Tumor suppressor FRMD3 controls mammary epithelial cell fate determination via notch signaling pathway.

The luminal-to-basal transition in mammary epithelial cells (MECs) is accompanied by changes in epithelial cell lineage plasticity; however, the underlying mechanism remains elusive. Here, we report that deficiency of Frmd3 inhibits mammary gland lineage development and induces stemness of MECs, subsequently leading to the occurrence of triple-negative breast cancer. Loss of Frmd3 in PyMT mice results in a luminal-to-basal transition phenotype. Single-cell RNA sequencing of MECs indicated that knockout of Frmd3 inhibits the Notch signaling pathway. Mechanistically, FERM domain-containing protein 3 (FRMD3) promotes the degradation of Disheveled-2 by disrupting its interaction with deubiquitinase USP9x. FRMD3 also interrupts the interaction of Disheveled-2 with CK1, FOXK1/2, and NICD and decreases Disheveled-2 phosphorylation and nuclear localization, thereby impairing Notch-dependent luminal epithelial lineage plasticity in MECs. A low level of FRMD3 predicts poor outcomes for breast cancer patients. Together, we demonstrated that FRMD3 is a tumor suppressor that functions as an endogenous activator of the Notch signaling pathway, facilitating the basal-to-luminal transformation in MECs.

Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain.

Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.

CD206 modulates the role of M2 macrophages in the origin of metastatic tumors.

Tumor metastasis is a key factor affecting the life of patients with malignant tumors. For the past hundred years, scientists have focused on how to kill cancer cells and inhibit their metastasis in vivo, but few breakthroughs have been made. Here we hypothesized a novel mode for cancer metastasis. We show that the phagocytosis of apoptotic tumor cells by macrophages leads to their polarization into the M2 phenotype, and that the expression of stem cell related as well as drug resistance related genes was induced. Therefore, it appears that M2 macrophages have "defected" and have been transformed into the initial "metastatic cancer cells", and thus are the source, at least in part, of the distal tissue tumor metastasis. This assumption is supported by the presence of fused cells with characteristics of both macrophage and tumor cell observed in the peripheral blood and ascites of patients with ovarian cancer. By eliminating the expression of CD206 in M2 macrophages using siRNA, we show that the growth and metastasis of tumors was suppressed using both in vitro cell line and with experimental in vivo mouse models. In summary, we show that M2 macrophages in the blood circulation underwent a "change of loyalty" to become "cancer cells" that transformed into distal tissue metastasis, which could be suppressed by the knockdown of CD206 expression.

Competition of Carrier Kinetics Contributes to Amplified Spontaneous Emission in Quasi-2D/3D (PBA)2MAn-1PbnBr3n+1 Thin Films under Strip Light Mode.

Quasi-2D halide perovskites have potential in lasing due to their amplified spontaneous emission (ASE) properties. The ASE of (PBA)2MAn-1PbnBr3n+1 thin films has been confirmed by photoluminescence (PL) testing using stripe light excitation (SLE). The ASE threshold decreases with decreasing environmental temperature (TE) or increasing number of inorganic layers (n). Using the transient absorption technique, the Auger recombination and the cooling process of the high-activity carrier are accelerated with the decrease of n or TE. A new ASE mechanism is proposed where high-activity carriers directly emit photons under photon perturbation from adjacent sites, leading to the accumulation and amplification of emitted photons only in the SLE region for ASE to occur. In addition, the reduction of n promotes light scattering between nano-thin layers, which supports a rapid increase in the ASE signal after the ASE threshold is crossed.

Activity enhancement of a photo-generated carrier in CsPbBr3 nanocrystals improved by Cd element.

Doping Cd element into perovskite materials is an effective strategy to improve the photoelectric property. However, the further discussion for carrier dynamic behavior in perovskites affected by Cd element remains not sufficient. In this research letter, based on steady and transient spectroscopy, it is found that adding Cd element into CsPbBr3 nanocrystals can enhance the activity of photo-generated carriers and accompany with the optimization of crystal structure. The former improves the carrier heating effect, which makes carrier keep high temperature for a long time and accelerate the bimolecular and the Auger recombination simultaneously. The latter can restrict the monomolecular recombination through passivating the defect states. Finally, they together improve the photoluminescence characteristics of the Cd doped CsPbBr3 nanocrystals and make them exhibit a huge potential in the fields of optoelectronics or photo-catalysis.

Kindlin-2 in Sertoli cells is essential for testis development and male fertility in mice.

Kindlin-2 is known to play important roles in the development of mesoderm-derived tissues including myocardium, smooth muscle, cartilage and blood vessels. However, nothing is known for the role of Kindlin-2 in mesoderm-derived reproductive organs. Here, we report that loss of Kindlin-2 in Sertoli cells caused severe testis hypoplasia, abnormal germ cell development and complete infertility in male mice. Functionally, loss of Kindlin-2 inhibits proliferation, increases apoptosis, impairs phagocytosis in Sertoli cells and destroyed the integration of blood-testis barrier structure in testes. Mechanistically, Kindlin-2 interacts with LATS1 and YAP, the key components of Hippo pathway. Kindlin-2 impedes LATS1 interaction with YAP, and depletion of Kindlin-2 enhances LATS1 interaction with YAP, increases YAP phosphorylation and decreases its nuclear translocation. For clinical relevance, lower Kindlin-2 expression and decreased nucleus localization of YAP was found in SCOS patients. Collectively, we demonstrated that Kindlin-2 in Sertoli cells is essential for sperm development and male reproduction.

Study of the Photoluminescence Characteristics of 4,4'-((1E,1'E)-Quinoxaline-2,3-diylbis(ethene-2,1-diyl))bis(N,N-dimethylaniline).

A comparative investigation on the photophysical properties of a quinoxaline derivative 4,4'-((1E,1'E)-quinoxaline-2,3-diylbis(ethene-2,1-diyl))bis(N,N-dimethylaniline) (QDMA2) was performed by employing many spectroscopies. Based on the pump-dump/push-probe measurement, it is found that a solvent-stabilized charge-transfer state can participate in the relaxation of excited QDMA2 with increasing solvent polarity. Meanwhile, the aggregated QDMA2 molecules were engineered into the organic light-emitting diode test, which showed a correlated color temperature value of 1875 K. With the help of a diamond anvil cell, the pressure-dependent photoluminescence of aggregated QDMA2 shows that the intermolecular interaction can affect the color and intensity of photoluminescence through adjusting the band gap and irradiative channel of the aggregated molecules. These results are important for understanding the structure-property relationships and the rational design of functional materials for optoelectronic applications.

Cooling and diffusion characteristics of a hot carrier in the monolayer WS2.

The characteristics of a hot carrier distributed in the C excitonic state of the monolayer WS2 is investigated by exploiting the transient absorption (TA) spectroscopy. The hot carrier cooling lifetime gradually prolongs from 0.58 ps to 2.68 ps with the absorbed photon flux owing to the hot phonon bottleneck effect, as the excitation photon energy is 2.03 eV. Meanwhile, the normalized TA spectra shows that the spectral feature of hot carriers is different from that of normal carriers. Based on the modified Lennard-Jones model, the average distance among hot carriers can be estimated according to the peak shift of TA spectra and the diffusion velocity can also be calculated simultaneously. The hot carrier limits the diffusion of the photo-generated carrier at the initial several picoseconds. These results help people to elucidate the hot carrier dynamics in 2D TMDCs and give guidance on the designing and optimizing the TMDC-based electronic devices of high performance.

Investigation of Hot Carrier Cooling Dynamics in Monolayer MoS2.

The hot carrier cooling dynamics in the C-excitonic state of monolayer MoS2 is slowed down by the hot phonon bottleneck and Auger heating effects, as exploited by ultrafast transient absorption spectroscopy. The hot carrier cooling process, determined by the hot phonon bottleneck, can be prolonged through rising the excitation photon energy or increasing the absorbed photon flux. By inducing the Auger heating effect under higher absorbed photon flux, the hot carrier lifetime also increases at the low excitation photon energy. When these two effects are combined under higher excitation photon energy and higher absorbed photon flux, the hot phonon bottleneck is gradually weakened because of Auger recombination. In addition, the similar hot carrier phenomenon can be observed in A/B excitonic states owing to the same physical mechanism. Our work establishes a solid photophysics foundation for 2D transition-metal dichalcogenide applications in advanced energy conversion, optical quantum communication, quantum technology, etc.

Kindlin-2 deficiency induces fatal intestinal obstruction in mice.

Rationale: Smooth muscle-motility disorders are mainly characterized by impaired contractility and functional intestinal obstruction. Some of these cases are caused by genetic mutations of smooth muscle genes ACTA2, ACTG2, MYH11, MYLK and LMOD1. Still the etiology is complex and multifactorial and the underlying pathology is poorly understood. Integrin interaction protein Kindlin-2 is widely expressed in striated and smooth muscle cells (SMC). However, the function of Kindlin-2 in the smooth muscle remains elusive. Methods: We generated two mouse models using different cre promoter transgenic mice, Kindlin-2fl/fl SM22α-cre+ (cKO mice) and Kindlin-2fl/fl; MYH-cre+ (iKO mice). Embryos and adult tissues were prepared for hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) apoptosis assay. We investigated ultrastructure changes of mouse smooth muscle using transmission electron microscopy (TEM) and measured smooth muscle contractile force in mounting aortic and intestinal rings using the multiwire myograph system (DMT 620M). In addition, cell traction force microscopy (CTFM) was applied to observe the functional change of primary SMC after Kindlin-2 depletion by RNAi. Results: Depletion of Kindlin-2 encoding gene Fermt2 in embryonic smooth muscles leads to apoptosis, downregulates the key components of SMC, impairs smooth muscle development, and finally causes embryonic death at E14.5. Tamoxifen-induced Kindlin-2-specific knockout in adult mouse smooth muscle showed decreased blood pressure, intestinal hypoperistalsis, and eventually died of intestinal obstruction. Kindlin-2 depletion also leads to downregulated Myh11, α-SMA, and CNN, shortened myofilament, broken myofibrils, and impaired contractility of the smooth muscles in iKO mice. Mechanistically, loss of Kindlin-2 decreases Ca2+ influx in primary vascular smooth muscle cells (PVSMC) by downregulating the expression of calcium-binding protein S100A14 and STIM1. Conclusion: We demonstrated that Kindlin-2 is essential for maintaining the normal structure and function of smooth muscles. Loss of Kindlin-2 impairs smooth muscle formation during embryonic development by inducing apoptosis and jeopardizes the contraction of adult smooth muscle by blocking Ca2+ influx that leads to intestinal obstruction. Mice with Kindlin-2 depletion in adult smooth muscle could be a potent animal model of intestinal obstruction for disease research, drug treatment and prognosis.

Solvent-dependent ultrafast optical response of conjugated push-pull chromophores.

Two new difluoroboron ß-carbonyl cyclic ketonate complexes C2B and DC2B were investigated using several spectroscopic methods. Relative to the absorption spectra, the fluorescence spectra were more affected by the polarity of the solvent. Also, compound C2B showed a more pronounced Stokes' shift after solvent polarity increased. Transient absorption measurements then demonstrated the relaxation behaviour of the excited state compound molecule. The kinetic results showed that the excited state C2B in tetrahydrofuran (THF) can return from the intramolecular charge-transfer (ICT) state and the initial excited state to the ground state. The kinetic relaxation pathway after THF was replaced by dimethyl sulfoxide became single. When the carbazole unit was introduced, DC2B also exhibited an ICT state but there was no significant difference in the excited state relaxation path after solvent polarity was changed. The results indicated that C2B is more susceptible to solvent polarity regulation. The global fit results revealed that an increase in the solvent polarity prolonged the lifetime of the ICT state of compound C2B and had the opposite effect on compound DC2B. These results provide guidance for understanding the relationship between solvent polarity and the designing and synthesizing advanced compound materials.

Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1.

The Hippo signaling pathway plays a key role in development and cancer progression. However, molecules that intrinsically inhibit this pathway are less well known. Here, we report that the focal adhesion molecule Kindlin-2 inhibits Hippo signaling by interacting with and degrading MOB1 and promoting the interaction between MOB1 and the E3 ligase praja2. Kindlin-2 thus inhibits the phosphorylation of LATS1 and YAP and promotes YAP translocation into the nucleus, where it activates downstream Hippo target gene transcription. Kindlin-2 depletion activates Hippo/YAP signaling and alleviates renal fibrosis in Kindlin-2 knockout mice with unilateral ureteral occlusion (UUO). Moreover, Kindlin-2 levels are negatively correlated with MOB1 and phosphorylated (p) YAP in samples from patients with renal fibrosis. Altogether, these results demonstrate that Kindlin-2 inhibits Hippo signaling through degradation of MOB1. A specific long-lasting siRNA against Kindlin-2 effectively alleviated UUO-induced renal fibrosis and could be a potential therapy for renal fibrosis.

Kindlin-2 suppresses transcription factor GATA4 through interaction with SUV39H1 to attenuate hypertrophy.

Kindlin-2 plays an important role in the regulation of cardiac structure and function. Depletion of Kindlin-2 contributes to cardiac hypertrophy and progressive heart failure, however, the precise mechanisms involved in this process remain unclear. GATA4 is a critical transcription factor in regulating cardiogenesis. We found that Kindlin-2 suppresses the expression of GATA4 through binding to its promoter and prevents cardiomyocytes from hypertrophy induced by isoproterenol (ISO) treatment. Mechanistically, Kindlin-2 interacts with histone methyltransferase SUV39H1 and recruits it to GATA4 promoter leading to the occupancy of histone H3K9 di- and tri-methylation. Furthermore, to confirm the function of Kindlin-2 in vivo, we generated mice with targeted deletion of cardiac Kindlin-2. We found that 6-month-old Kindlin-2 cKO mice have developed hypertrophic cardiomyopathy and that this pathological process can be accelerated by ISO-treatment. GATA4 expression was markedly activated in cardiac tissues of Kindlin-2 cKO mice compared to wild-type animals. Collectively, our data revealed that Kindlin-2 suppresses GATA4 expression by triggering histone H3K9 methylation in part and protects heart from pathological hypertrophy.

Study on photoelectric characteristics of monolayer WS2 films.

It is important to determine the time-dependent evolution of the excited monolayer WS2, which will provide a basis for the reasonable design of optoelectronic devices based on two-dimensional transition metal dichalcogenides. Here, we made a simple and large-area photodetector based on the monolayer WS2, with high light sensitivity and fast response, benefiting from the special dynamics of carrier involving the exciton, trion, and charge. Moreover, we tested the relaxation behavior of the excited monolayer WS2 by employing transient absorption (TA). It was found that the multi-body interaction among exciton would occur after the density of pump photon increases to 3.45 × 1014 photons per cm2. The exciton dissociation accompanying the generation of trion would appear in the photo-induced relaxation process, which would be a benefit for the operation of this photodetector. Increasing the energy of the exciton is good for the generation of carrier by comparing the relaxation behavior of WS2 excited to A and B exciton states. However, the bound exciton relaxation, originating from the capture process of the defect state, would exist and play an unfavorable role during the functioning of devices.

Correction: Study on photoelectric characteristics of monolayer WS2 films.

[This corrects the article DOI: 10.1039/C9RA07924F.].

Integrin-interacting protein Kindlin-2 induces mammary tumors in transgenic mice.

Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus (MMTV) long terminal repeat (LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and ß-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway.

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency.

Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research. VIDEO ABSTRACT.

Ultrastable Quantum-Dot Light-Emitting Diodes by Suppression of Leakage Current and Exciton Quenching Processes.

A study of hybrid inverted quantum-dot (QD) light-emitting diodes constructed with and without Al2O3 interlayers is presented. The Al2O3 interlayers are deposited at ZnO/QDs or/and QDs/4,4'-bis(carbazol-9-yl)biphenyl interfaces, resulting in large improvement of device performance, including luminance, current efficiency, and device lifetime. Especially, the devices with QD emitters sandwiched by two Al2O3 layers exhibits outstanding performance, the longest operation lifetime, and mediate efficiency. The maximum current efficiency of 15.3 cd/A is obtained, an enhancement factor of 35% in comparison to that (11.3 cd/A) of conventional device without Al2O3 layer. Moreover, device lifetime is also largely enhanced, over 110 000 h for the device containing two Al2O3 interlayers, nearly 40% enhancement relative to that of conventional device that shows a lifetime of only 80 000 h. On the basis of electrical property and photoluminescence spectroscopy studies, we demonstrate that the Al2O3 interlayers play crucial roles in suppressing the leakage current across the device and reducing exciton quenching induced by ZnO.

Depletion of Kindlin-2 induces cardiac dysfunction in mice.

Kindlin-2, a member of the Kindlin family focal adhesion proteins, plays an important role in cardiac development. It is known that defects in the Z-disc proteins lead to hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Our previous investigation showed that Kindlin-2 is mainly localized at the Z-disc and depletion of Kindlin-2 disrupts the structure of the Z-Disc. Here, we reported that depletion of Kindlin-2 leads to the disordered myocardial fibers, fractured and vacuolar degeneration in myocardial fibers. Interestingly, depletion of Kindlin-2 in mice induced cardiac myocyte hypertrophy and increased the heart weight. Furthermore, decreased expression of Kindlin-2 led to cardiac dysfunction and also markedly impairs systolic function. Our data indicated that Kindlin-2 not only maintains the cardiac structure but also is required for cardiac function.

Exciton Relaxation Dynamics in Photo-Excited CsPbI3 Perovskite Nanocrystals.

The exciton relaxation process of CsPbI3 perovskite nanocrystals (NCs) has been investigated by using transient absorption (TA) spectroscopy. The hot exciton relaxation process is confirmed to exist in the CsPbI3 NCs, through comparing the TA data of CsPbI3 NCs in low and high energy excitonic states. In addition, the Auger recombination and intrinsic decay paths also participate in the relaxation process of CsPbI3 NCs, even the number of exciton per NC is estimated to be less than 1. Excitation intensity-dependent TA data further confirms the existence of Auger recombination. Meanwhile, the spectral data also confirms that the weight of hot exciton also increase together with that of Auger recombination at high excitation intensity when CsPbI3 NCs in high energy excitonic states.