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Upregulation of vascular endothelial growth factor (VEGF) and enhanced angiogenesis have been implicated in the severe progression of age-related macular degeneration (AMD). Abnormal arachidonate 5-lipoxygenase (ALOX5) is associated with AMD pathogenesis. However, no reports have shown the causal role of ALOX5 in angiogenesis during AMD. In the present study, ARPE-19 cells were exposed to hypoxia, an inducer of VEGF expression. Potential proteins implicated in AMD progression were predicted using bioinformatics. RNA affinity antisense purification-mass spectrometry (RAP-MS) was applied to identify the binding proteins of ALOX5 3'UTR. Expression of ALOX5 and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) was detected by qRT-PCR and western blotting. VEGF expression and secretion were assessed by immunofluorescence and ELISA, respectively. The chicken embryo chorioallantoic membrane (CAM) was used to analyze the effect of ALOX5 on angiogenesis. RNA stability was assayed using the Actinomycin D assay. The results show that hypoxia promoted cell growth and increased VEGF expression in ARPE-19 cells. ALOX5 was associated with AMD progression, and hypoxia upregulated ALOX5 expression in ARPE-19 cells. ALOX5 silencing reduced VEGF expression induced by hypoxia in ARPE-19 cells. Moreover, the conditioned medium of ALOX5-silenced ARPE-19 cells could suppress the viability and migration of HUVECs and diminish angiogenesis in the CAM. Furthermore, YTHDF1 was validated to bind to ALOX5 3'UTR, and YTHDF1 promoted ALOX5 expression by elevating the stability of ALOX5 mRNA. In conclusion, our findings demonstrate that YTHDF1-regulated ALOX5 increases VEGF expression in hypoxia-exposed ARPE-19 cells and enhances the viability, migration, and angiogenesis of vascular endothelial cells., (© 2024. The Author(s).)

Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability 1 . LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1) 2 . However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation., (© 2024. The Author(s).)

Thick-coal-seam with complex structures and thick-hard roof in the initial mining phase pose various challenges, including a long weighting interval, strong rock pressure, poor top coal caving performance (TCCP), and significant coal loss. These problems directly affect the safety and efficiency of the mining operations. This study employs the principles of elastic thin plates and ellipsoidal bodies to unravel the formation mechanism of strong rock pressure in thick-hard roof and the influence of parting on the TCCP. In addition, a hydraulic fracturing technique is proposed for safe-efficient recovery during the initial mining phase. The reliability of this technique is verified through numerical simulations and field experiments. The research findings reveal the following. (1) The primary causes of strong rock pressure in the mining face are attributed to a long weighting interval and wide collapse range of the main roof, and the weighting interval is primarily influenced by the thickness and tensile strength of the main roof. (2)The key factor affecting the TCCP is the cantilever beam structure formed by the fracture of the thick-hard parting, as it intersects the ellipsoidal body during coal caving. The simultaneous fracturing of both the top coal and roof can reduce the weighting interval on the working face. This process effectively decreased the strength of the thick-hard parting within the top coal, while simultaneously enhancing its load strength and eliminating the cantilever structure resulting from the parting fracture. It not only reduces the first weighting intensity but also promotes the early and proper coal release, thereby enhancing the TCCP and ensuring safe-efficient mining during the initial mining phase. (3) Aiming at the difference in the strengths of the top coal and roof, a graded hydraulic fracturing technique and system were proposed. Fracturing boreholes with a diameter of 60 mm, spacing of 10 m, and height of 20.85 m, which can economically and effectively ensure the fracturing results. Field applications have demonstrated that fractured coal and rocks in fracturing areas exhibit well-developed fractures. During the initial mining phase, the weighting interval in the working face was reduced by 20 m, resulting in a decrease in the overburden pressure and 26.9% reduction in the lumpiness of the top coal. Additionally, the recovery rate increased by 31.19%., (© 2024. The Author(s).)

The increasing prevalence of myopia worldwide presents a significant public health challenge. A key strategy to combat myopia is with early detection and prediction in children as such examination allows for effective intervention using readily accessible imaging technique. To this end, we introduced DeepMyopia, an artificial intelligence (AI)-enabled decision support system to detect and predict myopia onset and facilitate targeted interventions for children at risk using routine retinal fundus images. Based on deep learning architecture, DeepMyopia had been trained and internally validated on a large cohort of retinal fundus images (n = 1,638,315) and then externally tested on datasets from seven sites in China (n = 22,060). Our results demonstrated robustness of DeepMyopia, with AUCs of 0.908, 0.813, and 0.810 for 1-, 2-, and 3-year myopia onset prediction with the internal test set, and AUCs of 0.796, 0.808, and 0.767 with the external test set. DeepMyopia also effectively stratified children into low- and high-risk groups (p < 0.001) in both test sets. In an emulated randomized controlled trial (eRCT) on the Shanghai outdoor cohort (n = 3303) where DeepMyopia showed effectiveness in myopia prevention compared to NonCyc-based model, with an adjusted relative reduction (ARR) of -17.8%, 95% CI: -29.4%, -6.4%. DeepMyopia-assisted interventions attained quality-adjusted life years (QALYs) of 0.75 (95% CI: 0.53, 1.04) per person and avoided blindness years of 13.54 (95% CI: 9.57, 18.83) per 1 million persons compared to natural lifestyle with no active intervention. Our findings demonstrated DeepMyopia as a reliable and efficient AI-based decision support system for intervention guidance for children., (© 2024. The Author(s).)

The Daling River Basin is an important ecological functional area in the western region of Liaoning with outstanding environmental problems. The monitoring of ecological and environmental quality in the basin and the analysis of driving factors are of great importance for the protection of the ecological environment and the improvement of economic quality. In this paper, the three periods of Landsat remote sensing images in 1995, 2010 and 2020 are used as the basic data, and platforms and technical means such as RS and GIS are used to decipher and extract the three periods of land use information, and to construct the land use type transfer matrix. The remote sensing ecological index (RSEI) was improved, and the principal component analysis method was applied to construct the improved remote sensing ecological index (IRSEI) model based on the greenness (NDVI), moisture (WET), heat (LST) and new dryness (N-NDBSI), so as to realize the dynamic monitoring of ecological and environmental quality in the study area. Based on the land use change, combined with the trend of improved remote sensing ecological index (IRSEI) of Daling River Basin, thus achieving the purpose of rapid and efficient dynamic monitoring of ecological quality of Daling River Basin from 1995 to 2020. A geoprobe model was then used to systematically assess the drivers of ecological quality in the catchment. The results show that the improved remote sensing ecological index (IRSEI) can efficiently and accurately obtain the spatial distribution pattern and temporal variation trend of IRSEI in the study area, which is more in line with the characteristics of indicators in this study area. The IRSEI in the study area showed an increasing trend from 1995 to 2020, from 0.4794 to 0.5615, and the proportion of benign ecological classes increased year by year during the period. Among the evaluation indicators, NDVI and N-NDBSI are the main factors affecting the environmental and ecological quality of the Daling River Basin, and the increase of vegetation cover, climate regulation and human activities have obvious promoting effects on the improvement of the ecological environment of the Daling River Basin. This study provides a scientific theoretical basis for the implementation of further ecological environmental protection measures., (© 2024. The Author(s).)

Phagocytosis is the process by which myeloid phagocytes bind to and internalize potentially dangerous microorganisms 1 . During phagocytosis, innate immune receptors and associated signalling proteins are localized to the maturing phagosome compartment, forming an immune information processing hub brimming with microorganism-sensing features 2-8 . Here we developed proximity labelling of phagosomal contents (PhagoPL) to identify proteins localizing to phagosomes containing model yeast and bacteria. By comparing the protein composition of phagosomes containing evolutionarily and biochemically distinct microorganisms, we unexpectedly identified programmed death-ligand 1 (PD-L1) as a protein that specifically enriches in phagosomes containing yeast. We found that PD-L1 directly binds to yeast upon processing in phagosomes. By surface display library screening, we identified the ribosomal protein Rpl20b as a fungal protein ligand for PD-L1. Using an auxin-inducible depletion system, we found that detection of Rpl20b by macrophages cross-regulates production of distinct cytokines including interleukin-10 (IL-10) induced by the activation of other innate immune receptors. Thus, this study establishes PhagoPL as a useful approach to quantifying the collection of proteins enriched in phagosomes during host-microorganism interactions, exemplified by identifying PD-L1 as a receptor that binds to fungi., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The posterolateral tibial plateau fracture is a special type of intra-articular fracture, for which there is no simple, safe, and effective standardized procedure. In this paper, we evaluate the clinical efficacy and the advantages of the treatment of posterolateral tibial plateau fracture by using our designed proximal lateral tibial rim plate for the posterolateral condyle of the tibial plateau via the space above the fibula head. Thirty-eight patients with posterolateral tibial plateau fractures from June 2018 to June 2021 were retrospectively analyzed. CT scans were used to classify the degree of injury in the included patients. All of them were fixed with reduction using an approach above the fibula head combined with a homemade anatomical plate. The regular postoperative review was performed to instruct functional knee exercises. Postoperative complications were observed and follow-up visits were performed to assess the functional outcome. A total of 38 patients with posterolateral tibial plateau fractures, 13 males and 25 females were included in the study. All patients were followed up for 13-26 months, with a mean of 15.3 months. There were no postoperative complications such as numbness of the limb, knee joint instability, etc. X-ray review showed that the fractures were all healed, and the healing time was 10-16 weeks, with an average of 12.1 weeks; none of the internal fixation loosening and loss of articular surface occurred during the follow-up period. At the last follow-up, according to the HSS knee function score criteria, the scores were 79-98, with an average of 91.3. The HSS score presented excellent in 34 cases (89%) and good in 4 cases (11%). The Rasmussen score was graded as excellent in 29 cases (76%) and good in 9 cases (24%). In conclusion, The treatment of posterolateral tibial plateau fractures by an approach above the fibula head has the advantages of simplicity and safety, small trauma, and no risk of vascular and nerve injuries, and the anatomical proximal lateral tibial rim plate can play a direct and effective supporting role for the bone fragments of the posterolateral condyle, and the combination of both of them has obvious advantages in the treatment of posterolateral condylar fracture of the tibial plateau, and it is a method worth borrowing and popularizing., (© 2024. The Author(s).)

Chemotherapy is an important therapuetic strategy for colorectal cancer (CRC), but chemoresistance severely affects its efficacy, and the underlying mechanism has not been fully elucidated. Increasing evidence suggests that lipid peroxidation imbalance-mediated ferroptosis is closely associated with chemoresistance. Hence, targeting ferroptosis pathways or modulating the tolerance to oxidative stress might be an effective strategy to reverse tumor chemoresistance. HtrA serine protease 1 (HTRA1) was screened out as a CRC progression- and chemoresistance-related gene. It is highly expressed in CRC cells and negatively correlated with the prognosis of CRC patients. Gain- and loss-of-function analyses demonstrated a stimulatory role of HTRA1 on the proliferation of CRC cells. The enrichment analysis of HTRA1-interacting proteins indicated the involvement of ferroptosis in the HTRA1-mediated chemoresistance. Moreover, electron microscope analysis, as well as the ROS and MDA levels in CRC cells also confirmed the effect of HTRA1 on ferroptosis. We also verified that HTRA1 could interact with SLC7A11 through its Kazal structural domain and up-regulate the expression of SLC7A11, which in turn inhibited the ferroptosis and leaded to the chemoresistance of CRC cells to 5-FU/L-OHP. Hence, we propose that HTRA1 may be a potential therapeutic target and a prognostic indicator in CRC., (© 2024. The Author(s).)

Topological photonic crystals, which offer topologically protected and back-scattering-immune transport channels, have recently gained significant attention for both scientific and practical reasons. Although most current studies focus on dielectric materials with weak dispersions, this study focuses on topological phases in dispersive materials and presents a numerical study of Chern insulators in gaseous-phase plasma cylinder cells. We develop a numerical framework to address the complex material dispersion arising from the plasma medium and external magnetic fields and identify Chern insulator phases that are experimentally achievable. Using this numerical tool, we also explain the flat bands commonly observed in periodic plasmonic structures, via local resonances, and how edge states change as the edge termination is periodically modified. This work opens up opportunities for exploring band topology in new materials with non-trivial dispersions and has potential radio frequency (RF) applications, ranging from plasma-based lighting to plasma propulsion engines., (© 2023. The Author(s).)

Simple, rapid, and accurate detection of Fluoroquinolone (FQ) resistance is essential for early initiation of appropriate anti-tuberculosis treatment regimen among rifampicin-resistant tuberculosis (RR-TB). In this study, we developed a new assay, which combines multienzyme isothermal rapid amplification and a lateral flow strip (MIRA-LF), to identify the mutations on codons 90 and 94 of gyrA for detecting levofloxacin (LFX) resistance. Compared to conventional phenotypic drug susceptibility testing, the new assay detected fluoroquinolone resistance with a sensitivity, specificity, and accuracy of 92.4%, 98.5%, and 96.5%, respectively. Thus, these characteristics of the newly developed MIRA-LF assay make it particularly useful and accurate for detecting FQ resistance in Mycobacterium tuberculosis in resource-limited condition., (© 2023. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Edible rose is one of the main cash crops in Yunnan, China. Due to the high degree of lignification of rose stalks which is difficult to cut, and roses can only be pruned by hand after picking. Most of Yunnan Province is hilly landscape. Therefore, it is necessary to design an efficient small rose pruner for hills. Based on the experimental results of the physical and mechanical properties of rose stems, a simulation experiment of three different cutting methods was conducted to determine the optimal scheme. The results showed that single disc cutter is the best cutting method. An improved disc cutter with variable sliding angle is designed. In order to study the effects of the different structure parameters on the performance of the pruning machine and get the optimal combination of parameters, the orthogonal test was conducted. Forward speed, rotational speed of cutter, number of blades, cutting angle and knife-edge angle as factors, and the quality of pruning was selected as the evaluation index. The experiment results indicated that the working performance of machine was the highest when the number of blades was 6, rotational speed of cutter was 2000 rpm, cutting angle was 20°, knife-edge angle was 10°, forward speed was 0.5 m s -1 . The average quality of pruning index, miss cutting index and tearing index were 90.6%, 5.68% and 3.72%, respectively. The designed machine can meet the agronomic requirements of Yunnan edible rose pruning operation. The research provides a reference for the design and extending of the pruning machine for edible rose., (© 2023. The Author(s).)

N7-methyladenosine (m 7 G) modifications have been the subject of growing research interest with respect to their relationship with the progression and treatment of various cancers. This analysis was designed to examine the association between m 7 G-related gene expression and colorectal cancer (CRC) patient outcomes. Initial training analyses were performed using the TCGA dataset, with the GSE28722 dataset then being used to validate these results. Univariate Cox analyses were initially conducted to screen out prognostic m 7 G-related genes, after which a LASSO approach was used to construct an m 7 G risk score (MRS) model. Kaplan-Meier curves, ROC curves, and Cox analyses were subsequently used to validate the prognostic utility of this model in CRC patients. The R maftools package was further employed to assess mutational characteristics in CRC patients in different MRS subgroups, while the ESTIMATE, CIBERSORT, and ssGSEA tools were used to conduct immune infiltration analyses. A WGCNA was then performed to identify key immune-associated hub genes. The EIF4E3, GEMIN5, and NCBP2 genes were used to establish the MRS model. Patients with high MRS scores exhibited worse overall survival than patients with low scores. In Cox analyses, MRS scores were independently associated with CRC patient prognosis. Patients with low MRS scores exhibited a higher tumor mutational burden and higher levels of microsatellite instability. In immune infiltration analyses, higher immune checkpoint expression and greater immune cell infiltration were also observed in patients with low MRS scores. WGCNA analyses further identified 25 CD8+ T cell infiltration-associated genes. These findings suggest that MRS values represent a useful biomarker capable of differentiating among CRC patients with different immunological features and prognostic outcomes, offering an opportunity to better determine which patients are likely to benefit from immune checkpoint inhibitor treatment., (© 2022. The Author(s).)

The unique topology and physics of chiral superlattices make their self-assembly from nanoparticles highly sought after yet challenging in regard to (meta)materials 1-3 . Here we show that tetrahedral gold nanoparticles can transform from a perovskite-like, low-density phase with corner-to-corner connections into pinwheel assemblies with corner-to-edge connections and denser packing. Whereas corner-sharing assemblies are achiral, pinwheel superlattices become strongly mirror asymmetric on solid substrates as demonstrated by chirality measures. Liquid-phase transmission electron microscopy and computational models show that van der Waals and electrostatic interactions between nanoparticles control thermodynamic equilibrium. Variable corner-to-edge connections among tetrahedra enable fine-tuning of chirality. The domains of the bilayer superlattices show strong chiroptical activity as identified by photon-induced near-field electron microscopy and finite-difference time-domain simulations. The simplicity and versatility of substrate-supported chiral superlattices facilitate the manufacture of metastructured coatings with unusual optical, mechanical and electronic characteristics., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Different modeling techniques must be applied to manage production and statistical estimation to predict the expected harvest. By calculating advanced production methods and the rational valuation of different factors, we can accurately capture the variety of growth characteristics and the expected yield. This paper obtained 32 feature variables related to melons, including phenological features, shape features, and color features. The Gradient Boosted Decision Tree (GBDT) network and the Grid Search (GS) hyperparameter seeking method was applied to calculate the degree of importance of all melon fruits' characteristics and construct prediction models for three expected harvest indexes of melon yield, sugar content, and endocarp hardness. To facilitate growers to carry out prediction and estimation in the field without destroying the melon fruits. The reduced feature variables were selected as inputs. The GBDT model was used to provide a significant advantage in prediction compared to both Random Forest (RF) and Support Vector Regression (SVR) methods. In addition, to verify the feasibility of using only reduced feature variables as input for the evaluation work, this study also compares the predictive effects of the model when all feature variables and only reduced feature variables are used. The GBDT prediction model proposed in this paper predicted melon yield, sugar content, and hardness using reduced features as input, and the model R2 could reach more than 90%. Therefore, this method can effectively help growers carry out early non-destructive inspection and growth prediction of melons in the field., (© 2022. The Author(s).)

Accurate continuous non-invasive blood pressure (CNIBP) monitoring is the holy grail of digital medicine but remains elusive largely due to significant drifts in signal and motion artifacts that necessitate frequent device recalibration. To address these challenges, we developed a unique approach by creating a novel intra-beat biomarker (Diastolic Transit Time, DTT) to achieve highly accurate blood pressure (BP) estimations. We demonstrated our approach's superior performance, compared to other common signal processing techniques, in eliminating stochastic baseline wander, while maintaining signal integrity and measurement accuracy, even during significant hemodynamic changes. We applied this new algorithm to BP data collected using non-invasive sensors from a diverse cohort of high acuity patients and demonstrated that we could achieve close agreement with the gold standard invasive arterial line BP measurements, for up to 20 min without recalibration. We established our approach's generalizability by successfully applying it to pulse waveforms obtained from various sensors, including photoplethysmography and capacitive-based pressure sensors. Our algorithm also maintained signal integrity, enabling reliable assessments of BP variability. Moreover, our algorithm demonstrated tolerance to both low- and high-frequency motion artifacts during abrupt hand movements and prolonged periods of walking. Thus, our approach shows promise in constituting a necessary advance and can be applied to a wide range of wearable sensors for CNIBP monitoring in the ambulatory and inpatient settings., (© 2022. The Author(s).)

Primary liver cancer is the third leading cause of cancer death in the world, and the lack of effective treatments is the main reason for the high mortality. Corosolic acid (CA) has been proved to have antitumor activity. In this study, we found that CA can sensitize liver cancer cells to ferroptosis, which is a regulated form of cell death characterized by iron-dependent lipid peroxides reaching lethal levels. Here, we revealed that CA can inhibit glutathione (GSH) synthesis via HERPUD1, decreasing the cellular GSH level and causing liver cancer cells to become more sensitive to ferroptosis. Mechanistically, further studies found that HERPUD1 reduced the ubiquitination of the GSS-associated E3 ubiquitin ligase MDM2, which promoted ubiquitination of GSS, thereby inhibiting GSH synthesis to increase ferroptosis susceptibility. Importantly, a mouse xenograft model also demonstrated that CA inhibits tumor growth via HERPUD1. Collectively, our findings suggesting that CA is a candidate component for the development of treatments against liver cancer., (© 2022. The Author(s).)

Maize (Zea mays L.) is one of the most widely distributed and important crops in China. Maize ear differentiation plays an important role grain yield formation. However, it is unclear if ear and root morphophysiology status affects yield formation by altering ear differentiation and development under different nitrogen (N) conditions. The aim of this study is to understand how the ear differentiation and development are affected by ear and root morphophysiology traits, as affected by the N rate. The experiment consisted of two N rates: high nitrogen (180 kg ha -1 ), and low nitrogen (60 kg ha -1 ). Two N-efficient varieties (NEVs) and two N-inefficient varieties (NIVs) were grown in the field. The results showed higher nitrogen accumulation and grain yield in NEVs than in NIVs, which was mainly attributed to the increased N uptake by the larger root system under both N conditions. Under high N conditions, among ear differentiation-related traits, only FR was significantly positively correlated with grain yield, and NEVs ensure FR through higher N concentration and ZR content in ear at the fertilization stage. Under low N conditions, NEVs obtained higher FP, SR and FR through higher N concentration and IAA in ear at the early stage of ear differentiation, maintained lower AR and BTL by higher RA, R-ZR and E-ZR at the late stage of ear growth. These results suggest that NEVs have a more complex mechanism for obtaining higher grain yield under low N conditions than N sufficiency, and that phytohormones play an important role in this process., (© 2022. The Author(s).)

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels., (© 2022. The Author(s).)

To determine the differential impact of the irreversible eye diseases on vision-related quality of life (VRQoL) in a multi-ethnic Asian population. 2652 participants from the Singapore Epidemiology of Eye Disease Study, with any of the following early and late-stage eye conditions including age-related macular degeneration (AMD, n = 158), diabetic retinopathy (DR, n = 105; non vision threatening [non-VTDR]; VTDR), glaucoma (n = 57) and myopic macular degeneration (MMD, n = 106), or none of the above (controls, 2226 [83.9%]) were included. Rasch-scaled scores of the Emotional well-being Mobility and Reading subscales of the Impact of Vision Impairment (IVI) questionnaire, collectively referred to as "VRQoL" were assessed. Multivariable linear regression analyses and pairwise comparisons adjusting for age, gender, ethnicity, socio-economic status, BMI, smoking, alcohol use, presence of systemic diseases and presenting VI were performed to assess and compare the impact of the presence and severity of each eye condition on the three IVI domains. Multivariable adjusted pairwise comparisons of VRQoL between early stages of the four eye diseases showed no significant differences (all P > 0.05). For late stage diseases, individuals with VTDR had significantly larger decrements in Emotional well-being compared to glaucoma (β - 0.81; 95% CI - 1.47 to - 0.16) and MMD (β - 1.17; 95% CI - 2.16 to - 0.18); and Reading decrements compared to glaucoma (β - 0.66; 95% CI - 1.22 to - 0.11). When compared to late glaucoma, individuals with late AMD (β - 0.76; 95% CI - 1.50 to - 0.01) had significantly larger IVI Mobility subscale decrements. VTDR and late AMD, appear to have the greatest impact on VRQoL, compared to late glaucoma and MMD, suggesting a differential impact of late-stage eye disease categorization on VRQoL., (© 2022. The Author(s).)

Metastasis-initiating cells (MICs) display stem cell-like features, cause metastatic recurrences and defy chemotherapy, which leads to patients' demise. Here we show that prostate and breast cancer patients harbor contingents of tumor cells with high expression of CX3CR1, OCT4a (POU5F1), and NANOG. Impairing CX3CR1 expression or signaling hampered the formation of tumor spheroids by cell lines from which we isolated small subsets co-expressing CX3CR1 and stemness-related markers, similarly to patients' tumors. These rare CX3CR1 High cells show transcriptomic profiles enriched in pathways that regulate pluripotency and endowed with metastasis-initiating behavior in murine models. Cancer cells lacking these features (CX3CR1 Low ) were capable of re-acquiring CX3CR1-associated features over time, implying that MICs can continuously emerge from non-stem cancer cells. CX3CR1 expression also conferred resistance to docetaxel, and prolonged treatment with docetaxel selected CX3CR1 High phenotypes with de-enriched transcriptomic profiles for apoptotic pathways. These findings nominate CX3CR1 as a novel marker of stem-like tumor cells and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Breast cancer is the most common cancer worldwide. JWA is a microtubule-associated protein that has been identified as a tumor suppressor, and its downregulation in tumors is an independent adverse prognostic factor. The objective of this study was to explore the expression, regulation, and mechanism of JWA in trastuzumab-resistant breast cancers. In this study, we found that JWA expression was lower in trastuzumab-resistant breast cancers than that in trastuzumab-sensitive breast cancers. Furthermore, it was confirmed that overexpression of JWA inhibited proliferation and promoted apoptosis in trastuzumab-resistant breast cancers both in vitro and in vivo. In addition, the low expression of JWA in trastuzumab-resistant breast cancers is associated with a poor prognosis. Combining RNA-sequence datasets and next-generation sequencing, it was found that JWA negatively regulated CDK12, and was involved in the G1-to-S transition of the cell cycle. It has been reported that CDK12 drives breast cancer initiation and induces trastuzumab resistance. Taken together, high expression of JWA could inhibit the growth of trastuzumab-resistant breast cancer, and JWA is a potential predictive marker for trastuzumab resistance. In addition, targeted therapy with JWA may be a novel therapeutic strategy to improve the survival rate of trastuzumab-resistant breast cancer., (© 2021. The Author(s).)

Microcrystalline cellulose (MCC) was prepared easily from Rabdosia rubescens residue to realize the efficient utilization of waste resources. The yield was about 95.03% under the optimal conditions. Then, MCC membrane was prepared by phase transformation method and its structure and mechanical properties were studied systemically. The results showed the cellulose crystal structure changed from type I to type II in the process of forming membrane, and the thermal stability decreased simultaneously. The content of MCC in casting solution has great influence on the mechanical properties of membranes. The higher the content of MCC, the better the comprehensive mechanical properties of the membranes is. When MCC content is 9%, the tensile strength and elongation at break can reach 8.38 MPa and 26.72%, which is better than traditional cellulose membranes. Finally, the separation properties were studied by separation BSA from water. The results showed that the rejection rate and water flux changed positively and negatively with the change of MCC content. When the content was 5%, the membrane demonstrated the best comprehensive performance, its rejection for BSA was 37.23 g/(m 2  h), the corresponding rejection rate and water flux were 88.87% and 41.89 L/(m 2  h) respectively., (© 2021. The Author(s).)

Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeutic strategy. The extent to the N6-methyladenosine (m6A)-regulatory pathway functions in MM remains unknown. Here, we show that an imbalance of RNA methylation may underlies the tumorigenesis of MM. Mechanistically, isocitrate dehydrogenase 2 (IDH2) is highly expressed in CD138 + cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

We collected blood from coronavirus disease 2019 (COVID-19) convalescent individuals and investigated SARS-CoV-2-specific humoral and cellular immunity in these discharged patients. Follow-up analysis in a cohort of 171 patients at 4-11 months after the onset revealed high levels of IgG antibodies. A total of 78.1% (164/210) of the specimens tested positive for neutralizing antibody (NAb). SARS-CoV-2 antigen peptide pools-stimulated-IL-2 and -IFN-γ response can distinguish COVID-19 convalescent individuals from healthy donors. Interestingly, NAb survival was significantly affected by the antigen peptide pools-stimulated-IL-2 response, -IL-8 response, and -IFN-γ response. The antigen peptide pools-activated CD8+ T cell counts were correlated with NAb. The antigen peptide pools-activated natural killer (NK) cell counts in convalescent individuals were correlated with NAb and disease severity. Our data suggested that the development of NAb is associated with the activation of T cells and NK cells. Our work provides a basis for further analysis of the protective immunity to SARS-CoV-2 and for understanding the pathogenesis of COVID-19. It also has implications for the development of an effective vaccine for SARS-CoV-2 infection.

T follicular helper (T FH ) cells are crucial for B cell-mediated humoral immunity 1 . Although transcription factors such as BCL6 drive the differentiation of T FH cells 2,3 , it is unclear whether and how post-transcriptional and metabolic programs enforce T FH cell programming. Here we show that the cytidine diphosphate (CDP)-ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of T FH cells and humoral immunity. Using in vivo CRISPR-Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI-enzymes in the CDP-ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)-as selective post-transcriptional regulators of T FH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. T FH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP-ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP-choline pathway), in activated T cells impairs the differentiation of T FH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for T FH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The efficiency of nanoparticle (NP) solar cells has grown impressively in recent years, exceeding 16%. However, the carrier mobility in NP solar cells, and in other optoelectronic applications remains low, thus critically limiting their performance. Therefore, carrier transport in NP solids needs to be better understood to further improve the overall efficiency of NP solar cell technology. However, it is technically challenging to simulate experimental scale samples, as physical processes from atomic to mesoscopic scales all crucially impact transport. To rise to this challenge, here we report the development of TRIDENS: the Transport in Defected Nanoparticle Solids Simulator, that adds three more hierarchical layers to our previously developed HINTS code for nanoparticle solar cells. In TRIDENS, we first introduced planar defects, such as twin planes and grain boundaries into individual NP SLs superlattices (SLs) that comprised the order of 10 3 NPs. Then we used HINTS to simulate the transport across tens of thousands of defected NP SLs, and constructed the distribution of the NP SL mobilities with planar defects. Second, the defected NP SLs were assembled into a resistor network with more than 10 4 NP SLs, thus representing about 10 7 individual NPs. Finally, the TRIDENS results were analyzed by finite size scaling to explore whether the percolation transition, separating the phase where the low mobility defected NP SLs percolate, from the phase where the high mobility undefected NP SLs percolate drives a low-mobility-to-highmobility transport crossover that can be extrapolated to genuinely macroscopic length scales. For the theoretical description, we adapted the Efros-Shklovskii bimodal mobility distribution percolation model. We demonstrated that the ES bimodal theory's two-variable scaling function is an effective tool to quantitatively characterize this low-mobility-to-high-mobility transport crossover.

Metastatic melanoma remains a challenging disease. Understanding the molecular mechanisms how melanoma becomes metastatic is therefore of interest. Herein we show that downregulation of the AP-1 transcription factor member Fra-2 in melanoma cells is associated with an aggressive melanoma phenotype in vitro and in vivo. In vitro, Fra-2 knockdown in melanoma cells promoted cell migration and invasion associated with increased Snail-1, Twist-1/2, and matrix metalloproteinase-2 (MMP-2) expression. In vivo, Fra-2 knockdown in a melanoma cell line led to increased metastasis into the lungs and liver. The increased metastatic potential of Fra-2 knockdown melanoma cells was likely due to an accelerated cell cycle transition and increased tissue angiogenesis. Using Fra-2 knockdown cell lines microarray analysis, we identified the protein Fam212b (family with sequence similarity 212 member B) as a downstream target of Fra-2. By additional knockdown of Fam212b in Fra-2 mutant cells, we mitigated the cell migration, invasion, and cell cycle transition phenotype induced by Fra-2 knockdown. Furthermore, Fam212b overexpression enhanced β-catenin pathway. Finally, Fam212b expression is correlated with increased melanoma metastasis and poor clinical outcomes in human patients. In summary, these findings reveal the Fra-2-Fam212b axis as a new pathway of melanoma metastasis, which can be in the future used as potential marker of the metastatic properties of melanoma.

USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of > 200 T-ALL transcriptomes linked USP7 haploinsufficiency with decreased activities of E-proteins. E-proteins are also negatively regulated by TAL1, leading to concerted down-regulation of E-protein target genes involved in T-cell development. In T-ALL cell lines, we showed the physical interaction of USP7 with E-proteins and TAL1 by mass spectrometry and ChIP-seq. Haploinsufficient but not complete CRISPR knock-out of USP7 showed accelerated cell growth and validated transcriptional down-regulation of E-protein targets. Our study unveiled the synergistic effect of USP7 haploinsufficiency with aberrant TAL1 activation on T-ALL, implicating USP7 as a haploinsufficient tumor suppressor in T-ALL. Our findings caution against a universal oncogene designation for USP7 while emphasizing the dosage-dependent consequences of USP7 inhibitors currently under development as potential cancer therapeutics.

The accurate and prompt diagnosis of SARS-CoV-2 infection is required for the control and treatment of the coronavirus infection disease 2019 (COVID-19). In this study, we aimed to investigate the time courses of the anti-severe acute corona respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and IgG titers and to evaluate the sensitivity and specificity of such tests according to the specific day after the onset of COVID-19 among a patient population in Japan. We measured the titers of SARS-CoV-2 IgM and IgG in sera from 105 subjects, including 26 symptomatic COVID-19 patients, using chemiluminescent immunoassay (CLIA) methods utilizing magnetic beads coated with SARS-CoV-2 nucleocapsid protein and spike protein. The results of a ROC analysis suggested the possibility that the cutoff values in Japan might be lower than the manufacturer's reported cutoff (10 AU/mL): 1  AU/mL for IgM and 5  AU/mL for IgG. The sensitivity of the test before Day 8 after symptom onset was less than 50%; at Days 9-10, however, we obtained a much higher sensitivity of 81.8% for both IgM and IgG. At 15 days or later after symptom onset, the SARS-CoV-2 IgG test had a sensitivity of 100%. These results suggest that if the number of days since disease onset is taken into consideration, these antibody tests could be very useful for the diagnosis of COVID-19 and similar diseases.

The biological processes involved in a drug's mechanisms of action are oftentimes dynamic, complex and difficult to discern. Time-course gene expression data is a rich source of information that can be used to unravel these complex processes, identify biomarkers of drug sensitivity and predict the response to a drug. However, the majority of previous work has not fully utilized this temporal dimension. In these studies, the gene expression data is either considered at one time-point (before the administration of the drug) or two time-points (before and after the administration of the drug). This is clearly inadequate in modeling dynamic gene-drug interactions, especially for applications such as long-term drug therapy. In this work, we present a novel REcursive Prediction (REP) framework for drug response prediction by taking advantage of time-course gene expression data. Our goal is to predict drug response values at every stage of a long-term treatment, given the expression levels of genes collected in the previous time-points. To this end, REP employs a built-in recursive structure that exploits the intrinsic time-course nature of the data and integrates past values of drug responses for subsequent predictions. It also incorporates tensor completion that can not only alleviate the impact of noise and missing data, but also predict unseen gene expression levels (GEXs). These advantages enable REP to estimate drug response at any stage of a given treatment from some GEXs measured in the beginning of the treatment. Extensive experiments on two datasets corresponding to multiple sclerosis patients treated with interferon are included to showcase the effectiveness of REP.

Coral reefs are in alarming decline due to climate emergency, pollution and other man-made disturbances. The numerous ecosystem services derived from coral reefs are underpinned by the growth and physical complexity of reef-forming corals. Our knowledge of their fundamental biology is limited by available technology. We need a better understanding of larval settlement and development, skeletogenesis, interactions with pathogens and symbionts, and how this biology interacts with environmental factors such as light exposure, temperature, and ocean acidification. We here focus on a fast-growing key coloniser, Acropora muricata (Linnaeus, 1758). To enable dynamic imaging of this photosensitive organism at different scales, we developed light-sheet illumination for fluorescence microscopy of small coral colonies. Our approach reveals live polyps in previously unseen detail. An imaging range for Acropora muricata with no measurable photodamage is defined based upon polyp expansion, coral tissue reaction, and photobleaching. We quantify polyp retraction as a photosensitive behavioural response and show coral tissue rupture at higher irradiance with blue light. The simple and flexible technique enables non-invasive continuous dynamic imaging of highly photosensitive organisms with sizes between 1 mm 3 and 5 cm 3 , for eight hours, at high temporal resolution, on a scale from multiple polyps down to cellular resolution. This live imaging tool opens a new window into the dynamics of reef-building corals.

Förster Resonance Energy Transfer (FRET) allows for the visualization of nanometer-scale distances and distance changes. This sensitivity is regularly achieved in single-molecule experiments in vitro but is still challenging in biological materials. Despite many efforts, quantitative FRET in living samples is either restricted to specific instruments or limited by the complexity of the required analysis. With the recent development and expanding utilization of FRET-based biosensors, it becomes essential to allow biologists to produce quantitative results that can directly be compared. Here, we present a new calibration and analysis method allowing for quantitative FRET imaging in living cells with a simple fluorescence microscope. Aside from the spectral crosstalk corrections, two additional correction factors were defined from photophysical equations, describing the relative differences in excitation and detection efficiencies. The calibration is achieved in a single step, which renders the Quantitative Three-Image FRET (QuanTI-FRET) method extremely robust. The only requirement is a sample of known stoichiometry donor:acceptor, which is naturally the case for intramolecular FRET constructs. We show that QuanTI-FRET gives absolute FRET values, independent of the instrument or the expression level. Through the calculation of the stoichiometry, we assess the quality of the data thus making QuanTI-FRET usable confidently by non-specialists.

Flowering time is one of the most critical traits for plants' life cycles, which is influenced by various environment changes, such as global warming. Previous studies have suggested that to guarantee reproductive success, plants have shifted flowering times to adapt to global warming. Although many studies focused on the molecular mechanisms of early flowering, little was supported by the repeated sampling at different time points through the changing climate. To fully dissect the temporal and spatial evolutionary genetics of flowering time, we investigated nucleotide variation in ten flowering time candidate genes and nine reference genes for the same ten wild-barley populations sampled 28 years apart (1980-2008). The overall genetic differentiation was significantly greater in the descendant populations (2008) compared with the ancestral populations (1980); however, local adaptation tests failed to detect any single-nucleotide polymorphism (SNP)/indel under spatial-diversifying selection at either time point. By contrast, the WFABC (Wright-Fisher ABC-based approach) that detected 54 SNPs/indels was under strong selection during the past 28 generations. Moreover, all these 54 alleles were segregated in the ancestral populations, but fixed in the descendent populations. Among the top ten SNPs/indels, seven were located in genes of FT1 (FLOWERING TIME LOCUS T 1), CO1 (CONSTANS-LIKE PROTEIN 1), and VRN-H2 (VERNALIZATION-H2), which have been documented to be associated with flowering time regulation in barley cultivars. This study might suggest that all ten populations have undergone parallel evolution over the past few decades in response to global warming, and even an overwhelming local adaptation and ecological differentiation.

Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells 1 . Here we use an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8 + T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8 + T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8 + T cells. By contrast, the targeting of additional signalling factors-including PTPN2 and SOCS1-improves the therapeutic efficacy of REGNASE-1-deficient CD8 + T cells. Our findings suggest that T cell persistence and effector function can be coordinated in tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.

In mammals, urorectal development starts at early embryonic stage, defective urorectal development results in anorectal malformations, which are common congenital developmental defects of the anus and the urethra in newborns. The etiology and embryology of the defects are still largely unknown. Platelet-derived growth factor receptor alpha (Pdgfra) is a cell surface receptor tyrosine kinase, upon binding to its ligands (Pdgfa-d), mediates intracellular signaling and regulates embryonic development. The expression of Pdgfra is tightly regulated in the developing urorectal mesenchyme, and its dysregulation is associated with urorectal defects in animals with urorectal defects. Knockout of Pdgfra induces early embryo lethality which precludes investigation of Pdgfra in urorectal development. To address the temporal requirement of Pdgfra in urorectal development, we conditionally deleted Pdgfra in Pdgfra-expressing tissues using a tamoxifen inducible Cre-loxP approach in mice, examined the urorectal development in Pdgfra conditional knockout (Pdgfra-cKO) embryos. We showed that conditional deletion of Pdgfra in Pdgfra-expressing tissues at E10-E11 caused cloaca septation defect, anteriorly displaced anus, defective urogenital folds development and abnormal urethra tubularization in both male and female mice. Furthermore, we showed that Pdgfra was required for the survival of urorectal mesenchyme, deletion of Pdgfra caused apoptosis in the peri-cloacal, the peri-urethra and the urorectal septum mesenchyme of Pdgfra-cKO mutants, associated with an induction of p53, Ndrg1 and activation of caspase-3 in Pdgfra-cKO embryos. In conclusion, Pdgfra is required for the development and survival of the urorectal mesenchyme in embryo, dysregulated Pdgfra signaling induced urorectal defects in mice resembling human congenital diseases of anorectal malformations and hypospadias. Perturbation of PDGFRA signaling may contribute to anorectal malformations and hypospadias in human.

Dendritic cells (DCs) play a pivotal role in priming adaptive immunity. However, the involvement of DCs in controlling excessive and deleterious T cell responses remains poorly defined. Moreover, the metabolic dependence and regulation of DC function are unclear. Here we show that LKB1 signaling in DCs functions as a brake to restrain excessive tumor-promoting regulatory T cell (Treg) and Th17 cell responses, thereby promoting protective anti-tumor immunity and maintaining proper immune homeostasis. LKB1 deficiency results in dysregulated metabolism and mTOR activation of DCs. Loss of LKB1 also leads to aberrant DC maturation and production of cytokines and immunoregulatory molecules. Blocking mTOR signaling in LKB1-deficient DCs partially rectifies the abnormal phenotypes of DC activation and Treg expansion, whereas uncontrolled Th17 responses depend upon IL-6-STAT3 signaling. By coordinating metabolic and immune quiescence of DCs, LKB1 acts as a crucial signaling hub in DCs to enforce protective anti-tumor immunity and normal immune homeostasis.

Multiple myeloma (MM) is characterized by the decreased osteogenic potential of mesenchymal stem cells (MSCs). Communication between cancer cells and cancer stromal cells is a driving factor in tumor progression. Understanding the myeloma-stroma interactions is critical to the development of effective strategies that can reverse bone diseases. Here we identified that bioactive lncRNA RUNX2-AS1 in myeloma cells could be packed into exosomes and transmitted to MSCs, thus repressing the osteogenesis of MSCs. RUNX2-AS1, which arises from the antisense strand of RUNX2, was enriched in MSCs derived from MM patients (MM-MSCs). RUNX2-AS1 was capable of forming an RNA duplex with RUNX2 pre-mRNA at overlapping regions and this duplex transcriptionally repressed RUNX2 expression by reducing the splicing efficiency, resulting in decreased osteogenic potential of MSCs. In vivo mouse models, administered an inhibitor of exosome secretion, GW4869, was found to be effective in preventing bone loss, sustained by both bone formation and anticatabolic activities. Therefore, exosomal lncRNA RUNX2-AS1 may serve as a potential therapeutic target for bone lesions in MM. In summary, our results indicated a key role of exosomal lncRUNX2-AS1 in transferring from MM cells to MSCs in osteogenic differentiation, through a unique exosomal lncRUNX2-AS1/RUNX2 pathway.

Stem cell therapy may provide a safe and promising treatment for retinal diseases. Wet age-related macular degeneration (wet-AMD) is a leading cause of blindness in China. We developed a clinical-grade human embryonic stem cell (hESC) line, Q-CTS-hESC-2, under xeno-free conditions that differentiated into retinal pigment epithelial cells (Q-CTS-hESC-2-RPE). A clinical trial with three wet-AMD patients was initiated in order to study the safety and tolerance to Q-CTS-hESC-2-RPE cell transplants. The choroidal neovascularization membrane was removed and then a suspension of 1 × 10 6 Q-CTS-hESC-2-RPE cells were injected into a subfoveal pocket. The patients were followed for 12 months during which no adverse effects resulting from the transplant were observed. Anatomical evidence suggested the existence of new RPE-like cell layer in the previously damaged area. Visual and physiological testing indicated limited functional improvement, albeit to different degrees between patients. This study provides some promising early results concerning the use of transplanted hESC-RPE cells to alleviate wet-AMD., Competing Interests: The authors declare that they have no conflict of interest.

Research into gene therapy for heart failure has gained renewed interest as a result of improved safety and availability of adeno-associated viral vectors (AAV). While magnetic resonance imaging (MRI) is standard for functional assessment of gene therapy outcomes, quantitation of gene transfer/expression relies upon tissue biopsy, fluorescence or nuclear imaging. Imaging of gene expression through the use of genetically encoded chemical exchange saturation transfer (CEST)-MRI reporter genes could be combined with clinical cardiac MRI methods to comprehensively probe therapeutic gene expression and subsequent outcomes. The CEST-MRI reporter gene Lysine Rich Protein (LRP) was cloned into an AAV9 vector and either administered systemically via tail vein injection or directly injected into the left ventricular free wall of mice. Longitudinal in vivo CEST-MRI performed at days 15 and 45 after direct injection or at 1, 60 and 90 days after systemic injection revealed robust CEST contrast in myocardium that was later confirmed to express LRP by immunostaining. Ventricular structure and function were not impacted by expression of LRP in either study arm. The ability to quantify and link therapeutic gene expression to functional outcomes can provide rich data for further development of gene therapy for heart failure.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for treatment of some malignant and non-malignant hematological diseases. However, post-HSCT patients are severely immunocompromised and susceptible to viral infections, which are a major cause of morbidity and mortality. Although antiviral agents are now available for most types of viral infections, they are not devoid of side effects and their efficacy is limited when there is no concomitant antiviral immune reconstitution. In recent decades, adoptive transfer of viral-specific T cells (VSTs) became an alternative treatment for viral infection after HSCT. However, two major issues are concerned in VST transfer: the risk of GVHD and antiviral efficacy. We report an exhaustive review of the published studies that focus on prophylactic and/or curative therapy by donor VST transfer for post-HSCT common viral infections. A low incidence of GVHD and a good antiviral efficacy was observed after adoptive transfer of VSTs from HSCT donor. Viral-specific T-cell transfer is a promising approach for a broad clinical application. Nevertheless, a randomized controlled study in a large cohort of patients comparing antiviral treatment alone to antiviral treatment combined with VSTs is still needed to demonstrate efficacy and safety.

QianghuoErhuang Decoction (QED) is an effective recipe in treating rheumatoid arthritis. The present study aimed to explore the effects of QED on Treg and Th17 in adjuvant arthritis (AA) model. The study included 6 group rats: normal control group, AA group, AA + methotrexate (MTX) group, AA + high, moderate, and low dose QED groups. The arthritis score was significantly decreased in the MTX and high-dose QED groups compared with the AA group on days 24 and 28 (P < 0.01), respectively. The synovial tissue inflammation was attenuated by histological observation, and the proliferation of splenocytes was significantly inhibited in MTX and high-dose QED groups (P < 0.01). High-dose QED can up-regulated the percentage of Treg cells (P < 0.01) and down-regulated the percentage of Th17 cells (P < 0.05). Notably, the serum levels of IL-6, IL-17 and TNF-α were significantly decreased, while TGF-β levels were apparently elevated compared with AA group (P < 0.05, P < 0.01). Interestingly, moderate and low-dose QED had no such similar effects. In summary, high-dose QED had a therapeutic effect against adjuvant arthritis and regulated the related cytokine levels in serum. The underlying mechanism might be mediated via restoration of the imbalance in CD4 + T lymphocyte subsets, Treg/Th17.

A Wireless Amplified NMR Detector (WAND) with cylindrical symmetry has been fabricated and non-surgically inserted into a rodent lower digestive track to improve the imaging quality of deep-lying vessels inside the abdominal cavity. This symmetric detector has a compact design using two end-rings and two vertical legs to create two orthogonal resonance modes. Based on the principle of parametric amplification, the detector can harvest wireless pumping power with its end-rings and amplify Magnetic Resonance signals induced on its vertical legs. With good longitudinal and azimuthal homogeneity, the WAND can achieve up to 21-times sensitivity gain over a standard external detector for immediately adjacent regions, and at least 5-times sensitivity gain for regions separated by one diameter away from the detector's cylindrical surface. The WAND can approach the region of interest through the lower digestive track, similar as a colonoscopy detector. But unlike an optical camera, the amplified MR detector can "see" across intestinal boundaries and clearly identify the walls of bifurcated vessels that are susceptible to atherosclerotic lesions. In addition to vascular wall imaging, this detector may also be used as a swallowable capsule to enhance the detection sensitivity of deep-lying organs near the digestive track.

Specific size, shape and surface chemistry influence the biological activity of nanoparticles. In the case of lipophilic nanoparticles, which are widely used in consumer products, there is evidence that particle size and formulation influences skin permeability and that lipophilic particles smaller than 6 nm can embed in lipid bilayers. Since most nanoparticle synthetic procedures result in mixtures of different particles, post-synthetic purification promises to provide insights into nanostructure-function relationships. Here we used size-selective precipitation to separate lipophilic allyl-benzyl-capped silicon nanoparticles into monodisperse fractions within the range of 1 nm to 5 nm. We measured liposomal encapsulation and cellular uptake of the monodisperse particles and found them to have generally low cytotoxicities in Hela cells. However, specific fractions showed reproducibly higher cytotoxicity than other fractions as well as the unseparated ensemble. Measurements indicate that the cytotoxicity mechanism involves oxidative stress and the differential cytotoxicity is due to enhanced cellular uptake by specific fractions. The results indicate that specific particles, with enhanced suitability for incorporation into lipophilic regions of liposomes and subsequent in vitro delivery to cells, are enriched in certain fractions.

Transient receptor potential vanilloid 4 (TRPV4) is a Ca 2+ -permeable nonselective cation channel and can be activated during ischemia/reperfusion (I/R). This study tested whether blockade of TRPV4 can alleviate myocardial I/R injury in mice. TRPV4 expression began to increase at 1 h, reached statistically at 4 h, and peaked at 24-72 h. Treatment with the selective TRPV4 antagonist HC-067047 or TRPV4 knockout markedly ameliorated myocardial I/R injury as demonstrated by reduced infarct size, decreased troponin T levels and improved cardiac function at 24 h after reperfusion. Importantly, the therapeutic window for HC-067047 lasts for at least 12 h following reperfusion. Furthermore, treatment with HC-067047 reduced apoptosis, as evidenced by the decrease in TUNEL-positive myocytes, Bax/Bcl-2 ratio, and caspase-3 activation. Meanwhile, treatment with HC-067047 attenuated the decrease in the activation of reperfusion injury salvage kinase (RISK) pathway (phosphorylation of Akt, ERK1/2, and GSK-3β), while the activation of survival activating factor enhancement (SAFE) pathway (phosphorylation of STAT3) remained unchanged. In addition, the anti-apoptotic effects of HC-067047 were abolished by the RISK pathway inhibitors. We conclude that blockade of TRPV4 reduces apoptosis via the activation of RISK pathway, and therefore might be a promising strategy to prevent myocardial I/R injury.

The complete mitochondrial genome (mitogenome) of Leucoma salicis (Lepidoptera: Lymantriidae) was sequenced and annotated. It is a circular molecule of 15,334 bp, containing the 37 genes usually present in insect mitogenomes. All protein-coding genes (PCGs) are initiated by ATN codons, other than cox1, which is initiated by CGA. Three of the 13 PCGs had an incomplete termination codon, T or TA, while the others terminated with TAA. The relative synonymous codon usage of the 13 protein-coding genes (PCGs) was consistent with those of published lepidopteran sequences. All tRNA genes had typical clover-leaf secondary structures, except for the tRNA Ser (AGN), in which the dihydrouridine (DHU) arm could not form a stable stem-loop structure. The A + T-rich region of 325 bp had several distinctive features, including the motif 'ATAGA' followed by an 18 bp poly-T stretch, a microsatellite-like (AT) 7 element, and an 11-bp poly-A present immediately upstream of tRNA Met . Relationships among 32 insect species were determined using Maximum Likelihood (ML), Neighbor Joining (NJ) and Bayesian Inference (BI) phylogenetic methods. These analyses confirm that L. salicis belongs to the Lymantriidae; and that Lymantriidae is a member of Noctuoidea, and is a sister taxon to Erebidae, Nolidae and Noctuidae, most closely related to Erebidae.

The aims of this study were to fabricate a novel titanium/silicon carbide (Ti/SiC) metal matrix nanocomposite (MMNC) by friction stir processing (FSP) and to investigate its microstructure and mechanical properties. In addition, the adhesion, proliferation and osteogenic differentiation of rat bone marrow stromal cells (BMSCs) on the nanocomposite surface were investigated. The MMNC microstructure was observed by both scanning and transmission electron microscopy. Mechanical properties were characterized by nanoindentation and Vickers hardness testing. Integrin β1 immunofluorescence, cell adhesion, and MTT assays were used to evaluate the effects of the nanocomposite on cell adhesion and proliferation. Osteogenic and angiogenic differentiation were evaluated by alkaline phosphatase (ALP) staining, ALP activity, PCR and osteocalcin immunofluorescence. The observed microstructures and mechanical properties clearly indicated that FSP is a very effective technique for modifying Ti/SiC MMNC to contain uniformly distributed nanoparticles. In the interiors of recrystallized grains, characteristics including twins, fine recrystallized grains, and dislocations formed concurrently. Adhesion, proliferation, and osteogenic and angiogenic differentiation of rat BMSCs were all enhanced on the novel Ti/SiC MMNC surface. In conclusion, nanocomposites modified using FSP technology not only have superior mechanical properties under stress-bearing conditions but also provide improved surface and physicochemical properties for cell attachment and osseointegration.