Robust and Sustained STING Pathway Activation via Hydrogel-Based In Situ Vaccination for Cancer Immunotherapy.

The stimulator of interferon genes (STING) pathway is crucial for tumor immunity, leading to the exploration of STING agonists as potential immunotherapy adjuvants. However, their clinical application faces obstacles including poor pharmacokinetics, transient activation, and an immunosuppressive tumor microenvironment (TME). Addressing these limitations, our study aims to develop an injectable silk fibroin hydrogel-based in situ vaccine. It incorporates a nanoscale STING agonist, an immunogenic cell death (ICD) inducer, and an immunomodulator to ensure their controlled and sustained release. cGAMP nanoparticles (cGAMPnps) with a core-shell structure ensure optimal delivery of cGAMP to dendritic cells (DCs), thereby activating the STING pathway and fostering DC maturation. ICD-associated damage-associated molecular patterns amplify and prolong STING activation via enhanced type I IFN and other inflammatory pathways, along with delayed degradation of cGAMP and STING. Furthermore, the STING-driven vascular normalization by cGAMPnps and ICD, in conjunction with immunomodulators like antiprogrammed cell death protein 1 antibody (anti-PD-1 Ab) or OX40 ligand (OX40L), effectively remodels the immunosuppressive TME. This in situ gel vaccine, when used independently or with surgery as neoadjuvant/adjuvant immunotherapy, enhances DC and CD8+ T-cell activation, suppressing tumor progression and recurrence across various immunologically cold tumor models. It revolutionizes the application of STING agonists in cancer immunotherapy, offering substantial promise for improving outcomes across a broad spectrum of malignancies.

Enhancement of Abnormal Grain Growth by Surface Quenching Treatment to Eliminate Cu-Cu Bonding Interfaces Using (111)-Oriented Nanotwinned Copper.

Cu-Cu joints have been adopted for ultra-high density of packaging for high-end devices. However, the processing temperature must be kept relatively low, preferably below 300 °C. In this study, a novel surface modification technique, quenching treatment, was applied to achieve Cu-to-Cu direct bonding using (111)-oriented nanotwinned Cu. The quenching treatment enabled grain growth across the Cu-Cu bonding interface at 275 °C. During quenching treatment, strain energy was induced in the Cu film, resulting in a wrinkled surface morphology. To analyze the strain energy, we utilized an electron backscattered diffraction system to obtain crystallographic information and confirmed it using kernel average misorientation analysis.

Eliminating Cu-Cu Bonding Interfaces Using Electroplated Copper and (111)-Oriented Nanotwinned Copper.

Cu-Cu joints have been adopted for ultra-high-density packaging for high-end devices. However, the atomic diffusion rate is notably low at the preferred processing temperature, resulting in clear and distinct weak bonding interfaces, which, in turn, lead to reliability issues. In this study, a new method for eliminating the bonding interfaces using two types of Cu films in Cu-Cu bonding is proposed. The difference in grain size was utilized as the primary driving force for the migration of bonding interfaces/interfacial grain boundaries. Additionally, the columnar nanotwinned Cu structure acted as a secondary driving force, making the migration more significant. When bonded at 300 °C, the grains from one side grew and extended to the bottom, eliminating the bonding interfaces. A mechanism for the evolution of the Cu bonding interfaces/interfacial grain boundaries is proposed.

Enhanced Nanotwinned Copper Bonding through Epoxy-Induced Copper Surface Modification.

For decades, Moore's Law has neared its limits, posing significant challenges to further scaling it down. A promising avenue for extending Moore's Law lies in three-dimensional integrated circuits (3D ICs), wherein multiple interconnected device layers are vertically bonded using Cu-Cu bonding. The primary bonding mechanism involves Cu solid diffusion bonding. However, the atomic diffusion rate is notably low at temperatures below 300 °C, maintaining a clear and distinct weak bonding interface, which, in turn, gives rise to reliability issues. In this study, a new method of surface modification using epoxy resin to form fine grains on a nanotwinned Cu film was proposed. When bonded at 250 °C, the interfacial grains grew significantly into both sides of the Cu film. When bonded at 300 °C, the interfacial grains extended extensively, eventually eliminating the original bonding interface.

Enhanced Copper Bonding Interfaces by Quenching to Form Wrinkled Surfaces.

For decades, Moore's Law has been approaching its limits, posing a huge challenge for further downsizing to nanometer dimensions. A promising avenue to replace Moore's Law lies in three-dimensional integrated circuits, where Cu-Cu bonding plays a critical role. However, the atomic diffusion rate is notably low at temperatures below 300 °C, resulting in a distinct weak bonding interface, which leads to reliability issues. In this study, a quenching treatment of the Cu film surface was investigated. During the quenching treatment, strain energy was induced due to the variation in thermal expansion coefficients between the Si substrate and the Cu film, resulting in a wrinkled surface morphology on the Cu film. Grain growth was observed at the Cu-Cu bonding interface following bonding at 300 °C for 2 and 4 h. Remarkably, these procedures effectively eliminated the bonding interface.

Clinical Benefits of Golden-Antrodia Camphorata Containing Antroquinonol in Liver Protection and Liver Fat Reduction After Alcoholic Hepatitis.

Objective: It has been reported that antroquinonol extracted from Golden-Antrodia camphorate exerts protective effects on liver function both in vitro and in vivo. However, the protective effects of Golden-Antrodia camphorata on liver function have not been fully investigated in human clinical studies. Therefore, the present study aimed to evaluate the beneficial effects of Golden-Antrodia camphorata on hepatic function after alcohol consumption in human subjects. Methods: A total of 80 participants with increased γ-glutamyl transferase levels (60-180 U/L) were enrolled in the current study and were randomly divided into two groups. Participants in the first group were orally administrated with 300 mg/day Golden-Antrodia camphorata (tablets), while those in the second group received placebo tablets for 12 weeks. Biochemical routine blood tests were performed at 6 and 12 weeks following the first administration. Results: At 12 weeks post the first Golden-Antrodia camphorata administration, the serum levels of aspartate aminotransferase (AST; p < 0.0001), alanine aminotransferase (ALT; p = 0.0002) and triglyceride (p = 0.0158) were notably declined in the Golden-Antrodia camphorata treatment group compared with the placebo group. No clinically significant differences were observed between the Golden-Antrodia camphorata treatment and placebo groups in terms of general safety parameters. Conclusion: A statistically significant difference was obtained in the serum levels of AST, ALT and triglycerides between the Golden-Antrodia camphorata and placebo groups. However, no clinical significance was observed in any of the safety parameters examined. Overall, these findings indicated that treatment with Golden-Antrodia camphorata exerted protective effects on liver function.

Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response.

Microsatellite-instable (MSI), a predictive biomarker for immune checkpoint blockade (ICB) response, is caused by mismatch repair deficiency (MMRd) that occurs through genetic or epigenetic silencing of MMR genes. Here, we report a mechanism of MMRd and demonstrate that protein phosphatase 2A (PP2A) deletion or inactivation converts cold microsatellite-stable (MSS) into MSI tumours through two orthogonal pathways: (i) by increasing retinoblastoma protein phosphorylation that leads to E2F and DNMT3A/3B expression with subsequent DNA methylation, and (ii) by increasing histone deacetylase (HDAC)2 phosphorylation that subsequently decreases H3K9ac levels and histone acetylation, which induces epigenetic silencing of MLH1. In mouse models of MSS and MSI colorectal cancers, triple-negative breast cancer and pancreatic cancer, PP2A inhibition triggers neoantigen production, cytotoxic T cell infiltration and ICB sensitization. Human cancer cell lines and tissue array effectively confirm these signaling pathways. These data indicate the dual involvement of PP2A inactivation in silencing MLH1 and inducing MSI.

Timing and magnitude of climatic extremes differentially elevate mortality but enhance recovery in a fish population.

The countervailing effects of disturbances (e.g., high mortality and enhanced recovery) on population dynamics can occur through demographic processes under rapidly increasing climatic extremes. Across an extreme-event gradient, we mechanistically demonstrated how dramatic changes in streamflow have affected the population persistence of endangered salmon in monsoonal Taiwan over a three-decade period. Our modeling indicated that the dynamics of the age-structured population were attributed to demographic processes, in which extensive mortality was characterized as a function of climatic extremes and vulnerability in the young stage of fish. In the stochastic simulations, we found that the extensive mortality and high proportion of large fish resulted from extreme flooding, which caused high values of postimpact population recovery. Our empirical evidence suggests that the magnitudes and timing of disturbance can explain the population persistence when facing climatic extremes and thereby challenges the understanding of the mechanistic drivers of these countervailing phenomena under changing environmental conditions.

PP2A in LepR+ mesenchymal stem cells contributes to embryonic and postnatal endochondral ossification through Runx2 dephosphorylation.

It has not been well studied which cells and related mechanisms contribute to endochondral ossification. Here, we fate mapped the leptin receptor-expressing (LepR+) mesenchymal stem cells (MSCs) in different embryonic and adult extremities using Lepr-cre; tdTomato mice and investigated the underling mechanism using Lepr-cre; Ppp2r1afl/fl mice. Tomato+ cells appear in the primary and secondary ossification centers and express the hypertrophic markers. Ppp2r1a deletion in LepR+ MSCs reduces the expression of Runx2, Osterix, alkaline phosphatase, collagen X, and MMP13, but increases that of the mature adipocyte marker perilipin, thereby reducing trabecular bone density and enhancing fat content. Mechanistically, PP2A dephosphorylates Runx2 and BRD4, thereby playing a major role in positively and negatively regulating osteogenesis and adipogenesis, respectively. Our data identify LepR+ MSC as the cell origin of endochondral ossification during embryonic and postnatal bone growth and suggest that PP2A is a therapeutic target in the treatment of dysregulated bone formation.

Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy.

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

Down-Regulation of miR-194-5p for Predicting Metastasis in Breast Cancer Cells.

MicroRNAs (miRNAs), as key negative regulators of gene expression, are closely related to tumor occurrence and progression. miR-194-5p (miR-194-1) has been shown to play a regulatory role in various cancers however, its biological function and mechanism of action in breast cancer have not yet been well explored. In this study, we use the UALCAN and LinkedOmics databases to analyze transcription expression in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA). The epithelial-mesenchymal transition status of breast cancer cells was evaluated by wound-healing assay, trans-well assays, and gelatin zymography, while protein expression was assessed by Western blotting. miR-194-5p expression was found to be up-regulated in breast cancer clinical specimens but down-regulated in the triple-negative breast cancer (TNBC) cell line MDA-MB-231 and breast cancer clinical specimens in The Cancer Genome Atlas (TCGA). miR-194-5p significantly inhibited the expression of the epithelial marker ZO-1 and increased the expression of mesenchymal markers, including ZEB-1 and vimentin, in MDA-MB-231 cells. miR-194-5p significantly reduced the gelatin-degrading activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 in zymography assays. In MDA-MB-231 cells and TCGA patient samples, ZEB-1 expression was significantly inversely correlated with miR-194-5p expression. High levels of miR-194-5p were associated with good overall survival. miR-194-5p regulates epithelial-mesenchymal transition (EMT) in TNBC. Our findings suggest that miR-194-5p functions as a tumor biomarker in breast cancer, providing new insights for the study of breast cancer development and metastasis.

Approaches towards fighting the COVID­19 pandemic (Review).

The coronavirus disease 2019 (COVID­19) outbreak, which has caused >46 millions confirmed infections and >1.2 million coronavirus related deaths, is one of the most devastating worldwide crises in recent years. Infection with COVID­19 results in a fever, dry cough, general fatigue, respiratory symptoms, diarrhoea and a sore throat, similar to those of acute respiratory distress syndrome. The causative agent of COVID­19, SARS­CoV­2, is a novel coronavirus strain. To date, remdesivir has been granted emergency use authorization for use in the management of infection. Additionally, several efficient diagnostic tools are being actively developed, and novel drugs and vaccines are being evaluated for their efficacy as therapeutic agents against COVID­19, or in the prevention of infection. The present review highlights the prevalent clinical manifestations of COVID­19, characterizes the SARS­CoV­2 viral genome sequence and life cycle, highlights the optimal methods for preventing viral transmission, and discusses possible molecular pharmacological mechanisms and approaches in the development of anti­SARS­CoV­2 therapeutic agents. In addition, the use of traditional Chinese medicines for management of COVID­19 is discussed. It is expected that novel anti­viral agents, vaccines or an effective combination therapy for treatment/management of SARS­CoV­2 infection and spread therapy will be developed and implemented in 2021, and we would like to extend our best regards to the frontline health workers across the world in their fight against COVID­19.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) Hull Extract and Active Compounds Inhibit Proliferation of Primary Human Leiomyoma Cells and Protect against Sexual Hormone-Induced Mice Smooth Muscle Hyperproliferation.

Uterine leiomyomas, also known as fibroids, are benign neoplasms of the uterus and have a high incidence rate in women of reproductive age. Hysterectomy or myomectomy is the initial treatment, but fibroids will recur if the patient is still exposed to similar risk factors. Therefore, developing new therapeutic strategies are urgently necessary. In this study, the anti-proliferation effects of each fraction of adlay seeds were evaluated in uterine leiomyomas, and we identified the potential phytochemical compounds. We found that the ethyl acetate fraction of adlay hull (AHE-ea) appeared to be highly efficient in the anti-proliferation of rat uterine leiomyoma ELT3 cells and primary human uterine leiomyoma (hUL) cells. The proliferation of primary human normal uterine smooth muscle (UtSMC) and normal uterine myometrial (hUM) cells were also suppressed by AHE-ea. Two phytosterols, stigmasterol and ß-sitosterol, were identified from AHE-ea fraction. Mice treated with AHE-ea and stigmasterol alone demonstrated reduced diethylstilbestrol/medroxyprogesterone 17-acetate (DES/MPA)-induced uterine myometrial hyperplasia, which is the critical step for the development of leiomyoma. Taken together, our results suggest that the AHE-ea fraction could be considered as a natural plant-based medicine in the prevention or treatment of uterine leiomyoma growth.

Enhanced Photocarrier Generation with Selectable Wavelengths by M-Decorated-CuInS2 Nanocrystals (M = Au and Pt) Synthesized in a Single Surfactant Process on MoS2 Bilayers.

A facile approach for the synthesis of Au- and Pt-decorated CuInS2 nanocrystals (CIS NCs) as sensitizer materials on the top of MoS2 bilayers is demonstrated. A single surfactant (oleylamine) is used to prepare such heterostructured noble metal decorated CIS NCs from the pristine CIS. Such a feasible way to synthesize heterostructured noble metal decorated CIS NCs from the single surfactant can stimulate the development of the functionalized heterostructured NCs in large scale for practical applications such as solar cells and photodetectors. Photodetectors based on MoS2 bilayers with the synthesized nanocrystals display enhanced photocurrent, almost 20-40 times higher responsivity and the On/Off ratio is enlarged one order of magnitude compared with the pristine MoS2 bilayers-based photodetectors. Remarkably, by using Pt- or Au-decorated CIS NCs, the photocurrent enhancement of MoS2 photodetectors can be tuned between blue (405 nm) to green (532 nm). The strategy described here acts as a perspective to significantly improve the performance of MoS2 -based photodetectors with the controllable absorption wavelengths in the visible light range, showing the feasibility of the possible color detection.

PP2A Deficiency Enhances Carcinogenesis of Lgr5+ Intestinal Stem Cells Both in Organoids and In Vivo.

In most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of carcinogenesis and genetically engineered mouse models. We show in organoids that treatment of any of three carcinogens, DMBA, MNU, or PhIP, with protein phosphatase 2A (PP2A) knockout induced tumorigenesis in Lgr5+ intestinal lineage, but not in differentiated cells. These transformed cells increased in stem cell signature, were upregulated in EMT markers, and acquired tumorigenecity. A mechanistic approach demonstrated that tumorigenesis was dependent on Wnt, PI3K, and RAS-MAPK activation. In vivo combination with carcinogen and PP2A depletion also led to tumor formation. Using whole-exome sequencing, we demonstrate that these intestinal tumors display mutation landscape and core driver pathways resembling human intestinal tumor in The Cancer Genome Atlas (TCGA). These data provide a basis for understanding the interplay between extrinsic carcinogen and intrinsic genetic modification and suggest that PP2A functions as a tumor suppressor in intestine carcinogenesis.

A facile chemical-mechanical polishing lift-off transfer process toward large scale Cu(In,Ga)Se2 thin-film solar cells on arbitrary substrates.

The fabrication of Cu(In,Ga)Se2 (CIGS) solar cells on flexible substrates is a non-trivial task due to thermal and ion diffusion related issues. In order to circumvent these issues, we have developed a chemical-mechanical polishing lift-off (CMPL) transfer process, enabling the direct transfer of CIGS solar cells from conventional soda-lime glass (SLG) onto arbitrary flexible substrates up to 4 cm(2) in size. The structural and compositional nature of the pre- and post-transferred films is examined using electron microscopy, X-ray diffraction analysis, Raman and photoluminescence spectroscopy. We demonstrate the fabrication of solar cells on a range of flexible substrates while being able to maintain 75% cell efficiency (η) when compared to pre-transferred solar cells. The results obtained in this work suggest that our transfer process offers a highly promising approach toward large scale fabrication of CIGS-based solar cells on a wide variety of flexible substrates, suitable for use in the large scale CIGS photovoltaic industry.

Transfer-Free Growth of Atomically Thin Transition Metal Disulfides Using a Solution Precursor by a Laser Irradiation Process and Their Application in Low-Power Photodetectors.

Although chemical vapor deposition is the most common method to synthesize transition metal dichalcogenides (TMDs), several obstacles, such as the high annealing temperature restricting the substrates used in the process and the required transfer causing the formation of wrinkles and defects, must be resolved. Here, we present a novel method to grow patternable two-dimensional (2D) transition metal disulfides (MS2) directly underneath a protective coating layer by spin-coating a liquid chalcogen precursor onto the transition metal oxide layer, followed by a laser irradiation annealing process. Two metal sulfides, molybdenum disulfide (MoS2) and tungsten disulfide (WS2), are investigated in this work. Material characterization reveals the diffusion of sulfur into the oxide layer prior to the formation of the MS2. By controlling the sulfur diffusion, we are able to synthesize continuous MS2 layers beneath the top oxide layer, creating a protective coating layer for the newly formed TMD. Air-stable and low-power photosensing devices fabricated on the synthesized 2D WS2 without the need for a further transfer process demonstrate the potential applicability of TMDs generated via a laser irradiation process.

Enhanced Conversion Efficiency of Cu(In,Ga)Se2 Solar Cells via Electrochemical Passivation Treatment.

Defect control in Cu(In,Ga)Se2 (CIGS) materials, no matter what the defect type or density, is a significant issue, correlating directly to PV performance. These defects act as recombination centers and can be briefly categorized into interface recombination and Shockley-Read-Hall (SRH) recombination, both of which can lead to reduced PV performance. Here, we introduce an electrochemical passivation treatment for CIGS films that can lower the oxygen concentration at the CIGS surface as observed by X-ray photoelectron spectrometer analysis. Temperature-dependent J-V characteristics of CIGS solar cells reveal that interface recombination is suppressed and an improved rollover condition can be achieved following our electrochemical treatment. As a result, the surface defects are passivated, and the power conversion efficiency performance of the solar cell devices can be enhanced from 4.73 to 7.75%.

Short-range plasmonic nanofocusing within submicron regimes facilitates in situ probing and promoting of interfacial reactions.

In this study, a simple configuration, based on high-index dielectric nanoparticles (NPs) and plasmonic nanostructures, is employed for the nanofocusing of submicron-short-range surface plasmon polaritons (SPPs). The excited SPPs are locally bound and focused at the interface between the dielectric NPs and the underlying metallic nanostructures, thereby greatly enhancing the local electromagnetic field. Taking advantage of the surface properties of the dielectric NPs, this system performs various functions. For example, the nanofocusing of submicron-short-range SPPs is used to enhance the Raman signals of gas molecules adsorbed on the dielectric NPs. In addition, the presence of the local strong electromagnetic field accelerates the rates of interfacial reactions on the surfaces of the dielectric NPs. Therefore, the proposed nanofocusing configuration can both promote and probe interfacial reactions simultaneously. Herein, the promotion and probing of the desorption of EtOH vapor are described, as well as the photodegradation of methylene blue. Moreover, the nanofocusing of SPPs is demonstrated on an aluminum surface in both the visible and UV regimes, a process that has not been achieved using conventional tapered waveguide nanofocusing structures. Therefore, the nanofocusing of submicron-short-range SPPs by dielectric NPs on plasmonic nanostructures is not limited to low-loss noble metals. Accordingly, this system has potential for use in light management and on-chip green devices and sensors.

Astronomical liquid mirrors as highly ultrasensitive, broadband-operational surface-enhanced Raman scattering-active substrates.

In this study, we found that an astronomical liquid mirror can be prepared as a highly ultrasensitive, low-cost, highly reproducible, broadband-operational surface-enhanced Raman scattering (SERS)-active substrate. Astronomical liquid mirrors are highly specularly reflective because of their perfectly dense-packed silver nanoparticles; they possess a large number and high density of hot spots that experience a very high intensity electric field, resulting in excellent SERS performance. When using the liquid mirror-based SERS-active substrate to detect 4-aminothiophenol (4-ATP), we obtained measured analytical enhancement factors (AEFs) of up to 2.7×10(12) and detection limits as low as 10(-15) M. We also found that the same liquid mirror could exhibit superior SERS capability at several distinct wavelengths (532, 632.8, and 785 nm). The presence of hot spots everywhere in the liquid mirror provided highly repeatable Raman signals from low concentrations of analytes. In addition, the astronomical liquid mirrors could be transferred readily onto cheap, flexible, and biodegradable substrates and still retain their excellent SERS performance, suggesting that they might find widespread applicability in various (bio)chemical detection fields.