SperMD: the expression atlas of sperm maturation.

The impairment of sperm maturation is one of the major pathogenic factors in male subfertility, a serious medical and social problem affecting millions of global couples. Regrettably, the existing research on sperm maturation is slow, limited, and fragmented, largely attributable to the lack of a global molecular view. To fill the data gap, we newly established a database, namely the Sperm Maturation Database (SperMD, http://bio-add.org/SperMD ). SperMD integrates heterogeneous multi-omics data (170 transcriptomes, 91 proteomes, and five human metabolomes) to illustrate the transcriptional, translational, and metabolic manifestations during the entire lifespan of sperm maturation. These data involve almost all crucial scenarios related to sperm maturation, including the tissue components of the epididymal microenvironment, cell constituents of tissues, different pathological states, and so on. To the best of our knowledge, SperMD could be one of the limited repositories that provide focused and comprehensive information on sperm maturation. Easy-to-use web services are also implemented to enhance the experience of data retrieval and molecular comparison between humans and mice. Furthermore, the manuscript illustrates an example application demonstrated to systematically characterize novel gene functions in sperm maturation. Nevertheless, SperMD undertakes the endeavor to integrate the islanding omics data, offering a panoramic molecular view of how the spermatozoa gain full reproductive abilities. It will serve as a valuable resource for the systematic exploration of sperm maturation and for prioritizing the biomarkers and targets for precise diagnosis and therapy of male subfertility.

Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach.

Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.

ROS-induced oxidative stress is a major contributor to sperm cryoinjury.

STUDY QUESTION: What is the mechanism behind cryoinjury in human sperm, particularly concerning the interplay between reactive oxygen species (ROS) and autophagy, and how does it subsequently affect sperm fate? SUMMARY ANSWER: The freeze-thaw operation induces oxidative stress by generating abundant ROS, which impairs sperm motility and activates autophagy, ultimately guiding the sperm toward programmed cell death such as apoptosis and necrosis, as well as triggering premature capacitation. WHAT IS KNOWN ALREADY: Both ROS-induced oxidative stress and autophagy are thought to exert an influence on the quality of frozen-thawed sperm. STUDY DESIGN, SIZE, DURATION: Overall, 84 semen specimens were collected from young healthy fertile males, with careful quality evaluation. The specimens were split into three groups to investigate the ROS-induced cryoinjury: normal control without any treatment, sperm treated with 0.5 mM hydrogen peroxide (H2O2) for 1 h, and sperm thawed following cryopreservation. Samples from 48 individuals underwent computer-assisted human sperm analysis (CASA) to evaluate sperm quality in response to the treatments. Semen samples from three donors were analyzed for changes in the sperm proteome after H2O2 treatment, and another set of samples from three donors were analyzed for changes following the freeze-thaw process. The other 30 samples were used for fluorescence-staining and western blotting. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm motility parameters, including progressive motility (PR %) and total motility (PR + NP %), were evaluated using the CASA system on a minimum of 200 spermatozoa. The proteomic profiles were determined with label-free mass spectrometry (MS/MS) and protein identification was performed via ion search against the NCBI human database. Subsequently, comprehensive bioinformatics was applied to detect significant proteomic changes and functional enrichment. Fluorescence-staining and western blot analyses were also conducted to confirm the proteomic changes on selected key proteins. The ROS level was measured using 2',7'-dichlorodihydrofluorescein diacetate labeling and the abundance of bioactive mitochondria was determined by evaluating the inner mitochondrial membrane potential (MMP) level. Molecular behaviors of sequestosome-1 (p62 or SQSTM1) and microtubule-associated proteins 1A/1B light chain 3 (LC3) were monitored to evaluate the state of apoptosis in human sperm. Fluorescent probes oxazole yellow (YO-PRO-1) and propidium iodide (PI) were utilized to monitor programmed cell death, namely apoptosis and necrosis. Additionally, gradient concentrations of antioxidant coenzyme Q10 (CoQ10) were introduced to suppress ROS impacts on sperm. MAIN RESULTS AND THE ROLE OF CHANCE: The CASA analysis revealed a significant decrease in sperm motility for both the H2O2-treatment and freeze-thaw groups. Fluorescence staining showed that high ROS levels were produced in the treated sperm and the MMPs were largely reduced. The introduction of CoQ10 at concentrations of 20 and 30 µM resulted in a significant rescue of progressive motility (P < 0.05). The result suggested that excessive ROS could be the major cause of sperm motility impairment, likely by damaging mitochondrial energy generation. Autophagy was significantly activated in sperm when they were under oxidative stress, as evidenced by the upregulation of p62 and the increased conversion of LC3 as well as the upregulation of several autophagy-related proteins, such as charged multivesicular body protein 2a, mitochondrial import receptor subunit TOM22 homolog, and WD repeat domain phosphoinositide-interacting protein 2. Additionally, fluorescent staining indicated the occurrence of apoptosis and necrosis in both H2O2-treated sperm and post-thaw sperm. The cell death process can be suppressed when CoQ10 is introduced, which consolidates the view that ROS could be the major contributor to sperm cryoinjury. The freeze-thaw process could also initiate sperm premature capacitation, demonstrated by the prominent increase in tyrosine phosphorylated proteins, verified with anti-phosphotyrosine antibody and immunofluorescence assays. The upregulation of capacitation-related proteins, such as hyaluronidase 3 and Folate receptor alpha, supported this finding. LARGE SCALE DATA: The data underlying this article are available in the article and its online supplementary material. LIMITATIONS, REASONS FOR CAUTION: The semen samples were obtained exclusively from young, healthy, and fertile males with progressive motility exceeding 60%, which might overemphasize the positive effects while possibly neglecting the negative impacts of cryoinjury. Additionally, the H2O2 treatment conditions in this study may not precisely mimic the oxidative stress experienced by sperm after thawing from cryopreservation, potentially resulting in the omission of certain molecular alterations. WIDER IMPLICATIONS OF THE FINDINGS: This study provides substantial proteomic data for a comprehensive and deeper understanding of the impact of cryopreservation on sperm quality. It will facilitate the design of optimal protocols for utilizing cryopreserved sperm to improve applications, such as ART, and help resolve various adverse situations caused by chemotherapy, radiotherapy, and surgery. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Major Innovation Project of Research Institute of National Health Commission (#2022GJZD01-3) and the National Key R&D Program of China (#2018YFC1003600). All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Generation and characterization of nanobodies targeting human pepsinogens.

Human pepsinogens (mainly pepsinogen I and pepsinogen II) are the major inactive precursor forms of the digestive enzyme pepsin which play a crucial role in protein digestion. The levels and ratios of human pepsinogens have demonstrated potential as diagnostic biomarkers for gastrointestinal diseases, particularly gastric cancer. Nanobodies are promising tools for the treatment and diagnosis of diseases, owing to their unique recognition properties. In this study, recombinant human pepsinogens proteins were expressed and purified as immunized antigens. We constructed a VHH phage library and identified several nanobodies via phage display bio-panning. We determined the binding potency and cross-reactivity of these nanobodies. Our study provides technical support for developing immunodiagnostic reagents targeting human pepsinogens.

Pectate lyase genes from Radopholus similis and their application in pathotype identification.

Radopholus similis is a destructive, migratory, and endophytoparasitic nematode. It has two morphologically indistinguishable pathotypes (or physiological races): banana and citrus pathotypes. At present, the only reliable method to differentiate the two pathotypes is testing the infestation and parasitism of nematodes on Citrus spp. via inoculation. However, differences in inoculation methods and conditions adopted by different researchers complicate obtaining consistent results. In this study, the parasitism and pathogenicity of 10 R. similis populations on rough lemon (Citrus limon) seedlings and the tropism and invasion of rough lemon roots were tested. It revealed that populations SWK, GJ, FZ, GZ, DBSR, and YJ were citrus pathotypes, which showed parasitism and pathogenicity on rough lemon and could invade rough lemon roots, whereas populations XIN, ML, HN6, and HL were banana pathotypes, having no parasitism and pathogenicity on rough lemon and they did not invade the rough lemon roots. Four pectate lyase genes (Rs-pel-2, Rs-pel-3, Rs-pel-4, and Rs-pel-5) belonging to the Class III family from these populations were amplified and analysed. The gene Rs-pel-3 could be amplified from six citrus pathotype populations and was stably expressed in the four developmental stages of the nematode, whereas it could not be amplified from the four banana pathotypes. Rs-pel-3 expression may be related to the parasitism and pathogenicity of R. similis on rough lemon. Hence, it can be used as a molecular marker to distinguish between banana and citrus pathotypes and as a target gene for the molecular identification of these two pathotypes. KEY POINTS: • Four pectate lyase genes (Rs-pels) from Radopholus similis were cloned and analysed. • The expression of Rs-pels is different in two pathotypes of Radopholus similis. • A molecular identification method for two pathotypes of Radopholus similis using pectate lyase gene Rs-pel-3 as the target gene was established.

Mode-locked fiber laser based on a small-period long-period fiber grating inscribed by femtosecond laser.

We demonstrate stable mode-locked pulses in an erbium-doped fiber laser (EDFL) using a femtosecond laser-inscribed small-period long-period grating (SP-LPG). The SP-LPG has a period of 25 µm and a length of 2.5 mm. The polarization dependent loss (PDL) of the SP-LPG reaches 20 dB at the wavelength of 1556 nm and 25 dB at the wavelength of 1607 nm, which is sufficient to trigger the mode-locking mechanism. In addition, a mode-locked fiber laser (MLFL) based on the SP-LPG has been demonstrated to generate 1.58-ps pulses at 1577 nm with a bandwidth of 4 nm and a repetition rate of 1.54 MHz. The signal-to-noise ratio (SNR) of 50 dB shows the high stability of this system. This work indicates various potential applications of the SP-LPG in ultra-fast laser technologies due to its simple fabrication, compact structure, and high damage threshold.

AI in medical education: medical student perception, curriculum recommendations and design suggestions.

Medical AI has transformed modern medicine and created a new environment for future doctors. However, medical education has failed to keep pace with these advances, and it is essential to provide systematic education on medical AI to current medical undergraduate and postgraduate students. To address this issue, our study utilized the Unified Theory of Acceptance and Use of Technology model to identify key factors that influence the acceptance and intention to use medical AI. We collected data from 1,243 undergraduate and postgraduate students from 13 universities and 33 hospitals, and 54.3% reported prior experience using medical AI. Our findings indicated that medical postgraduate students have a higher level of awareness in using medical AI than undergraduate students. The intention to use medical AI is positively associated with factors such as performance expectancy, habit, hedonic motivation, and trust. Therefore, future medical education should prioritize promoting students' performance in training, and courses should be designed to be both easy to learn and engaging, ensuring that students are equipped with the necessary skills to succeed in their future medical careers.

Significance of tumor markers combined with neutrophil to lymphocyte ratio, D-dimer and T-lymphocyte in the diagnosis of colon cancer.

Objective: To analyze the value of combined detection of tumor markers, neutrophil to lymphocyte ratio (NLR), D-dimer and T lymphocyte in the diagnosis of colon cancer. Methods: This is a retrospective study. A total of 80 patients with colon cancer and 80 patients with benign colon mass admitted to Baoding NO.1 Central Hospital from June 10, 2021 to December 10, 2022 were divided into the study group and the control group. Further comparison was performed on the tumor markers, NLR, D-dimer and T-lymphocyte levels between the two groups, associated with the comparison of corresponding levels of colon cancer at different stages. In addition, correlation analysis was carried out focusing on the above indicators with colon cancer. Results: Carcinoembryonic antigen (CEA), CA199, NLR, D-dimer and CD8+ cell count levels in the study group were significantly higher than those in the control group, while CD4+ cell count and CD4+/CD8+ ratio were obviously lower (P<0.05). Among I-IV colon cancer, the highest levels of CEA, CA199, NLR, D-dimer, CD4+ and CD4+/CD8+ ratio were found in patients with Stage-IV colon cancer, while the level of CD8+ was the lowest (P<0.05). Correlation analysis indicated that CEA, CA199, NLR, D-dimer and CD8+ were positively correlated with whether the patient had colon cancer (r=0.841, 747,991,889,565, all P<0.05), but negative correlations with CD4+ and CD4+/CD8+ ratio (r=-0.999, -0.994, all P<0.05). Conclusion: The detection of tumor markers combined with NLR, D-dimer and T-lymphocytes has reference value in the diagnosis of colon cancer.

Generation of different mode-locked states in a Yb-doped fiber laser based on nonlinear multimode interference.

We demonstrated an ultrafast Yb-doped fiber laser with a single mode fiber-graded index multimode fiber-single mode fiber (SMF-GIMF-SMF) structure based saturable absorber. The GIMF was placed in the groove of an in-line fiber polarization controller to adjust its birefringence, enabling the SMF-GIMF-SMF structure to realize efficient saturable absorption based on nonlinear multimode interference without strict length restriction. By adjusting two intra-cavity polarization controllers, stable dissipation solitons and noise-like pulses were achieved in the 1030 nm waveband with pulse durations of 10.67 ps and 276 fs, respectively. We also realized Q-switched mode-locked pulses in the same fiber laser cavity. By the dispersive Fourier transform method, the real-time spectral evolution in the buildup process of the Q-switched mode-locked state was captured, which showed that the continuous-wave in this laser could gradually evolved into the stable Q-switched mode-locked pulses through unstable self-pulsation, relaxation oscillation and rogue Q-switching stage. To the best of our knowledge, our work reveals the buildup dynamics of the Q-switched mode-locked operation in a fiber laser for the first time. And we also studied the real-time spectral evolution of the stable Q-switched mode-locked pulses, which exhibited periodic breathing property.

Presence of Tertiary Lymphoid Organ in Nasal Inverted Papilloma Is Correlated with Eosinophil Infiltration and Local Immunoglobulin Production.

INTRODUCTION: Nasal inverted papilloma (NIP) is a benign tumour with multiple inflammatory cell infiltration. Tertiary lymphoid organs (TLOs) support local antibody production and play important roles in airway inflammation. However, the evidence of TLOs and local immunoglobulins in NIP has not been reported yet. We investigated the presence of TLOs and immunoglobulins in NIP tissues and their association with the clinical-pathological characteristics of NIPs. METHODS: We analyzed the occurrence and composition of TLOs and local immunoglobulins by immunohistochemistry and evaluated the lymph organogenesis associated genes and cytokines by quantitative qPCR and Luminex assays, respectively, in papilloma tissues from 84 NIP cases. RESULTS: TLOs were present in 54% (45/84) of the NIP patients but not in control subjects. TLOs were composed of T cells, B cells, follicular dendritic cells, macrophages, and natural killer cells. Compared to NIP tissues without TLOs, tissues with TLOs showed significantly higher eosinophil infiltration levels (3.5-fold), elevation of lymphorganogenic genes (CXCL12, CXCL13, CCL20, CCL21, CD21L, and lymphotoxin alpha and beta), and increased Th17 (IL-21, IL-22, and GM-CSF) and Th2 (IL-5 and IL-13) cytokine production. Moreover, NIP with TLOs demonstrated a higher number of follicular T helper cells and immunoglobulin-producing plasma cells (CD138+ IgA+, CD138+ IgM+, CD138+ IgE+, and CD138+ IgG+) than those without TLOs, and these antibody-producing cells were positively correlated with the eosinophil number. CONCLUSION: The high frequency of TLOs and excess local immunoglobulin production are associated with an eosinophilic and Th2 skew microenvironment in the NIP mucosa, which would contribute to an important immunopathogenic response during NIP pathogenesis.

Local IL-17 positive T cells are functionally associated with neutrophil infiltration and their development is regulated by mucosal microenvironment in nasal polyps.

OBJECTIVE AND DESIGN: IL-17 plays essential roles in neutrophilic inflammation in the lower respiratory tract, however, the characteristics of local IL-17+ T cells in nasal inflammatory mucosa are not fully understood. We investigated the roles of IL-17+ T cells in regulating neutrophil infiltration and the effect of the mucosal microenvironment in modulating IL-17+ T cell differentiation in CRSwNP tissues. SUBJECTS: 47 polyp tissues from chronic rhinosinusitis with nasal polyps (CRSwNP) patients without corticosteroid therapy and 26 tissues from healthy mucosa were obtained. METHODS: Immunohistochemistry and flow cytometry were used to analyze the neutrophil infiltration, local IL-17+ T cell subsets, as well as cytokine producing profiles of IL-17+ T cell; tissue homogenates were used to study neutrophil migration and IL-17+ T cell differentiation. RESULTS: Increase of IL-17+ cells and IL-17+ T cell subsets was significant in polyp tissues versus controls, IL-17+ cell number was positively correlated with neutrophil infiltration; while homogenates from polyp tissues with high IL-17 promoted neutrophil migration in vitro. IL-17 response was found in polyp-derived T cells upon Staphylococcus aureus infection. IL-17+ T cells were also down-regulated in polyps from patients treated with glucocorticoid steroids, and exhibited poly-functionality patterns in polyp tissues. Finally, IL-17+ T cell differentiation could be induced by IL-23, and homogenates from polyps could enhance IL-17+ T cell development. CONCLUSIONS: This study determined a functional association of IL-17+ T cells with neutrophils in CRSwNP, and revealed that polyp microenvironment could promote IL-17+ T cell differentiation, suggesting a potential feedback role for IL-17+ T cell development and local neutrophilic inflammation.

Vancomycin-modified poly-l-lysine magnetic separation combined with multiplex polymerase chain reaction assay for efficient detection of Bacillus cereus in milk.

In this study, a new vancomycin (Van)-modified poly-l-lysine (PLL) magnetic bead (MB) technique was developed for isolation of gram-positive bacteria. The method combines magnetic separation with a multiplex PCR (mPCR) assay and gel electrophoresis for easy and rapid detection of Bacillus cereus. Vancomycin was used as a molecular ligand between the MB and the d-alanyl-d-alanine moieties on the cell wall surface of B. cereus. The PLL served as a flexible molecular tether between the MB and Van that reduced steric hindrance maintaining the biological activity of Van. The MB-PLL-Van capture nanoprobes exhibited excellent capture and isolation efficiency for B. cereus in spiked milk matrix samples without interference from the complex food matrix. The subsequent mPCR assay showed high specificity for the 4 target genes in B. cereus, the entFM, cesB, cer, and 16S rRNA genes, that were used to achieve efficient genotyping and detection. Under optimum conditions, the limit of detection reached 103 cfu/mL, with a dynamic range of detection at 103 to 107 cfu/mL in pure culture. Application of the MB-PLL-Van mediated mPCR assay for B. cereus in milk matrix samples achieved results similar to those of the pure culture. In addition, with a 6-h pre-enrichment of B. cereus that was spiked in milk matrix samples, the limit of detection reached 101 cfu/mL. The MB-PLL-Van mediated mPCR assay developed in this study could be used as a universal technology platform for the efficient enrichment and genotyping of gram-positive bacteria.

UiO-68-PT MOF-Based Sensor and Its Mixed Matrix Membrane for Detection of HClO in Water.

As an important type of reactive oxygen species (ROS), hypochloric acid (HClO) is closely linked with our daily life, and its convenient and rapid detection is very significant and imperative. Fluorescent and visual probes are being recognized as powerful and convenient tools for detection of ROS in the environment and living organisms by visualizing and imaging. In this contribution, a new metal-organic framework-based fluorescent probe UiO-68-PT, which was generated from a phenthiazine-decorated benzimidazole bridging dicarboxyl ligand and ZrCl4 under solvothermal conditions via in situ one-pot approach, is reported. The obtained UiO-68-PT features a unique HClO and Vitamin C-triggered reversible redox process, which is accompanied by both visual and fluorescence changes. Therefore, it can be a highly sensitive, specific, and reusable sensor to detect HClO species in water via both visual and fluorogenic observation (turn-on). Furthermore, its mixed membrane material (MMM) was fabricated by the combination of UiO-68-PT and poly(vinyl alcohol), and the obtained hydrophilic MMM can be used as a reversible colorimetric card for visual detection of the HClO in aqueous solution.

Chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis promote chemoresistance by activating the NF-κB pathway in breast cancer cells.

BACKGROUND: Chemotherapy is the primary established systemic treatment for patients with breast cancer, especially those with the triple-negative subtype. Simultaneously, the resistance of triple-negative breast cancer (TNBC) to chemotherapy remains a major clinical problem. Our previous study demonstrated that the expression levels of PTN and its receptor PTPRZ1 were upregulated in recurrent TNBC tissue after chemotherapy, and this increase was closely related to poor prognosis in those patients. However, the mechanism and function of chemotherapy-driven increases in PTN/PTPRZ1 expression are still unclear. METHODS: We compared the expression of PTN and PTPRZ1 between normal breast and cancer tissues as well as before and after chemotherapy in cancer tissue using the microarray analysis data from the GEPIA database and GEO database. The role of chemotherapy-driven increases in PTN/PTPRZ1 expression was examined with a CCK-8 assay, colony formation efficiency assay and apoptosis analysis with TNBC cells. The potential upstream pathways involved in the chemotherapy-driven increases in PTN/PTPRZ1 expression in TNBC cells were explored using microarray analysis, and the downstream mechanism was dissected with siRNA. RESULTS: We demonstrated that the expression of PTN and PTPRZ1 was upregulated by chemotherapy, and this change in expression decreased chemosensitivity by promoting tumour proliferation and inhibiting apoptosis. CDKN1A was the critical switch that regulated the expression of PTN/PTPRZ1 in TNBC cells receiving chemotherapy. We further demonstrated that the mechanism of chemoresistance by chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis depended on the NF-κB pathway. CONCLUSIONS: Our studies indicated that chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis play a critical role in chemoresistance, which suggests a novel strategy to enhance chemosensitivity in breast cancer cells, especially in those of the triple-negative subtype.

UiO-68-ol NMOF-Based Fluorescent Sensor for Selective Detection of HClO and Its Application in Bioimaging.

Fluorescent probes are powerful tools for the investigations of reactive oxygen species (ROS) in living organisms by visualization and imaging. As one of the most important of the natural reactive oxygen species (ROS), hypochlorous acid (HClO) plays a crucial role in various physiological and pathological processes. We report herein a new redox-switchable NMOF of UiO-68-ol via a direct ligand modification approach. The obtained UiO-68-ol NPs, which contains organic-based molecular redox switches, exhibit excellent photophysical properties for biological application and can be highly sensitive and selective fluorescent probes to detect HClO species in living cells.

[Corrigendum] All­trans retinoic acid alters the expression of the tight junction proteins Claudin­1 and ­4 and epidermal barrier function­associated genes in the epidermis.

Following the publication of the above article, the authors contacted the Editorial Office to explain that they had identified a pair of duplicate images in the control (Vehicle) group of mouse images in Fig. 1A on p. 1792. Specifically, the same image (corresponding correctly to the 'Day 5' experiment) was inadvertently chosen to represent the cutaneous manifestations of mice in the Vehicle group on 'Day 3' and 'Day 5' in Fig. 1A. This error arose as a consequence of repetitive application and duplication procedures within the image set, resulting in the inadvertent reuse of the same photo. Additionally, due to minimal alterations observed in the skin condition of mice from the control group following treatment, each mouse exhibited a similar appearance; this similarity further contributed to the delayed identification of this error during the paper revision stage. Consequently, this duplication of the same image was made as a result of insufficient scrutiny. The revised version of Fig. 1, showing the correct image for the 'Day 3' experiment in Fig. 1A, is shown on the next page. The authors can confirm that the error associated with the assembly of this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 1789­1805, 2019; DOI: 10.3892/ijmm.2019.4098].

Dickkopf-1 drives perineural invasion via PI3K-AKT signaling pathway in head and neck squamous cancer.

Perineural invasion (PNI) leads to the poor prognosis of head and neck squamous cancer (HNSCC) patients, but the mechanism of PNI remains unclear. Dickkopf-1 (DKK1), a secretory protein in the Wnt signaling pathway, was found indeed upregulated in HNSCC cells and tissues. Higher expression of DKK1 was statistically relevant to T stage, N stage, PNI, and poor prognosis of HNSCC. DKK1 overexpression enhanced the migration abilities of cancer cells. Moreover, DKK1-overexpressing cancer cells promoted cancer cells invasion of peripheral nerves in vitro and in vivo. Mechanistically, DKK1 could promote the PI3K-AKT signaling pathway. The migration abilities of neuroblastoma cells, which were enhanced by DKK1-overexpressing HNSCC cell lines, could be reversed by an inhibitor of Akt (MK2206). The association of DKK1 with PNI was also confirmed in HNSCC samples. Variables, including T stage, N stage, DKK1 expression, and PNI, were used to establish a nomogram to predict the survival probability and disease-free probability at 3 and 5 years. In summary, DKK1 can promote the PI3K-AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI.

Synergistic Brilliance: Engineered Bacteria and Nanomedicine Unite in Cancer Therapy.

Engineered bacteria are widely used in cancer treatment because live facultative/obligate anaerobes can selectively proliferate at tumor sites and reach hypoxic regions, thereby causing nutritional competition, enhancing immune responses, and producing anticancer microbial agents in situ to suppress tumor growth. Despite the unique advantages of bacteria-based cancer biotherapy, the insufficient treatment efficiency limits its application in the complete ablation of malignant tumors. The combination of nanomedicine and engineered bacteria has attracted increasing attention owing to their striking synergistic effects in cancer treatment. Engineered bacteria that function as natural vehicles can effectively deliver nanomedicines to tumor sites. Moreover, bacteria provide an opportunity to enhance nanomedicines by modulating the TME and producing substrates to support nanomedicine-mediated anticancer reactions. Nanomedicine exhibits excellent optical, magnetic, acoustic, and catalytic properties, and plays an important role in promoting bacteria-mediated biotherapies. The synergistic anticancer effects of engineered bacteria and nanomedicines in cancer therapy are comprehensively summarized in this review. Attention is paid not only to the fabrication of nanobiohybrid composites, but also to the interpromotion mechanism between engineered bacteria and nanomedicine in cancer therapy. Additionally, recent advances in engineered bacteria-synergized multimodal cancer therapies are highlighted.

Aggregation-Induced Emission Photosensitizer-Engineered Anticancer Nanomedicine for Synergistic Chemo/Chemodynamic/Photodynamic Therapy.

Photodynamic therapy (PDT) with aggregation-induced emission (AIE) photosensitizers (PSs) is a promising therapeutic strategy to achieve better anticancer results. However, eradicating solid tumors completely by PDT alone can be difficult owing to the inherent drawbacks of this treatment, and the combination of PDT with other therapeutic modalities provides opportunities to achieve cooperative enhancement interactions among various treatments. Herein, this work presents the construction of a biocompatible nanocomposite, namely CaO2@DOX@ZIF@ASQ, featuring light-responsive reactive oxygen species (ROS) generation and tumor-targeting oxygen and hydrogen peroxide discharge, as well as controlled doxorubicin (DOX) and copper ion release, thus allowing the combined PDT/CT/CDT effect by AIE PS-enhanced PDT, DOX-based chemotherapy (CT), and copper-involved Fenton-like reaction-driven chemodynamic therapy (CDT). In vitro and in vivo studies verify that the generation of both ROS and O2 by this nanomedicine, stimulated by light, exhibits superior anticancer efficacy, alleviating tumor hypoxia and achieving synergistic PDT/CT/CDT therapeutic effect. This multifunctional nanomedicine remarkably suppresses the tumor growth with minimized systemic toxicity, providing a new strategy for constructing multimodal PDT/CT/CDT therapeutic systems to overcome hypoxia limitations, and potentially increase the antitumor efficacy at lower doses of PSs and chemotherapeutic drugs, thus minimizing potential toxicity to non-malignant tissues.

CytoSIP: an annotated structural atlas for interactions involving cytokines or cytokine receptors.

Therapeutic agents targeting cytokine-cytokine receptor (CK-CKR) interactions lead to the disruption in cellular signaling and are effective in treating many diseases including tumors. However, a lack of universal and quick access to annotated structural surface regions on CK/CKR has limited the progress of a structure-driven approach in developing targeted macromolecular drugs and precision medicine therapeutics. Herein we develop CytoSIP (Single nucleotide polymorphisms (SNPs), Interface, and Phenotype), a rich internet application based on a database of atomic interactions around hotspots in experimentally determined CK/CKR structural complexes. CytoSIP contains: (1) SNPs on CK/CKR; (2) interactions involving CK/CKR domains, including CK/CKR interfaces, oligomeric interfaces, epitopes, or other drug targeting surfaces; and (3) diseases and phenotypes associated with CK/CKR or SNPs. The database framework introduces a unique tri-level SIP data model to bridge genetic variants (atomic level) to disease phenotypes (organism level) using protein structure (complexes) as an underlying framework (molecule level). Customized screening tools are implemented to retrieve relevant CK/CKR subset, which reduces the time and resources needed to interrogate large datasets involving CK/CKR surface hotspots and associated pathologies. CytoSIP portal is publicly accessible at https://CytoSIP.biocloud.top , facilitating the panoramic investigation of the context-dependent crosstalk between CK/CKR and the development of targeted therapeutic agents.