A step towards 6D WAXD tensor tomography.

X-ray scattering/diffraction tensor tomography techniques are promising methods to acquire the 3D texture information of heterogeneous biological tissues at micrometre resolution. However, the methods suffer from a long overall acquisition time due to multi-dimensional scanning across real and reciprocal space. Here, a new approach is introduced to obtain 3D reciprocal information of each illuminated scanning volume using mathematic modeling, which is equivalent to a physical scanning procedure for collecting the full reciprocal information required for voxel reconstruction. The virtual reciprocal scanning scheme was validated by a simulated 6D wide-angle X-ray diffraction tomography experiment. The theoretical validation of the method represents an important technological advancement for 6D diffraction tensor tomography and a crucial step towards pervasive applications in the characterization of heterogeneous materials.

Value of quantitative microsurface structure analysis for evaluating the invasion depth of type 0-II early gastric cancer.

Background and Aim: The microsurface structure reflects the degree of damage to the glands, which is related to the invasion depth of early gastric cancer. To evaluate the diagnostic value of quantitative microsurface structure analysis for estimating the invasion depth of early gastric cancer. Methods: White-light imaging and narrow-band imaging (NBI) endoscopy were used to visualize the lesions of the included patients. The area ratio and depth-predicting score (DPS) of each patient were calculated; meanwhile, each lesion was examined by endoscopic ultrasonography (EUS). Results: Ninety-three patients were included between 2016 and 2019. Microsurface structure is related to the histological differentiation and progression of early gastric cancer. The receiver operating characteristic curve showed that when an area ratio of 80.3% was used as a cut-off value for distinguishing mucosal (M) and submucosal (SM) type 0-II gastric cancers, the sensitivity, specificity, and accuracy were 82.9%, 80.2%, and 91.6%, respectively. The accuracies for distinguishing M/SM differentiated and undifferentiated early gastric cancers were 87.4% and 84.8%, respectively. The accuracy of EUS for distinguishing M/SM early gastric cancer was 74.9%. DPS can only distinguish M-SM1 (SM infiltration <500 µm)/SM (SM infiltration ≥500 µm) with an accuracy of 83.8%. The accuracy of using area ratio for distinguishing 0-II early gastric cancers was better than those of using DPS and EUS (P < 0.05). Conclusion: Quantitative analysis of microsurface structure can be performed to assess M/SM type 0-II gastric cancer and is expected to be effective for judging the invasion depth of gastric cancer.

Rapid Self-Assembly Mini-Livers Protect Mice Against Severe Hepatectomy-Induced Liver Failure.

The construction of bioartificial livers, such as liver organoids, offers significant promise for disease modeling, drug development, and regenerative medicine. However, existing methods for generating liver organoids have limitations, including lengthy and complex processes (taking 6-8 weeks or longer), safety concerns associated with pluripotency, limited functionality of pluripotent stem cell-derived hepatocytes, and small, highly variable sizes (typically ≈50-500 µm in diameter). Prolonged culture also leads to the formation of necrotic cores, further restricting size and function. In this study, a straightforward and time-efficient approach is developed for creating rapid self-assembly mini-livers (RSALs) within 12 h. Additionally, primary hepatocytes are significantly expanded in vitro for use as seeding cells. RSALs exhibit consistent larger sizes (5.5 mm in diameter), improved cell viability (99%), and enhanced liver functionality. Notably, RSALs are functionally vascularized within 2 weeks post-transplantation into the mesentery of mice. These authentic hepatocyte-based RSALs effectively protect mice from 90%-hepatectomy-induced liver failure, demonstrating the potential of bioartificial liver-based therapy.

Plasmonic Alloys Enhanced Metabolic Fingerprints for the Diagnosis of COPD and Exacerbations.

Accurate diagnosis of chronic obstructive pulmonary disease (COPD) and exacerbations by metabolic biomarkers enables individualized treatment. Advanced metabolic detection platforms rely on designed materials. Here, we design mesoporous PdPt alloys to characterize metabolic fingerprints for diagnosing COPD and exacerbations. As a result, the optimized PdPt alloys enable the acquisition of metabolic fingerprints within seconds, requiring only 0.5 µL of native plasma by laser desorption/ionization mass spectrometry owing to the enhanced electric field, photothermal conversion, and photocurrent response. Machine learning decodes metabolic profiles acquired from 431 individuals, achieving a precise diagnosis of COPD with an area under the curve (AUC) of 0.904 and an accurate distinction between stable COPD and acute exacerbations of COPD (AECOPD) with an AUC of 0.951. Notably, eight metabolic biomarkers identified accurately discriminate AECOPD from stable COPD while providing valuable information on disease progress. Our platform will offer an advanced nanoplatform for the management of COPD, complementing standard clinical techniques.

Advancements of 3D bioprinting in regenerative medicine: Exploring cell sources for organ fabrication.

3D bioprinting has unlocked new possibilities for generating complex and functional tissues and organs. However, one of the greatest challenges lies in selecting the appropriate seed cells for constructing fully functional 3D artificial organs. Currently, there are no cell sources available that can fulfill all requirements of 3D bioprinting technologies, and each cell source possesses unique characteristics suitable for specific applications. In this review, we explore the impact of different 3D bioprinting technologies and bioink materials on seed cells, providing a comprehensive overview of the current landscape of cell sources that have been used or hold potential in 3D bioprinting. We also summarized key points to guide the selection of seed cells for 3D bioprinting. Moreover, we offer insights into the prospects of seed cell sources in 3D bioprinted organs, highlighting their potential to revolutionize the fields of tissue engineering and regenerative medicine.

Prediction of Clinical Precision Chemotherapy by Patient-Derived 3D Bioprinting Models of Colorectal Cancer and Its Liver Metastases.

Methods accurately predicting the responses of colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) to personalized chemotherapy remain limited due to tumor heterogeneity. This study introduces an innovative patient-derived CRC and CRLM tumor model for preclinical investigation, utilizing 3d-bioprinting (3DP) technology. Efficient construction of homogeneous in vitro 3D models of CRC/CRLM is achieved through the application of patient-derived primary tumor cells and 3D bioprinting with bioink. Genomic and histological analyses affirm that the CRC/CRLM 3DP tumor models effectively retain parental tumor biomarkers and mutation profiles. In vitro tests evaluating chemotherapeutic drug sensitivities reveal substantial tumor heterogeneity in chemotherapy responses within the 3DP CRC/CRLM models. Furthermore, a robust correlation is evident between the drug response in the CRLM 3DP model and the clinical outcomes of neoadjuvant chemotherapy. These findings imply a significant potential for the application of patient-derived 3DP cancer models in precision chemotherapy prediction and preclinical research for CRC/CRLM.

Conjugated Phosphonic Acids Enable Robust Hole Transport Layers for Efficient and Intrinsically Stable Perovskite Solar Cells.

High efficiency and long-term stability are the prerequisites for the commercialization of perovskite solar cells (PSCs). However, inadequate and non-uniform doping of hole transport layers (HTLs) still limits the efficiency improvements, while the intrinsic instability of HTLs caused by ion migration and accumulation is difficult to be addressed by external encapsulation. Here it is shown that the addition of a conjugated phosphonic acid (CPA) to the Spiro-OMeTAD benchmark HTL can greatly enhance the device efficiency and intrinsic stability. Featuring an optimal diprotic-acid structure, indolo(3,2-b)carbazole-5,11-diylbis(butane-4,1-diyl) bis(phosphonic acid) (BCZ) is developed to promote morphological uniformity and mitigate ion migration across both perovskite/HTL and HTL/Ag interfaces, leading to superior charge conductivity, reinforced ion immobilization, and remarkable film stability. The dramatically improved interfacial charge collection endows BCZ-based n-i-p PSCs with a champion power conversion efficiency of 24.51%. More encouragingly, the BCZ-based devices demonstrate remarkable stability under harsh environmental conditions by retaining 90% of initial efficiency after 3000 h in air storage. This work paves the way for further developing robust organic HTLs for optoelectronic devices.

Gas Sensor Array Fault Diagnosis Based on Multi-Dimensional Fusion, an Attention Mechanism, and Multi-Task Learning.

With the development of gas sensor arrays and computational technology, machine olfactory systems have been widely used in environmental monitoring, medical diagnosis, and other fields. The reliable and stable operation of gas sensing systems depends heavily on the accuracy of the sensors outputs. Therefore, the realization of accurate gas sensor array fault diagnosis is essential to monitor the working status of sensor arrays and ensure the normal operation of the whole system. The existing methods extract features from a single dimension and require the separate training of models for multiple diagnosis tasks, which limits diagnostic accuracy and efficiency. To address these limitations, for this study, a novel fault diagnosis network based on multi-dimensional feature fusion, an attention mechanism, and multi-task learning, MAM-Net, was developed and applied to gas sensor arrays. First, feature fusion models were applied to extract deep and comprehensive features from the original data in multiple dimensions. A residual network equipped with convolutional block attention modules and a Bi-LSTM network were designed for two-dimensional and one-dimensional signals to capture spatial and temporal features simultaneously. Subsequently, a concatenation layer was constructed using feature stitching to integrate the fault details of different dimensions and avoid ignoring useful information. Finally, a multi-task learning module was designed for the parallel learning of the sensor fault diagnosis to effectively improve the diagnosis capability. The experimental results derived from using the proposed framework on gas sensor datasets across different amounts of data, balanced and unbalanced datasets, and different experimental settings show that the proposed framework outperforms the other available methods and demonstrates good recognition accuracy and robustness.

Structures of sperm flagellar doublet microtubules expand the genetic spectrum of male infertility.

Sperm motility is crucial for successful fertilization. Highly decorated doublet microtubules (DMTs) form the sperm tail skeleton, which propels the movement of spermatozoa. Using cryo-electron microscopy (cryo-EM) and artificial intelligence (AI)-based modeling, we determined the structures of mouse and human sperm DMTs and built an atomic model of the 48-nm repeat of the mouse sperm DMT. Our analysis revealed 47 DMT-associated proteins, including 45 microtubule inner proteins (MIPs). We identified 10 sperm-specific MIPs, including seven classes of Tektin5 in the lumen of the A tubule and FAM166 family members that bind the intra-tubulin interfaces. Interestingly, the human sperm DMT lacks some MIPs compared with the mouse sperm DMT. We also discovered variants in 10 distinct MIPs associated with a subtype of asthenozoospermia characterized by impaired sperm motility without evident morphological abnormalities. Our study highlights the conservation and tissue/species specificity of DMTs and expands the genetic spectrum of male infertility.

Tumor microenvironment-responsive spherical nucleic acid nanoparticles for enhanced chemo-immunotherapy.

Certain chemotherapeutics can induce tumor cells' immunogenic cell death (ICD), release tumor antigens, and thereby trigger personalized antitumor immune responses. Co-delivery of adjuvants using nanocarriers could amplify the ICD-induced tumor-specific immunity achieving a synergistic chemo-immunotherapeutic effect. However, complicated preparation, low drug loading efficiency, and potential carrier-associated toxicity are the major challenges that limited its clinical applications. Herein, a carrier-free core-shell nanoparticle (MPLA-CpG-sMMP9-DOX, MCMD NPs) was constructed by facile self-assembly of spherical nucleic acids (SNA) with two adjuvants of CpG ODN and monophosphoryl lipid A (MPLA) as a core and doxorubicin (DOX) radially around the dual-adjuvants SNA as a shell. The results demonstrated that MCMD NPs could enhance drugs accumulation in tumors, and release DOX upon enzymatic degradation of matrix metalloproteinase-9 (MMP-9) peptide in the tumor microenvironment (TME), which enhanced the direct-killing effect of DOX on tumor cells. The core of MPLA-CpG SNA efficiently boosted the ICD-induced antitumor immune response to further attack tumor cells. Thus, MCMD NPs achieved a synergistic therapeutic effect of chemo-immunotherapy with reduced off-target toxicity. This study provided an efficient strategy for the development of a carrier-free nano-delivery system for enhanced cancer chemo-immunotherapy.

PIM1 promotes hepatic conversion by suppressing reprogramming-induced ferroptosis and cell cycle arrest.

Protein kinase-mediated phosphorylation plays a critical role in many biological processes. However, the identification of key regulatory kinases is still a great challenge. Here, we develop a trans-omics-based method, central kinase inference, to predict potentially key kinases by integrating quantitative transcriptomic and phosphoproteomic data. Using known kinases associated with anti-cancer drug resistance, the accuracy of our method denoted by the area under the curve is 5.2% to 29.5% higher than Kinase-Substrate Enrichment Analysis. We further use this method to analyze trans-omic data in hepatocyte maturation and hepatic reprogramming of human dermal fibroblasts, uncovering 5 kinases as regulators in the two processes. Further experiments reveal that a serine/threonine kinase, PIM1, promotes hepatic conversion and protects human dermal fibroblasts from reprogramming-induced ferroptosis and cell cycle arrest. This study not only reveals new regulatory kinases, but also provides a helpful method that might be extended to predict central kinases involved in other biological processes.

Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis.

Acute liver failure (ALF) is a severe clinical syndrome characterized by massive death of hepatocytes in a short time, resulting in coagulopathy and hepatic encephalopathy, with a high mortality in patients without pre-existing liver disease. Effective treatment of ALF is currently limited to liver transplantation, highlighting the need for new target therapies. Here, we found that expression of hepatic tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor tumor necrosis factor receptor superfamily member 12A (Tnfrsf12a) were significantly increased during ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Inhibition of TWEAK/Tnfrsf12a axis markedly attenuated TAA or APAP-induced ALF. Moreover, our results demonstrated that TWEAK/Tnfrsf12a axis induced receptor-interacting protein kinase 1 (RIPK1)-dependent apoptosis of hepatocytes, instead of necroptosis or pyroptosis. Notably, hepatic TNFRSF12A and TWEAK levels were also significantly increased in liver biopsies from ALF patients. In summary, our results demonstrate that during ALF, TWEAK/Tnfrsf12a axis activates RIPK1 in hepatocytes, leading to RIPK1-dependent apoptosis and subsequent liver injury. Therefore, inhibition of either TWEAK/Tnfrsf12a axis or RIPK1-dependent apoptosis attenuates liver injury, providing a new potential therapeutic target for the treatment of ALF.

Snare-assisted flexible endoscope in trans-gastric endoscopic gallbladder-preserving surgery: A pilot animal study.

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) gallbladder-preserving surgery by flexible endoscopy is an emerging technology. However, the gallbladder fails to obtain traction and positioning functions during the operation. AIM: To evaluate the feasibility and safety of a new surgical method, "snare-assisted pure NOTES gallbladder-preserving surgery". METHODS: Eight miniature pigs were randomly divided into the experimental group [NOTES gallbladder-preserving surgery using the snare device, snare assisted (SA)] and the control group (NOTES gallbladder-preserving surgery without using the snare device, NC), with four cases in each group. The differences between the two groups of animals in operating time, operating workload, complications, adverse events, white blood cells, and liver function were determined. RESULTS: No differences were found in the surgical success rate, gallbladder incision closure, white blood cell count, or liver function between the two groups. The total operating time, gallbladder incision blood loss, gallbladder disorientation time, gallbladder incision closure time, and workload scores on the National Aeronautics and Space Administration-Task Load Index were significantly reduced in the SA group (P < 0.05). CONCLUSION: These results indicated that snare-assisted pure NOTES gallbladder-preservation surgery using standard endoscopic instruments reduced the difficulty of operation, shortened operation time, and did not increase complications in pigs. A new method for pure NOTES gallbladder-preservation surgery was provided.

Evaluating an external quality assurance program for semen analysis in China during 2009-2020.

INTRODUCTION: Semen analysis (SA) plays a key role in guiding treatments of male reproductive diseases and infertility due to male factors; however, it remains challenging to conduct an accurate SA due to lack of standardization, highly subjective assessments, and problems with automated procedures. Therefore, quality assurance (QA) and teaching courses are essential for making the laboratory results more consistent. MATERIALS AND METHODS: The external quality assurance (EQA) scheme was organized by national human sperm bank technology training bases in Guangdong province in China between 2009 and 2020. Until 2020, 124 laboratories from China participated in the EQA program. The EQA scheme per year has been organized involving two semen aliquots for sperm concentration, two video recordings for motility, and two smears for sperm morphology. All samples used in the EQA scheme were obtained from different healthy donors or patients. RESULTS: We estimated that the median coefficient of variation (CV) of sperm concentration, ignoring the method used, was 26.6%. Using a 100 µm deep counting chamber led to a decreasing CV of 13.6%. For sperm motility, the median CV of nonprogressive motility was high (50.8%), but the CV of progressive motility (13.2%), immotile sperm (14.3%), and total motility (11.8%) were acceptable. The morphology assessment revealed large variability (44.4%) irrespective of the classification criteria. DISCUSSION: The reduction of interlaboratory variability is still a challenge during SA in China. Therefore, it is critical to increase awareness of joining EQA schemes and establish standardized training centers to follow WHO-recommended procedures toward Chinese standards.

Doxorubicin and CpG loaded liposomal spherical nucleic acid for enhanced Cancer treatment.

Chemotherapeutics that can trigger immunogenic cell death (ICD) and release tumor-specific antigens are effective on treating a variety of cancers. The codelivery of chemotherapeutics with adjuvants is a promising strategy to achieve synergistic therapeutic effect. However, low drug loading and complicated preparation of current delivery systems lead to carrier-associated toxicity and immunogenicity. Herein, we developed a facile approach to construct liposomal spherical nucleic acids (SNA) by the self-assembly of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-doxorubicin conjugate and DOPE-matrix metalloproteinases-9 (MMP-9) responsive peptide-CpG conjugate (DOPE-MMP-CpG). Liposomal SNAs efficiently co-delivered DOX and CpG into tumors and released the two drugs upon biological stimuli of MMP-9 enzyme in tumor microenvironment (TME) and high concentration of endogenous glutathione in tumor cells. We demonstrated that liposomal SNA enhanced activation of dendritic cells (DCs), promoted expansion of CD8+ and CD4+ T cells in both tumors and spleen, inhibited tumor growth, and extended animal survival. This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors with synergistic therapeutic effect and reduced side effect.

Tripronuclear Zygotes in IVF Laboratory Quality Control: Experimental Evaluation and Potential Applications.

This study set out to evaluate quality control within a new in vitro fertilization (IVF) laboratory environment and of new incubators based on the culture results of tripronuclear zygotes. The representative environmental indicators within new and old IVF laboratories were monitored, and tripronuclear zygotes were cultured in the two laboratories; the results were analyzed and compared. Subsequently, tripronuclear (3PN) zygotes were cultured in both new and old incubators and the culture results were compared. No differences were found in embryo development between 3PN zygotes in the old and new laboratories. However, in the quality control test, the degeneration rate and developmental arrest rate in the new incubator early phase group were significantly increased when compared with the old incubators. Moreover, the grade I embryo rate also decreased significantly. Nevertheless, all the above comparisons in the new incubator later phase group showed no statistical significance as compared to those observed in old incubators. Tripronuclear zygotes are sensitive to the environment in IVF laboratories and can be considered useful during quality control trials of new IVF laboratories and new equipment including incubators.

The effect of age and abstinence time on semen quality: a retrospective study.

This study analyzed the effects of male age and abstinence time on semen quality and explored the best abstinence time for Chinese males among different age groups. Semen parameters, including sperm kinetics, morphology, and DNA fragmentation index (DFI), were reviewed from 2952 men. Samples were divided into six age groups (≤25 years, 26-30 years, 31-35 years, 36-40 years, 41-45 years, and >45 years) and were divided into six groups according to different abstinence time (2 days, 3 days, 4 days, 5 days, 6 days, and 7 days). The differences in semen quality between the groups were compared, and the effect of age and abstinence time on semen quality was analyzed. Significant differences were observed in semen volume, progressive motility (PR), and DFI among the age groups (all P < 0.05), and no significant differences were observed in sperm morphological parameters (all P > 0.05). There were significant differences in semen volume, PR, and DFI among different abstinence time groups (all P < 0.05) and no significant differences in sperm morphological parameters (all P > 0.05). Pearson analysis showed that male age and abstinence time were both significantly correlated with sperm kinetics and DFI (both P < 0.05), while no significant correlation was found with sperm morphological parameters (all P > 0.05). The box plots and histograms of men's age, abstinence time, and semen quality show that most semen quality parameters differ significantly between the 2 days and 7 days abstinence groups and other groups at different ages. Except for the sperm morphology parameters, sperm kinetic parameters and sperm DFI are linearly related to male age and abstinence time.

Identification of Three Potential circRNA Biomarkers of Polycystic Ovary Syndrome by Bioinformatics Analysis and Validation.

OBJECTIVE: It is well known that circRNAs are closely involved in the progression of various diseases. However, their functions and potential regulatory mechanisms in polycystic ovary syndrome (PCOS) remain largely unknown. In the present study, our aim was to investigate the potential diagnostic value of circRNAs in PCOS. METHODS: The circRNA dataset GSE145296, mRNA dataset GSE155489 and miRNA GSE138572 were downloaded from Gene Expression Omnibus (GEO) database. Then, differentially expressed genes (DEGs) were identified. Based on the potential interactions, a network of cirRNA-related competing endogenous RNAs (ceRNAs) was constructed. Biological functions were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. For further validation, qRT-PCR method was used to detect the expression level of the candidate circRNAs. Then, receiver operating characteristics (ROC) were constructed to evaluate the diagnostic value of the three differentially expressed circRNA (DE-circRNA). RESULTS: We constructed a network of cirRNA-related ceRNA network. Hsa_circ_0075691, hsa_circ_0075692 and hsa_circ_0085997 were validate to be dysregulated in PCOS. CONCLUSION: Hsa_circ_0075691, hsa_circ_0075692 and hsa_circ_0085997 may be potential diagnostic biomarkers of PCOS, but their specific regulatory mechanisms still need to be further studied.