High Contrast Bioimaging of Tumor and Inflammation with a Bicyclic Dioxetane Chemiluminescent Probe.

The link between inflammation and the evolution of cancer is well established. Visualizing and tracking both tumor proliferation and the associated inflammatory response within a living organism are vital for dissecting the nexus between these two processes and for crafting precise treatment modalities. We report the creation and synthesis of an advanced NIR chemiluminescence probe that stands out for its exceptional selectivity, extraordinary sensitivity at nanomolar concentrations, swift detection capabilities, and broad application prospects. Crucially, this probe has been successfully utilized to image endogenous ONOO- across different inflammation models, including abdominal inflammation triggered by LPS, subcutaneous inflammatory conditions, and tumors grafted onto mice. These findings highlight the significant promise of chemiluminescence imaging in enhancing our grasp of the intricate interplay between cancer and inflammation and in steering the development of potent, targeted therapeutic strategies.

Polyfluoroalkyl Tag Decoration Enables Significantly Enhanced Tumor Penetration Ability of a PTK7 Targeting Aptamer.

Aptamers are widely used molecular recognition tools in targeted therapy, but their ability to effectively penetrate deep into solid tumors remains a significant challenge, leading to suboptimal treatment efficacy. Here, we developed a polyfluoroalkyl (PFA) decoration strategy to enhance aptamer recognition, cell internalization, and solid tumor penetration. Our results indicate that PFA with around 11 fluorine atoms significantly improves aptamer internalization both in vitro and in vivo settings. However, we also observed that the use of PFA tags containing 19 and 23 fluorine atoms on aptamers resulted in nonspecific cell anchoring in control cell lines, affecting the specificity of aptamers. Overall, we found that using a chemical modification strategy could enhance the deep tumor penetration ability of aptamers and validate their effectiveness in vivo. This approach has significant practical applications in targeted drug delivery for cancer treatment.

Association of persistent musculoskeletal pain with dementia risk score in adults aged 45 years or older: The China health and retirement longitudinal study.

BACKGROUND: Recent studies have confirmed an association between pain and dementia. Whether musculoskeletal pain in the spine, upper limbs, and lower limbs is associated with dementia risk remains unclear. The longitudinal effect of musculoskeletal pain on dementia risk also remains unclear. AIMS: This work aimed to investigate the association between musculoskeletal pain and dementia risk score. METHODS: We conducted cross-sectional and longitudinal analyses using data from the China Health and Retirement Longitudinal Study. Participants aged 45 years or older were recruited in 2011. A total of 10,759 participants with complete pain information at baseline were eligible for the cross-sectional analysis, and 5,855 were eligible for the longitudinal analyses. We utilized the Rotterdam Study Basic Dementia Risk Model (BDRM) to assess dementia risk. Generalized estimating equations were used to investigate the associations. RESULTS: Compared with participants without persistent musculoskeletal pain, those with persistent musculoskeletal pain (standardized, ß = 0.83; 95 % CI: 0.06, 1.61, p = 0.036), multisite pain (sites≧5; ß = 1.52; 95 % CI: 0.13, 2.91, p = 0.032), neck pain (ß = 2.33; 95 % CI: 0.41, 4.25, p = 0.018), back pain (ß = 2.12; 95 % CI: 0.43, 3.82, p = 0.014), waist pain (ß = 1.09; 95 % CI: 0.07, 2.11, p = 0.037), shoulder pain (ß = 1.74; 95 % CI: 0.46, 3.02, p = 0.008), wrist pain (ß = 2.72; 95 % CI: 0.42, 5.02, p = 0.021), and knee pain (ß = 1.91; 95 % CI: 0.70, 3.13, p = 0.002) had a higher BDRM score during 4 years of follow-up. CONCLUSIONS: Promoting the management of musculoskeletal pain may be beneficial in reducing the dementia risk score.

Associations between adverse childhood experiences and pain in middle-aged and older adults: findings from the China Health and Retirement Longitudinal Study.

OBJECTIVE: Adverse childhood experiences (ACEs) have been associated with a range of adverse health outcomes, with pain being potentially one of them. This population-based cross-sectional study aimed to investigate the associations between Adverse Childhood Experiences (ACEs) and pain in Chinese adults and evaluate whether physical activity and demographic and socioeconomic characteristics modify this associations. METHODS: Cross-sectional data from the China Health and Retirement Longitudinal Study (CHARLS), were utilized in this study. A total of 9923 respondents with information on 12 ACE indicators and 15 self-reported body pains were included. Logistic regression models were used to assess associations of the ACEs and pain. Modification of the associations by physical activity, demographic and socioeconomic characteristics was assessed by stratified analyses and tests for interaction. RESULTS: Among the 9923 individuals included in the primary analyses, 5098 (51.4%) males and the mean (SD) age was 61.18 (10·.44) years. Compared with individuals with 0 ACEs, those who with ≥ 5 ACEs had increased risk of single pains and multiple pain. A dose-response association was found between the number of ACEs and the risk of pain (e.g. neck pain for ≥ 5 ACEs vs. none: OR, 1.107; 95% CI, 0.903-1.356; p < 0.001 for trend). In the associations of each body pain with each ACE indicator, most ACE indicators were associated with an increased risk of pain. In addition, physical activity, sociodemographic and socioeconomic characteristics, such as age, sex, educational level, area of residence, childhood economic hardship, did not demonstrate a significant modify on the associations between ACEs and pain. CONCLUSIONS: These findings indicate that cumulative ACE exposure is associated with increased odds of self-reported pain in Chinese adults, regardless of adult physical activity, sociodemographic and socioeconomic characteristics.

Physical therapy for acute and sub-acute low back pain: A systematic review and expert consensus.

OBJECTIVE: To review the effectiveness of different physical therapies for acute and sub-acute low back pain supported by evidence, and create clinical recommendations and expert consensus for physiotherapists on clinical prescriptions. DATA SOURCES: A systematic search was conducted in PubMed and the Cochrane Library for studies published within the previous 15 years. REVIEW METHODS: Systematic review and meta-analysis, randomized controlled trials assessing patients with acute and sub-acute low back pain were included. Two reviewers independently screened relevant studies using the same inclusion criteria. The Physiotherapy Evidence Database and the Assessment of Multiple Systematic Reviews tool were used to grade the quality assessment of randomized controlled trials and systematic reviews, respectively. The final recommendation grades were based on the consensus discussion results of the Delphi of 22 international experts. RESULTS: Twenty-one systematic reviews and 21 randomized controlled trials were included. Spinal manipulative therapy and low-level laser therapy are recommended for acute low back pain. Core stability exercise/motor control, spinal manipulative therapy, and massage can be used to treat sub-acute low back pain. CONCLUSIONS: The consensus statements provided medical staff with appliable recommendations of physical therapy for acute and sub-acute low back pain. This consensus statement will require regular updates after 5-10 years.

OsNAC5 orchestrates OsABI5 to fine-tune cold tolerance in rice.

Due to its tropical origins, rice (Oryza sativa) is susceptible to cold stress, which poses severe threats to production. OsNAC5, a NAC-type transcription factor, participates in the cold stress response of rice, but the detailed mechanisms remain poorly understood. Here, we demonstrate that OsNAC5 positively regulates cold tolerance at germination and in seedlings by directly activating the expression of ABSCISIC ACID INSENSITIVE 5 (OsABI5). Haplotype analysis indicated that single nucleotide polymorphisms in a NAC-binding site in the OsABI5 promoter are strongly associated with cold tolerance. OsNAC5 also enhanced OsABI5 stability, thus regulating the expression of cold-responsive (COR) genes, enabling fine-tuned control of OsABI5 action for rapid, precise plant responses to cold stress. DNA affinity purification sequencing coupled with transcriptome deep sequencing identified several OsABI5 target genes involved in COR expression, including DEHYDRATION-RESPONSIVE ELEMENT BINDING FACTOR 1A (OsDREB1A), OsMYB20, and PEROXIDASE 70 (OsPRX70). In vivo and in vitro analyses suggested that OsABI5 positively regulates COR gene transcription, with marked COR upregulation in OsNAC5-overexpressing lines and downregulation in osnac5 and/or osabi5 knockout mutants. This study extends our understanding of cold tolerance regulation via OsNAC5 through the OsABI5-CORs transcription module, which may be used to ameliorate cold tolerance in rice via advanced breeding.

Emission Wavelength-Tunable Bicyclic Dioxetane Chemiluminescent Probes for Precise In Vitro and In Vivo Imaging.

Chemiluminescent probes have become increasingly popular in various research areas including precise tumor imaging and immunofluorescence analysis. Nevertheless, previously developed chemiluminescence probes are mainly limited to studying oxidation reaction-associated biological events. This study presents the first example of bioimaging applicable bicyclic dioxetane chemiluminescent probes with tunable emission wavelengths that range from 525 to 800 nm. These newly developed probes were able to detect the analytes of ß-Gal, H2O2, and superoxide with high specificity and a limit of detection of 77 mU L-1, 96, and 28 nM, respectively. The bioimaging application of the probes was verified in ovarian and liver cancer cells and macrophage cells, allowing the detection of the content of ß-Gal, H2O2, and superoxide inside the cells. The high specificity allowed us to image the xenografted tumor in mice. We expect that our probes will receive extensive applications in recording complex biomolecular events using noninvasive imaging techniques.

Genetic-based dissection of resistance to bacterial leaf streak in rice by GWAS.

BACKGROUND: Rice is the second-largest food crop in the world and vulnerable to bacterial leaf streak disease. A thorough comprehension of the genetic foundation of agronomic traits was essential for effective implementation of molecular marker-assisted selection. RESULTS: Our study aimed to evaluate the vulnerability of rice to bacterial leaf streak disease (BLS) induced by the gram-negative bacterium Xanthomonas oryzae pv. oryzicola (Xoc). In order to accomplish this, we first analyzed the population structure of 747 accessions and subsequently assessed their phenotypes 20 days after inoculation with a strain of Xoc, GX01. We conducted genome-wide association studies (GWAS) on a population of 747 rice accessions, consisting of both indica and japonica subpopulations, utilizing phenotypic data on resistance to bacterial leaf streak (RBLS) and sequence data. We identified a total of 20 QTLs associated with RBLS in our analysis. Through the integration of linkage mapping, sequence analysis, haplotype analysis, and transcriptome analysis, we were able to identify five potential candidate genes (OsRBLS1-OsRBLS5) that possess the potential to regulate RBLS in rice. In order to gain a more comprehensive understanding of the genetic mechanism behind resistance to bacterial leaf streak, we conducted tests on these genes in both the indica and japonica subpopulations, ultimately identifying superior haplotypes that suggest the potential utilization of these genes in breeding disease-resistant rice varieties. CONCLUSIONS: The findings of our study broaden our comprehension of the genetic mechanisms underlying RBLS in rice and offer significant insights that can be applied towards genetic improvement and breeding of disease-resistant rice in rapidly evolving environmental conditions.

Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial.

BACKGROUND: The majority of existing clinical studies used active transcranial direct current stimulation (tDCS) over superficial areas of the pain neuromatrix to regulate pain, with conflicting results. Few studies have investigated the effect of tDCS on pain thresholds by focusing on targets in deep parts of the pain neuromatrix. METHODS: This study applied a single session of high-definition tDCS (HD-tDCS) targeting the anterior cingulate cortex (ACC) and used a parallel and sham-controlled design to compare the antinociceptive effects in healthy individuals by assessing changes in pain thresholds. Sixty-six female individuals (mean age, 20.5 ± 2.4 years) were randomly allocated into the anodal, cathodal, or sham HD-tDCS groups. The primary outcome of the study was pain thresholds (pressure pain threshold, heat pain threshold, and cold pain threshold), which were evaluated before and after stimulation through the use of quantitative sensory tests. RESULTS: Only cathodal HD-tDCS targeting the ACC significantly increased heat pain threshold (P < 0.05) and pressure pain threshold (P < 0.01) in healthy individuals compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain threshold. Furthermore, no statistically significant difference was found in pain thresholds between anodal and sham HD-tDCS (P > 0.38). Independent of HD-tDCS protocols, the positive and negative affective schedule scores were decreased immediately after stimulation compared with baseline. CONCLUSIONS: The present study has found that cathodal HD-tDCS targeting the ACC provided a strong antinociceptive effect (increase in pain threshold), demonstrating a positive biological effect of HD-tDCS.

Skeleton-Based Fall Detection with Multiple Inertial Sensors Using Spatial-Temporal Graph Convolutional Networks.

The application of wearable devices for fall detection has been the focus of much research over the past few years. One of the most common problems in established fall detection systems is the large number of false positives in the recognition schemes. In this paper, to make full use of the dependence between human joints and improve the accuracy and reliability of fall detection, a fall-recognition method based on the skeleton and spatial-temporal graph convolutional networks (ST-GCN) was proposed, using the human motion data of body joints acquired by inertial measurement units (IMUs). Firstly, the motion data of five inertial sensors were extracted from the UP-Fall dataset and a human skeleton model for fall detection was established through the natural connection relationship of body joints; after that, the ST-GCN-based fall-detection model was established to extract the motion features of human falls and the activities of daily living (ADLs) at the spatial and temporal scales for fall detection; then, the influence of two hyperparameters and window size on the algorithm performance was discussed; finally, the recognition results of ST-GCN were also compared with those of MLP, CNN, RNN, LSTM, TCN, TST, and MiniRocket. The experimental results showed that the ST-GCN fall-detection model outperformed the other seven algorithms in terms of accuracy, precision, recall, and F1-score. This study provides a new method for IMU-based fall detection, which has the reference significance for improving the accuracy and robustness of fall detection.

Validity and reliability of upper extremity star excursion balance test in adolescent swimmers.

Background: Upper limb balance is one of the important physical fitness parameters for all populations, especially overhead athletes like swimmers. Upper extremity star excursion balance test (UESEBT) is a comprehensive dynamic balance assessment, this study aims to explore the reliability and validity of UESEBT among adolescent swimmers. Methods: This cross-sectional study recruited 70 adolescent swimmers. All participants were required to complete UESEBT, upper quarter Y-balance test (UQYBT), maximal isometric strength (MIS) tests in upper limb, closed kinetic chain upper extremity stability test (CKCUEST), trunk flexor endurance test (TFET) and lateral trunk endurance test (LTET). The intra- and inter-operator reliability and the correlation of UESEBT with other physical performances were conducted. Results: For reliability, the intra- and inter-operator reliability of all directions and composite score were high-to-excellent (ICC = 0.706-1.000) among all participants. For validity, the UESEBT has a moderate-to-strong correlation with UQYBT (r = 0.42-0.72, p < 0.001), and a weak-to moderate one with CKCUEST (r = 0.25-0.42, p < 0.05). Furthermore, the UESEBT performance showed weak-to-moderate correlations with MIS (r = 0.24-0.44, p < 0.05). UESEBT was correlated to LTET (r = 0.24-0.33, p < 0.05) whereas no relationship was found with TFET. Conclusions: UESEBT was a reliable and valid tool to screen upper extremity dynamic balance among adolescent swimmers. UESEBT provides more detailed information in eight directions to assess the upper limb sport performance. Further study should explore the prediction ability of UESEBT for injury.

Evolution of different rice ecotypes and genetic basis of flooding adaptability in Deepwater rice by GWAS.

BACKGROUND: Rice is the world's second largest food crop and accelerated global climate change due to the intensification of human activities has a huge impact on rice. Research on the evolution of different rice ecotypes is essential for enhancing the adaptation of rice to the unpredictable environments. RESULTS: The sequencing data of 868 cultivated and 140 wild rice accessions were used to study the domestication history and signatures of adaptation in the distinct rice ecotypes genome. The different populations had formed distinct rice ecotypes by phylogenetic analyses and were domesticated independently in the two subspecies of rice, especially deepwater and upland rice. The domestication history of distinct rice ecotypes was confirmed and the four predicted admixture events mainly involved gene flow between wild rice and cultivated rice. Importantly, we identified numerous selective sweeps that have occurred during the domestication of different rice ecotypes and one candidate gene (LOC_Os11g21804) for deepwater based on transcriptomic evidence. In addition, many regions of genomic differentiation between the different rice ecotypes were identified. Furthermore, the main reason for the increase in genetic diversity in the ecotypes of xian (indica) rice was the high proportion of alternative allele frequency in new mutations. Genome-wide association analysis revealed 28 QTLs associated with flood tolerance which contained 12 related cloned genes, and 20 candidate genes within 13 deepwater QTLs were identified by transcriptomic and haplotype analyses. CONCLUSIONS: These results enhanced our understanding of domestication history in different rice ecotypes and provided valuable insights for genetic improvement and breeding of rice in the current changing environments.

RGN1 controls grain number and shapes panicle architecture in rice.

Yield in rice is determined mainly by panicle architecture. Using map-based cloning, we identified an R2R3 MYB transcription factor REGULATOR OF GRAIN NUMBER1 (RGN1) affecting grain number and panicle architecture. Mutation of RGN1 caused an absence of lateral grains on secondary branches. We demonstrated that RGN1 controls lateral grain formation by regulation of LONELY GUY (LOG) expression, thus controlling grain number and shaping panicle architecture. A novel favourable allele, RGN1C , derived from the Or-I group in wild rice affected panicle architecture by means longer panicles. Identification of RGN1 provides a theoretical basis for understanding the molecular mechanism of lateral grain formation in rice; RGN1 will be an important gene resource for molecular breeding for higher yield.

Mechanism and Origin of Stereoselectivity of Ni-Catalyzed Cyclization/Carboxylation of Bromoalkynes with CO2.

Bromoalkynes play important roles in coupling reactions because they can show obvious stereoselectivity to form E- and Z-isomers when substituents are different. However, the origin of the stereoselectivity in the bromoalkynes reaction is still unclear. Density functional theory (DFT) calculations were performed to provide an in-depth study of the reaction mechanism, clarifying the mechanistic details of the main reaction and the origin of the stereoselectivity. By comparing the syn-insertion mechanism of alkynes and the radical pathway, it is indicated that the electrostatic effect caused by the different charge distributions of the reactants is the main reason that Ni(I) species are more prone to syn-insertion of alkynes than Ni(II) species. In addition, the lower reaction energy barrier in the radical pathway suggests that it is more advantageous in terms of kinetics. The bond between Ni(I) species and alkenylation products has two directions to generate products of different configurations, which are the direct stereoselectivity-determining stages. The distortion/interaction analysis shows that the distortion energy mainly affects the product configuration, and the steric hindrance is the main factor controlling the stereoselectivity.

Bibliometric Study of Exercise and Tendinopathy Research from 2001 to 2020.

BACKGROUND Tendinopathy is a tendon disease that often occurs in athletes. Many studies have revealed that exercise therapy is beneficial for the nonoperative management of tendinopathy. However, the general aspect bibliometric analysis of this global research topic associated with exercise and tendinopathy is lacking. The present study aimed to make a bibliometric analysis of worldwide development tendency and research hotspots in exercise and tendinopathy research from 2001 to 2020. MATERIAL AND METHODS Using the Web of Science, articles and reviews published between 2001 and 2020 were retrieved from the Science Citation Index Expanded database. CiteSpace was used to analyze the relationship among publications, countries, institutions, journals, authors, references, and keywords. RESULTS In total, 857 articles were found in this study. Over the past 20 years, there was a marked increase in the number of publications. A total of 194 different scholarly journals were dedicated to the categories Sport Sciences, Orthopedics, and Rehabilitation. The USA and La Trobe University were the most prolific country and institution, respectively. The British Journal of Sports Medicine was the prominent journal for research on exercise and tendinopathy and had the most publications. The analysis of keywords showed that rehabilitation, rotator cuff tendinopathy, stiffness, and disability of individuals with tendinopathy had become the research focus in this field. CONCLUSIONS Bibliometric analysis provides a historical and scientific perspective on exercise and tendinopathy research, providing relevant researchers, funding agencies, and policymakers with valuable information to explore the current research status, hotspots, and new directions for future research.

Pressure pain threshold and somatosensory abnormalities in different ages and functional conditions of post-stroke elderly.

BACKGROUND: Somatosensory deficits and abnormal pain sensitivity are highly prevalent among stroke survivors, which negatively impacts their quality of life and recovery process. However, the factors for pressure pain threshold (PPT) and somatosensory abnormalities in post-stroke elderly remain unknown. The aim of this study was to explore the effects of age, side and other functional conditions, such as spasticity and motor functions, on PPT and sensory abnormalities among elderly after stroke. METHODS: The cross-sectional study finally included 43 post-stroke elderly aged over 60 and assessed the PPT of 14 bilateral muscles widely located in the whole body by using a digital force gage. Meanwhile, spasticity, motor function, joint pain and activity of daily living (ADL) were evaluated by the Modified Ashworth scale, Fugl-Meyer, and Barthel Index, respectively. All participants were divided into higher-aged and lower-aged groups based on the median age of all of them. RESULTS: Higher age tended to be associated with higher sensitivity but not significant except for one upper limb muscle, and the affected side showed significantly higher PPTs than the unaffected side in three out of seven muscles (p < 0.05). Furthermore, the somatosensory abnormalities in the affected side, particularly hypoalgesia, were more frequent in higher-aged than lower-aged patients in most assessed muscles. Meanwhile, patients with spasticity showed more increment of PPTs in affected muscles around the knee joint than patients without spasticity (p < 0.05). Patients with better motor functions, less joint pain and higher ADL performed less bilateral differences of PPTs than other patients in some muscles (p < 0.05). CONCLUSIONS: The age and side differences of mechanical pain sensitivity were found among post-stroke elderly. Older patients show higher sensitivity in both sides compared with the younger ones, and the affected side of the elder shows more somatosensory abnormalities, particularly hypoalgesia, than that of the younger ones. Post-stroke elderly in good functional conditions, such as normal muscle tone, better physical function and daily activities, and less joint pain, seems to have more equal pain sensitivity between both sides than those in poor conditions.

A Dual-Targeting Circular Aptamer Strategy Enables the Recognition of Different Leukemia Cells with Enhanced Binding Ability.

Currently, the broad use of monovalent aptamers in oncology faces challenges, including insufficient recognition and internalization caused by a finite number of receptors on the cell surface, as well as a confined recognition spectrum. Herein, we describe the development of a dual-targeting circular aptamer (DTCA) that can recognize two different biomarkers on living cells to augment aptamer-receptor interactions, thus enhancing recognition of the target cells. This improvement not only boosts binding and internalization abilities, but also expands the recognition spectrum of these aptamers to different leukemia cells. Moreover, the stability of DTCA in serum can be significantly improved by an enzyme-promoted terminal ligation strategy. The chemical incorporation of 5-fluorodeoxyuridine into DTCA resulted in a pharmaceutically functional aptamer that exhibited excellent selectivity, as demonstrated by its high cytotoxicity against target cancer cells, but not to normal cells. The superiority of our newly developed strategy was further highlighted by its precise tumor-imaging capability.

Genetic architecture to cause dynamic change in tiller and panicle numbers revealed by genome-wide association study and transcriptome profile in rice.

Panicle number (PN) is one of the three yield components in rice. As one of the most unstable traits, the dynamic change in tiller number (DCTN) may determine the final PN. However, the genetic basis of DCTN and its relationship with PN remain unclear. Here, 377 deeply re-sequenced rice accessions were used to perform genome-wide association studies (GWAS) for tiller/PN. It was found that the DCTN pattern rather than maximum tiller number or effective tiller ratio is the determinant factor of high PN. The DCTN pattern that affords more panicles exhibits a period of stable tillering peak between 30 and 45 days after transplant (called DT30 and DT45, respectively), which was believed as an ideal pattern contributing to the steady transition from tiller development to panicle development (ST-TtP). Consistently, quantitative trait loci (QTL) expressed near DT30-DT45 were especially critical to the rice DCTN and in supporting the ST-TtP. The spatio-temporal expression analysis showed that the expression pattern of keeping relatively high expression in root at 24:00 (R24-P2) from about DT30 to DT45 is a typical expression pattern of cloned tiller genes, and the candidate genes with R24-P2 can facilitate the prediction of PN. Moreover, gene OsSAUR27 was identified by an integrated approach combining GWAS, bi-parental QTL mapping and transcription. These findings related to the genetic basis underlying the DCTN will provide the genetic theory in making appropriate decisions on field management, and in developing new varieties with high PN and ideal dynamic plant architecture.

Regulating the Anticancer Efficacy of Sgc8-Combretastatin A4 Conjugates: A Case of Recognizing the Significance of Linker Chemistry for the Design of Aptamer-Based Targeted Drug Delivery Strategies.

The unique merits of aptamers, including specificity, high binding affinity, easy cell internalization, and rapid tissue accumulation abilities, have led aptamer-drug conjugates to evolve into one of the most attractive strategies for targeted drug delivery purposes. Nevertheless, the critical role of linkers in regulating anticancer efficacy of these conjugates, especially those engineered by automated modular synthesis techniques, has been rarely explored. In this work, we utilized Sgc8c aptamer and combretastatin A4 to develop three conjugates with either a phosphodiester bond linker, a disulfide bond linker, or a carbamate linker to study their payload release mechanisms and the influence on anticancer efficacy. These investigations allowed us to identify the unique activation pathway of the phosphodiester bond linker that is activated by both nucleophilic attack of glutathione and degradation caused by phosphodiesterase, which is highly associated with the higher cytotoxicity of the conjugate. Importantly, the understanding of the chemistry of phosphodiester bond linker activation allowed us to further design another XQ-2d-CA4 conjugate that can induce pancreatic cancer cells apoptosis in a more efficient manner.

Loci and natural alleles underlying robust roots and adaptive domestication of upland ecotype rice in aerobic conditions.

A robust (long and thick) root system is characteristic of upland japonica rice adapted to drought conditions. Using deep sequencing and large scale phenotyping data of 795 rice accessions and an integrated strategy combining results from high resolution mapping by GWAS and linkage mapping, comprehensive analyses of genomic, transcriptomic and haplotype data, we identified large numbers of QTLs affecting rice root length and thickness (RL and RT) and shortlisted relatively few candidate genes for many of the identified small-effect QTLs. Forty four and 97 QTL candidate genes for RL and RT were identified, and five of the RL QTL candidates were validated by T-DNA insertional mutation; all have diverse functions and are involved in root development. This work demonstrated a powerful strategy for highly efficient cloning of moderate- and small-effect QTLs that is difficult using the classical map-based cloning approach. Population analyses of the 795 accessions, 202 additional upland landraces, and 446 wild rice accessions based on random SNPs and SNPs within robust loci suggested that there could be much less diversity in robust-root candidate genes among upland japonica accessions than in other ecotypes. Further analysis of nucleotide diversity and allele frequency in the robust loci among different ecotypes and wild rice accessions showed that almost all alleles could be detected in wild rice, and pyramiding of robust-root alleles could be an important genetic characteristic of upland japonica. Given that geographical distribution of upland landraces, we suggest that during domestication of upland japonica, the strongest pyramiding of robust-root alleles makes it a unique ecotype adapted to aerobic conditions.