Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

TIF1-γ Positive Dermatomyositis with Spontaneous Muscular Hematoma in the Context of Ovarian Cancer: A Novel Survival Case Report.

Background: Dermatomyositis (DM) represents a group of inflammatory myopathies, with TIF1-γ positive DM strongly associated with malignancies. Spontaneous muscular hematoma in DM patients is exceedingly rare and often prognosticates a severe clinical outcome, especially in the context of concurrent malignancy. Case Presentation: We describe a novel survival case of a patient with TIF1-γ positive DM and an underlying ovarian tumor who developed a spontaneous muscular hematoma. Despite the traditionally poor prognosis of these conditions, the patient survived through a comprehensive treatment regimen. This included targeted chemotherapy for ovarian cancer (Carboplatin and Paclitaxel), alongside corticosteroids, immunoglobulins, and immunosuppressants for DM, as well as component blood transfusions, coagulation correction therapy to control hematoma, and integrated management: nutritional support, lung function exercise, volume management. Results: The integrated treatment strategy stabilized the patient's condition and resolved the hematoma, a significant achievement given the usual high mortality rate of such complications. Conclusion: This case underscores the importance of a multidisciplinary approach in the early diagnosis and treatment of TIF1-γ positive DM with complex comorbidities, including spontaneous muscular hematoma and ovarian cancer. It highlights the potential for favorable outcomes with aggressive and coordinated treatment strategies.

Hierarchically Assembled Gigantic Fe/Co Cyanometallate Clusters Exhibiting Electron Transfer Behavior Above Room Temperature.

The construction of large and complex supramolecular architectures through self-assembly is at the forefront of contemporary coordination chemistry. Notwithstanding great success in various systems using anionic bridges (e.g., O2- or S2-) or organic ligands (e.g., pyridine or carboxylate ligands), the assembly of large cyanide-bridged clusters with increasing nuclearity remains a formidable synthetic challenge. In this study, it is achieved in preparing two heterometallic cyanometallate clusters with unprecedented complexity, [Fe20Co20] (1) and [Fe12Co15] (2), by creating the "flexibility" through a versatile ligand of bis((1H-imidazol-4-yl)methylene)hydrazine (H2L) and low-coordinate cobalt. Complex 1 features a super-square array of four cyanide-bridged [Fe4Co4] cube subunits as the corners that are interconnected by four additional [FeCo] units, resulting in a torus-shaped architecture. Complex 2 contains a lantern-like core-shell cluster with a triple-helix kernel of [Co3L3] enveloped by a [Fe12Co12] shell. The combined structure analysis and mass spectrometry study reveal a hierarchical assembly mechanism, which sheds new light on constructing cyanometallate nanoclusters with atomic precision. Moreover, complex 1 undergoes a thermally induced electron-transfer-coupled spin transition (ETCST) between the diamagnetic {FeII LS(µ-CN)CoIII LS} and paramagnetic {FeIII LS(µ-CN)CoII HS} configurations (LS = low spin, HS = high spin) above room temperature, representing the largest molecule displaying electron transfer and spin transition characteristic.

Mitochondrial DNA evidence reflects high genetic divergence of Amynthas aspergillum (Oligochaeta: Megascolecidae) in southern China.

Amynthas aspergillum (Perrier, 1872), a natural resource used in traditional Chinese medicine (Guang-dilong) with high economic value, is widely distributed in forests and farmland habitats in the hilly areas of southern China. To investigate the extent of genetic differentiation and diversity in A. aspergillum, a population genetic structure study was performed on 157 samples from 75 locations in southern China using the mitochondrial genes COI, COII, 12S rRNA, 16S rRNA, and NDI. The results indicated that A. aspergillum had a high level of genetic diversity, and variation within populations was the main source of the total variation. Six deeply divergent mitochondrial clades (I-VI) were detected using both phylogenetic tree and haplotype network analyses. This finding was supported by the high Kimura two-parameter genetic distance and the pairwise fixation index value obtained based on the COI gene. No significant phylogeographic structures were observed. The widespread geographic distribution of clades II, IV, and VI suggested a recent demographic expansion based on multiple analysis results. These results include a high level of Hd and low π, star-shaped haplotype network structures with a high number of less frequent haplotypes, significantly negative neutrality test values, and a unimodal mismatch distribution pattern. The divergence time estimates and reconstruction of the ancestral area revealed that A. aspergillum originated in Guangxi Province and underwent initial intraspecific diversification in the early Pliocene to generate clade I. Then, it gradually dispersed eastward and rapidly differentiated into clades II-V during the Pleistocene. The Yunnan-Guizhou Plateau and Nanling and Wuyi Mountains might act as geographical barriers for the spread of A. aspergillum to the west and north.

Three new species of the genus Amynthas (Oligochaeta: Megascolecidae) from Guangxi Zhuang Autonomous Region, China.

Three new earthworm species of the genus Amynthas Kinberg, 1867 were found in Guangxi Zhuang Autonomous Region, China: Amynthas huapingensis sp. nov., Amynthas retentus sp. nov. and Amynthas linguiensis sp. nov. Amynthas huapingensis sp. nov. belongs to Amynthas corticis-group characterized by having four pairs of spermathecal pores in 5/68/9; Amynthas retentus sp. nov., without spermathecal pores, belongs to Amynthas illotus-group; Amynthas huapingensis sp. nov. and Amynthas retentus sp. nov. have similar characteristics of male porophores medially surrounded by 23 genital papillae in a pulvinate pad within the male pore area. Amynthas linguiensis sp. nov. has variable spermathecal pores, three pairs in 6/78/9 or four pairs in 5/68/9. And its male pores each on the center of a large elliptical glandular porophore which extends from 1/4xvii to 1/4xix. The morphological comparison and COI gene data of these three new species and their similar species are given in this paper.

WP1066, a small molecule inhibitor of STAT3, chemosensitizes paclitaxel-resistant ovarian cancer cells to paclitaxel by simultaneously inhibiting the activity of STAT3 and the interaction of STAT3 with Stathmin.

Paclitaxel is widely used to treat cancer, however, drug resistance limits its clinical utility. STAT3 is constitutively activated in some cancers, and contributes to chemotherapy resistance. Currently, several STAT3 inhibitors including WP1066 are used in cancer clinical trials. However, whether WP1066 reverses paclitaxel resistance and the mechanismremains unknown. Here, we report that in contrast to paclitaxel-sensitive parental cells, the expressions of several pro-survival BCL2 family members such as BCL-2, BCL-XL and MCL-1 are higher in paclitaxel-resistant ovarian cancer cells. Meanwhile, STAT3 is constitutively activated while stathmin loses its activity in paclitaxel-resistant cells. Importantly, WP1066 amplifies the inhibition of cell proliferation, colony-forming ability and apoptosis of ovarian cancer cells induced by paclitaxel. Mechanistically, WP1066, on the one hand, interferes the STAT3/Stathmin interaction, causing unleash of STAT3/Stathmin from microtubule, thus destroying microtubule stability. This process results in reduction of Ac-α-tubulin, further causing MCL-1 reduction. On the other hand, WP1066 inhibits phosphorylation of STAT3 by JAK2, and blocks its nuclear translocation, therefore repressing the transcription of pro-survival targets such as BCL-2, BCL-XL and MCL-1. Finally, the two pathways jointly promote cell death. Our findings reveal a new mechanism wherein WP1066 reverses paclitaxel-resistance of ovarian cancer cells by dually inhibiting STAT3 activity and STAT3/Stathmin interaction, which may layfoundation for WP1066 combined with paclitaxel in treating paclitaxel-resistant ovarian cancer.

3 nm-wide Cyanometallate Fe-Co Tape Exhibiting Single-Chain Magnet Behavior.

Treatment of Co(OTf)2·6H2O, Li[(pzTp)FeIII(CN)3], and H3PMo12O40·nH2O in protic solvents afforded two structurally related Fe-Co cyanometallate complexes: [{(pzTp)Fe(CN)3}3Co3(MeOH)10][PMo12O40]·H2O·11MeOH (1, pzTp- = tetra(pyrazolyl)borate) and {[(pzTp)Fe(CN)3]4Co3(MeOH)5(H2O)3}n[HPMo12O40]n·3 nMeOH·6.5nH2O (2). Complex 1 consists of a cyanide-bridged hexanuclear [Fe3Co3] cage, characterized by the fused conjunction of two mutually perpendicular trigonal bipyramids (TBPs, [Fe2Co3] and [Co2Fe3]), while complex 2 showcases an intricate cyanide-bridged Fe-Co tape comprising a central chain backbone of vertex-sharing [Fe2Co3] TBPs alongside peripheral [Fe2Co2] squares. Complex 2 is among the widest one-dimensional coordination assemblies characterized by the single-crystal X-ray diffraction technique. Magnetic studies revealed that complex 2 behaved as a single chain magnet with an effective energy barrier (Ueff/kB) of 46.8 K. Our findings highlight the possibilities in the development of cyanometallate-POM hybrid materials with captivating magnetic properties.

The Role of the Dysregulated JNK Signaling Pathway in the Pathogenesis of Human Diseases and Its Potential Therapeutic Strategies: A Comprehensive Review.

JNK is named after c-Jun N-terminal kinase, as it is responsible for phosphorylating c-Jun. As a member of the mitogen-activated protein kinase (MAPK) family, JNK is also known as stress-activated kinase (SAPK) because it can be activated by extracellular stresses including growth factor, UV irradiation, and virus infection. Functionally, JNK regulates various cell behaviors such as cell differentiation, proliferation, survival, and metabolic reprogramming. Dysregulated JNK signaling contributes to several types of human diseases. Although the role of the JNK pathway in a single disease has been summarized in several previous publications, a comprehensive review of its role in multiple kinds of human diseases is missing. In this review, we begin by introducing the landmark discoveries, structures, tissue expression, and activation mechanisms of the JNK pathway. Next, we come to the focus of this work: a comprehensive summary of the role of the deregulated JNK pathway in multiple kinds of diseases. Beyond that, we also discuss the current strategies for targeting the JNK pathway for therapeutic intervention and summarize the application of JNK inhibitors as well as several challenges now faced. We expect that this review can provide a more comprehensive insight into the critical role of the JNK pathway in the pathogenesis of human diseases and hope that it also provides important clues for ameliorating disease conditions.

Glucose-Regulated Protein 78 Targeting ICG and DOX Loaded Hollow Fe3O4 Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy.

Purpose: Liver cancer is considered as the third leading cause of cancer-related deaths, with hepatocellular carcinoma (HCC) accounting for approximately 90% of liver cancers. Improving the treatment of HCC is a serious challenge today. The primary objective of this study was to construct SP94-Fe3O4@ICG&DOX nanoparticles and investigate their potential diagnosis and treatment effect benefits on HCC. Methods: Firstly, we synthesized and characterized SP94-Fe3O4@ICG&DOX nanoparticles and confirmed their in vitro release behavior, photothermal and photodynamic performance. Moreover, the in vivo imaging capability was also observed. Finally, the inhibitory effects on Hepa1-6 in vitro and in vivo were observed as well as biosafety. Results: SP94-Fe3O4@ICG&DOX nanoparticles have a size of ~22.1 nm, with an encapsulation efficiency of 45.2% for ICG and 42.7% for DOX, showing excellent in vivo MPI and fluorescence imaging capabilities for precise tumor localization, and synergistic photo-chemotherapy (pH- and thermal-sensitive drug release) against tumors under irradiation. With the assistance of a fluorescence molecular imaging system or MPI scanner, the location and contours of the tumor were clearly visible. Under a constant laser irradiation (808 nm, 0.6 W/cm2) and a set concentration (50 µg/mL), the temperature of the solution could rapidly increase to ~45 °C, which could effectively kill the tumor cells. It could be effectively uptaken by HCC cells and significantly inhibit their proliferation under the laser irradiation (100% inhibition rate for HCC tumors). And most importantly, our nanoparticles exhibited favorable biocompatibility with normal tissues and cells. Conclusion: This versatile agent can serve as an intelligent and promising nanoplatform that integrates multiple accurate diagnoses, precise positioning of cancer tissue, and effective coordination with synergistic tumor photodynamic therapy.

Exploring a prototype for cooperative structural phase transition in cobalt(II) spin crossover compounds.

The creation of magnetically switchable materials that concurrently incorporate spin crossover (SCO) and a structural phase transition (SPT) presents a significant challenge in materials science. In this study, we prepared four structurally related cobalt(II)-based SCO compounds: two one-dimensional (1D) chains of {[(enbzp)Co(µ-L)](ClO4)2·sol}n (L = bpee, sol = 2MeOH·H2O, 1; L = bpea, sol = none, 2; enbzp = N,N'-(ethane-1,2-diyl)bis(1-phenyl-1-(pyridin-2-yl)methanimine); bpee = 1,2-bis(4-pyridyl)ethylene; and bpea = 1,2-bis(4-pyridyl)ethane) and their discrete segments, [{(enbzp)Co}2(µ-L)](ClO4)4·2MeOH (L = bpee, 3; L = bpea, 4). In all of these complexes, each Co(II) center is equatorially chelated by the planar tetradentate ligand enbzp and connected to a chain or dinuclear structure through bpee or bpea ligands along its axial direction. All of the complexes, including their desolvated phases, displayed overall incomplete and gradual SCO properties. Interestingly, the desolvated phase of 1 exhibited an additional non-spin magnetic transition characterized by wide room-temperature hysteresis (>40 K), which was reversible and rate-dependent, showcasing the synergy between SCO and SPT manifested through slow kinetics. We discuss the possible reasons for the distinct features and our findings demonstrate that the combination of a rigid polymeric framework with flexible substituents holds promise for achieving synergy between SCO and SPT.

Cyanide-Bridged Rope-like Chains Based on Trigonal-Bipyramidal [Fe2Cu3] Subunits.

Extending a selected cyanometalate block into a higher dimensional framework continues to present intriguing challenges in the fields of chemistry and material science. Here, we prepared two rope-like chain compounds of {[(Tp*Me)Fe(CN)3]2Cu2X2(L)}·sol (1, X = Cl, L = (MeCN)0.5(H2O/MeOH)0.5, sol = 2MeCN·1.5H2O; 2, X = Br, L = MeOH, sol = 2MeCN·0.75H2O; Tp*Me = tris(3, 4, 5-trimethylpyrazole)borate) in which the cyanide-bridged trigonal-bipyramidal [Fe2Cu3] subunits were linked with the adjacent ones via two vertex Cu(II) centers, providing a new cyanometallate chain archetype. Direct current magnetic study revealed the presence of ferromagnetic couplings between Fe(III) and Cu(II) ions and uniaxial anisotropy due to a favorable alignment of the anisotropic tricyanoiron(III) units. Moreover, compound 1 exhibits single-chain magnet behavior with an appreciable energy barrier of 72 K, while 2 behaves as a metamagnet, likely caused by the subtle changes in the interchain interactions.

Abrogation of ATR function preferentially augments cisplatin-induced cytotoxicity in PTEN-deficient breast cancer cells.

Targeting replication stress response is currently emerging as new therapeutic strategy for cancer treatment, based on monotherapy and combination approaches. As a key sensor in response to DNA damage, ataxia telangiectasia and rad3-related (ATR) kinase has become a potential therapeutic target as tumor cells are to rely heavily on ATR for survival. The tumor suppressor phosphatase and tensin homolog (PTEN) plays a crucial role in maintaining chromosome integrity. Although ATR inhibition was recently confirmed to show a synergistic inhibitory effect in PTEN-deficient triple-negative breast cancer cells, the molecular mechanism needs to be further elucidated. Additionally, whether the PTEN-deficient breast cancer cells are more preferentially sensitized than PTEN-wild type breast cancer cells to cisplatin plus ATR inhibitor remains unanswered. We demonstrate PTEN dysfunction promotes the killing effect of ATR blockade through the use of RNA interference for PTEN and a highly selective ATR inhibitor VE-821, and certify that VE-821 (1.0 µmol/L) aggravates cytotoxicity of cisplatin on breast cancer cells, especially PTEN-null MDA-MB-468 cells which show more chemoresistance than PTEN-expressing MDA-MB-231 cells. The co-treatment with VE-821 and cisplatin significantly reduced cell viability and proliferative capacity compared with cisplatin mono-treatment (P < 0.05). The increased cytotoxic activity is tied to the enhanced poly (ADP-ribose) polymerase (PARP) cleavage and consequently cell death due to the decrease in phosphorylation levels of checkpoint kinases 1 and 2 (CHK1/2), the reduction of radiation sensitive 51 (RAD51) foci and the increase in phosphorylation of the histone variant H2AX (γ-H2AX) foci (P < 0.05) as well. Together, these findings suggest combination therapy of ATR inhibitor and cisplatin may offer a potential therapeutic strategy for breast tumors.

Molecular imaging-guided extracellular vesicle-based drug delivery for precise cancer management: Current status and future perspectives.

Extracellular vesicles (EVs), the mediators of intercellular communication, have attracted the attention of researchers for the important roles they play in cancer treatment. Compared with other inorganic nano-materials, EVs possess the advantages of higher biocompatibility, better physiochemical stability, easier surface modification, and excellent biosafety. They can be used as an advanced drug delivery system with an improved therapeutic index for various therapeutic agents. Engineered EV-based imaging and therapeutic agents (engineered EVs) have emerged as useful tools in targeted cancer diagnosis and therapy. Non-invasive tracing of engineered EVs contributes to a better evaluation of their functions in cancer progression, in vivo dynamic biodistribution, therapeutic response, and drug-loading efficiency. Recent advances in real-time molecular imaging (MI), and innovative EV labeling strategies have led to the development of novel tools that can evaluate the pharmacokinetics of engineered EVs in cancer management, which may accelerate further clinical translation of novel EV-based drug delivery platforms. Herein, we review the latest advances in EVs, their characteristics, and current examples of EV-based targeted drug delivery for cancer. Then, we discuss the prominent applications of MI for tracing both natural and engineered EVs. Finally, we discuss the current challenges and considerations of EVs in targeted cancer treatment and the limitations of different MI modalities. In the coming decades, EV-based therapeutic applications for cancer with improved drug loading and targeting abilities will be developed, and better anti-cancer effects of drug delivery nanoplatform will be achieved.

Anthryl-functionalized cyanide-bridged Fe/Co cubes.

Two anthryl-functionalized cyanide-bridged [Fe4Co4] cube complexes, [(pzTp)Fe(CN)3Co(TpEtOAn)]4[OTf]4·8MeCN·7Et2O (1) and [NEt4]3[(pzTp)Fe(CN)3Co(TpEtOAn)]4[OTf]7·5MeCN·2Et2O (2) (pzTp- = tetrapyrazolylborate, TpEtOAn = 2,2,2-tris-(pyrazol-1-yl)ethoxy(9-methyl-anthracene)), were synthesized and characterized. The crystallographic study revealed that the [Fe4Co4] cubes are arranged into a linear supramolecular chain through significant anthryl-anthryl π-π stacking interactions in complex 1, whereas a zigzag supramolecular 1D assembly is observed in 2. The magnetic measurements showed that both compounds exhibited incomplete transitions from the paramagnetic {FeIIILS(µ-CN)CoIIHS} state to the diamagnetic {FeIILS(µ-CN)CoIIILS} state at about 200 K. The luminescence measurement of 1 in solution revealed an enhancement of the emission upon dilution or addition of perfluoronaphthalene (PFN) molecules, which could be attributed to the suppression of the aggregation-caused quenching (ACQ) effect, suggesting possible aggregation of the cube units in the solution.

The protein phosphatase PC1 dephosphorylates and deactivates CatC to negatively regulate H2O2 homeostasis and salt tolerance in rice.

Catalase (CAT) is often phosphorylated and activated by protein kinases to maintain hydrogen peroxide (H2O2) homeostasis and protect cells against stresses, but whether and how CAT is switched off by protein phosphatases remains inconclusive. Here, we identified a manganese (Mn2+)-dependent protein phosphatase, which we named PHOSPHATASE OF CATALASE 1 (PC1), from rice (Oryza sativa L.) that negatively regulates salt and oxidative stress tolerance. PC1 specifically dephosphorylates CatC at Ser-9 to inhibit its tetramerization and thus activity in the peroxisome. PC1 overexpressing lines exhibited hypersensitivity to salt and oxidative stresses with a lower phospho-serine level of CATs. Phosphatase activity and seminal root growth assays indicated that PC1 promotes growth and plays a vital role during the transition from salt stress to normal growth conditions. Our findings demonstrate that PC1 acts as a molecular switch to dephosphorylate and deactivate CatC and negatively regulate H2O2 homeostasis and salt tolerance in rice. Moreover, knockout of PC1 not only improved H2O2-scavenging capacity and salt tolerance but also limited rice grain yield loss under salt stress conditions. Together, these results shed light on the mechanisms that switch off CAT and provide a strategy for breeding highly salt-tolerant rice.

Manipulating Electron-Transfer Events in [Fe4 Co4 ] Cubes via a Mixed-Ligand Approach: The Impact of Elastic Frustration.

The engineering of intermolecular interaction is challenging but critical for magnetically switchable molecules. Here, we prepared two cyanide-bridged [Fe4 Co4 ] cube complexes via the alkynyl- and alcohol-functionalized trispyrazoyl capping ligands. The alkynyl-functionalized complex 1 exhibited a thermally-induced incomplete metal-to-metal electron transfer (MMET) behaviour at around 220 K, while the mixed alkynyl/alcohol-functionalized cube of 2 showed a complete and abrupt MMET behaviour at 232 K. Remarkably, both compounds showed a long-lived photo-induced metastable state up to 200 K. The crystallographic study demonstrated that the incomplete transition of 1 was likely due to the possible elastic frustration originating from the competition between the anion-propagated elastic interactions and inter-cluster alkynyl-alkynyl & CH-alkynyl interactions, whereas the latter are eliminated in 2 as a result of the partial substitution by the alcohol-functionalized ligand. Additionally, the introduction of chemically distinguishable cobalt centers within the cube unit of 2 did not lead to a two-step but a one-step transition, possibly because of the strong ferroelastic intramolecular interaction through the cyanide bridges.

Using immunohistochemistry to classify the molecular subtypes of Paget's disease of the breast.

PURPOSE: To classify the molecular subtypes of Paget's disease of the breast, and then compare them with general breast cancer to get deeper understanding of this disease and offer better management of associate patients in clinical decisions. METHODS: We used immunohistochemistry to examine 42 cases of this disease by antibodies against estrogen and progesterone receptors, Ki-67, as well as human epidermal growth factor receptor 2 (HER-2). Due to damage and loss of specimens, etc., we obtained 36 pathological specimens from the 42 patients. For 30 of 36 pathological specimens (83.3%), we obtained a complete molecular subtype. Cause the other 6 pathological specimens have missing immunohistochemistry items. For patients with bilateral breast cancer, only information on the side with PDB is listed. For patients with recurrence, only information on the first onset was included. We finally compared and studied the molecular subtype of 26 samples. We calculated the relative frequencies of molecular subtypes including luminal A, luminal B, HER-2-enriched, and basal-like and compared them between PDB and general breast carcinomas in other studies. RESULTS: The luminal A and B subtype were found, respectively, in 3 (11.5%) and 6 (23.1%) of all patients, and 15 cases of HER-2-enriched subtype was detected (57.7%). In addition, 2 (7.7%) showed a basal-like subtype. CONCLUSION: The molecular subtypes of common breast cancer and PDB-associated breast cancer differ. Luminal subtypes are the most common in the former, while within our samples HER-2 positive subtype was the highest in PDB-associated breast carcinoma. With further understanding of this disease, rational therapies will be applied in different patients and cures for PDB and PDB-associated carcinoma will be achieved.

Applications and prospects of cryo-EM in drug discovery.

Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

Global Decrease in H3K9 Acetylation in Sorghum Seed Postgermination Stages.

Sorghum seed germination is accompanied by increases in nutrient contents and reduced levels of antinutrients and is therefore being applied to food processing. However, the characterization of acetylated histone H3 at lysine residue 9 (H3K9ac) in sorghum postgermination has lagged. In this study, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to identify H3K9ac enrichment and obtained transcriptome in postgermination stages. More than 10,000 hypoacetylated genes gained H3K9ac marks in the postgermination stages. In addition, we observed that the expression of the main histone deacetylase (HDAC) genes was elevated. The application of the HDAC inhibitor trichostatin A (TSA) resulted in seed growth arrest, suggesting that the repression of the H3K9ac modification is critical for postgermination. Additionally, we obtained a comprehensive view of abundant genomic changes in H3K9ac-marked regions and transcription between the mock and TSA treatment groups, which suggested that H3K9ac was required in the late stage of autotrophic seedling establishment. Metabolic profiling, transcriptome analyses, and ChIP-seq revealed that H3K9ac is enriched at genes involved in phenylpropanoid, including lignin and flavonoid, biosynthesis. Our results suggest important roles of H3K9ac in sorghum seed postgermination stages.

Fibronectin-targeting and metalloproteinase-activatable smart imaging probe for fluorescence imaging and image-guided surgery of breast cancer.

Residual lesions in the tumor bed have been a challenge for conventional white-light breast-conserving surgery. Meanwhile, lung micro-metastasis also requires improved detection methods. Intraoperative accurate identification and elimination of microscopic cancer can improve surgery prognosis. In this study, a smart fibronectin-targeting and metalloproteinase-activatable imaging probe CREKA-GK8-QC is developed. CREKA-GK8-QC possesses an average diameter of 21.7 ± 2.5 nm, excellent MMP-9 protein responsiveness and no obvious cytotoxicity. In vivo experiments demonstrate that NIR-I fluorescence imaging of CREKA-GK8-QC precisely detects orthotopic breast cancer and micro-metastatic lesions (nearly 1 mm) of lungs with excellent imaging contrast ratio and spatial resolution. More notably, fluorescence image-guided surgery facilitates complete resection and avoids residual lesions in the tumor bed, improving survival outcomes. We envision that our newly developed imaging probe shows superior capacity for specific and sensitive targeted imaging, as well as providing guidance for accurate surgical resection of breast cancer.