Organisms are inherently three dimensional, thus comprehensive understanding of the complicated biological system requires analysis of organs or even whole bodies in the context of three dimensions. ...However, this is a tremendous task since the biological specimens are naturally opaque, a major obstacle in whole‐body and whole‐organ imaging. Tissue clearing technique provides a prospective solution and has become a powerful tool for three‐dimensional imaging and quantification of organisms. Tissue clearing technique aims to make tissue transparent by minimizing light scattering and light absorption, thus allowing deep imaging of large volume samples. When combined with diverse molecular labeling methods and high‐throughput optical sectioning microscopes, tissue clearing technique enables whole‐body and whole‐organ imaging at cellular or subcellular resolution, providing detailed and comprehensive information about the intact biological systems. Here, we give an overview of recent progress and biomedical applications of tissue clearing technique. We introduce the mechanisms and basic principles of tissue clearing, and summarize the current tissue clearing methods. Moreover, the available imaging techniques and software packages for data processing are also presented. Finally, we introduce the recent advances in applications of tissue clearing in biomedical fields. Tissue clearing contributes to the investigation of structure‐function relationships in intact mammalian organs, and opens new avenues for cellular and molecular mapping of intact human organs. We hope this review contributes to a better understanding of tissue clearing technique and can help researchers to select the best‐suited clearing protocol for their experiments.
Tissue clearing technique achieves tissue transparency by reducing light scattering and light absorption. Tissue clearing enables whole‐body and whole‐organ imaging and facilitates the understanding of intact organisms at system‐level. Tissue clearing contributes to the investigation of structure‐function relationships in intact mammalian organs, and opens new avenues for cellular and molecular mapping of intact human organs.
Robotic control in a continuous action space has long been a challenging topic. This is especially true when controlling robots to solve compound tasks, as both basic skills and compound skills need ...to be learned. In this paper, we propose a hierarchical deep reinforcement learning algorithm to learn basic skills and compound skills simultaneously. In the proposed algorithm, compound skills and basic skills are learned by two levels of hierarchy. In the first level of hierarchy, each basic skill is handled by its own actor, overseen by a shared basic critic. Then, in the second level of hierarchy, compound skills are learned by a meta critic by reusing basic skills. The proposed algorithm was evaluated on a Pioneer 3AT robot in three different navigation scenarios with fully observable tasks. The simulations were built in Gazebo 2 in a robot operating system Indigo environment. The results show that the proposed algorithm can learn both high performance basic skills and compound skills through the same learning process. The compound skills learned outperform those learned by a discrete action space deep reinforcement learning algorithm.
Small cell lung cancer (SCLC) is an aggressive disease characterized by rapid growth and metastases. It has been recognized that the inflammation of the microenvironment plays a critical role in the ...development of malignancies. However, little is known about the role of multiple inflammatory and hematological markers in the prognosis of SCLC. The aim of this study was to determine the clinical significance of pre-treatment inflammation-based scores and characteristics as prognostic indicators for the survival of SCLC patients. A retrospective analysis of 919 SCLC cases was performed. Patients’ characteristics and hematologic tests data at initial diagnosis were collected. The univariate analysis of all SCLC patients indicated that favorable prognostic factors were age ˂ 70 years, non-smokers, good performance status, limited disease and response to treatment. Moreover, univariate analysis of inflammation-based scores and other blood parameters showed that neutrophil-lymphocyte ratio ≥ 5, platelet-lymphocyte ratio ≥ 250, systemic immune-inflammation index (SII) ≥ 1,600 × 109/L, prognostic nutritional index (albumin + 5 × lymphocyte) < 45, and elevated serum lactate dehydrogenase (LDH) predicted poor prognosis in SCLC patients. SII represents the score that is calculated as follows: platelet count × neutrophil count/lymphocyte count. In the multivariate analysis, SII, together with serum LDH, stage and response to therapy, were associated with overall survival (OS). This study demonstrated that the combination of platelet count and neutrophil-lymphocyte ratio could help to predict poor prognosis in SCLC. Our findings will facilitate the understanding of survival differences in SCLC patients in clinical practice.
Neural stem cells (NSCs) in the adult mammalian central nervous system (CNS) hold the key to neural regeneration through proper activation, differentiation, and maturation, to establish nascent ...neural networks, which can be integrated into damaged neural circuits to repair function. However, the CNS injury microenvironment is often inhibitory and inflammatory, limiting the ability of activated NSCs to differentiate into neurons and form nascent circuits. Here we report that neurotrophin-3 (NT3)-coupled chitosan biomaterial, when inserted into a 5-mm gap of completely transected and excised rat thoracic spinal cord, elicited robust activation of endogenous NSCs in the injured spinal cord. Through slow release of NT3, the biomaterial attracted NSCs to migrate into the lesion area, differentiate into neurons, and form functional neural networks, which interconnected severed ascending and descending axons, resulting in sensory and motor behavioral recovery. Our study suggests that enhancing endogenous neurogenesis could be a novel strategy for treatment of spinal cord injury.
Spinal cord injury (SCI) often leads to permanent loss of motor, sensory, and autonomic functions.We have previously shown that neurotrophin3 (NT3)-loaded chitosan biodegradable material allowed for ...prolonged slow release of NT3 for 14 weeks under physiological conditions. Here we report that NT3-loaded chitosan, when inserted into a 1-cm gap of hemisectioned and excised adult rhesus monkey thoracic spinal cord, elicited robust axonal regeneration. Labeling of cortical motor neurons indicated motor axons in the corticospinal tract not only entered the injury site within the biomaterial but also grew across the 1-cm-long lesion area and into the distal spinal cord. Through a combination of magnetic resonance diffusion tensor imaging, functional MRI, electrophysiology, and kinematics-based quantitative walking behavioral analyses, we demonstrated that NT3-chitosan enabled robust neural regeneration accompanied by motor and sensory functional recovery. Given that monkeys and humans share similar genetics and physiology, our method is likely translatable to human SCI repair.
Dysregulation of microRNAs (miRNAs) plays a key role during the pathogenesis of chemoresistance in lung cancer (LCa). Previous study suggests that miR-324-5p may serve as a unique miRNA signature for ...LCa, but its role and the corresponding molecular basis remain largely explored. Herein, we report that miR-324-5p expression was significantly increased in cisplatin (CDDP)-resistant LCa tissues and cells, and this upregulation predicted a poor post-chemotherapy prognosis in LCa patients. miR-324-5p was further shown to impact CDDP response: Ectopic miR-324-5p expression in drug-naïve LCa cells was sufficient to attenuate sensitivity to CDDP and to confer more robust tumour growth in CDDP-challenged nude mice. Conversely, ablation of miR-324-5p expression in resistant cells effectively potentiated CDDP-suppressed cell growth in vitro and in vivo. Using multiple approaches, we further identified the tumour suppressor FBXO11 as the direct down-stream target of miR-324-5p. Stable expression of FBXO11 could abrogate the pro-survival effects of miR-324-5p in CDDP-challenged LCa cells. Together, these findings suggest that miR-324-5p upregulation mediates, at least partially, the CDDP resistance by directly targeting FBXO11 signalling in LCa cells. In-depth elucidation of the molecular basis underpinning miR-324-5p action bears potential implications for mechanism-based strategies to improve CDDP responses in LCa.
This study aimed to discover concurrences of adverse drug reactions (ADRs) and derive models of the most frequent items of ADRs based on the SIDER database, which included 1430 marketed drugs and ...5868 ADRs. First, common ADRs of organic drugs were manually reclassified according to side effects in the human system and followed by an association rule analysis, which found ADRs of digestive and nervous systems often occurred at the same time with a good association rule. Then, three algorithms, linear discriminant analysis (LDA), support vector machine (SVM) and deep learning, were used to derive models of ADRs of digestive and nervous systems based on 497 organic monomer drugs and to identify key structural features in defining these ADRs. The statistical results indicated that these kinds of QSAR models were good tools for screening ADRs of digestive and nervous systems, which gave the ROC AUC values of 81.5%, 98.9%, 91.5%, 69.5%, 78.4% and 78.8%, respectively. Then, these models were applied to investigate ADRs of 1536 organic compounds with four phase and zero rule-of-five (RO5) violations from the ChEMBL database. Based on the consensus ADRs' predictions of models, 58.1% and 42.6% of compounds were predicted to cause these two ADRs, respectively, indicating the significance of initial assessment of ADRs in early drug discovery.
People judge the nature of human behaviors based on underlying intentions and possible outcomes. Recent studies have demonstrated a causal role of the right temporoparietal junction (rTPJ) in ...modulating both intention and intention-based outcome evaluations during social judgments. However, these studies mainly used hypothetical scenarios with socially undesirable contexts (bad/neutral intentions and bad/neutral outcomes), leaving the role of rTPJ in judging good intentions and good outcomes unclear. In the current study, participants were instructed to make goodness judgments as a third party toward the monetary allocations from one proposer to another responder. Critically, in some cases, the initial allocation by the proposer could be reversed by the computer, yielding combinations of good/bad intentions (of the proposer) with good/bad outcomes (for the responder). Anodal (n = 20), cathodal (n = 21), and sham (n = 21) transcranial direct current stimulation (tDCS) over the rTPJ were randomly assigned to 62 subjects to further examine the effects of stimulation over the rTPJ in modulating intention-based outcome evaluation. Compared to the anodal and sham stimulations, cathodal tDCS over the rTPJ reduced the goodness ratings of good/bad outcomes when the intentions were good, whereas it showed no significant effect on outcome ratings under unknown and bad intentions. Our results provide the first evidence that deactivating the rTPJ modulates outcome evaluation in an intention-dependent fashion, mainly by reducing the goodness rating towards both good/bad outcomes when the intentions are good. Our findings argue for a causal role of the rTPJ in modulating intention-based social judgments and point to nuanced effects of rTPJ modulation.
Spinal cord injury (SCI) is considered incurable because axonal regeneration in the central nervous system (CNS) is extremely challenging, due to harsh CNS injury environment and weak intrinsic ...regeneration capability of CNS neurons. We discovered that neurotrophin-3 (NT3)-loaded chitosan provided an excellent microenvironment to facilitate nerve growth, new neurogenesis, and functional recovery of completely transected spinal cord in rats. To acquire mechanistic insight, we conducted a series of comprehensive transcriptome analyses of spinal cord segments at the lesion site, as well as regions immediately rostral and caudal to the lesion, over a period of 90 days after SCI. Using weighted gene coexpression network analysis (WGCNA), we established gene modules/programs corresponding to various pathological events at different times after SCI. These objective measures of gene module expression also revealed that enhanced new neurogenesis and angiogenesis, and reduced inflammatory responses were keys to conferring the effect of NT3-chitosan on regeneration.
Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable ...first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N.sup.6-methyladenosine (m.sup.6A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m.sup.6A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m.sup.6A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m.sup.6A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m.sup.6A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m.sup.6A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators--ZCCHC4, G3BP1, and RBMX--may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m.sup.6A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m.sup.6A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC. Keywords: Small-cell lung cancer, m.sup.6A regulators, Epigenetic modification, Chemotherapy resistance, Individualized medicine
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