Denticleless E3 ubiquitin protein ligase (DTL) maintains the proliferation and differentiation of epidermis and hair follicles during skin development.

BACKGROUND: A precise balance between the proliferation and differentiation of epidermal progenitors is required to achieve the barrier function during the development of epidermis. During the entire process of skin development, the newly formed basal layer cells divide, differentiate, and migrate outward to the surface of the skin, which is tightly regulated by a series of events related to cell cycle progression. The CRL4DTL complex (Cullin 4 RING ligase, in association with the substrate receptor DTL) has long emerged as a master regulator in various cellular processes, which mediates the degradation of key cell cycle proteins. However, the roles of DTL in regulating epidermal morphogenesis during skin development remain unclear. RESULTS: We showed that DTL deficiency in epidermal progenitor cells leads to defects in epidermal stratification and loss of hair follicles accompanied by reduced epidermal progenitor cells and disturbed cell cycle progression during skin development. Transcriptome analysis revealed that p53 pathway is activated in DTL-depleted epidermal progenitor cells. The apoptosis of epidermal cells showed in DTL deficiency mice is rescued by the absence of p53, but the proliferation and differentiation defects were p53-independent. CONCLUSION: Our findings indicate that DTL plays a vital role in epidermal malformation during skin development.

Enhanced BMP signaling through ALK2 attenuates keratinocyte differentiation.

Accumulated studies have suggested that bone morphogenetic proteins (BMPs) are critical for skin development. However, it remains elusive how BMP signaling via ALK2 (aka ACVR1), one of the important BMP type I receptors, regulates keratinocyte differentiation. To address this question, we utilized a genetic system that enhances BMP signaling via ALK2 in an epidermis-specific manner in mice (hereafter ca-Alk2:K14-Cre). Ca-Alk2:K14-Cre mice displayed a sticky and hairless skin phenotype with a thinner epidermis incapable of differentiating. Although cellular proliferation and survival were comparable between wild-type and ca-Alk2:K14-Cre mice, skin differentiation was severely hampered in ca-Alk2:K14-Cre mice. To uncover the mechanism of altered keratinocyte differentiation, we performed a transcriptome analysis. As a result, we found that the expression levels of cell cycle inhibitor p21 were increased in ca-Alk2:K14-Cre mice. Our findings suggest that aberrant BMP signaling via ALK2 positively regulates p21 expression that attenuates keratinocyte differentiation, and further highlights the critical role of BMP signaling in skin development.

Fetal neurodevelopmental spatio-temporal dynamic transcriptional landscape of maternal insult-induce autism spectrum disorder risk.

Maternal insults during pregnancy induces an increased risk of autism spectrum disorders (ASD) in offspring, but the neuropathological changes in this process remains not to be established. To shed light on this, the transcriptome datasets of maternal blood samples with children later diagnosed with ASD and typical development, and tissue samples of multiple brain regions from ASD patients and human neurodevelopment were conducted to identify the non-chasm differentially expressed genes (DEGs) to generate the spatio-temporal dynamic change. Combined enrichment and interaction network analysis revealed that non-chasm DEGs with similar expression trajectories in the same brain regions, were involved in neural, immune and metabolic GO functions and KEGG pathways, respectively, suggesting that did not performed exactly the same functions. Interestingly, our results found that non-chasm DEGs in frontal cortex and temporal cortex were associated with COVID-19, suggesting that as an environmental risk factor COVID-19 affects an increased risk of ASD.

Self-powered, ultraviolet-to-near infrared broadband photodetector based on Ag-doped CsPbI3/PEDOT:PSS heterojunction.

Metal halide perovskites are studied for photodetection applications because of their outstanding optical and electrical properties. A self-powered ultraviolet-to-near infrared broadband photodetector based on a Ag-doped CsPbI3/PEDOT:PSS heterojunction was investigated. The photodetector using a CsPbI3:Ag/PEDOT:PSS heterostructure with a planar photoconductive structure operated over a broad 355-1560 nm wavelength range in self-powered mode. A terahertz signal was modulated with the CsPbI3:Ag/PEDOT:PSS structure at low optical excitation intensity to investigate its photodetection mechanism. The experimentally designed detector can present images of the letters "C", "N" and "U" in the visible and near-infrared wavelengths, indicating a potential broadband imaging application.

Ultraviolet-to-infrared broadband photodetector and imaging application based on a perovskite single crystal.

The organic-inorganic hybrid perovskite CH3NH3PbBr3(MAPbBr3) has been well developed in the X-ray to visible light band due to its superior optoelectronic properties, but this material is rarely studied in the infrared band. In this paper, a UV-NIR broadband optical detector based on MAPbBr3 single crystal is studied, and the response range can reach the near-infrared region. In the visible light band, the optical response of the device is mainly caused by the photoelectric effect; in the near-infrared band, the optical response of the device is mainly caused by the thermal effect. The carrier response of MAPbBr3 material under different wavelengths of light was investigated using a non-contact measurement method (optical pump terahertz (THz) probe spectroscopy). This paper also builds a set of photoelectric sensor array components, and successfully realizes the conversion of optical image signals to electrical image signals in the visible light band and infrared band. The experimental results show that MAPbBr3 crystals provide a new possibility for UV-NIR broadband photodetectors.

Morphology engineering of a hybrid perovskite for active terahertz memory modulation.

Morphology engineering was investigated for hybrid perovskites CH3NH3PbI3:Ag/Poly(3, 4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) that were fabricated in both air and nitrogen environments for active terahertz (THz) memory modulation. Under low optical excitation or an applied bias, THz amplitude modulation or rapid restore in both CH3NH3PbI3:Ag/PEDOT:PSS hybrid structures were demonstrated. The recovery time of the modulated THz wave in the sample fabricated in air was considerably longer than that of the sample fabricated in nitrogen because of defect states induced by a high degree of roughness. THz transmissions were used as coded pixel units and were programmed to store a 4×4 image or a multi-order signal. Hence, active THz memory modulation was demonstrated. It also has potential applications as a visible to near-infrared broad-spectrum light detector.

Silencing integrin α6 enhances the pluripotency-differentiation transition in human dental pulp stem cells.

OBJECTIVES: Although integrins have been shown to be associated with proliferation and differentiation in some stem cells, the regulatory effect of integrin α6 (ITGα6) on the human dental pulp stem cells (hDPSCs) has not been reported. Here, we detected the roles of ITGα6 in hDPSCs. MATERIALS AND METHODS: Attached to Cytodex 3 microcarriers, hDPSCs grown under stimulated microgravity (SMG) or conventional culture conditions were measured the proliferation and different gene expression. Further, ITGα6 was silenced in hDPSCs, and its effect on proliferation, differentiation, and cytoskeletal organization was analyzed. RESULTS: SMG conditions increased the number of Ki67-positive hDPSCs and progression into S phase of cell cycle. WB analysis showed the expression of ITGα6 was upregulated in hDPSCs under SMG conditions. Knockdown of ITGα6 decreased the expression of stemness markers, CD105 and STRO-1 in hDPSCs, but promoted the osteogenic and odontogenic differentiation by increased ALP expression and Alizarin Red nodules. Moreover, RNA-seq demonstrated that RHO/ROCK signaling pathway upregulated silencing ITGα6-hDPSCs. Treatment with Y-27632 inhibited the effect of ITGα6 depletion on hDPSCs stemness, rearranged the cytoskeleton, promoted the pluripotency, proliferation ability, and inhibited the differentiation. CONCLUSION: ITGα6 promotes hDPSCs stemness via inhibiting RHO/ROCK and restoring cytoskeleton.

Terahertz nonvolatile in situ electrically erasable-rewritable photo-memory based on indium oxide/PEDOT:PSS.

A terahertz (THz) nonvolatile in situ electrically erasable-rewritable photo-memory based on indium oxide (In2O3) nanoparticles is reported. The In2O3/PEDOT:PSS/quartz sample increases its conductivity and attenuates its THz transmission under optical excitation. When this optical excitation is terminated, the modulated THz transmission recovers to its original value in an air environment slightly. The modulated THz transmission recovered more rapidly with increasing bias voltage. Nonvolatile digital information storage is enabled when the In2O3/PEDOT:PSS/quartz structure is encapsulated in nitrogen. The photo-memory can be rewritten after in situ electrical erasure. The results show that in situ electrically erasable terahertz nonvolatile rewritable photo-memories are feasible.

Amyloid deposition in a mouse model humanized at the transthyretin and retinol-binding protein 4 loci.

Familial amyloidotic polyneuropathy is an autosomal dominant disorder caused by a point mutation in the transthyretin (TTR) gene. The process of TTR amyloidogenesis begins with rate-limiting dissociation of the TTR tetramer. Thus, the TTR stabilizers, such as Tafamidis and Diflunisal, are now in clinical trials. Mouse models will be useful to testing the efficacy of these drugs. Although several mouse models have been generated, they all express mouse Rbp4. Thus, human TTR associates with mouse RBP4, resulting in different kinetic and thermodynamic stability profiles of TTR tetramers. To overcome this problem, we previously produced humanized mouse strains at both the TTR and Rbp4 loci (Ttr hTTRVal30 , Ttr hTTRMet30 , and Rbp4 hRBP4 ). By mating these mice, we produced double-humanized mouse strains, Ttr hTTRVal30/hTTRVal30 :Rbp4 hRBP4/hRBP4 and Ttr hTTRVal30/Met30 :Rbp4 hRBP4/hRBP4 . We used conventional transgenic mouse strains on a wild-type (Ttr +/+ :Tg[6.0hTTRMet30]) or knockout Ttr background (Ttr-/-:Tg[6.0hTTRMet30]) as reference strains. The double-humanized mouse showed 1/25 of serum hTTR and 1/40 of serum hRBP4 levels. However, amyloid deposition was more pronounced in Ttr hTTRVal30/Met30 :Rbp4 hRBP4/hRBP4 than in conventional transgenic mouse strains. In addition, a similar amount of amyloid deposition was also observed in Ttr hTTRVal30/ hTTRVal30 :Rbp4 hRBP4/ hRBP4 mice that carried the wild-type human TTR gene. Furthermore, amyloid deposition was first observed in the sciatic nerve without any additional genetic change. In all strains, anti-TTR antibody-positive deposits were found in earlier age and at higher percentage than amyloid fibril deposition. In double-humanized mice, gel filtration analysis of serum revealed that most hTTR was free of hRBP4, suggesting importance of free TTR for amyloid deposition.

Ultraviolet light-induced terahertz modulation of an indium oxide film.

Active ultraviolet light-induced terahertz modulation of an indium oxide film is investigated. A large absorption modulation of ~66% is achieved upon illumination with a low intensity UV laser (11 mW/cm2). The interaction between indium oxide and a flexible metamaterial structure is investigated owing to the large UV-induced enhancement of photo carriers observed in an indium oxide film. We are able to realize absorption peak shifts of 37 GHz by changing the UV excitation light intensity. We also propose a multi-frequency switch by building a circular metallic split ring resonator whose gaps are filled with silicon, germanium, and indium oxide. In future, a photo-excited tunable multi-frequency metamaterial switch can be realized by irradiating the structure with multi-wavelength laser beam.

Active bidirectional electrically-controlled terahertz device based on dimethyl sulfoxide-doped PEDOT:PSS.

A high-efficiency active bidirectional electrically-controlled terahertz device based on DMSO-doped PEDOT:PSS with low-power photoexcitation is investigated. Under low-power optical excitation of 30 mW (0.5 W/cm2) and under bias voltages ranging from -0.6 V to 0.5 V, spectrally broadband modulation of THz transmission over a range from -54% to 60% is obtained over the frequency range from 0.2 to 2.6 THz in a MEH-PPV/PEDOT:PSS:DMSO/Si/PEDOT:PSS:DMSO hybrid structure. By considering the combined carrier density characteristics of the proposed device, it is found that the large-scale amplitude modulation can be ascribed to the electrically-controlled carrier density in the silicon layer with the assistance of the p-n junction that consists of the DMSO-doped PEDOT:PSS and silicon. Bidirectional modulation has a larger modulation range and is easier to use in communications applications when compared with unidirectional modulation. These results show great potential for application to the design of active broadband terahertz devices.

Rescue of retinal morphology and function in a humanized mouse at the mouse retinol-binding protein locus.

Retinol-binding protein RBP4 is the specific carrier for retinol in the blood. We previously produced a Rbp4-deficient (Rbp4-/-) mouse that showed electroretinogram (ERG) abnormalities, accompanied by histological and electron-microscopic changes such as fewer synapses in the inner plexiform layer in the central retina. To address whether human RBP4 gene expression can rescue the phenotypes observed in Rbp4-/- mice, we produced a humanized (Rbp4hRBP4orf/ hRBP4orf) mouse with a human RBP4 open reading frame in the mouse Rbp4 locus using a Cre-mutant lox recombination system. In Rbp4hRBP4orf/hRBP4orf mice, the tissue-specific expression pattern of hRBP4orf was roughly the same as that of mouse Rbp4. ERG and morphological abnormalities observed in Rbp4-/- mice were rescued in Rbp4hRBP4orf/hRBP4orf mice as early as 7 weeks of age. The temporal expression pattern of hRBP4orf in the liver of Rbp4hRBP4orf/hRBP4orf mice was similar to that of mouse Rbp4 in Rbp4+/+mice. In contrast, hRBP4orf expression levels in eyes were significantly lower at 6 and 12 weeks of age compared with mouse Rbp4 but were restored to the control levels at 24 weeks. The serum hRBP4 levels in Rbp4hRBP4orf/hRBP4orf mice were approximately 30% of those in Rbp4+/+ at all ages examined. In accordance with this finding, the plasma retinol levels remained low in Rbp4hRBP4orf/hRBP4orf mice. Retinol accumulation in the liver occurred in control and Rbp4hRBP4orf/hRBP4orf mice but was higher in Rbp4hRBP4orf/hRBP4orf mice at 30 weeks of age. Mouse transthyretin expression was not altered in Rbp4-/- or Rbp4hRBP4orf/hRBP4orf mice. Taken together, 30% of the serum RBP4 level was sufficient to correct the abnormal phenotypes observed in Rbp4-/- mice.

Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background.

Retinol-binding protein 4 (RBP4) is a specific carrier for retinol in the blood. In hepatocytes, newly synthesized RBP4 associates with retinol and transthyretin and is secreted into the blood. The ternary transthyretin-RBP4-retinol complex transports retinol in the circulation and delivers it to target tissues. Rbp4-deficient mice in a mixed genetic background (129xC57BL/6J) have decreased sensitivity to light in the b-wave amplitude on electroretinogram. Sensitivity progressively improves and approaches that of wild-type mice at 24 weeks of age. In the present study, we produced Rbp4-deficient mice in the C57BL/6 genetic background. These mice displayed more severe phenotypes. They had decreased a- and b-wave amplitudes on electroretinograms. In accordance with these abnormalities, we found structural changes in these mice, such as loss of the peripheral choroid and photoreceptor layer in the peripheral retinas. In the central retinas, the distance between the inner limiting membrane and the outer plexiform layer was much shorter with fewer ganglion cells and fewer synapses in the inner plexiform layer. Furthermore, ocular developmental defects of retinal depigmentation, optic disc abnormality, and persistent hyaloid artery were also observed. All these abnormalities had not recovered even at 40 weeks of age. Our Rbp4-deficient mice accumulated retinol in the liver but it was undetectable in the serum, indicating an inverse relation between serum and liver retinol levels. Our results suggest that RBP4 is critical for the mobilization of retinol from hepatic storage pools, and that such mobilization is necessary for ocular development and visual function.

Abnormal dynamic changes in ß-tubulin in somatic nuclear transfer cloned mouse embryos.

The efficiency of somatic cell nuclear transfer (SCNT) cloning remains low, thus limiting the applications of this technique. In this study, we used immunochemistry and confocal microscopy to detect the microtubule component, ß-tubulin, in SCNT, parthenogenetic (PA), and intracytoplasmic sperm injection (ICSI) embryos before the first mitotic division. ß-Tubulin is the component subunit of microtubule, which plays critical roles in regulating localization of cellular organelles, and the growth, maturation and fertilization of oocytes. Our results demonstrated similar changes of spindle patterns in PA and ICSI embryos. The second meiotic division resumed 1 h post-treatment, and the cytoplasmic asters (CAs) disappeared. After about 4-6 h of treatment, pronuclei formed with the midbodies connecting each other. Meanwhile, the CAs reappeared and a microtubule network developed in the cytoplasm. However, SCNT embryos showed abnormal multipolar spindles, and the pseudopronuclei that contained many nucleoli existed after 6 h of SrCl2 activation. Enucleated oocytes alone did not form spindle-like structures when they were artificially activated for 6 h, indicating that somatic cell chromosomes might be necessary for spindle formation in SCNT embryos. These results demonstrated abnormal changes of ß-tubulin in mouse SCNT embryos, compared with PA and ICSI embryos.

Morphological changes and germ layer formation in the porcine embryos from days 7-13 of development.

Morphogenesis and identification of embryonic differentiation in porcine embryos are crucial issues for developmental biology and laboratory animal science. The current paper presents a study on the asynchronous development of hatched porcine embryos from days 7 to 13 post-insemination. Examination of semi-thin sections of the hypoblast showed that it had characteristics similar to those of the mouse anterior visceral endoderm during embryonic disc formation. Also, a cavity appeared in the epiblast, which was similar to a mouse proamniotic cavity. With the gradual disappearance of Rauber's layer, the cavity opened and contacted the external environment directly, all of which formed the embryonic disc. To confirm the differentiation characteristics, we performed immunohistochemical analyses and showed that GATA6 was detected clearly in parietal endoderm cells during embryonic disc establishment. OCT4 was expressed in the inner cell mass (ICM) and trophoblast of hatched blastocysts and in the epiblast during formation of the embryonic disc. However, OCT4 showed comparatively decreased expression in the posterior embryonic disc, primitive streak and migrating cells. SOX2 was present in the ICM and epiblast. Therefore, both SOX2 and OCT4 can be used as markers of pluripotent cells in the porcine embryonic disc. At the start of gastrulation, staining revealed VIMENTIN in the posterior of the embryonic disc, primitive streak and in migrating cells that underlay the embryonic disc and was also expressed in epiblast cells located in the anterior primitive streak. Together with serial sections of embryos stained by whole mount immunohistochemistry, the mesoderm differentiation pattern was shown as an ingression movement that took place at the posterior of the embryonic disc and with bilateral migration along the embryonic disc borders.

[Identification of Six Isomers of Dimethylbenzoic Acid by Using Terahertz Time-Domain Spectroscopy Technique].

In this paper, the absorption spectra of 6 isomers of dimethylbenzoic acid, which were widely used in chemical and pharmaceutical production as intermediate substance, were measured by using the terahertz time-domain spectroscopy (THz-TDS) system in the range 0.2-2.2 THz at room temperature. The experimental results show that the six measured isomers present apparent different spectral response. However, the results of using infrared spectroscopy indicates that different isomers show high similarity in absorption spectra in the range 1450-1700 cm⁻¹. The vibrational frequencies are calculated by using the density functional theory (DFT), and identification of vibrational modes are given. It is clear that the absorption peaks of the 6 isomers in the range 1450-1700 cm⁻¹ come from the stretching vibration of benzene ring and C==O, while the absorption peaks in the terahertz range are caused by the relative wagging of benzene ring and all the chains out of plane, which lead to the different absorption characteristics of the 6 isomers in the range 0.2-2.2 THz. The results suggest that the difference and similarity of the absorption spectra observed in the two different frequency range are resulted from the difference and similarity of the molecular structures of the six isomers. By using the different absorption characteristics, we can identify the six isomers of dimethylbenzoic acid effectively. Our study indicates that it is feasible to distinguish the isomers by using terahertz and infrared spectroscopy technique. It provides an effective way to identify different isomers and test the purity of the intermediate substance in the process of production quickly and accurately.

[A Double Split Ring Terahertz Filter on Ploymide Substrate].

Metamaterials are artificial composites that acquire their electromagnetic properties from embeded subwavelength metalic structure. With proper design of metamaterials, numerrous intriguing phenomena that not exhibited naturally can be realized, such as invisible cloaking, perfect absorption, negative refractive index and so on. In recent years, With the development of THz technology, the extensive research onTHz metamaterials devices areattracting more and more attentions. Since silicon (Si) has a higher transmittance for THz wave, it is usually selected as substrate in metamaterials structure. However, Si has the shortcomings of hardness, not easy to bend, and fragile, which limit the application of THz metamaterials. In this work, we use polyimide as the substrate to overcome the shortcomings of the Si substrate. Polyimide is flexible, smooth, suitable for conventional lithography process and the THz transmittance can compete with that of the Si. Frist, we test the THz optical properties of polymide, and get the refractive index of 1.9, and the transmittance of 80%. Second, we design a double splits ring resonators (DSRRs), and study the properties of transmission by changing the THz incidence angle and curvature of the sample. We find the resonant amplitude and resonant frequencies are unchanged. Fabricating metamaterials structures on a thin plastic substrate is a possible way to extend plane surface filtering to curved surface filtering. Third, we try to make a broadband filter by stacking two samples, and the 181GHz bandwidth at 50% has been achieved. By stacking several plane plastic metamaterial layers with different resonance responses into a multi-layer structure, a broadband THz filter can be built. The broadband filter has the advantages of simple manufacture, obvious filtering effect, which provides a new idea for the production of terahertz band filter.

Generation of neural progenitors from induced Bama miniature pig pluripotent cells.

Pig pluripotent cells may represent an advantageous experimental tool for developing therapeutic application in the human biomedical field. However, it has previously been proven to be difficult to establish from the early embryo and its pluripotency has not been distinctly documented. In recent years, induced pluripotent stem (iPS) cell technology provides a new method of reprogramming somatic cells to pluripotent state. The generation of iPS cells together with or without certain small molecules has become a routine technique. However, the generation of iPS cells from pig embryonic tissues using viral infections together with small molecules has not been reported. Here, we reported the generation of induced pig pluripotent cells (iPPCs) using the iPS technology in combination with valproic acid (VPA). VPA treatment significantly increased the expression of pluripotent genes and played an important role in early reprogramming. We showed that iPPCs resembled pig epiblast cells in their morphology and pluripotent markers, such as OCT4, NANOG, and SSEA1. It had a normal karyotype and could form embryoid bodies, which express three germ layer markers in vitro. In addition, the iPPCs might directly differentiate into neural progenitors after being induced with the retinoic acid and extracellular matrix. Our study established a reasonable method to generate pig pluripotent cells, which might be a new donor cell source for human neural disease therapy.

Conjugated polymer-based broadband terahertz wave modulator.

An optical broadband terahertz (THz) wave modulator, based on a polymer-inorganic interface, is investigated. The THz pulse transmission was efficiently modulated by an external continuous wave (CW) laser. The effects on the poly[2-methoxy-5-(2'-ethylhexyloxy)-1, 4-phenylenevinylene] (MEH-PPV)/silicon interface were measured by THz time-domain spectroscopy. The modulation factor reached 99.6%, at an external laser beam intensity of 6.3 W/cm2. In the proposed THz-CW system, a significant fall (in both THz transmission and reflection) was also observed at the MEH-PPV/Si interface. This reduction in THz transmission and reflection has been induced by absorption at the MEH-PPV/Si interface. The results show that an optically controlled polymer/inorganic broadband THz modulator can be realized.

Lack of association between the G+2044A polymorphism of interleukin-13 gene and chronic obstructive pulmonary disease: a meta-analysis.

Numerous studies have investigated association of interleukin-13 (IL-13) G+2044A polymorphism with COPD susceptibility; however, the results were inconsistent and inconclusive. To evaluate the association between the IL-13 G+2044A polymorphism and susceptibility to COPD, a meta-analysis of published case-control studies was performed. Based on PubMed and Chinese database, this research selected studies that examined the association of the IL-13 G+2044A polymorphism with COPD. A genetic model-free approach was used to assess whether the combined data showed this association. Then a subgroup analysis was also performed, with stratifications for race, study design, and sample size. Six studies (total 1,213 COPD patients and 801 control subjects) for the IL-13 G+2044A polymorphism with COPD were included in the meta-analysis (G- vs A-allele: OR 1.12, 95 % CI 0.96-1.32, P = 0.15; genotypes GG+GA vs genotype AA: OR 0.99, 95 % CI 0.49-2.00, P = 0.98; genotype GG vs genotypes GA+AA: OR 1.18, 95 % CI 0.97-1.44, P = 0.09; genotype GA vs genotypes GG+AA: OR 0.85, 95 % CI 0.70-1.04, P = 0.11). This meta-analysis demonstrates that the IL-13 G+2044A polymorphism does not confer susceptibility to COPD. More detailed data about individual and environment, larger sample sizes with unbiased genotyping methods and matched controls in different populations are required.