TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer.

Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance.

A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs.

Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM-like organoid (LEGO: Laboratory Engineered Glioblastoma-like Organoid) models and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides new human GBM models and a research path toward effective GBM therapy.

Climate warming could free cold-adapted trees from C-conservative allocation strategy of storage over growth.

Carbon allocation has been fundamental for long-lived trees to survive cold stress at their upper elevation range limit. Although carbon allocation between non-structural carbohydrate (NSC) storage and structural growth is well-documented, it still remains unclear how ongoing climate warming influences these processes, particularly whether these two processes will shift in parallel or respond divergently to warming. Using a combination of an in situ downward-transplant warming experiment and an ex situ chamber warming treatment, we investigated how subalpine fir trees at their upper elevation limit coordinated carbon allocation priority among different sinks (e.g., NSC storage and structural growth) at whole-tree level in response to elevated temperature. We found that transplanted individuals from the upper elevation limit to lower elevations generally induced an increase in specific leaf area, but there was no detected evidence of warming effect on leaf-level saturated photosynthetic rates. Additionally, our results challenged the expectation that climate warming will accelerate structural carbon accumulation while maintaining NSC constant. Instead, individuals favored allocating available carbon to NSC storage over structural growth after 1 year of warming, despite the amplification in total biomass encouraged by both in situ and ex situ experimental warming. Unexpectedly, continued warming drove a regime shift in carbon allocation priority, which was manifested in the increase of NSC storage in synchrony to structural growth enhancement. These findings imply that climate warming would release trees at their cold edge from C-conservative allocation strategy of storage over structural growth. Thus, understanding the strategical regulation of the carbon allocation priority and the distinctive function of carbon sink components is of great implication for predicting tree fate in the future climate warming.

Distinct aneuploid evolution of astrocytoma and glioblastoma during recurrence.

Astrocytoma and glioblastoma (GB) are reclassified subtypes of adult diffuse gliomas based on distinct isocitrate dehydrogenase (IDH) mutation in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The recurrence of gliomas is a common and inevitable challenge, and analyzing the distinct genomic alterations in astrocytoma and GB could provide insights into their progression. This study conducted a longitudinal investigation, utilizing whole-exome sequencing, on 65 paired primary/recurrent gliomas. It examined chromosome arm aneuploidies, copy number variations (CNVs) of cancer-related genes and pathway enrichments during the relapse. The veracity of these findings was verified through the integration of our data with multiple public resources and by corroborative immunohistochemistry (IHC). The results revealed a greater prevalence of aneuploidy changes and acquired CNVs in recurrent lower grade astrocytoma than in relapsed grade 4 astrocytoma and GB. Larger aneuploidy changes were predictive of an unfavorable prognosis in lower grade astrocytoma (P < 0.05). Further, patients with acquired gains of 1q, 6p or loss of 13q at recurrence had a shorter overall survival in lower grade astrocytoma (P < 0.05); however, these prognostic effects were confined in grade 4 astrocytoma and GB. Moreover, acquired gains of 12 genes (including VEGFA) on 6p during relapse were associated with unfavorable prognosis for lower grade astrocytoma patients. Notably, elevated VEGFA expression during recurrence corresponded to poorer survival, validated through IHC and CGGA data. To summarize, these findings offer valuable insights into the progression of gliomas and have implications for guiding therapeutic approaches during recurrence.

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1.

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.

Enhanced Electrochemical Performance of Metallic CoS-Based Supercapacitor by Cathodic Exfoliation.

Two-dimensional nanomaterials hold great promise as electrode materials for the construction of excellent electrochemical energy storage and transformation apparatuses. In the study, metallic layered cobalt sulfide was, firstly, applied to the area of energy storage as a supercapacitor electrode. By a facile and scalable method for cathodic electrochemical exfoliation, metallic layered cobalt sulfide bulk can be exfoliated into high-quality and few-layered nanosheets with size distributions in the micrometer scale range and thickness in the order of several nanometers. With a two-dimensional thin sheet structure of metallic cobalt sulfide nanosheets, not only was a larger active surface area created, but also, the insertion/extraction of ions in the procedure of charge and discharge were enhanced. The exfoliated cobalt sulfide was applied as a supercapacitor electrode with obvious improvement compared with the original sample, and the specific capacitance increased from 307 F∙g-1 to 450 F∙g-1 at the current density of 1 A∙g-1. The capacitance retention rate of exfoliated cobalt sulfide enlarged to 84.7% from the original 81.9% of unexfoliated samples while the current density multiplied by 5 times. Moreover, a button-type asymmetric supercapacitor assembled using exfoliated cobalt sulfide as the positive electrode exhibits a maximum specific energy of 9.4 Wh∙kg-1 at the specific power of 1520 W∙kg-1.

Tb3+ and Sm3+ co-doped Ca2La3(SiO4)3F phosphor: synthesis, color regulation, and luminescence properties.

The polychromatic phosphor with an apatite structure Ca2La3(SiO4)3F:0.15Tb3+,xSm3+ (CLSOF:0.15Tb3+,xSm3+) was synthesized via a solid-state route. The phase and morphology of the phosphor has been investigated by means of X-ray diffraction (XRD) and scanning electron microscopy (SEM). The structures of the as-prepared phosphor were verified by means of the Rietveld method. The optical performance was investigated thoroughly and the phosphors could emit multicolor light from short wavelengths to long wavelengths by gradually increasing the doping contents of samarium. All the results support that the energy transfer in CLSOF:0.15Tb3+,xSm3+ contributes to the color tunable property of the phosphor.

Defective 2D silicon phosphide monolayers for the nitrogen reduction reaction: a DFT study.

Electroreduction of N2 is a highly promising route for NH3 production. The lack of efficient catalysts that can activate and then reduce N2 into NH3 limits this as a pragmatic application. In this work, a 2D layered group IV-V material, silicon phosphide (SiP), is evaluated as a suitable substrate for the electrochemical nitrogen reduction reaction (ENRR). To capture N2, one phosphorus (P) defect was introduced on the plane of SiP. DFT calculations found that the defective SiP monolayer (D1-SiP, which is defined by the P-defect on SiP) exhibits enormous prospects towards the ENRR because of enhanced electron conductivity, good activation on N2, lower limiting potential (UL = -0.87 V) through the enzymatic pathway, smooth charge transfer between the catalyst and the reaction species, and robust thermal stability. Importantly, D1-SiP demonstrates the suppressed activities on producing of H2 and N2H4 side-products. This research demonstrates the potential of 2D metal-free Si-based catalysts for nitrogen fixation and further enriches the study of group IV-V materials for the ENRR.

Structure and Photoluminescence Properties of Dy3+ Doped Phosphor with Whitlockite Structure.

Whitlockite has the advantages of a low sintering temperature, high stability, and a low fabrication cost, and it is widely used as the host for luminescent material. In this study, Ca1.8Li0.6La0.6-x(PO4)2:xDy3+ phosphor was prepared by the high-temperature solid-state method, and its structure, composition, and luminescence properties were systematically studied. The results showed that a new whitlockite type matrix was prepared by replacing Ca2+ in whitlockite with monovalent and trivalent cations. The prepared phosphors belonged to a hexagonal crystal system with a particle size in the range of 5-20 µm. Under the excitation of 350 nm UV light, the samples emitted white light, and there were mainly two stronger emission peaks at 481 nm in the blue band and 573 nm in the yellow band, which correspond to the electron transitions at 4F9/2→6H15/2 and 4F9/2→6H13/2 of Dy3+, respectively. The optimal doping concentration of Dy3+ in Ca1.8Li0.6La0.6(PO4)2 matrix was 0.03 (mol%). The main mechanism of concentration quenching in the sample was dipole-dipole energy transfer. When the temperature was 130 °C, the luminescence intensity of the samples was 78.7% of that at 30 °C, and their thermal quenching activation energy was 0.25 eV. The CIE coordinates of the sample at 30 °C were (0.2750, 0.3006), and their luminescent colors do not change with temperature. All the results indicate that Ca1.8Li0.6La0.6-x(PO4)2:xDy3+ phosphor is a luminescent material with good luminescence performance and thermal stability, which shows a promising application in the field of LED display.

Nanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis.

Atherosclerosis and atherothrombosis, the major contributors to cardiovascular diseases (CVDs), represent the leading cause of death worldwide. Current pharmacological therapies have been associated with side effects or are insufficient at halting atherosclerotic progression effectively. Pioneering work harnessing the passive diffusion or endocytosis properties of nanoparticles and advanced biotechnologies in creating recombinant proteins for site-specific delivery have been utilized to overcome these limitations. Since CVDs are complex diseases, the most challenging aspect of developing site-specific therapies is the identification of an individual and unique antigenic epitope that is only expressed in lesions or diseased areas. This review focuses on the pathological mechanism of atherothrombosis and discusses the unique targets that are important during disease progression. We review recent advances in site-specific therapy using novel targeted drug-delivery and nanoparticle-carrier systems. Furthermore, we explore the limitations and future perspectives of site-specific therapy for CVDs.

Structure, luminescence properties and energy transfer of terbium and samarium co-doped barium based apatite phosphor with tunable emission colour.

Ba2La2.85-x Tb0.15Sm x (SiO4)3F (BLSOF:0.15Tb3+,xSm3+) is a polychromatic phosphor with an apatite structure that was manufactured through a solid-state process. X-ray diffraction (XRD) and a scanning electron microscope (SEM) were utilized to examine the phosphor's phase and morphology. Using the Rietveld technique, the as-prepared phosphor structure was validated. By progressively raising the doping contents of the samarium, the phosphors emitted multicoloured luminescence from short to long wavelengths as indicated by analysis of the optical performance. Overall, the data provide strong evidence that the transfer of energy in BLSOF:0.15Tb3+,xSm3+ is responsible for the phosphor's colour-tunable property.

Assessment of Normal Tissue Radiosensitivity by Evaluating DNA Damage and Repair Kinetics in Human Brain Organoids.

DNA-double strand break (DSB), detected by immunostaining of key proteins orchestrating repair, like γH2AX and 53BP1, is well established as a surrogate for tissue radiosensitivity. We hypothesized that the generation of normal brain 3D organoids ("mini-brains") from human induced pluripotent stem cells (hiPSC) combined with detection of DNA damage repair (DDR) may hold the promise towards developing personalized models for the determination of normal tissue radiosensitivity. In this study, cerebral organoids, an in vitro model that stands in its complexity between 2D cellular system and an organ, have been used. To quantify radiation-induced response, immunofluorescent staining with γH2AX and 53BP1 were applied at early (30 min, initial damage), and late time points (18 and 72 h, residual damage), following clinical standard 2 Gy irradiation. Based on our findings, assessment of DDR kinetics as a surrogate for radiosensitivity in hiPSC derived cerebral organoids is feasible. Further development of mini-brains recapitulating mature adult neuronal tissue and implementation of additional signaling and toxicity surrogates may pave the way towards development of next-generation personalized assessment of radiosensitivity in healthy neuronal tissue.

CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum.

Regulation of chromatin plays fundamental roles in the development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes chromatin accessibility, active histone modifications, and RNA polymerase recruitment at enhancers. In vivo profiling of genome architecture reveals that CHD7 concordantly regulates epigenomic modifications associated with enhancer activation and gene expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a potential cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define epigenomic regulation by CHD7 in granule cell precursors and identify abnormal cerebellar patterning upon CHD7 depletion, with potential implications for our understanding of CHARGE syndrome.

Prioritized carbon allocation to storage of different functional types of species at the upper range limits is driven by different environmental drivers.

The upper elevational range limit of tree species (including treeline and non-treeline species) is generally considered to result from either carbon limitation or sink limitation. Some evidence also suggests that tree line might reflect preferential carbon allocation to NSC storage at the expense of growth. How might the importance of these potential mechanisms be determined? We used an elevational gradient to examine light-saturated photosynthesis (Asat) and NSC concentrations in plant tissues of three different functional types of tree species. We also examined the effects of consecutive 4 years of in situ defoliation on growth and NSCs at the upper elevational range limit. Declining temperature with increasing elevation did not reduce Asat in any of the species. We found NSC increased with elevation in major storage tissues (e.g., roots and twigs) but not in leaves. The defoliation showed that C storage took priority over growth. Such preferential carbon allocation, directly caused by growth decline, always existed in the deciduous tree species. In the evergreen tree species, however, growth decline resulted from preferential carbon allocation to storage was only detected in 2017 and then disappeared as the intensity of defoliation increased. Our results showed that trees prioritized sustaining stores of C more highly than allocation of growth, regardless of the trees' C or sink limitations. At the cold range limits, the prioritized carbon allocation to storage in deciduous tree species was in response to low temperature stress, while in evergreen tree species, the prioritization of carbon allocation was only a transient physiological response to defoliation disturbances.

A Set of Cell Lines Derived from a Genetic Murine Glioblastoma Model Recapitulates Molecular and Morphological Characteristics of Human Tumors.

Glioblastomas (GBM) are the most aggressive tumors affecting the central nervous system in adults, causing death within, on average, 15 months after diagnosis. Immunocompetent in-vivo models that closely mirror human GBM are urgently needed for deciphering glioma biology and for the development of effective treatment options. The murine GBM cell lines currently available for engraftment in immunocompetent mice are not only exiguous but also inadequate in representing prominent characteristics of human GBM such as infiltrative behavior, necrotic areas, and pronounced tumor heterogeneity. Therefore, we generated a set of glioblastoma cell lines by repeated in vivo passaging of cells isolated from a neural stem cell-specific Pten/p53 double-knockout genetic mouse brain tumor model. Transcriptome and genome analyses of the cell lines revealed molecular heterogeneity comparable to that observed in human glioblastoma. Upon orthotopic transplantation into syngeneic hosts, they formed high-grade gliomas that faithfully recapitulated the histopathological features, invasiveness and immune cell infiltration characteristic of human glioblastoma. These features make our cell lines unique and useful tools to study multiple aspects of glioblastoma pathomechanism and to test novel treatments in an intact immune microenvironment.

Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype.

Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis. Here, we perform multi-omic profiling of 60 glioblastoma primary tumours and use orthogonal analysis of chromatin and RNA-derived gene regulatory networks to identify 38 subtype master regulators, whose cell population-specific activities we further map in published single-cell RNA sequencing data. These analyses identify the oligodendrocyte precursor marker and chromatin modifier SOX10 as a master regulator in RTK I-subtype tumours. In vitro functional studies demonstrate that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. SOX10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects.

Preparation, structure and up-conversion luminescence properties of novel cryolite K3YF6:Er3+, Yb3.

Cryolite is a suitable host for up-conversion luminescent materials due to its low phonon energy and good optical transparency. In this work, a novel up-conversion material K3YF6:Yb3+, Er3+ with a cryolite structure was prepared successfully by a solid state method. The crystal structure, morphology, composition and up-conversion luminescence properties of the as-prepared sample were characterized by X-ray diffractometry (XRD), field emission scanning electron microscopy (SEM) and fluorescence spectrometer in detail. K3YF6:Er3+, Yb3+ has a cryolite structure. Under 980 nm excitation, the as-prepared sample can generate slight green emission at 524 and 546 nm (attributed to 2H11/2 → 4I15/2 transition, 4S3/2→4I15/2 transition of Er3+) and strong red emission at 661 and 672 nm (corresponding to 4F9/2 → 4I15/2 transition, 4I9/2 → 4I15/2 transition of Er3+). All the green and red up-conversion emission of K3YF6:Er3+, Yb3+ transfer and electronic transition process of the red and green light the sample emitted, the possible luminescence mechanism is discussed in this paper.

Structure and luminescence properties of a novel broadband green-emitting oxyapatite-type phosphor.

In recent years, synthetic apatite-doped rare-earth luminescent materials and their optical properties have attracted extensive worldwide attention. In this study, a series of novel green phosphors Sr2Y3(SiO4)2(PO4)O:Eu2+ with apatite structure was fabricated via a high temperature solid-state reaction. X-ray diffraction, structure refinement, photoluminescence excitation, emission spectra, and temperature-dependent emission intensity were employed to describe the phase and property of the samples. Under the excitation of 365 nm, the phosphors emit strong green emission in the broad band range from 400 nm to 700 nm, which almost covers the visible light spectrum. The quenching concentration of Eu2+ in Sr2Y3(SiO4)2(PO4)O was about 0.05, which was attributed to the dipole-dipole interactions. The evidence that the as-prepared phosphor can be successfully excited by near ultraviolet light indicates that it can be potentially used as a near UV-convertible phosphor for white light-emitting diodes.

Glutamatergic synaptic input to glioma cells drives brain tumour progression.

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.