Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex.

The role of WNT/ß-catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/ß-catenin regulates progenitor self-renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)-mediated protein degradation. We show that mice mutant for cyclin Y and cyclin Y-like 1 (Ccny/l1), key regulators of WNT/STOP signalling, display reduced neurogenesis in the developing neocortex. Specifically, basal progenitors, which exhibit delayed cell cycle progression, were drastically decreased. Ccny/l1-deficient apical progenitors show reduced asymmetric division due to an increase in apical-basal astral microtubules. We identify the neurogenic transcription factors Sox4 and Sox11 as direct GSK3 targets that are stabilized by WNT/STOP signalling in basal progenitors during mitosis and that promote neuron generation. Our work reveals that WNT/STOP signalling drives cortical neurogenesis and identifies mitosis as a critical phase for neural progenitor fate.

True-color light-field display system with large depth-of-field based on joint modulation for size and arrangement of halftone dots.

A true-color light-field display system with a large depth-of-field (DOF) is demonstrated. Reducing crosstalk between viewpoints and increasing viewpoint density are the key points to realize light-field display system with large DOF. The aliasing and crosstalk of light beams in the light control unit (LCU) are reduced by adopting collimated backlight and reversely placing the aspheric cylindrical lens array (ACLA). The one-dimensional (1D) light-field encoding of halftone images increases the number of controllable beams within the LCU and improves viewpoint density. The use of 1D light-field encoding leads to a decrease in the color-depth of the light-field display system. The joint modulation for size and arrangement of halftone dots (JMSAHD) is used to increase color-depth. In the experiment, a three-dimensional (3D) model was constructed using halftone images generated by JMSAHD, and a light-field display system with a viewpoint density of 1.45 (i.e. 1.45 viewpoints per degree of view) and a DOF of 50 cm was achieved at a 100 ° viewing angle.

Ultrasonic Auxiliary Ozone Oxidation-Extraction Desulfurization: A Highly Efficient and Stable Process for Ultra-Deep Desulfurization.

For ultra-deep desulfurization of diesel fuel, this study applied the ultrasound-assisted catalytic ozonation process to the dibenzothiophene (DBT) removal process with four Keggin-type heteropolyacids (HPA) as catalysts and acetonitrile as extractant. Through experimental evaluations, H3PMo12O40 was found to be the most effective catalyst for the oxidative removal of DBT. Under favorable operating conditions with a temperature of 0 °C, H3PMo12O40 dosage of 2.5 wt.% of n-octane, and ultrasonic irradiation, DBT can be effectively removed from simulated diesel. Moreover, the reused catalyst exhibited good catalytic activity in recovery experiments. This desulfurization process has high potential for ultra-deep desulfurization of diesel.

Influence of behavioral state on the neuromodulatory effect of low-intensity transcranial ultrasound stimulation on hippocampal CA1 in mouse.

In process of brain stimulation, the influence of any external stimulus depends on the features of the stimulus and the initial state of the brain. Understanding the state-dependence of brain stimulation is very important. However, it remains unclear whether neural activity induced by ultrasound stimulation is modulated by the behavioral state. We used low-intensity focused ultrasound to stimulate the hippocampal CA1 regions of mice with different behavioral states (anesthesia, awake, and running) and recorded the neural activity in the target area before and after stimulation. We found the following: (1) there were different spike firing rates and response delays computed as the time to reach peak for all behavioral states; (2) the behavioral state significantly modulates the spike firing rate linearly increased with an increase in ultrasound intensity under different behavioral states; (3) the mean power of local field potential induced by TUS significantly increased under anesthesia and awake states; (4) ultrasound stimulation enhanced phase-locking between spike and ripple oscillation under anesthesia state. These results suggest that ultrasound stimulation-induced neural activity is modulated by the behavioral state. Our study has great potential benefits for the application of ultrasound stimulation in neuroscience.

Self-Amplification of Coherent Energy Modulation in Seeded Free-Electron Lasers.

The spectroscopic techniques for time-resolved fine analysis of matter require coherent x-ray radiation with femtosecond duration and high average brightness. Seeded free-electron lasers (FELs), which use the frequency up-conversion of an external seed laser to improve temporal coherence, are ideal for providing fully coherent soft x-ray pulses. However, it is difficult to operate seeded FELs at a high repetition rate due to the limitations of present state-of-the-art laser systems. Here, we report a novel self-modulation method for enhancing laser-induced energy modulation, thereby significantly reducing the requirement of an external laser system. Driven by this scheme, we experimentally realize high harmonic generation in a seeded FEL using an unprecedentedly small external laser-induced energy modulation. An electron beam with a laser-induced energy modulation as small as 1.8 times the slice energy spread is used for lasing at the seventh harmonic of a 266-nm seed laser in a single-stage high-gain harmonic generation (HGHG) setup and the 30th harmonic of the seed laser in a two-stage HGHG setup. The results mark a major step toward a high-repetition-rate, fully coherent x-ray FEL.

Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals.

Previous data suggested a negative role of phosphatase and tensin homolog (Pten) and a positive function of SH2-containing tyrosine phosphatase (Shp2)/Ptpn11 in myelopoiesis and leukemogenesis. Herein we demonstrate that ablating Shp2 indeed suppressed the myeloproliferative effect of Pten loss, indicating directly opposing functions between pathways regulated by these two enzymes. Surprisingly, the Shp2 and Pten double-knockout mice suffered lethal anemia, a phenotype that reveals previously unappreciated cooperative roles of Pten and Shp2 in erythropoiesis. The lethal anemia was caused collectively by skewed progenitor differentiation and shortened erythrocyte lifespan. Consistently, treatment of Pten-deficient mice with a specific Shp2 inhibitor suppressed myeloproliferative neoplasm while causing anemia. These results identify concerted actions of Pten and Shp2 in promoting erythropoiesis, while acting antagonistically in myeloproliferative neoplasm development. This study illustrates cell type-specific signal cross-talk in blood cell lineages, and will guide better design of pharmaceuticals for leukemia and other types of cancer in the era of precision medicine.

Skin-interfaced microfluidic biosensors for colorimetric measurements of the concentrations of ketones in sweat.

Ketones, such as beta-hydroxybutyrate (BHB), are important metabolites that can be used to monitor for conditions such as diabetic ketoacidosis (DKA) and ketosis. Compared to conventional approaches that rely on samples of urine or blood evaluated using laboratory techniques, processes for monitoring of ketones in sweat using on-body sensors offer significant advantages. Here, we report a class of soft, skin-interfaced microfluidic devices that can quantify the concentrations of BHB in sweat based on simple and low-cost colorimetric schemes. These devices combine microfluidic structures and enzymatic colorimetric BHB assays for selective and accurate analysis. Human trials demonstrate the broad applicability of this technology in practical scenarios, and they also establish quantitative correlations between the concentration of BHB in sweat and in blood. The results represent a convenient means for managing DKA and aspects of personal nutrition/wellness.

Remote optogenetic control of the enteric nervous system and brain-gut axis in freely-behaving mice enabled by a wireless, battery-free optoelectronic device.

Wireless activation of the enteric nervous system (ENS) in freely moving animals with implantable optogenetic devices offers a unique and exciting opportunity to selectively control gastrointestinal (GI) transit in vivo, including the gut-brain axis. Programmed delivery of light to targeted locations in the GI-tract, however, poses many challenges not encountered within the central nervous system (CNS). We report here the development of a fully implantable, battery-free wireless device specifically designed for optogenetic control of the GI-tract, capable of generating sufficient light over large areas to robustly activate the ENS, potently inducing colonic motility ex vivo and increased propulsion in vivo. Use in in vivo studies reveals unique stimulation patterns that increase expulsion of colonic content, likely mediated in part by activation of an extrinsic brain-gut motor pathway, via pelvic nerves. This technology overcomes major limitations of conventional wireless optogenetic hardware designed for the CNS, providing targeted control of specific neurochemical classes of neurons in the ENS and brain-gut axis, for direct modulation of GI-transit and associated behaviours in freely moving animals.

Patterned wireless transcranial optogenetics generates artificial perception.

Synthesizing perceivable artificial neural inputs independent of typical sensory channels remains a fundamental challenge in the development of next-generation brain-machine interfaces. Establishing a minimally invasive, wirelessly effective, and miniaturized platform with long-term stability is crucial for creating a clinically meaningful interface capable of mediating artificial perceptual feedback. In this study, we demonstrate a miniaturized fully implantable wireless transcranial optogenetic encoder designed to generate artificial perceptions through digitized optogenetic manipulation of large cortical ensembles. This platform enables the spatiotemporal orchestration of large-scale cortical activity for remote perception genesis via real-time wireless communication and control, with optimized device performance achieved by simulation-guided methods addressing light and heat propagation during operation. Cue discrimination during operant learning demonstrates the wireless genesis of artificial percepts sensed by mice, where spatial distance across large cortical networks and sequential order-based analyses of discrimination performance reveal principles that adhere to general perceptual rules. These conceptual and technical advancements expand our understanding of artificial neural syntax and its perception by the brain, guiding the evolution of next-generation brain-machine communication.

A rapid, straightforward, and print house compatible mass fabrication method for integrating 3D paper-based microfluidics.

Three-dimensional (3D) paper-based microfluidics, which is featured with high performance and speedy determination, promise to carry out multistep sample pretreatment and orderly chemical reaction, which have been used for medical diagnosis, cell culture, environment determination, and so on with broad market prospect. However, there are some drawbacks in the existing fabrication methods for 3D paper-based microfluidics, such as, cumbersome and time-consuming device assembly; expensive and difficult process for manufacture; contamination caused by organic reagents from their fabrication process. Here, we present a simple printing-bookbinding method for mass fabricating 3D paper-based microfluidics. This approach involves two main steps: (i) wax-printing, (ii) bookbinding. We tested the delivery capability, diffusion rate, homogeneity and demonstrated the applicability of the device to chemical analysis by nitrite colorimetric assays. The described method is rapid (<30 s), cheap, easy to manipulate, and compatible with the flat stitching method that is common in a print house, making itself an ideal scheme for large-scale production of 3D paper-based microfluidics.

Inhibition of ß-catenin signaling involved in the biological activities of a lignan E2S isolated from Carya cathayensis fruits.

Carya cathayensis is a fruit-bearing plant that belongs to the Juglandaceae family and is widely distributed throughout the world. It possesses various important biological activities. We have previously isolated an antitumor compound from the shell of C. cathayensis fruits and named it E2S ((E)-3-[(2S,3R)-2,3-dihydro-2-(4'-hydroxy-3'-methoxyphenyl)-3-hydroxymethyl-7-methoxy-1-benzo[b]furan-5-yl]-2-propenal). In this study, we investigated the antitumor activity of E2S against various human colorectal cancer cell lines (HCT116, HT29, SW480, LoVo). The results showed that E2S could significantly inhibit the growth of cancer cells in a dose-dependent manner, as well as disrupt the progression of the cell cycle. Mechanistic study revealed that E2S could decrease the protein levels of ß-catenin and its downstream targets (such as c-myc, a key transcriptional target of ß-catenin) in the cells. In addition, it also significantly suppressed ß-catenin/TCF transcriptional activity. Taken together, the results suggested that E2S might partially exert an antiproliferative effect on human colorectal cancer cells by targeting ß-catenin signaling, a finding that might potentially translate into a chemotherapeutic strategy for the treatment of cancer. It might also have implications for cancer prevention strategies.

Mucociliary Wnt signaling promotes cilia biogenesis and beating.

It is widely thought that Wnt/Lrp6 signaling proceeds through the cytoplasm and that motile cilia are signaling-inert nanomotors. Contrasting both views, we here show in the mucociliary epidermis of X. tropicalis embryos that motile cilia transduce a ciliary Wnt signal that is distinct from canonical ß-catenin signaling. Instead, it engages a Wnt-Gsk3-Ppp1r11-Pp1 signaling axis. Mucociliary Wnt signaling is essential for ciliogenesis and it engages Lrp6 co-receptors that localize to cilia via a VxP ciliary targeting sequence. Live-cell imaging using a ciliary Gsk3 biosensor reveals an immediate response of motile cilia to Wnt ligand. Wnt treatment stimulates ciliary beating in X. tropicalis embryos and primary human airway mucociliary epithelia. Moreover, Wnt treatment improves ciliary function in X. tropicalis ciliopathy models of male infertility and primary ciliary dyskinesia (ccdc108, gas2l2). We conclude that X. tropicalis motile cilia are Wnt signaling organelles that transduce a distinct Wnt-Pp1 response.

Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis.

WNT signaling is important in development, stem cell maintenance, and disease. WNT ligands typically signal via receptor activation across the plasma membrane to induce ß-catenin-dependent gene activation. Here, we show that in mammalian primary cilia, WNT receptors relay a WNT/GSK3 signal that ß-catenin-independently promotes ciliogenesis. Characterization of a LRP6 ciliary targeting sequence and monitoring of acute WNT co-receptor activation (phospho-LRP6) support this conclusion. Ciliary WNT signaling inhibits protein phosphatase 1 (PP1) activity, a negative regulator of ciliogenesis, by preventing GSK3-mediated phosphorylation of the PP1 regulatory inhibitor subunit PPP1R2. Concordantly, deficiency of WNT/GSK3 signaling by depletion of cyclin Y and cyclin-Y-like protein 1 induces primary cilia defects in mouse embryonic neuronal precursors, kidney proximal tubules, and adult mice preadipocytes.

New antitumor compounds from Carya cathayensis.

A new lignan (7R,8S,8'R)-4,4',9-trihydroxy-7,9'-epoxy-8,8'-lignan, and three new phenolics, carayensin-A, carayensin-B, and carayensin-C, together with 13 known compounds were isolated from the shells of Carya cathayensis. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. All the compounds were evaluated for cytotoxicity against several human tumor types including human colorectal cancer cell lines (HCT-116, HT-29), human lung cancer cell line (A549), and human breast cancer cell line (MCF-7). The compounds 1, 5, 6, and 16 are considered to be potential as antitumor agents, which could significantly inhibit the cancer cell growth in a dose-dependent manner.

Online single-shot characterization of ultrafast pulses from high-gain free-electron lasers.

X-ray free-electron lasers (FELs) provide cutting-edge tools for fundamental researches to study nature down to the atomic level at a time-scale that fits this resolution. A precise knowledge of temporal information of FEL pulses is the central issue for its applications. Here we proposed and demonstrated a novel method to determine the FEL temporal profiles online. This robust method, designed for ultrafast FELs, allows researchers to acquire real-time longitudinal profiles of FEL pulses as well as their arrive times with respect to the external optical laser with a resolution better than 6 fs. Based on this method, we can also directly measure various properties of FEL pulses and correlations between them online. This helps us to further understand the FEL lasing processes and realize the generation of stable, nearly fully coherent soft X-ray laser pulses at the Shanghai Soft X-ray FEL facility. This method will enhance the experimental opportunities for ultrafast science in various areas.

All roads lead to Rome - a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer's disease.

Age-related neurodegenerative disorders such as Alzheimer's disease (AD) have become a critical public health issue due to the significantly extended human lifespan, leading to considerable economic and social burdens. Traditional therapies for AD such as medicine and surgery remain ineffective, impractical, and expensive. Many studies have shown that a variety of bioactive substances released by physical exercise (called "exerkines") help to maintain and improve the normal functions of the brain in terms of cognition, emotion, and psychomotor coordination. Increasing evidence suggests that exerkines may exert beneficial effects in AD as well. This review summarizes the neuroprotective effects of exerkines in AD, focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise. The findings described in this review will help direct research into novel targets for the treatment of AD and develop customized exercise therapy for individuals of different ages, genders, and health conditions.

CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia.

The heterogeneous response of acute myeloid leukemia (AML) to current anti-leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)-enriched compartments with different self-renewal capacities. How these compartments self-renew remained unclear. Here, we show that GPR56+ LSC compartments are promoted in a complex network involving epithelial-to-mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56+ CD34+ fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co-activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC-enriched subsets in vivo and synergize with the Bcl-2 inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56high AML and propose combined CDK7 and Bcl-2 inhibition as LSC-directed therapy in this disease.

The Effect of Low-Intensity Transcranial Ultrasound Stimulation on Neural Oscillation and Hemodynamics in the Mouse Visual Cortex Depends on Anesthesia Level and Ultrasound Intensity.

OBJECTIVE: Low-intensity transcranial ultrasound stimulation (TUS) can induce motor responses, neural oscillation and hemodynamic responses. Early studies demonstrated that the motor responses evoked by TUS critically depend on anesthesia levels and ultrasound intensity. However, the neural mechanism of how anesthesia levels and ultrasound intensity influence on brain responses during TUS has never been explored yet. To investigate this question, we applied different anesthesia levels and ultrasound intensities on the visual cortex of mouse and observed neural oscillation change and hemodynamic responses during TUS. METHODS: low-intensity ultrasound was delivered to mouse visual cortex under different anesthesia levels, and simultaneous recordings for local field potentials (LFPs) and hemodynamic responses were carried out to measure and analyze the changes quantitatively. RESULTS: (i) The change of mean amplitude and mean relative power of sharp wave-ripple (SPW-R) in LFPs induced by TUS decreased as the anesthesia level increased (from awake to 1.5% isoflurane). (ii) The hemodynamic response level induced by TUS decreased as the anesthesia level increased (from awake to1.5% isoflurane). (iii) The coupling strength between neural activities and hemodynamic responses was dependent on anesthesia level. (iv) The neural activities and hemodynamic responses increase as a function of ultrasound intensity. CONCLUSION: These results support that the neural activities and hemodynamic response of the mouse visual cortex induced by TUS are related to the anesthesia level and ultrasound intensity. SIGNIFICANCE: This finding suggests that careful maintenance of anesthesia level and ultrasound intensity is required to acquire accurate LFP and hemodynamic data from samples with TUS.

Pyroelectric Catalysis-Based "Nano-Lymphatic" Reduces Tumor Interstitial Pressure for Enhanced Penetration and Hydrodynamic Therapy.

Because of the deficiency of lymphatic reflux in the tumor, the retention of tumor interstitial fluid causes aggravation of the tumor interstitial pressure (TIP), which leads to unsatisfactory tumor penetration of nanomedicine. It is the main inducement of tumor recurrence and metastasis. Herein, we design a pyroelectric catalysis-based "Nano-lymphatic" to decrease the TIP for enhanced tumor penetration and treatments. It realizes photothermal therapy and decomposition of tumor interstitial fluid under NIR-II laser irradiation after reaching the tumor, which reduces the TIP for enhanced tumor penetration. Simultaneously, reactive oxygen species generated during the pyroelectric catalysis can further damage deep tumor stem cells. The results indicate that the "Nano-lymphatic" relieves 52% of TIP, leading to enhanced tumor penetration, which effectively inhibits the tumor proliferation (93.75%) and recurrence. Our finding presents a rational strategy to reduce TIP by pyroelectric catalysis for enhanced tumor penetration and improved treatments, which is of great significance for drug delivery.