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.

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.

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.

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.

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.

Dengue viral protease interaction with NF-κB inhibitor α/ß results in endothelial cell apoptosis and hemorrhage development.

Hemorrhagic manifestations occur frequently accompanying a wide range of dengue disease syndromes. Much work has focused on the contribution of immune factors to the pathogenesis of hemorrhage, but how dengue virus (DENV) participates in the pathogenic process has never been explored. Although there is no consensus that apoptosis is the basis of vascular permeability in human dengue infections, we showed in dengue hemorrhage mouse model that endothelial cell apoptosis is important to hemorrhage development in mice. To explore the molecular basis of the contribution of DENV to endothelial cell death, we show in this study that DENV protease interacts with cellular IκBα and IκBß and cleaves them. By inducing IκBα and IκBß cleavage and IκB kinase activation, DENV protease activates NF-κB, which results in endothelial cell death. Intradermal inoculation of DENV protease packaged in adenovirus-associated virus-9 induces endothelial cell death and dermal hemorrhage in mice. Although the H51 activity site is not involved in the interaction between DENV protease and IκB-α/ß, the enzymatic activity is critical to the ability of DENV protease to induce IκBα and IκBß cleavage and trigger hemorrhage development. Moreover, overexpression of IκBα or IκBß protects endothelial cells from DENV-induced apoptosis. In this study, we show that DENV protease participates in the pathogenesis of dengue hemorrhage and discover IκBα and IκBß to be the new cellular targets that are cleaved by DENV protease.

Romantic Story or Raman Scattering? Rose Petals as Ecofriendly, Low-Cost Substrates for Ultrasensitive Surface-Enhanced Raman Scattering.

In this Article, we present a facile approach for the preparation of ecofriendly substrates, based on common rose petals, for ultrasensitive surface-enhanced Raman scattering (SERS). The hydrophobic concentrating effect of the rose petals allows us to concentrate metal nanoparticle (NP) aggregates and analytes onto their surfaces. From a systematic investigation of the SERS performance when using upper and lower epidermises as substrates, we find that the lower epidermis, with its quasi-three-dimensional (quasi-3D) nanofold structure, is the superior biotemplate for SERS applications. The metal NPs and analytes are both closely packed in the quasi-3D structure of the lower epidermis, thereby enhancing the Raman signals dramatically within the depth of focus (DOF) of the Raman optical system. We have also found the effect of the pigment of the petals on the SERS performance. With the novel petal-based substrate, the SERS measurements reveal a detection limit for rhodamine 6G below the femtomolar regime (10(-15) M), with high reproducibility. Moreover, when we employ an upside-down drying process, the unique effect of the Wenzal state of the hydrophobic petal surface further concentrate the analytes and enhanced the SERS signals. Rose petals are green, natural materials that appear to have great potential for use in biosensors and biophotonics.

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.

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.

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.

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.

The interaction between bamboo mosaic virus replication protein and coat protein is critical for virus movement in plant hosts.

Bamboo mosaic virus (BaMV) is a positive-sense RNA virus belonging to the genus Potexvirus. Open reading frame 1 (ORF1) encodes the viral replication protein that consists of a capping enzyme domain, a helicase-like domain (HLD), and an RNA-dependent RNA polymerase domain from the N to C terminus. ORF5 encodes the viral coat protein (CP) required for genome encapsidation and the virus movement in plants. In this study, application of a yeast-two hybrid assay detected an interaction between the viral HLD and CP. However, the interaction did not affect the NTPase activity of the HLD. To identify the critical amino acids of CP interacting with the HLD, a random mutational library of CP was created using error-prone PCR, and the mutations adversely affecting the interaction were screened by a bacterial two-hybrid system. As a result, the mutations A209G and N210S in CP were found to weaken the interaction. To determine the significance of the interaction, the mutations were introduced into a BaMV infectious clone, and the mutational effects on viral replication, movement, and genome encapsidation were investigated. There was no effect on accumulations of BaMV CP and genomic RNAs within protoplasts; however, the virus cell-to-cell movement in plants was restricted. Sequence alignment revealed that A209 of BaMV CP is conserved in many potexviruses. Mutation of the corresponding residue in Foxtail mosaic virus CP also reduced the viral HLD-CP interaction and restricted the virus movement, suggesting that interaction between CP and a widely conserved HLD in the potexviral replication protein is crucial for viral trafficking through plasmodesmata.

Large scale single-crystal Cu(In,Ga)Se2 nanotip arrays for high efficiency solar cell.

In this paper, we demonstrated direct formation of large area Cu(In,Ga)Se(2) nanotip arrays (CIGS NTRs) by using one step Ar(+) milling process without template. By controlling milling time and incident angles, the length of CIGS NTRs with adjustable tilting orientations can be precisely controlled. Formation criteria of these CIGS NTRs have been discussed in terms of surface curvature, multiple components, and crystal quality, resulting in a highly anisotropic milling effect. The CIGS NTRs have very low reflectance <0.1% at incident wavelengths between 300 to 1200 nm. Open circuit voltage and short circuit current of CIGS NTRs solar cell were measured to be ∼390 mV and ∼22.56 mA/cm(2), yielding the filling factor and the efficiency of 59 and 5.2%, respectively. In contrast to CIGS thin film solar cell with efficiency of 3.2%, the nanostructured CIGS NTRs can have efficiency enhancement of ∼160% due to the higher light absorption ability because of the nanostructure. The merits of current approach include the latest way via template-free direct creating process of nanostructured CIGS NTRs with controllable dimensionality and large scale production without postselenization process.

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.

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.

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.

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.

Enhancement by tumor necrosis factor alpha of dengue virus-induced endothelial cell production of reactive nitrogen and oxygen species is key to hemorrhage development.

Hemorrhage is a severe manifestation of dengue disease. Virus strain and host immune response have been implicated as the risk factors for hemorrhage development. To delineate the complex interplay between the virus and the host, we established a dengue hemorrhage model in immune-competent mice. Mice inoculated intradermally with dengue virus develop hemorrhage within 3 days. In the present study, we showed by the presence of NS1 antigen and viral nuclei acid that dengue virus actively infects the endothelium at 12 h and 24 h after inoculation. Temporal studies showed that beginning at day 2, there was macrophage infiltration into the vicinity of the endothelium, increased tumor necrosis factor alpha (TNF-alpha) production, and endothelial cell apoptosis in the tissues. In the meantime, endothelial cells in the hemorrhage tissues expressed inducible nitric oxide synthase (iNOS) and nitrotyrosine. In vitro studies showed that primary mouse and human endothelial cells were productively infected by dengue virus. Infection by dengue virus induced endothelial cell production of reactive nitrogen and oxygen species and apoptotic cell death, which was greatly enhanced by TNF-alpha. N(G)-nitro-L-arginine methyl ester and N-acetyl cysteine reversed the effects of dengue virus and TNF-alpha on endothelial cells. Importantly, hemorrhage development and the severity of hemorrhage were greatly reduced in mice lacking iNOS or p47(phox) or treatment with oxidase inhibitor, pointing to the critical roles of reactive nitrogen and oxygen species in dengue hemorrhage.

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.