Palette of Rechargeable Mechanoluminescent Fluids Produced by a Biomineral-Inspired Suppressed Dissolution Approach.

Mechanoluminescent materials, which emit light in response to mechanical stimuli, have recently been explored as promising candidates for photonic skins, remote optogenetics, and stress sensing. All mechanoluminescent materials reported thus far are bulk solids with micron-sized grains, and their light emission is only produced when fractured or deformed in bulk form. In contrast, mechanoluminescence has never been observed in liquids and colloidal solutions, thus limiting its biological application in living organisms. Here, we report the synthesis of mechanoluminescent fluids via a suppressed dissolution approach. We demonstrate that this approach yields stable colloidal solutions comprising mechanoluminescent nanocrystals with bright emissions in the range of 470-610 nm and diameters down to 20 nm. These colloidal solutions can be recharged and discharged repeatedly under photoexcitation and hydrodynamically focused ultrasound, respectively, thus yielding rechargeable mechanoluminescent fluids that can store photon energy in a reversible manner. This rechargeable fluid can facilitate a systemically delivered light source gated by tissue-penetrant ultrasound for biological applications that require light in the tissue, such as optogenetic stimulation in the brain.

A transparent, self-powered photodetector based on p-CuI/n-TiO2heterojunction film with high on-off ratio.

Ultraviolet(UV) photodetectors(PDs) can monitor UV radiation, enabling it to be effective for many applications, such as communication, imaging and sensing. The rapid progress on portable and wearable optoelectronic devices places a great demand on self-powered PDs. However, high-performance self-powered PDs are still limited. Herein we display a transparent and self-powered PD based on a p-CuI/n-TiO2heterojunction, which exhibits a high on-off ratio (∼104at 310 nm) and a fast response speed (rise time/decay time = 0.11 ms/0.72 ms) without bias. Moreover, the device shows an excellent UV-selective sensitivity as a solar-blind UV PD with a high UV/visible rejection ratio (R300 nm/R400 nm= 5.3 × 102), which can be ascribed to the wide bandgaps of CuI and TiO2. This work provides a feasible route for the construction of transparent, self-powered PDs based on p-n heterojunctions.

Long-term toxicological studies on the Chinese medicine 2036 Specialty-Qiangxin recipe in rats.

CONTEXT: The traditional medicine 2036 Specialty-Qiangxin recipe (2036S-QXR) has been widely used in China to improve cardiac function, prevent stroke, and strengthen the immune system. However, its long-term toxicity remains unknown. OBJECTIVE: The present study evaluates the long-term toxicity of 2036S-QXR in rats. MATERIALS AND METHODS: 2036S-QXR (0.6, 1.2, and 2.4 g/kg body weight per day) was orally administered for 26 weeks to Wistar rats, while the rats in the control group received distilled water. The effects on urinary, hematological, biochemical, and histopathological parameters were investigated during the study period. RESULTS: No significant changes in all tested parameters were observed in the 0.6 and 1.2 g/kg groups, compared with the control group (p < 0.05). Higher levels of alanine aminotransferase (46.00 ± 12.85 vs. 25.40 ± 3.36) and aspartate aminotransferase (152.40 ± 32.52 vs. 111.40 ± 18.78) were observed after 13 weeks in the female rats in the 2.4 g/kg group compared with the control group (p < 0.05), but these returned to the control levels after the recovery period (p > 0.05). Several cases displayed the presence of urine protein (3/7 males and 3/7 females) and mild lesions in the kidney (10/20) and thymus (5/20) in the 2.4 g/kg group, without significant changes compared with the control group (p > 0.05). DISCUSSION AND CONCLUSIONS: The present study shows that 2036S-QXR does not cause long-term toxicity, supporting its therapeutic use. To further determine the optimal doses, future studies should test more doses and include more animals in each group.

Induced pluripotent stem cells and neurological disease models.

The availability of human stem cells heralds a new era for in vitro cell-based modeling of neurodevelopmental and neurodegenerative diseases. Adding to the excitement is the discovery that somatic cells of patients can be reprogrammed to a pluripotent state from which neural lineage cells that carry the disease genotype can be derived. These in vitro cell-based models of neurological diseases hold promise for monitoring of disease initiation and progression, and for testing of new drug treatments on the patient-derived cells. In this review, we focus on the prospective applications of different stem cell types for disease modeling and drug screening. We also highlight how the availability of patient-specific induced pluripotent stem cells (iPS cells) offers a unique opportunity for studying and modeling human neurodevelopmental and neurodegenerative diseases in vitro and for testing small molecules or other potential therapies for these disorders. Finally, the limitations of this technology from the standpoint of reprogramming efficiency and therapeutic safety are discussed.

Transcriptomic Investigation of the Virus Spectrum Carried by Midges in Border Areas of Yunnan Province.

Yunnan province in China shares its borders with three neighboring countries: Myanmar, Vietnam, and Laos. The region is characterized by a diverse climate and is known to be a suitable habitat for various arthropods, including midges which are notorious for transmitting diseases which pose significant health burdens affecting both human and animal health. A total of 431,100 midges were collected from 15 different locations in the border region of Yunnan province from 2015 to 2020. These midges were divided into 37 groups according to the collection year and sampling site. These 37 groups of midges were then homogenized to extract nucleic acid. Metatranscriptomics were used to analyze their viromes. Based on the obtained cytochrome C oxidase I gene (COI) sequences, three genera were identified, including one species of Forcipomyia, one species of Dasyhelea, and twenty-five species of Culicoides. We identified a total of 3199 viruses in five orders and 12 families, including 1305 single-stranded positive-stranded RNA viruses (+ssRNA) in two orders and seven families, 175 single-stranded negative-stranded RNA viruses (-ssRNA) in two orders and one family, and 1719 double-stranded RNA viruses in five families. Six arboviruses of economic importance were identified, namely Banna virus (BAV), Japanese encephalitis virus (JEV), Akabane virus (AKV), Bluetongue virus (BTV), Tibetan circovirus (TIBOV), and Epizootic hemorrhagic disease virus (EHDV), all of which are capable, to varying extents, of causing disease in humans and/or animals. The survey sites in this study basically covered the current distribution area of midges in Yunnan province, which helps to predict the geographic expansion of midge species. The complexity and diversity of the viral spectrum carried by midges identified in the study calls for more in-depth research, which can be utilized to monitor arthropod vectors and to predict the emergence and spread of zoonoses and animal epidemics, which is of great significance for the control of vector-borne diseases.

Ganoderma spore lipid ameliorates docetaxel, cisplatin, and 5-fluorouracil chemotherapy-induced damage to bone marrow mesenchymal stem cells and hematopoiesis.

BACKGROUND: A triplet chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TPF) is used to treat head and neck squamous cell carcinoma; however, it is toxic to bone marrow mesenchymal stem cells (BMSCs). We previously demonstrated that Ganoderma spore lipid (GSL) protect BMSCs against cyclophosphamide toxicity. In this study, we investigated the protective effects of GSL against TPF-induced BMSCs and hematopoietic damage. METHODS: BMSCs and C57BL/6 mice were divided into control, TPF, co-treatment (simultaneously treated with GSL and TPF for 2 days), and pre-treatment (treated with GSL for 7 days before 2 days of TPF treatment) groups. In vitro, morphology, phenotype, proliferation, senescence, apoptosis, reactive oxygen species (ROS), and differentiation of BMSCs were evaluated. In vivo, peripheral platelets (PLTs) and white blood cells (WBCs) from mouse venous blood were quantified. Bone marrow cells were isolated for hematopoietic colony-forming examination. RESULTS: In vitro, GSL significantly alleviated TPF-induced damage to BMSCs compared with the TPF group, recovering their morphology, phenotype, proliferation, and differentiation capacity (p < 0.05). Annexin V/PI and senescence-associated ß-galactosidase staining showed that GSL inhibited apoptosis and delayed senescence in TPF-treated BMSCs (p < 0.05). GSL downregulated the expression of caspase-3 and reduced ROS formation (p < 0.05). In vivo, GSL restored the number of peripheral PLTs and WBCs and protected the colony-forming capacity of bone marrow cells (p < 0.05). CONCLUSIONS: GSL efficiently protected BMSCs from damage caused by TPF and recovered hematopoiesis.

Direct Lineage Reprogramming for Induced Keratinocyte Stem Cells: A Potential Approach for Skin Repair.

Severe trauma or chronic wounds can deplete the keratinocyte stem cells (KSCs) present in the epidermal basal layer or inhibit their migration leading to compromised wound healing. Supplementing KSCs is the key to solution while lineage reprogramming provides a new approach to acquiring KSCs. Through direct lineage reprogramming, induced KSCs (iKSCs) can be produced from somatic cells, which exhibit great application potential. Two strategies are currently being used to directly generate iKSCs, lineage transcription factor (TF)-mediated and pluripotency factors-mediated. This review focuses on lineage TF-mediated direct reprogramming and describes the conversion process along with the underlying epigenetic mechanisms. It also discusses other potential induction strategies to generate iKSCs and challenges associated with in situ reprogramming for skin repair.

The SDF-1/CXCR4 Signaling Pathway Directs the Migration of Systemically Transplanted Bone Marrow Mesenchymal Stem Cells Towards the Lesion Site in a Rat Model of Spinal Cord Injury.

BACKGROUND: It has been observed that bone marrow-derived mesenchymal stem cells (MSCs) migrate towards the injured spinal cord and promote functional recovery when systemically transplanted into the traumatized spinal cord. However, the mechanisms underlying their migration to the spinal cord remain poorly understood. METHODS: In this study, we systemically transplanted GFP- and luciferase-expressing MSCs into rat models of spinal cord injury and examined the role of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis in regulating the migration of transplanted MSCs to the spinal cord. After intravenous injection, MSCs migrated to the injured spinal cord where the expression of SDF-1 was increased. Spinal cord recruitment of MSCs was blocked by pre-incubation with an inhibitor of CXCR4. Their presence correlated with morphological and functional recovery. In vitro, SDF-1 or cerebrospinal fluid (CSF) collected from SCI rats promoted a dose-dependent migration of MSCs in culture, which was blocked by an inhibitor of CXCR4 or SDF-1 antibody. RESULTS AND CONCLUSION: The study suggests that SDF-1/CXCR4 interactions recruit exogenous MSCs to injured spinal cord tissues and may enhance neural regeneration. Modulation of the homing capacity may be instrumental in harnessing the therapeutic potential of MSCs.

Nanotransducer-Enabled Deep-Brain Neuromodulation with NIR-II Light.

The second near-infrared window (NIR-II window), which ranges from 1000 to 1700 nm in wavelength, exhibits distinctive advantages of reduced light scattering and thus deep penetration in biological tissues in comparison to the visible spectrum. The NIR-II window has been widely employed for deep-tissue fluorescence imaging in the past decade. More recently, deep-brain neuromodulation has been demonstrated in the NIR-II window by leveraging nanotransducers that can efficiently convert brain-penetrant NIR-II light into heat. In this Perspective, we discuss the principles and potential applications of this NIR-II deep-brain neuromodulation technique, together with its advantages and limitations compared with other existing optical methods for deep-brain neuromodulation. We also point out a few future directions where the advances in materials science and bioengineering can expand the capability and utility of NIR-II neuromodulation methods.

IPSC-Derived Sensory Neurons Directing Fate Commitment of Human BMSC-Derived Schwann Cells: Applications in Traumatic Neural Injuries.

The in vitro derivation of Schwann cells from human bone marrow stromal cells (hBMSCs) opens avenues for autologous transplantation to achieve remyelination therapy for post-traumatic neural regeneration. Towards this end, we exploited human induced pluripotent stem-cell-derived sensory neurons to direct Schwann-cell-like cells derived from among the hBMSC-neurosphere cells into lineage-committed Schwann cells (hBMSC-dSCs). These cells were seeded into synthetic conduits for bridging critical gaps in a rat model of sciatic nerve injury. With improvement in gait by 12-week post-bridging, evoked signals were also detectable across the bridged nerve. Confocal microscopy revealed axially aligned axons in association with MBP-positive myelin layers across the bridge in contrast to null in non-seeded controls. Myelinating hBMSC-dSCs within the conduit were positive for both MBP and human nucleus marker HuN. We then implanted hBMSC-dSCs into the contused thoracic cord of rats. By 12-week post-implantation, significant improvement in hindlimb motor function was detectable if chondroitinase ABC was co-delivered to the injured site; such cord segments showed axons myelinated by hBMSC-dSCs. Results support translation into a protocol by which lineage-committed hBMSC-dSCs become available for motor function recovery after traumatic injury to both peripheral and central nervous systems.

Current state of the development of mesenchymal stem cells into clinically applicable Schwann cell transplants.

Schwann cells are critically important in recovery from injuries to the peripheral nervous system, and their absence from the central nervous system (CNS) may be a critical limiting factor in the CNS regeneration capacity. Various types of stem cells have been investigated for their potential to be induced to develop a Schwann cell phenotype, with mesenchymal stem cells (MSCs) being the most promising among them. The methods for inducing MSCs differentiation into Schwann cell-like cells are presented in detail in this review. The evidence related to successful differentiation of MSCs to Schwann cell-like cells is particularly discussed herein, which includes the changes in morphology, phenotype, function, and proteome. The possible explanations for the differentiation of MSCs to Schwann cell-like cells are also presented. Finally, we suggest future research aims which will need to be fulfilled to elucidate the biology of Schwann cell differentiation and MSC transdifferentiation, to enable clinical application of therapeutic differentiated MSC transplantation into nerve injury sites.

Link Between Senescence and Cell Fate: Senescence-Associated Secretory Phenotype and Its Effects on Stem Cell Fate Transition.

Senescence is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells remain metabolically active and secrete a variety of factors collectively termed senescence-associated secretory phenotype (SASP). SASP is highly pleiotropic and can impact numerous biological processes in which it has both beneficial and deleterious roles. The underlying mechanisms by which SASP exerts its pleiotropic influence remain largely unknown. SASP serves as an environmental factor, which regulates stem cell differentiation and alters its routine. The latter can potentially be accomplished through dedifferentiation, transdifferentiation, or reprogramming. Behavioral changes that cells undergo when exposed to SASP are involved in several senescence-associated physiological and pathological phenomena. These findings provide clues for identifying possible interventions to reduce the deleterious effects without interfering in the beneficial outcomes. In this study, we discuss the multifaceted effects of SASP and the changes occurring in cellular states upon exposure to SASP factors.

A biomineral-inspired approach of synthesizing colloidal persistent phosphors as a multicolor, intravital light source.

Many in vivo biological techniques, such as fluorescence imaging, photodynamic therapy, and optogenetics, require light delivery into biological tissues. The limited tissue penetration of visible light discourages the use of external light sources and calls for the development of light sources that can be delivered in vivo. A promising material for internal light delivery is persistent phosphors; however, there is a scarcity of materials with strong persistent luminescence of visible light in a stable colloid to facilitate systemic delivery in vivo. Here, we used a bioinspired demineralization (BID) strategy to synthesize stable colloidal solutions of solid-state phosphors in the range of 470 to 650 nm and diameters down to 20 nm. The exceptional brightness of BID-produced colloids enables their utility as multicolor luminescent tags in vivo with favorable biocompatibility. Because of their stable dispersion in water, BID-produced nanophosphors can be delivered systemically, acting as an intravascular colloidal light source to internally excite genetically encoded fluorescent reporters within the mouse brain.

Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window.

Neural circuitry is typically modulated via invasive brain implants and tethered optical fibres in restrained animals. Here we show that wide-field illumination in the second near-infrared spectral window (NIR-II) enables implant-and-tether-free deep-brain stimulation in freely behaving mice with stereotactically injected macromolecular photothermal transducers activating neurons ectopically expressing the temperature-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1). The macromolecular transducers, ~40 nm in size and consisting of a semiconducting polymer core and an amphiphilic polymer shell, have a photothermal conversion efficiency of 71% at 1,064 nm, the wavelength at which light attenuation by brain tissue is minimized (within the 400-1,800 nm spectral window). TRPV1-expressing neurons in the hippocampus, motor cortex and ventral tegmental area of mice can be activated with minimal thermal damage on wide-field NIR-II illumination from a light source placed at distances higher than 50 cm above the animal's head and at an incident power density of 10 mW mm-2. Deep-brain stimulation via wide-field NIR-II illumination may open up opportunities for social behavioural studies in small animals.

Enhanced Electrical Properties of Lithography-Free Fabricated MoS2 Field Effect Transistors with Chromium Contacts.

Molybdenum disulfide (MoS2) as a two-dimensional semiconductor material has been actively explored for field-effect-transistors (FETs). The current prevailing method for MoS2 FET fabrication involves multiple complex steps, including electron beam (e-beam) lithography, annealing, etc., which are time-consuming and require polymer resists. As a consequence, the MoS2 exposed to chemicals during the patterning process may be unfavorably affected by residues and the performance of the final FET could be impaired while the annealing limits materials for FETs. Therefore, there is an urgent need to free the fabrication of FETs from e-beam lithography and annealing. In this study, we introduce an e-beam lithography-free method to fabricate MoS2 FETs by employing maze-like source/drain electrodes. In addition, an ohmic contact in multilayer MoS2 FETs using chromium (Cr) as source/drain electrodes is achieved without annealing. The underlying mechanism for contact performance is studied, and the tightness of the contact and the type of metal are found to be responsible because they determine the contact resistance. Furthermore, the long-term device degradation is explored, in which the oxidation of metal dominates. The facile fabrication process and mechanism explanation in this work might provide a new platform for future electronic devices.

Ultrafast Speed, Dark Current Suppression, and Self-Powered Enhancement in TiO2-Based Ultraviolet Photodetectors by Organic Layers and Ag Nanowires Regulation.

TiO2-based photodetectors (PDs) have been hotspots in recent years for their excellent thermal stabilities and optoelectronic performance under ultraviolet (UV) light. However, the high dark current caused by defects in TiO2 films has limited the detectivity (D) of these PDs. Here, the dark current of a TiO2-based PD was effectively reduced by 3 magnitudes (from 0.1 mA to 20 nA) and D was increased to 1.2 × 1014 Jones by introducing PC71BM. The TiO2/PC71BM heterojunction also made the PD self-powered, and by further introducing an interface layer of PEDOT:PSS and finely optimizing the electrode Ag nanowires (Ag NWs), the self-powered responsivity (R) was increased to 33 mA/W. Ultrafast rise/decay times (129 ns/1 ms at -1 V and 0.06 s/<1 µs at 0 V) were achieved. This work successfully applied an organic-inorganic heterojunction, an organic interface, and Ag NWs to suppress the dark current and enhance the self-powered photocurrent/R of inorganic PDs, providing a feasible strategy in high-performance UV PDs' design.

Dedifferentiation derived cells exhibit phenotypic and functional characteristics of epidermal stem cells.

Differentiated epidermal cells can dedifferentiate into stem cells or stem cell-like cells in vivo. In this study, we report the isolation and characterization of dedifferentiation-derived cells. Epidermal sheets eliminated of basal stem cells were transplanted onto the skin wounds in 47 nude athymic (BALB/c-nu/nu) mice. After 5 days, cells negative for CK10 but positive for CK19 and beta1-integrin emerged at the wound-neighbouring side of the epidermal sheets. Furthermore, the percentages of CK19 and beta1-integrin+ cells detected by flow cytometric analysis were increased after grafting (P < 0.01) and CK10+ cells in grafted sheets decreased (P < 0.01). Then we isolated these cells on the basis of rapid adhesion to type IV collagen and found that there were 4.56% adhering cells (dedifferentiation-derived cells) in the grafting group within 10 min. The in vitro phenotypic assays showed that the expressions of CK19, beta1-integrin, Oct4 and Nanog in dedifferentiation-derived cells were remarkably higher than those in the control group (differentiated epidermal cells) (P < 0.01). In addition, the results of the functional investigation of dedifferentiation-derived cells demonstrated: (1) the numbers of colonies consisting of 5-10 cells and greater than 10 cells were increased 5.9-fold and 6.7-fold, respectively, as compared with that in the control (P < 0.01); (2) more cells were in S phase and G2/M phase of the cell cycle (proliferation index values were 21.02% in control group, 45.08% in group of dedifferentiation); (3) the total days of culture (28 days versus 130 days), the passage number of cells (3 passages versus 20 passages) and assumptive total cell output (1 x 10(5) cells versus 1 x 10(12) cells) were all significantly increased and (4) dedifferentiation-derived cells, as well as epidermal stem cells, were capable of regenerating a skin equivalent, but differentiated epidermal cells could not. These results suggested that the characteristics of dedifferentiation-derived cells cultured in vitro were similar to epidermal stem cells. This study may also offer a new approach to yield epidermal stem cells for wound repair and regeneration.

Patient-Specific Cells for Modeling and Decoding Amyotrophic Lateral Sclerosis: Advances and Challenges.

Motor neuron loss or degeneration is the typical characteristic of amyotrophic lateral sclerosis (ALS), which often leads to weakness, paralysis, or even death. The underlying mechanisms of motor neuron degeneration and ALS progression remain elusive, and there is no effective treatment for ALS. The advances of stem cells and reprogramming techniques has made it possible to generate patient-specific motor neurons as cell models for studying disease mechanisms and drug discovery. This review comprehensively discusses recent approaches to generate motor neurons from stem cells and somatic cells and highlights the application of induced motor neurons to modeling ALS diseases, dissecting the pathogenesis, and screening new drugs. New perspectives are also discussed on generating patient-specific motor neuron subtypes that are affected by ALS or creating 3D spinal cord organoid models for better recapitulating and understanding ALS.

Generation of keratinocyte stem-like cells from human fibroblasts via a direct reprogramming approach.

Skin repair and reconstruction are important after severe wound and trauma. Keratinocyte stem cells (KSCs) in the basal layer of the epidermis can regrow the stratified epidermis but are almost depleted after skin injury. Thus, generating enough KSCs is indispensable for skin regeneration. Pluripotent stem cells such as ESC and iPSC can differentiate into KSCs, but their applications are challenged by ethical issues and risks of tumor formation. Lineage reprogramming from one cell type into another one makes it feasible to generate the desired cell type. Here, we develop a method to convert human fibroblasts into induced keratinocyte stem-like cells (iKSC) by coupling transient expression of reprogramming factors with a chemically defined culture medium, without the formation of iPSC. iKSC resemble normal KSC in the morphological and phenotypic features and can differentiate in vitro and regenerate stratified epidermis after transplantation in vivo. Therefore, iKSC may provide abundant cellular sources for skin repair and regeneration.

Migration of bone marrow-derived mesenchymal stem cells induced by tumor necrosis factor-alpha and its possible role in wound healing.

We aimed to investigate the effect of tumor necrosis factor-alpha (TNF-alpha) on the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the migration ability of mesenchymal stem cells (MSCs) in the context of wound healing. We also explored the role of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) signaling pathways in the migration of MSCs. MSCs were isolated from the bone marrow and cultured. Immunocytochemistry, Western blotting, and reverse transcription-polymerase chain reaction were used to observe the effect of TNF-alpha on the expression of ICAM-1 and VCAM-1 in MSCs. The chemotaxis effect of TNF-alpha on MSCs was investigated by the trans-well system and the inhibition effect of TNF-alpha using its antibody. Western blotting analysis was used to observe the activation of JAK-STAT and mitogen-activated protein kinase signaling pathways, and ERK was inhibited with PD98059 and p38 with SB203580 to observe the effect of TNF-alpha on MSC migration and ICAM-1 expression. The expression of ICAM-1 could be up-regulated by 50 microg/L TNF-alpha (p<0.05), whereas that of VCAM-1 remained unchanged (p>0.05). Also, TNF-alpha showed a chemotaxis effect by enhancing the migration ability of MSCs (p<0.05). TNF-alpha at 50 microg/L increased the expression of phospho-ERK and phospho-p38, and SB203580, but not PD98059, could suppress the chemotaxis effect and up-regulation of ICAM-1 induced by TNF-alpha in MSCs (p<0.05). Thus, TNF-alpha could up-regulate the expression of ICAM-1 in MSCs and enhance the cells' migration ability, and the p38 signaling pathway might be involved in the TNF-alpha-induced migration ability for a role in wound repair and regeneration.