CCKBR+ cancer cells contribute to the intratumor heterogeneity of gastric cancer and confer sensitivity to FOXO inhibition.

The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer.

Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear. METHODS: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.We treated age-matched SOD1-G93A mice with B022 (a NIK inhibitor) to investigate the role of NIK in the ALS animal model. We also established a new mice model by crossing SOD1-G93A mice with NIK+/- mice to further evaluate the interrelationship between the NIK and the disease progression in ALS animal model. RESULTS: In this study, we found the ncNF-κB pathway was activated in SOD1-G93A animal model and TBK1 deletion model. Inhibition of NIK activity by small molecule B022 significantly improved the motor performance of the ALS animal model. However, NIK deletion enhanced the mutant SOD1 toxicity by inflammatory infiltration. CONCLUSION: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.

LIMK1 promotes the development of cervical cancer by up-regulating the ROS/Src-FAK/cofilin signaling pathway.

OBJECTIVE: In this study, we investigated the mechanism of action of LIMK1 in cervical cancer progression. METHODS: The biological role of LIMK1 in regulating the growth, invasion, and metastasis of cervical cancer was studied in SiHa, CaSki cells and nude mice tumor models. The role of LIMK1 in the growth of cervical cancer was evaluated by HE staining. The role of LIMK1 in the invasion, metastasis, and proliferation of cervical cancer was evaluated by cell scratch, Transwell, and monoclonal experiments. The interaction among LIMK1, ROS, and Src was evaluated by Western blotting. The effects of regulating ROS and p-Src expression on LIMK1 in the migration/invasion and proliferation of cervical cancer cells were evaluated through cellular functional assays. RESULTS: Overexpression of LIMK1 promoted tumor growth in nude mice. Cell scratch, Transwell, and monoclonal experiments suggested that LIMK1 promoted the invasion, metastasis, and proliferation of cervical cancer cells. Western blotting suggested that LIMK1 can promote the expression of ROS-related proteins NOX2, NOX4, p-Src, and downstream proteins p-FAK, p-ROCK1/2, p-Cofilin-1, F-actin and inhibit the expression of p-SHP2 protein. Correction experiments showed that LIMK1 regulated the expression of p-FAK and p-Cofilin-1 proteins by regulating ROS and p-Src. Through the detection of cervical cancer cell functions, it was found that the activation of ROS and p-Src induced by LIMK1 is an early event that promotes the migration, proliferation, and invasion of cervical cancer cells. CONCLUSIONS: LIMK1 promotes the expression of F-actin and promotes the development of cervical cancer by regulating the oxidative stress/Src-mediated p-FAK/p-ROCK1/2/p-Cofilin-1 pathway.

Field-Free Manipulation of Two-Dimensional Ferromagnet CrTe2 by Spin-Orbit Torques.

Electrical manipulation of magnetic states in two-dimensional ferromagnetic systems is crucial in information storage and low-dimensional spintronics. Spin-orbit torque presents a rapid and energy-efficient method for electrical control of the magnetization. In this letter, we demonstrate a wafer-scale spin-orbit torque switching of two-dimensional ferromagnetic states. Using molecular beam epitaxy, we fabricate two-dimensional heterostructures composed of low crystal-symmetry WTe2 and ferromagnet CrTe2 with perpendicular anisotropy. By utilizing out-of-plane spins generated from WTe2, we achieve field-free switching of the CrTe2 perpendicular magnetization. The threshold switching current density in CrTe2/WTe2 is 1.2 × 106 A/cm2, 20 times smaller than that of the CrTe2/Pt control sample even with an external magnetic field. In addition, the switching behavior can be modulated by external magnetic fields and crystal symmetry. Our findings demonstrate a controllable and all-electric manipulation of perpendicular magnetization in a two-dimensional ferromagnet, representing a significant advancement toward the practical implementation of low-dimensional spintronic devices.

Dynamic tracking of onion-like carbon nanoparticles in cancer cells using limited-angle holographic tomography with self-supervised learning.

This research presents a novel approach for the dynamic monitoring of onion-like carbon nanoparticles inside colorectal cancer cells. Onion-like carbon nanoparticles are widely used in photothermal cancer therapy, and precise 3D tracking of their distribution is crucial. We proposed a limited-angle digital holographic tomography technique with unsupervised learning to achieve rapid and accurate monitoring. A key innovation is our internal learning neural network. This network addresses the information limitations of limited-angle measurements by directly mapping coordinates to measured data and reconstructing phase information at unmeasured angles without external training data. We validated the network using standard SiO2 microspheres. Subsequently, we reconstructed the 3D refractive index of onion-like carbon nanoparticles within cancer cells at various time points. Morphological parameters of the nanoparticles were quantitatively analyzed to understand their temporal evolution, offering initial insights into the underlying mechanisms. This methodology provides a new perspective for efficiently tracking nanoparticles within cancer cells.

Above-room-temperature chiral skyrmion lattice and Dzyaloshinskii-Moriya interaction in a van der Waals ferromagnet Fe3-xGaTe2.

Skyrmions in existing 2D van der Waals (vdW) materials have primarily been limited to cryogenic temperatures, and the underlying physical mechanism of the Dzyaloshinskii-Moriya interaction (DMI), a crucial ingredient for stabilizing chiral skyrmions, remains inadequately explored. Here, we report the observation of Néel-type skyrmions in a vdW ferromagnet Fe3-xGaTe2 above room temperature. Contrary to previous assumptions of centrosymmetry in Fe3-xGaTe2, the atomic-resolution scanning transmission electron microscopy reveals that the off-centered FeΙΙ atoms break the spatial inversion symmetry, rendering it a polar metal. First-principles calculations further elucidate that the DMI primarily stems from the Te sublayers through the Fert-Lévy mechanism. Remarkably, the chiral skyrmion lattice in Fe3-xGaTe2 can persist up to 330 K at zero magnetic field, demonstrating superior thermal stability compared to other known skyrmion vdW magnets. This work provides valuable insights into skyrmionics and presents promising prospects for 2D material-based skyrmion devices operating beyond room temperature.

Spin-orbit torque manipulation of sub-terahertz magnons in antiferromagnetic α-Fe2O3.

The ability to electrically manipulate antiferromagnetic magnons, essential for extending the operating speed of spintronic devices into the terahertz regime, remains a major challenge. This is because antiferromagnetic magnetism is challenging to perturb using traditional methods such as magnetic fields. Recent developments in spin-orbit torques have opened a possibility of accessing antiferromagnetic magnetic order parameters and controlling terahertz magnons, which has not been experimentally realised yet. Here, we demonstrate the electrical manipulation of sub-terahertz magnons in the α-Fe2O3/Pt antiferromagnetic heterostructure. By applying the spin-orbit torques in the heterostructure, we can modify the magnon dispersion and decrease the magnon frequency in α-Fe2O3, as detected by time-resolved magneto-optical techniques. We have found that optimal tuning occurs when the Néel vector is perpendicular to the injected spin polarisation. Our results represent a significant step towards the development of electrically tunable terahertz spintronic devices.

Study on Gamma sensory flicker for Insomnia.

OBJECTIVES: Insomnia has been the subject of much systematic research because it is a risk factor for a variety of diseases. There is some evidence that gamma sensory stimulation therapy has also been demonstrated to improve sleep quality for people with Alzheimer's disease. However, it is unclear whether this method is effective for treating insomnia. The principal objective of this project was to investigate the efficacy and safety of gamma sensory flicker in improving the sleep quality of insomnia patients. METHODS: Thirty-seven participants with insomnia were recruited for this prospective observational study. For a duration of 8 weeks, participants were exposed to flicker stimulation through a light and sound device. RESULTS: During the main phase of the study, adherence rates averaged 92.21%. Additionally, no severe adverse events were reported for flicker treatment. Analysis of sleep diaries indicated that 40 Hz flickers can enhance sleep quality by reducing sleep onset latencies, and arousals, and increasing total sleep duration. CONCLUSIONS: Gamma sensory flicker improves sleep quality in people suffering from insomnia.

A rare germline BMP15 missense mutation causes hereditary ovarian immature teratoma in human.

Ovarian immature teratomas (OITs) are malignant tumors originating from the ovarian germ cells that mainly occur during the first 30 y of a female's life. Early age of onset strongly suggests the presence of susceptibility gene mutations for the disease yet to be discovered. Whole exon sequencing was used to screen pathogenic mutations from pedigrees with OITs. A rare missense germline mutation (C262T) in the first exon of the BMP15 gene was identified. In silico calculation suggested that the mutation could impair the formation of mature peptides. In vitro experiments on cell lines confirmed that the mutation caused an 84.7% reduction in the secretion of mature BMP15. Clinical samples from OIT patients also showed a similar pattern of decrease in the BMP15 expression. In the transgenic mouse model, the spontaneous parthenogenetic activation significantly increased in oocytes carrying the T allele. Remarkably, a mouse carrying the T allele developed the phenotype of OIT. Oocyte-specific RNA sequencing revealed that abnormal activation of the H-Ras/MAPK pathway might contribute to the development of OIT. BMP15 was identified as a pathogenic gene for OIT which improved our understanding of the etiology of OIT and provided a potential biomarker for genetic screening of this disorder.

Phase separation of SHP2E76K promotes malignant transformation of mesenchymal stem cells by activating mitochondrial complexes.

Mesenchymal stem cells (MSCs), suffering from diverse gene hits, undergo malignant transformation and aberrant osteochondral differentiation. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a nonreceptor protein tyrosine phosphatase, regulates multicellular differentiation, proliferation, and transformation. However, the role of SHP2 in MSC fate determination remains unclear. Here, we showed that MSCs bearing the activating SHP2E76K mutation underwent malignant transformation into sarcoma stem-like cells. We revealed that the SHP2E76K mutation in mouse MSCs led to hyperactive mitochondrial metabolism by activating mitochondrial complexes I and III. Inhibition of complexes I and III prevented hyperactive mitochondrial metabolism and malignant transformation of SHP2E76K MSCs. Mechanistically, we verified that SHP2 underwent liquid-liquid phase separation (LLPS) in SHP2E76K MSCs. SHP2 LLPS led to its dissociation from complexes I and III, causing their hyperactivation. Blockade of SHP2 LLPS by LLPS-defective mutations or allosteric inhibitors suppressed complex I and III hyperactivation as well as malignant transformation of SHP2E76K MSCs. These findings reveal that complex I and III hyperactivation driven by SHP2 LLPS promotes malignant transformation of SHP2E76K MSCs and suggest that inhibition of SHP2 LLPS could be a potential therapeutic target for the treatment of activated SHP2-associated cancers.

Balancing the Ion/Electron Transport of Graphite Anodes by a La-Doped TiNb2O7 Functional Coating for Fast-Charging Li-Ion Batteries.

A functional coating layer (FCL) is widely applied in fast-charging lithium-ion batteries to improve the sluggish Li+ transport kinetics of traditional graphite anodes. However, blindly increasing the Li+ conductivity for FCL reduces the overall electron conductivity of the anodes. Herein, we decoupled the effect of La-doping on TiNb2O7 (TNO) in terms of the phase evolution, Li+/electron transport, and lithiation behavior, and then proposed a promising La0.1TNO FCL with balanced Li+/electron transport for a fast-charging graphite anode. By optimizing the doping concentration of La, more holes are introduced into the TNO as electron carriers without causing lattice distortion, thus maintaining the fast Li+ diffusion channel in TNO. As a result, the graphite with La0.1TNO FCL delivers an excellent capacity of 220.2 mAh g-1 (96.3% retention) after 450 cycles at 3 C, nearly twice that of the unmodified one.

Field-free switching of perpendicular magnetization by two-dimensional PtTe2/WTe2 van der Waals heterostructures with high spin Hall conductivity.

The key challenge of spin-orbit torque applications lies in exploring an excellent spin source capable of generating out-of-plane spins while exhibiting high spin Hall conductivity. Here we combine PtTe2 for high spin conductivity and WTe2 for low crystal symmetry to satisfy the above requirements. The PtTe2/WTe2 bilayers exhibit a high in-plane spin Hall conductivity σs,y ≈ 2.32 × 105 × h/2e Ω-1 m-1 and out-of-plane spin Hall conductivity σs,z ≈ 0.25 × 105 × h/2e Ω-1 m-1, where h is the reduced Planck's constant and e is the value of the elementary charge. The out-of-plane spins in PtTe2/WTe2 bilayers enable the deterministic switching of perpendicular magnetization at room temperature without magnetic fields, and the power consumption is 67 times smaller than that of the Pt control case. The high out-of-plane spin Hall conductivity is attributed to the conversion from in-plane spin to out-of-plane spin, induced by the crystal asymmetry of WTe2. Our work establishes a low-power perpendicular magnetization manipulation based on wafer-scale two-dimensional van der Waals heterostructures.

Morphological changes in the midface of Beagle dogs treated by trans-sutural distraction / Cambios morfológicos en la cara media de perros Beagle tratados por distracción trans-sutural

Trans-sutural distraction is a biological process that induces the formation of new bone and changes the position of bone by pulling on growing suture under the action of external forces. Currently, therapy to midfacial hypoplasia treated by trans-sutural distraction has been applied. In this study, Beagle dogs were selected as experimental animals, and a traction device designed by ourselves was applied to Beagle dogs to simulate the treatment process of trans-sutural distraction in human face, so as to provide a basis for the subsequent research on the related mechanism of trans-sutural distraction. The objective is that the animal model can provide the basis for the follow-up study of transsutural distraction. 45 month beagle dogs were randomly divided into two groups 3 in experiment group and 3 in control group. Implant nails were implanted as the bone marker in the bilateral zygomatic temporal suture, zygomandibular maxillary suture and palatine transverse suture in experimental group. The traction of the maxilla was carried out by the external cranial traction frame with canine fossa as bearing point, 800g force each side, elastic traction for 15 days. The control group only implanted the implant nail as the bone marker on both sides of the bone suture. The distance between two implant nails was measured by vernier calipers and X-ray examination, compared with preoperative and postoperative changes. X-ray and cephalometric measurements were used to measure change in the cranial basal angle. HE staining was used to observe the width of the bone seams, the morphology and structure of the cells and the tissue of the new bone under the phase contrast microscope. Then descriptive statistical analysis and t-test between two independent samples are carried out for the measurement data. The experimental group had a good retention of the beagle traction frame. In the experimental group, the maxillaries of dogs were protrudent in the process of traction gradually and the occlusal relationship changed to type II malocclusion. When the traction is 15 days, the coverage distance is about 8~9 mm. Before and after the traction, the distance between landmark points indicated that the spacing between the transverse palatine suture was the largest (experimental group: 5.52±0.19 mm control group 1.31±0.06 mm P<0.05), and zygomaticotemporal suture was the second (experimental group: 3.12±0.15 mm, control group 0.73±0.04 mm, P<0.05), and zygomaticomaxillary suture was less (experimental group: 2.60±0.34 mm, control group 0.53±0.05 mm, P<0.05). The cranial basal angle was no change before and after operation (controlgroup: 32.3±1.3°, experimental group: 33.2±1.1° P>0.05. Histology showed that the collagenous fibers in the suture of the control group were denser and the osteoblasts were visible on the edge of the suture, showing osteogenic activity. The experimental group significantly widened suture (experimental group: 1209.388±42.714 µm, control group 248.276±22.864 µm, P<0.05), the number of fibroblasts increased significantly with loose collagen fiber. The direction of cell and fiber arrangement were parallel to the traction force. There were many small blood vessels and marrow cavities, and the bone trabecula around the bone suture was thin (experimental group: 23.684±3.774 mm, control group: 86.810±9.219 mm, P < 0.05), showing active osteogenic activity. The growing beagle dog can be used to establish a suture traction animal model for experimental study. In the experiment, Kirschner wire was used to penetrate the bottom plane of the piriform hole of the maxilla (about the position of the canine fossa at the back) and the traction direction was basically the same as the growth direction, and the maxilla was basically parallel and moved forward.

La distracción trans-sutural es un proceso biológico que induce la formación de hueso nuevo y cambia la posición del éste al tirar de la sutura en crecimiento bajo la acción de fuerzas externas. Actualmente, se ha aplicado la terapia para la hipoplasia de la cara media tratada por distracción trans-sutural. En este estudio, fueron seleccionados perros Beagle como animales experimentales, y un dispositivo de tracción fue instalado a los perros para simular el proceso de tratamiento de la distracción trans-sutural en el rostro humano. El objetivo fue proporcionar una base para la investigación posterior sobre mecanismos relacionados con la distracción trans-sutural. El modelo animal puede proporcionar la base para este tipo de estudio de seguimiento de la distracción trans-sutural. Perros Beagle de 45 meses de edad se dividieron aleatoriamente en dos grupos: 3 en el grupo experimental y 3 en el grupo control. Los clavos de implante se usaron como marcadores óseos en la sutura temporal cigomática bilateral, la sutura maxilar cigomandibular y en la sutura transversal palatina en el grupo experimental. La tracción del maxilar se realizó mediante el marco de tracción craneal externo con fosa canina como punto de apoyo, 800 g de fuerza a cada lado, tracción elástica durante 15 días. En el grupo control solo se implantó el clavo del implante como marcador óseo en ambos lados de la sutura. La distancia entre dos clavos de implante se midió mediante calibradores de vernier y examen de rayos X, en comparación con los cambios preoperatorios y postoperatorios. Se utilizaron mediciones cefalométricas y de rayos X para medir el cambio en el ángulo basal craneal. La tinción con HE se usó para observar el ancho de las suturas óseas, la morfología y la estructura de las células y el tejido del hueso nuevo bajo el microscopio de contraste de fase. Luego se realizó un análisis estadístico descriptivo y una prueba t entre dos muestras independientes para los datos de medición. El grupo experimental tuvo una buena retención del cuadro de tracción del Beagle. En el grupo experimental, los maxilares de los perros sobresalieron gradualmente en el proceso de tracción y la relación oclusal cambió a maloclusión tipo II. Cuando la tracción era de 15 días, la distancia de cobertura fue de aproximadamente 8 ~ 9 mm. Antes y después de la tracción, la distancia entre los puntos de referencia indicaba que el espacio entre la sutura palatina transversal era más grande (grupo experimental: 5,52 ± 0,19 mm, grupo de control 1,31 ± 0,06 mm, P <0,05), y la sutura cigomáticotemporal fue la segunda. (Grupo experimental: 3,12 ± 0,15 mm, grupo control 0,73 ± 0,04 mm, P <0,05), y la sutura cigomaticomaxilar fue menor (grupo experimental, 2,60 ± 0,34 mm, grupo control 0,53 ± 0,05 mm, P <0,05). El ángulo basal craneal no cambió antes ni después de la operación (grupo control 32,3 ± 1,3, grupo experimental, 33,2 ± 1,1 ° , P> 0,05). La histología mostró que las fibras colágenas en la sutura del grupo control eran más densas y los osteoblastos se observaron en el margen de la sutura, mostrando actividad osteogénica. En el grupo experimental se amplió significativamente la sutura (1209,388 ± 42,714 µm, grupo control 248,276 ± 22,864 µm, P <0,05), el número de fibroblastos aumentó significativamente con fibras colágenas dispersas. La dirección de la disposición de la celda y las fibras era paralela a la fuerza de tracción. Se observó gran cantidad de vasos sanguíneos pequeños, cavidades medulares, y trabéculas óseas alrededor de la sutura ósea (grupo experimental: 23,684 ± 3,774 mm, grupo control: 86,810 ± 9,219 mm, P <0,05), que mostró actividad osteogénica activa. El perro Beagle en crecimiento se puede utilizar para estudios experimentales y así establecer un modelo animal de tracción de sutura. En el proceso, se usó alambre de Kirschner para penetrar en el plano inferior del foramen piriforme del maxilar (aproximadamente en la posición de la fosa canina en la parte posterior) y la dirección de tracción fue básicamente la misma que en el crecimiento.