Resurrection of endogenous retroviruses during aging reinforces senescence.

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.

Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.

The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for ß-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-ß-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy.

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.

Sutimlimab in Cold Agglutinin Disease.

BACKGROUND: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. METHODS: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. RESULTS: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. CONCLUSIONS: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.).

Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Detection of Treatment Response in Triple-Negative Breast Tumors to Paclitaxel Using MRI Cell Size Imaging.

BACKGROUND: Breast cancer treatment response evaluation using the response evaluation criteria in solid tumors (RECIST) guidelines, based on tumor volume changes, has limitations, prompting interest in novel imaging markers for accurate therapeutic effect determination. PURPOSE: To use MRI-measured cell size as a new imaging biomarker for assessing chemotherapy response in breast cancer. STUDY TYPE: Longitudinal; animal model. STUDY POPULATION: Triple-negative human breast cancer cell (MDA-MB-231) pellets (4 groups, n = 7) treated with dimethyl sulfoxide (DMSO) or 10 nM of paclitaxel for 24, 48, and 96 hours, and 29 mice with MDA-MB-231 tumors in right hind limbs treated with paclitaxel (n = 16) or DMSO (n = 13) twice weekly for 3 weeks. FIELD STRENGTH/SEQUENCE: Oscillating gradient spin echo and pulsed gradient spin echo sequences at 4.7 T. ASSESSMENT: MDA-MB-231 cells were analyzed using flowcytometry and light microscopy to assess cell cycle phases and cell size distribution. MDA-MB-231 cell pellets were MR imaged. Mice were imaged weekly, with 9, 6, and 14 being sacrificed for histology after MRI at weeks 1, 2, and 3, respectively. Microstructural parameters of tumors/cell pellets were derived by fitting diffusion MRI data to a biophysical model. STATISTICAL TESTS: One-way ANOVA compared cell sizes and MR-derived parameters between treated and control samples. Repeated measures 2-way ANOVA with Bonferroni post-tests compared temporal changes in MR-derived parameters. A P-value <0.05 was considered statistically significant. RESULTS: In vitro experiments showed that the mean MR-derived cell sizes of paclitaxel-treated cells increased significantly with a 24-hours treatment and decreased (P = 0.06) with a 96-hour treatment. For in vivo xenograft experiments, the paclitaxel-treated tumors showed significant decreases in cell size at later weeks. MRI observations were supported by flowcytometry, light microscopy, and histology. DATA CONCLUSIONS: MR-derived cell size may characterize the cell shrinkage during treatment-induced apoptosis, and may potentially provide new insights into the assessment of therapeutic response. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 4.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

BMAL1 moonlighting as a gatekeeper for LINE1 repression and cellular senescence in primates.

Aging in humans is intricately linked with alterations in circadian rhythms concomitant with physiological decline and stem cell exhaustion. However, whether the circadian machinery directly regulates stem cell aging, especially in primates, remains poorly understood. In this study, we found that deficiency of BMAL1, the only non-redundant circadian clock component, results in an accelerated aging phenotype in both human and cynomolgus monkey mesenchymal progenitor cells (MPCs). Unexpectedly, this phenotype was mainly attributed to a transcription-independent role of BMAL1 in stabilizing heterochromatin and thus preventing activation of the LINE1-cGAS-STING pathway. In senescent primate MPCs, we observed decreased capacity of BMAL1 to bind to LINE1 and synergistic activation of LINE1 expression. Likewise, in the skin and muscle tissues from the BMAL1-deficient cynomolgus monkey, we observed destabilized heterochromatin and aberrant LINE1 transcription. Altogether, these findings uncovered a noncanonical role of BMAL1 in stabilizing heterochromatin to inactivate LINE1 that drives aging in primate cells.

Rational design of functional amyloid fibrillar assemblies.

Amyloid fibrillar assemblies, originally identified as pathological entities in neurodegenerative diseases, have been widely adopted by various proteins to fulfill diverse biological functions in living organisms. Due to their unique features, such as hierarchical assembly, exceptional mechanical properties, environmental stability, and self-healing properties, amyloid fibrillar assemblies have been employed as functional materials in numerous applications. Recently, with the rapid advancement in synthetic biology and structural biology tools, new trends in the functional design of amyloid fibrillar assemblies have begun to emerge. In this review, we provide a comprehensive overview of the design principles for functional amyloid fibrillar assemblies from an engineering perspective, as well as through the lens of structural insights. Initially, we introduce the fundamental structural configurations of amyloid assemblies and highlight the functions of representative examples. We then focus on the underlying design principles of two prevalent strategies for the design of functional amyloid fibrillar assemblies: (1) introducing new functions via protein modular design and/or hybridization, with typical applications encompassing catalysis, virus disinfection, biomimetic mineralization, bio-imaging, and biotherapy; and (2) dynamically regulating living amyloid fibrillar assemblies using synthetic gene circuits, with typical applications in pattern formation, leakage repair, and pressure sensing. Next, we summarize how breakthroughs in characterization techniques have contributed to unveiling the structural polymorphism of amyloid fibrils at the atomic level, and further clarifying the highly diverse regulation mechanisms of amyloid fibrillar assembly and disassembly fine-tuned by various factors. The structural knowledge may significantly aid in the structure-guided design of amyloid fibrillar assemblies with diverse bio-activities and adjustable regulatory properties. Finally, we envision that a new trend in functional amyloid design may emerge by integrating structural tunability, synthetic biology and artificial intelligence.

Diffusion time dependency of extracellular diffusion.

PURPOSE: To quantify the variations of the power-law dependences on diffusion time t or gradient frequency f $$ f $$ of extracellular water diffusion measured by diffusion MRI (dMRI). METHODS: Model cellular systems containing only extracellular water were used to investigate the t / f $$ t/f $$ dependence of D ex $$ {D}_{ex} $$ , the extracellular diffusion coefficient. Computer simulations used a randomly packed tissue model with realistic intracellular volume fractions and cell sizes. DMRI measurements were performed on samples consisting of liposomes containing heavy water(D2 O, deuterium oxide) dispersed in regular water (H2 O). D ex $$ {D}_{ex} $$ was obtained over a broad t $$ t $$ range (∼1-1000 ms) and then fit power-law equations D ex ( t ) = D const + const · t - ϑ t $$ {D}_{ex}(t)={D}_{\mathrm{const}}+\mathrm{const}\cdotp {t}^{-{\vartheta}_t} $$ and D ex ( f ) = D const + const · f ϑ f $$ {D}_{ex}(f)={D}_{\mathrm{const}}+\mathrm{const}\cdotp {f}^{\vartheta_f} $$ . RESULTS: Both simulated and experimental results suggest that no single power-law adequately describes the behavior of D ex $$ {D}_{ex} $$ over the range of diffusion times of most interest in practical dMRI. Previous theoretical predictions are accurate over only limited t $$ t $$ ranges; for example, θ t = θ f = - 1 2 $$ {\theta}_t={\theta}_f=-\frac{1}{2} $$ is valid only for short times, whereas θ t = 1 $$ {\theta}_t=1 $$ or θ f = 3 2 $$ {\theta}_f=\frac{3}{2} $$ is valid only for long times but cannot describe other ranges simultaneously. For the specific t $$ t $$ range of 5-70 ms used in typical human dMRI measurements, θ t = θ f = 1 $$ {\theta}_t={\theta}_f=1 $$ matches the data well empirically. CONCLUSION: The optimal power-law fit of extracellular diffusion varies with diffusion time. The dependency obtained at short or long t $$ t $$ limits cannot be applied to typical dMRI measurements in human cancer or liver. It is essential to determine the appropriate diffusion time range when modeling extracellular diffusion in dMRI-based quantitative microstructural imaging.

Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice.

Diffuse large B-cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B cells, such as B-cell receptor (BCR) signaling and motility regulation, contribute to lymphomagenesis. Human germinal center associated lymphoma (HGAL) is a B-cell-specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B cells, it is expressed in germinal center (GC) B lymphocytes and promptly downregulated upon further differentiation. The majority of DLBCL tumors, primarily GC B-cell types, but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express human HGAL at different stages of hematopoietic development using 3 restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells, pro-B cells, or GC B cells. Following immune stimulation, we observed larger GCs in mice in which HGAL expression was initiated in GC B cells. All 3 mouse strains developed DLBCL at a frequency of 12% to 30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing revealed mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.

Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study.

Cold agglutinin disease (CAD) is a rare chronic autoimmune haemolytic anaemia, driven mainly by classical complement pathway activation, leading to profound fatigue and poor quality of life. In the Phase 3 CADENZA trial, sutimlimab-a C1s complement inhibitor-rapidly halted haemolysis, increased haemoglobin levels and improved fatigue versus placebo in patients with CAD without a recent history of transfusion. Patient-reported outcomes (PROs) included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change (PGIC) and Patient Global Impression of (fatigue) Severity (PGIS). Sutimlimab resulted in significant rapid and meaningful improvements versus placebo in PROs. From Week 1, the FACIT-Fatigue mean score increased >5 points above baseline (considered a clinically important change [CIC]). Least-squares (LS) mean change in FACIT-Fatigue score from baseline to treatment assessment timepoint was 10.8 vs. 1.9 points (sutimlimab vs. placebo; p < 0.001). Improvements in physical (PCS) and mental (MCS) component scores of the SF-12 were also considered CICs (LS mean changes from baseline to Week 26: PCS 5.54 vs. 1.57 [p = 0.064]; MCS 5.65 vs. -0.48 [p = 0.065]). These findings demonstrate that in addition to improving haematologic parameters, sutimlimab treatment demonstrates significant patient-reported benefits. Study registered at www.clinicaltrials.gov: NCT03347422.

Boosting photocatalytic performances of lamellar BiVO4by constructing S-scheme heterojunctions with AgBr for efficient charge transfer.

Successful construction of heterojunction can improve the utilization efficiency of solar light by broadening the absorption range, facilitating charge-carrier separation, promoting carrier transportation and influencing surface-interface reaction. Herein, visible-light-driven AgBr was deposited on the surface of lamellar BiVO4which was prepared by a facile hydrothermal process to improve charge carrier separation, and subsequent photocatalytic effectiveness. The catalyst with an optimal AgBr/BiVO4ratio exhibited a superbly enhanced photocatalytic decolorization ability (about 6.85 times higher than that of pure BiVO4) and high stability after four cycles. The unique photocatalytic mechanism of S-scheme carrier migration was investigated on the bases of radical trapping tests and photo/electrochemical characterizations. Results showed that the enhanced migration strategy and intimately interfacial collaboration guaranteed the effective charge carriers separation/transfer, leading to magnificent photocatalytic performance as well as excellent stability.

Base-edited cynomolgus monkeys mimic core symptoms of STXBP1 encephalopathy.

Presynaptic syntaxin binding protein 1 (STXBP1) is essential for neurotransmitter release. Heterozygous mutations in this protein cause STXBP1 encephalopathy (STXBP1-E), which is characterized by intellectual disabilities and epilepsies. Since nonhuman primates closely resemble humans, monkey models may advance studies on the pathogenesis and therapeutic treatments of STXBP1-E. We generated cynomolgus monkeys carrying STXBP1 (R292H) mutation through base editing of in vitro fertilized embryos to mimic a clinical condition. The newborn STXBP1-edited monkeys exhibited focal epilepsy, and the animal that survived beyond the first week postpartum presented typical EEG phenotypes. Biochemical analysis of brain biopsy samples showed reduced levels of STXBP1 (MUNC18-1) and SNARE complex proteins. Single-cell sequencing identified one specific cell cluster that may contribute to encephalopathy. Thus, our case report shows that base-edited STXBP1 mutant monkeys are a good animal model for STXBP1-E, and that a base-editing approach is useful for generating primate models of human genetic disorders.

Deep-learning-based inverse design of three-dimensional architected cellular materials with the target porosity and stiffness using voxelized Voronoi lattices.

Architected cellular materials are a class of artificial materials with cellular architecture-dependent properties. Typically, designing cellular architectures paves the way to generate architected cellular materials with specific properties. However, most previous studies have primarily focused on a forward design strategy, wherein a geometry is generated using computer-aided design modeling, and its properties are investigated experimentally or via simulations. In this study, we developed an inverse design framework for a disordered architected cellular material (Voronoi lattices) using deep learning. This inverse design framework is a three-dimensional conditional generative adversarial network (3D-CGAN) trained based on supervised learning using a dataset consisting of voxelized Voronoi lattices and their corresponding relative densities and Young's moduli. A well-trained 3D-CGAN adopts variational sampling to generate multiple distinct Voronoi lattices with the target relative density and Young's modulus. Consequently, the mechanical properties of the 3D-CGAN generated Voronoi lattices are validated through uniaxial compression tests and finite element simulations. The inverse design framework demonstrates potential for use in bone implants, where scaffold implants can be automatically generated with the target relative density and Young's modulus.

Efficient Photocatalytic Degradation of Tetracycline on the MnFe2O4/BGA Composite under Visible Light.

In this work, the MnFe2O4/BGA (boron-doped graphene aerogel) composite prepared via the solvothermal method is applied as a photocatalyst to the degradation of tetracycline in the presence of peroxymonosulfate. The composite's phase composition, morphology, valence state of elements, defect and pore structure were analyzed by XRD, SEM/TEM, XPS, Raman scattering and N2 adsorption-desorption isotherms, respectively. Under the radiation of visible light, the experimental parameters, including the ratio of BGA to MnFe2O4, the dosages of MnFe2O4/BGA and PMS, and the initial pH and tetracycline concentration were optimized in line with the degradation of tetracycline. Under the optimized conditions, the degradation rate of tetracycline reached 92.15% within 60 min, whereas the degradation rate constant on MnFe2O4/BGA remained 4.1 × 10-2 min-1, which was 1.93 and 1.56 times of those on BGA and MnFe2O4, respectively. The largely enhanced photocatalytic activity of the MnFe2O4/BGA composite over MnFe2O4 and BGA could be ascribed to the formation of type I heterojunction on the interfaces of BGA and MnFe2O4, which leads to the efficient transfer and separation of photogenerated charge carriers. Transient photocurrent response and electrochemical impedance spectroscopy tests offered solid support to this assumption. In line with the active species trapping experiments, SO4•- and O2•- radicals are confirmed to play crucial roles in the rapid and efficient degradation of tetracycline, and accordingly, a photodegradation mechanism for the degradation of tetracycline on MnFe2O4/BGA is proposed.

A Cell-Penetrating Peptide Modified Cu2-xSe/Au Nanohybrid with Enhanced Efficacy for Combined Radio-Photothermal Therapy.

Radiotherapy (RT) is one of the main clinical therapeutic strategies against cancer. Currently, multiple radiosensitizers aimed at enhancing X-ray absorption in cancer tissues have been developed, while limitations still exist for their further applications, such as poor cellular uptake, hypoxia-induced radioresistance, and unavoidable damage to adjacent normal body tissues. In order to address these problems, a cell-penetrating TAT peptide (YGRKKRRQRRRC)-modified nanohybrid was constructed by doping high-Z element Au in hollow semiconductor Cu2-xSe nanoparticles for combined RT and photothermal therapy (PTT) against breast cancer. The obtained Cu2-xSe nanoparticles possessed excellent radiosensitizing properties based on their particular band structures, and high photothermal conversion efficiency beneficial for tumor ablation and promoting RT efficacy. Further doping high-Z element Au deposited more high-energy radiation for better radiosensitizing performance. Conjugation of TAT peptides outside the constructed Cu2-xSe/Au nanoparticles facilitated their cellular uptake, thus reducing overdosage-induced side effects. This prepared multifunctional nanohybrid showed powerful suppression effects towards breast cancer, both in vitro and in vivo via integrating enhanced cell penetration and uptake, and combined RT/PTT strategies.

Characterizing spontaneous Ca2+ local transients in OPCs using computational modeling.

Spontaneous Ca2+ local transients (SCaLTs) in isolated oligodendrocyte precursor cells are largely regulated by the following fluxes: store-operated Ca2+ entry (SOCE), Na+/Ca2+ exchange, Ca2+ pumping through Ca2+-ATPases, and Ca2+-induced Ca2+-release through ryanodine receptors and inositol-trisphosphate receptors. However, the relative contributions of these fluxes in mediating fast spiking and the slow baseline oscillations seen in SCaLTs remain incompletely understood. Here, we developed a stochastic spatiotemporal computational model to simulate SCaLTs in a homogeneous medium with ionic flow between the extracellular, cytoplasmic, and endoplasmic-reticulum compartments. By simulating the model and plotting both the histograms of SCaLTs obtained experimentally and from the model as well as the standard deviation of inter-SCaLT intervals against inter-SCaLT interval averages of multiple model and experimental realizations, we revealed the following: (1) SCaLTs exhibit very similar characteristics between the two data sets, (2) they are mostly random, (3) they encode information in their frequency, and (4) their slow baseline oscillations could be due to the stochastic slow clustering of inositol-trisphosphate receptors (modeled as an Ornstein-Uhlenbeck noise process). Bifurcation analysis of a deterministic temporal version of the model showed that the contribution of fluxes to SCaLTs depends on the parameter regime and that the combination of excitability, stochasticity, and mixed-mode oscillations are responsible for irregular spiking and doublets in SCaLTs. Additionally, our results demonstrated that blocking each flux reduces SCaLTs' frequency and that the reverse (forward) mode of Na+/Ca2+ exchange decreases (increases) SCaLTs. Taken together, these results provide a quantitative framework for SCaLT formation in oligodendrocyte precursor cells.

Phase-only hologram generated by a convolutional neural network trained using low-frequency mixed noise.

A phase-only hologram generated through the convolution neutral network (CNN) which is trained by the low-frequency mixed noise (LFMN) is proposed. Compared with CNN based computer-generated holograms, the proposed training dataset named LFMN includes different kinds of noise images after low-frequency processing. This dataset was used to replace the real images used in the conventional hologram to train CNN in a simple and flexible approach. The results revealed that the proposed method could generate a hologram of 2160 × 3840 pixels at a speed of 0.094 s/frame on the DIV2K valid dataset, and the average peak signal-to-noise ratio of the reconstruction was approximately 29.2 dB. The results of optical experiments validated the theoretical prediction. The reconstructed images obtained using the proposed method exhibited higher quality than those obtained using the conventional methods. Furthermore, the proposed method considerably mitigated artifacts of the reconstructed images.

Improving MR cell size imaging by inclusion of transcytolemmal water exchange.

The goal of the current study is to include transcytolemmal water exchange in MR cell size imaging using the IMPULSED model for more accurate characterization of tissue cellular properties (e.g., apparent volume fraction of intracellular space v in ) and quantification of indicators of transcytolemmal water exchange. We propose a heuristic model that incorporates transcytolemmal water exchange into a multicompartment diffusion-based method (IMPULSED) that was developed previously to extract microstructural parameters (e.g., mean cell size d and apparent volume fraction of intracellular space v in ) assuming no water exchange. For t diff ≤ 5 ms, the water exchange can be ignored, and the signal model is the same as the IMPULSED model. For t diff ≥ 30 ms, we incorporated the modified Kärger model that includes both restricted diffusion and exchange between compartments. Using simulations and previously published in vitro cell data, we evaluated the accuracy and precision of model-derived parameters and determined how they are dependent on SNR and imaging parameters. The joint model provides more accurate d values for cell sizes ranging from 10 to 12 microns when water exchange is fast (e.g., intracellular water pre-exchange lifetime τ in ≤ 100 ms) than IMPULSED, and reduces the bias of IMPULSED-derived estimates of v in , especially when water exchange is relatively slow (e.g., τ in > 200 ms). Indicators of transcytolemmal water exchange derived from the proposed joint model are linearly correlated with ground truth τ in values and can detect changes in cell membrane permeability induced by saponin treatment in murine erythroleukemia cancer cells. Our results suggest this joint model not only improves the accuracy of IMPULSED-derived microstructural parameters, but also provides indicators of water exchange that are usually ignored in diffusion models of tissues.