the seven N-nitrosamines was 0.08-20.18 µg/kg. The detection rates and average contents of the N-nitrosamines in cooked air-dried yak meat samples were higher than those in traditional raw air-dried yak meat samples. Compared with the manual QuEChERS method, the one-step QuEChERS method developed integrated the extraction and clean-up procedures into one single run, and the detection efficiency was considerably improved. The developed method is simple, rapid, highly sensitive, and insusceptible to human errors. Thus, it is useful for the determination of N-nitrosamines in air-dried yak meat and can be extended to the qualitative and quantitative analysis of N-nitrosamines in other meat products. It also provides method support and a data reference for the general determination of N-nitrosamines, which is of great significance for food safety.

Whole-genome duplication in the Multicellularity Long Term Evolution Experiment.

Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution1-4. However, given the instability of newly-formed polyploid genomes5-7, understanding how WGDs arise in a population, persist, and underpin adaptations remains a challenge. Using our ongoing Multicellularity Long Term Evolution Experiment (MuLTEE)8, we show that diploid snowflake yeast (Saccharomyces cerevisiae) under selection for larger multicellular size rapidly undergo spontaneous WGD. From its origin within the first 50 days of the experiment, tetraploids persist for the next 950 days (nearly 5,000 generations, the current leading edge of our experiment) in ten replicate populations, despite being genomically unstable. Using synthetic reconstruction, biophysical modeling, and counter-selection experiments, we found that tetraploidy evolved because it confers immediate fitness benefits in this environment, by producing larger, longer cells that yield larger clusters. The same selective benefit also maintained tetraploidy over long evolutionary timescales, inhibiting the reversion to diploidy that is typically seen in laboratory evolution experiments. Once established, tetraploidy facilitated novel genetic routes for adaptation, playing a key role in the evolution of macroscopic multicellular size via the origin of evolutionarily conserved aneuploidy. These results provide unique empirical insights into the evolutionary dynamics and impacts of WGD, showing how it can initially arise due to its immediate adaptive benefits, be maintained by selection, and fuel long-term innovations by creating additional dimensions of heritable genetic variation.

Lymph node targeting strategy using a hydrogel sustained-release system to load effector memory T cells improves the anti-tumor efficacy of anti-PD-1.

Communication between tumors and lymph nodes carries substantial significance for antitumor immunotherapy. Remodeling the immune microenvironment of tumor-draining lymph nodes (TdLN) plays a key role in enhancing the anti-tumor ability of immunotherapy. In this study, we constructed a biomimetic artificial lymph node structure composed of F127 hydrogel loading effector memory T (TEM) cells and PD-1 inhibitors (aPD-1). The biomimetic lymph nodes facilitate the delivery of TEM cells and aPD-1 to the TdLN and the tumor immune microenvironment, thus realizing effective and sustained anti-tumor immunotherapy. Exploiting their unique gel-forming and degradation properties, the cold tumors were speedily transformed into hot tumors via TEM cell supplementation. Meanwhile, the efficacy of aPD-1 was markedly elevated compared with conventional drug delivery methods. Our finding suggested that the development of F127@TEM@aPD-1 holds promising potential as a future novel clinical drug delivery technique. STATEMENT OF SIGNIFICANCE: F127@TEM@aPD-1 show unique advantages in cancer treatment. When injected subcutaneously, F127@TEM@aPD-1 can continuously supplement TEM cells and aPD-1 to tumor draining lymph nodes (TdLN) and the tumor microenvironment, not only improving the efficacy of ICB therapy through slow release, but also exhibiting dual regulatory effects on the tumor and TdLN.

External Electrons Directly Stimulate Escherichia coli for Enhancing Biological Hydrogen Production.

External electric field has the potential to influence metabolic processes such as biological hydrogen production in microorganisms. Based on this concept, we designed and constructed an electroactive hybrid system for microbial biohydrogen production under an electric field comprised of polydopamine (PDA)-modified Escherichia coli (E. coli) and Ni foam (NF). In this system, electrons generated from NF directly migrate into E. coli cells to promote highly efficient biocatalytic hydrogen production. Compared to that generated in the absence of electric field stimulation, biohydrogen production by the PDA-modified E. coli-based system is significantly enhanced. This investigation has demonstrated the mechanism for electron transfer in a biohybrid system and gives insight into precise basis for the enhancement of hydrogen production by using the multifield coupling technology.

Enhancing Light Outcoupling Efficiency via Anisotropic Low Refractive Index Electron Transporting Materials for Efficient Perovskite Light-Emitting Diodes.

Thanks to the extensive efforts toward optimizing perovskite crystallization properties, high-quality perovskite films with near-unity photoluminescence quantum yield are successfully achieved. However, the light outcoupling efficiency of perovskite light-emitting diodes (PeLEDs) is impeded by insufficient light extraction, which poses a challenge to the further advancement of PeLEDs. Here, an anisotropic multifunctional electron transporting material, 9,10-bis(4-(2-phenyl-1H-benzo[d]imidazole-1-yl)phenyl) anthracene (BPBiPA), with a low extraordinary refractive index (ne) and high electron mobility is developed for fabricating high-efficiency PeLEDs. The anisotropic molecular orientations of BPBiPA can result in a low ne of 1.59 along the z-axis direction. Optical simulations show that the low ne of BPBiPA can effectively mitigate the surface plasmon polariton loss and enhance the photon extraction efficiency in waveguide mode, thereby improving the light outcoupling efficiency of PeLEDs. In addition, the high electron mobility of BPBiPA can facilitate balanced carrier injection in PeLEDs. As a result, high-efficiency green PeLEDs with a record external quantum efficiency of 32.1% and a current efficiency of 111.7 cd A-1 are obtained, which provides new inspirations for the design of electron transporting materials for high-performance PeLEDs.

Proteostatic tuning underpins the evolution of novel multicellular traits.

The evolution of multicellularity paved the way for the origin of complex life on Earth, but little is known about the mechanistic basis of early multicellular evolution. Here, we examine the molecular basis of multicellular adaptation in the multicellularity long-term evolution experiment (MuLTEE). We demonstrate that cellular elongation, a key adaptation underpinning increased biophysical toughness and organismal size, is convergently driven by down-regulation of the chaperone Hsp90. Mechanistically, Hsp90-mediated morphogenesis operates by destabilizing the cyclin-dependent kinase Cdc28, resulting in delayed mitosis and prolonged polarized growth. Reinstatement of Hsp90 or Cdc28 expression resulted in shortened cells that formed smaller groups with reduced multicellular fitness. Together, our results show how ancient protein folding systems can be tuned to drive rapid evolution at a new level of biological individuality by revealing novel developmental phenotypes.

Structural Engineering of Iridium(III) Phosphors with Imidazo[4,5-b]pyrazin-2-ylidene Cyclometalates for Efficient Blue Electroluminescence.

Iridium(III) complexes are particularly noted for their excellent potentials in fabrication of blue organic light-emitting diodes (OLEDs), but the severe efficiency roll-off largely hampered their practical applications. To reveal the underlying characteristics, three Ir(III) complexes, namely f-ct5c, f-ct5d, and f-ct11, bearing imidazo[4,5-b]pyrazin-2-ylidene cyclometalates are prepared and characterized in detail. Both f-ct5c and f-ct5d (also their mixture f-ct5mix) gave intensive blue emissions peaking at ≈465 nm with short radiative lifetimes of 1.76 and 2.45 µs respectively, in degassed toluene. Alternatively, f-ct11 with two 4-tert-butylphenyl substituents on each imidazo[4,5-b]pyrazin-2-ylidene entity, possessed a bluish-green emission (508 nm) together with an extended radiative lifetime of 34.3 µs in the dispersed PMMA matrix. Consequently, the resulting solution-processed OLED with f-ct11 delivered a maximum external quantum efficiency (EQEmax ) of 6.5% with serious efficiency roll-offs. In contrast, f-ct5mix based device achieved a high EQEmax of 27.2% and the EQE maintained at 23.0% of 1000 cd m-2 . Furthermore, the hyper-OLEDs with f-ct5mix as the sensitizer and v-DABNA as the terminal emitter afford narrowed emission with a considerably high EQEmax exceeding 32%, affirming the potential of f-ct5mix to serve as both the emitter and sensitizer in OLEDs.

Cascading Energy Transfer for Highly Efficient Deep-Red OLED Emission with Cyclometalated [3+2+1] Iridium Complexes.

The promising cyclometalated iridium (III) complexes have been proved to possess great potential in vacuum-deposited organic light-emitting diodes (OLEDs) applications for full-color displays and white solid-state lighting sources. Herein, based on the unique bidentate ligand of dibenzo[a,c]phenazine (dbpz) group with strong conjugated effect of aromatic rings for red emission, four novel [3+2+1] coordinated iridium (III) emissive materials have been rationally designed and synthesized. The monodentate ligands of -CN and -OCN have been effectively employed to tune the deep-red emission of 628-675 nm with high photoluminescence quantum yields up to 98%. Moreover, all devices displayed deep-red color coordinates ranging from (0.675, 0.325) to (0.716, 0.284), which is close to the standard-red color coordinates of (0.708, 0.292), as recommended by International Telecommunication Union Radiocommunication (ITU-R) BT.2020. The device based on nBuIr(dbpz)CN with an exciplex cohost has exhibited maximum external quantum efficiencies of 20.7% and good stability. With nBuIr(dbpz)CN as an effective sensitizer, the nBuIr(dbpz)OCN based phosphorescent OLED devices have successfully demonstrated cascading energy transfer processes, contributing to pure red emission with maximum luminance as high as 6471 cd m-2. Therefore, this work has been successfully demonstrated rational molecular design strategy of [3+2+1] iridium complexes to obtain highly efficient deep-red electrophosphorescent emission.

Proteostatic tuning underpins the evolution of novel multicellular traits.

The evolution of multicellularity paved the way for the origin of complex life on Earth, but little is known about the mechanistic basis of early multicellular evolution. Here, we examine the molecular basis of multicellular adaptation in the Multicellularity Long Term Evolution Experiment (MuLTEE). We demonstrate that cellular elongation, a key adaptation underpinning increased biophysical toughness and organismal size, is convergently driven by downregulation of the chaperone Hsp90. Mechanistically, Hsp90-mediated morphogenesis operates by destabilizing the cyclin-dependent kinase Cdc28, resulting in delayed mitosis and prolonged polarized growth. Reinstatement of Hsp90 or Cdc28 expression resulted in shortened cells that formed smaller groups with reduced multicellular fitness. Together, our results show how ancient protein folding systems can be tuned to drive rapid evolution at a new level of biological individuality by revealing novel developmental phenotypes.

Enhanced Horizontal Dipole Orientation by Novel Penta-Helicene Anthracene-Based Host for Efficient Blue Fluorescent OLEDs.

Due to the relatively low photoluminescence quantum yield (PLQY) and horizontal dipole orientation of doped films, anthracene-based fluorescent organic light-emitting diodes (F-OLEDs) have faced a great challenge to achieve high external quantum efficiency (EQE). Herein, a novel approach is introduced by incorporating penta-helicene into anthracene, presented as linear-shaped 3-(4-(10-phenylanthracen-9-yl)phenyl)dibenzo[c,g]phenanthrene (BABH) and 3-(4-(10-(naphthalen-2-yl)anthracen-9-yl)phenyl)dibenzo[c,g]phenanthrene (NABH). These blue hosts exhibit minimal intermolecular overlap of π-π stacking, effectively suppressing excimer formation, which facilitates the effective transfer of singlet energy to the fluorescent dopant for PLQY as high as 90%. Additionally, the as-obtained two hosts of BABH and NABH have effectively demonstrated major horizontal components transition dipole moments (TDM) and high thermal stability with glass transitional temperature (Tg) surpassing 188 °C, enhancing the horizontal dipole orientation of their doped films to be 89% and 93%, respectively. The OLEDs based on BABH and NABH exhibit excellent EQE of 10.5% and 12.4% at 462 nm and device lifetime up to 90% of the initial luminance over 4500 h at 100 cd m-2, which has firmly established them as among the most efficient blue F-OLEDs based on anthracene to date to the best knowledge. This work provides an instructive strategy to design an effective host for highly efficient and stable F-OLEDs.

Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis.

BACKGROUND: Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with the initiation and progression of Triple-negative breast cancer (TNBC). The publicly available TCGA database of breast cancer data was used to analyze the OTUD deubiquitinating family members that were correlated with survival of breast cancer and ovarian tumor domain-containing 2 (OTUD-2), or YOD1 was identified. The aim of present study was to assess YOD1 expression and function in human TNBC and then explored the underlying molecular events. METHODS: We detected the expression of YOD1 in 32 TNBC and 44 NTNBC samples by qRT-PCR, Western blot and immunohistochemistry. Manipulation of YOD1 expression was assessed in vitro and in vivo for TNBC cell proliferation, migration, invasion, cell-cycle and drug resistance, using colony formation assay, transwell assay, CCK8 assay, TUNEL assay, flow cytometric analysis and xenograft tumor assay. Next, proteomic analysis, Western blot, proximity ligation assay, Immunoprecipitation, and Immunofluorescence were conducted to assess downstream targets. RESULTS: It was found that YOD1 was significantly upregulated in TNBC tissues compared with non-triple-negative breast cancer (NTNBC), which was positively correlated with poor survival in TNBC patients. Knockdown of YOD1 effectively inhibited TNBC cell migration, proliferation, cell cycle and resistance to cisplatin and paclitaxel. Mechanistically, YOD1 promoted TNBC progression in a manner dependent on its catalytic activity through binding with CDK1, leading to de-polyubiquitylation of CDK1 and upregulation of CDK1 expression. In addition, YOD1 overexpression was found to be correlated with CDK1 overexpression in human TNBC specimens. Finally, in vivo study demonstrated that YOD1 knockdown or YOD1 inhibitor could inhibit CDK1 expression and suppress the growth and metastasis of TNBC tumors. CONCLUSION: Our study highlights that YOD1 functions as an oncogene in TNBC via binding to CDK1 and mediated its stability and oncogenic activity. Interfering with YOD1 expression or YOD1 inhibitor could suppress TNBC cells in vitro and in vivo, suggesting that YOD1 may prove to be a promising therapeutic target for TNBC.

New [3+2+1] Iridium Complexes as Effective Phosphorescent Sensitizers for Efficient Narrowband Saturated-Blue Hyper-OLEDs.

Two newly designed and synthesized [3+2+1] iridium complexes through introducing bulky trimethylsiliyl (TMS) groups are doped with a terminal emitter of v-DABNA to form an coincident overlapping spectra between the emission of these two phosphors and the absorption of v-DABNA, creating cascade resonant energy transfer for efficient triplet harvesting. To boost the color quality and efficiency, the fabricated hyper-OLEDs have been optimized to achieve a high external quantum efficiency of 31.06%, which has been among the highest efficiency results reported for phosphor sensitized saturated-blue hyper-OLEDs, and pure blue emission peak at 467 nm with the full width at half maxima (FWHM) as narrow as 18 nm and the CIEy values down to 0.097, satisfying the National Institute of Standards and Technology (NIST) requirement for saturated blue OLEDs display. Surprisingly, such hyper-OLEDs have obtained the converted lifetime (LT50 ) up to 4552 h at the brightness of 100 cd m-2 , demonstrating effective Förster resonance energy transfer (FRET) process. Therefore, employing these new bulky TMS substituent [3+2+1] iridium(III) complexes for effective sensitizers can greatly pave the way for further development of high efficiency and stable blue OLEDs in display and lighting applications.

Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity.

Aging is associated with progressive phenotypic changes. Virtually all cellular phenotypes are produced by proteins, and their structural alterations can lead to age-related diseases. However, we still lack comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contributions to age-related phenotypes. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry (LiP-MS). The results, compiled in online ProtAge catalog, unraveled age-related functional changes in regulators of translation, protein folding, and amino acid metabolism. Mechanistically, we found that folded glutamate synthase Glt1 polymerizes into supramolecular self-assemblies during aging, causing breakdown of cellular amino acid homeostasis. Inhibiting Glt1 polymerization by mutating the polymerization interface restored amino acid levels in aged cells, attenuated mitochondrial dysfunction, and led to lifespan extension. Altogether, this comprehensive map of protein structural changes enables identifying mechanisms of age-related phenotypes and offers opportunities for their reversal.

CircRNA-CIRH1A Promotes the Development of Osteosarcoma by Regulating PI3K/AKT and JAK2/STAT3 Signaling Pathways.

Osteogenic sarcoma (OS), one of the mesenchymal tumors with a high degree of malignancy, mainly occurs in the metaphysis of the long bones and around the knee joints in children and adolescents. The poor diagnosis in patients with OS can be attributed to the lack of early clinical symptoms, although the growth of tumor mass gradually results in severe pain and systemic symptoms. The mechanisms underlying the pathogenesis of OS are not fully understood. Thus, identifying early diagnostic biomarkers and novel targets involved in the progression of OS is of critical significance in the management of OS. CircRNA is a class of non-coding RNAs characterized by the close-loop structure and increased stability, which are implicated in the regulation of cell proliferation, differentiation, migration, and apoptosis. Moreover, circRNAs also play significant roles in aging and chronic disorders, such as cancer and cardiovascular diseases. Accordingly, we reported the upregulation of circRNA-CIRH1A in OS tissues and cell lines. Silencing circRNA-CIRH1A in OS cell lines (U2OS, HOS, Saos-2, and MG-63) could inhibit the cell proliferation, invasion, migration, and apoptosis, which was also validated in xenograft tumorigenesis mouse model. We further demonstrated that circRNA-CIRH1A sponged miR-1276, which subsequently disrupted the effect of miR-1276 on PI3K/AKT and JAK2/STAT3 signaling pathways. Together, our study revealed the oncogenic role of circRNA-CIRH1A in OS, and identified miR-1276/ PI3K-AKT and JAK2-STAT3 signaling axis as the key downstream mediators of circRNA-CIRH1A.

The early infection characterization of septic arthritis by Staphylococcus aureus after anterior cruciate ligament reconstruction in a novel rat model.

BACKGROUND: The present study aimed to explore the time of maximum bacterial load and main colonization knee site in bacterial infection process based on a novel rat model of septic arthritis (SA) after anterior cruciate ligament reconstruction (ACLR). METHODS: Ninety-five Wistar rats with unilateral ACLR, random enrolled into control surgery (CS) group; joint inject (JI) group; presoaking (PS) group, were injected with 30 µl sterile saline or 30 µl × 107 colony forming units/ml Staphylococcus aureus via the knee joint or graft with presoaked Staphylococcus aureus during ACLR, respectively. At 1, 4, 7, 11, and 14 days postoperatively, samples were harvested to evaluate progress of knee joint infection by postoperative body weight, body temperature, knee temperature, knee width, scales of tissue damage, serum inflammatory markers, microbiological counting, microcomputed tomography (Micro-CT), digital radiography, magnetic resonance imaging (MRI) examination, and scanning electron microscopy (SEM). RESULTS: No systemic infection was observed in all rats. Comparing with serum inflammatory markers, tissue scores of inflammatory reactions, bacterial counts in the CS group, these data were significantly elevated in the JI group and PS group. The bone mass around the bone tunnel was lower and the soft tissue of knee showed more obvious swelling on MRI in the infection groups than that in the CS group at 7 and 14 days postoperatively. Staphylococcus aureus clusters on the surface of screw and graft were observed in the infection group. The whole colony forming units of Staphylococcus aureus maintained a continuous upward trend peaking 7 and 11 days followed by a balanced curve in the infection groups. Bone and soft tissue were found to have more bacterial counts than graft and screws. CONCLUSION: This animal model effectively mimics the acute knee infection after ACLR. We found that the bacterial colonization exhibited the peak of acute infection between 7 and 11 days postoperatively, with the major bacteria loads found in the bone, soft tissue.