circCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models.

Chronic wounds are a major complication in patients with diabetes. Here, we identify a therapeutic circRNA and load it into small extracellular vesicles (sEVs) to treat diabetic wounds in preclinical models. We show that circCDK13 can stimulate the proliferation and migration of human dermal fibroblasts and human epidermal keratinocytes by interacting with insulin-like growth factor 2 mRNA binding protein 3 in an N6-Methyladenosine-dependent manner to enhance CD44 and c-MYC expression. We engineered sEVs that overexpress circCDK13 and show that local subcutaneous injection into male db/db diabetic mouse wounds and wounds of streptozotocin-induced type I male diabetic rats could accelerate wound healing and skin appendage regeneration. Our study demonstrates that the delivery of circCDK13 in sEVs may present an option for diabetic wound treatment.

Correlated electron-nuclear dynamics of photoinduced water dissociation on rutile TiO2.

Elucidating the mechanism of photoinduced water splitting on TiO2 is important for advancing the understanding of photocatalysis and the ability to control photocatalytic surface reactions. However, incomplete experimental information and complex coupled electron-nuclear motion make the microscopic understanding challenging. Here we analyse the atomic-scale pathways of photogenerated charge carrier transport and photoinduced water dissociation at the prototypical water-rutile TiO2(110) interface using first-principles dynamics simulations. Two distinct mechanisms are observed. Field-initiated electron migration leads to adsorbed water dissociation via proton transfer to a surface bridging oxygen. In the other pathway, adsorbed water dissociation occurs via proton donation to a second-layer water molecule coupled to photoexcited-hole transfer promoted by in-plane surface lattice distortions. Two stages of non-adiabatic in-plane lattice motion-expansion and recovery-are observed, which are closely associated with population changes in Ti3d orbitals. Controlling such highly correlated electron-nuclear dynamics may provide opportunities for boosting the performance of photocatalytic materials.

Interlayer Carrier Dynamics in Two-Dimensional Perovskites Determined by the Length of Conjugated Organic Cations.

Unlocking the restricted interlayer carrier transfer in a two-dimensional perovskite is a crucial means to achieve the harmonization of efficiency and stability in perovskite solar cells. In this work, the effects of conjugated organic molecules on the interlayer carrier dynamics of 2D perovskites were investigated through nonadiabatic molecular dynamics simulations. We found that elongated conjugated organic cations contributed significantly to the accelerated interlayer carrier dynamics, originating from lowered transport barrier and boosted π-p coupling between organic and inorganic layers. Utilizing conjugated molecules of moderate length as spacer cations can yield both superior efficiency and exceptional stability simultaneously. However, conjugated chains that are too long lead to structural instability and stronger carrier recombination. The potential of conjugated chain-like molecules as spacer cations in 2D perovskites has been demonstrated in our work, offering valuable insights for the development of high-performance perovskite solar cells.

SOX6 AU controls myogenesis by cis-modulation of SOX6 in cattle.

Long non-coding RNAs (lncRNAs) have been shown to be involved in the regulation of skeletal muscle development through multiple mechanisms. The present study revealed that the lncRNA SOX6 AU (SRY-box transcription factor 6 antisense upstream) is reverse transcribed from upstream of the bovine sex-determining region Y (SRY)-related high-mobility-group box 6 (SOX6) gene. SOX6 AU was significantly differentially expressed in muscle tissue among different developmental stages in Xianan cattle. Subsequently, knockdown and overexpression experiments discovered that SOX6 AU promoted primary skeletal muscle cells proliferation, apoptosis, and differentiation in bovine. The overexpression of SOX6 AU in bovine primary skeletal muscle cells resulted in 483 differentially expressed genes (DEGs), including 224 upregulated DEGs and 259 downregulated DEGs. GO functional annotation analysis showed that muscle development-related biological processes such as muscle structure development and muscle cell proliferation were significantly enriched. KEGG pathway analysis revealed that the PI3K/AKT and MAPK signaling pathways were important pathways for DEG enrichment. Notably, we found that SOX6 AU inhibited the mRNA and protein expression levels of the SOX6 gene. Moreover, knockdown of the SOX6 gene promoted the proliferation and apoptosis of bovine primary skeletal muscle cells. Finally, we showed that SOX6 AU promoted the proliferation and apoptosis of bovine primary skeletal muscle cells by cis-modulation of SOX6 in cattle. This work illustrates our discovery of the molecular mechanisms underlying the regulation of SOX6 AU in the development of beef.

Measles Virus-Based Vaccine Expressing Membrane-Anchored Spike of SARS-CoV-2 Inducing Efficacious Systemic and Mucosal Humoral Immunity in Hamsters.

As SARS-CoV-2 continues to evolve and COVID-19 cases rapidly increase among children and adults, there is an urgent need for a safe and effective vaccine that can elicit systemic and mucosal humoral immunity to limit the emergence of new variants. Using the Chinese Hu191 measles virus (MeV-hu191) vaccine strain as a backbone, we developed MeV chimeras stably expressing the prefusion forms of either membrane-anchored, full-length spike (rMeV-preFS), or its soluble secreted spike trimers with the help of the SP-D trimerization tag (rMeV-S+SPD) of SARS-CoV-2 Omicron BA.2. The two vaccine candidates were administrated in golden Syrian hamsters through the intranasal or subcutaneous routes to determine the optimal immunization route for challenge. The intranasal delivery of rMeV-S+SPD induced a more robust mucosal IgA antibody response than the subcutaneous route. The mucosal IgA antibody induced by rMeV-preFS through the intranasal routine was slightly higher than the subcutaneous route, but there was no significant difference. The rMeV-preFS vaccine stimulated higher mucosal IgA than the rMeV-S+SPD vaccine through intranasal or subcutaneous administration. In hamsters, intranasal administration of the rMeV-preFS vaccine elicited high levels of NAbs, protecting against the SARS-CoV-2 Omicron BA.2 variant challenge by reducing virus loads and diminishing pathological changes in vaccinated animals. Encouragingly, sera collected from the rMeV-preFS group consistently showed robust and significantly high neutralizing titers against the latest variant XBB.1.16. These data suggest that rMeV-preFS is a highly promising COVID-19 candidate vaccine that has great potential to be developed into bivalent vaccines (MeV/SARS-CoV-2).

Tislelizumab plus chemotherapy is an optimal option for second-line treatment for advanced gastroesophageal junction adenocarcinoma.

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab (P = 0.015 and P = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it.

Three-stage ultrafast demagnetization dynamics in a monolayer ferromagnet.

Intense laser pulses can be used to demagnetize a magnetic material on an extremely short timescale. While this ultrafast demagnetization offers the potential for new magneto-optical devices, it poses challenges in capturing coupled spin-electron and spin-lattice dynamics. In this article, we study the photoinduced ultrafast demagnetization of a prototype monolayer ferromagnet Fe3GeTe2 and resolve the three-stage demagnetization process characterized by an ultrafast and substantial demagnetization on a timescale of 100 fs, followed by light-induced coherent A1g phonon dynamics which is strongly coupled to the spin dynamics in the next 200-800 fs. In the third stage, chiral lattice vibrations driven by nonlinear phonon couplings, both in-plane and out-of-plane are produced, resulting in significant spin precession. Nonadiabatic effects are found to introduce considerable phonon hardening and suppress the spin-lattice couplings during demagnetization. Our results advance our understanding of dynamic charge-spin-lattice couplings in the ultrafast demagnetization and evidence angular momentum transfer between the phonon and spin degrees of freedom.

Femtosecond Electron Diffraction Reveals Local Disorder and Local Anharmonicity in Thermoelectric SnSe.

In addition to long-range periodicity, local disorder, with local structures deviating from the average lattice structure, dominates the physical properties of phonons, electrons, and spin subsystems in crystalline functional materials. Experimentally characterizing the 3D atomic configuration of such a local disorder and correlating it with advanced functions remains challenging. Using a combination of femtosecond electron diffraction, structure factor calculations, and time-dependent density functional theory molecular dynamics simulations, the static local disorder and its local anharmonicity in thermoelectric SnSe are identified exclusively. The ultrafast structural dynamics reveal that the crystalline SnSe is composed of multiple locally correlated configurations dominated by the static off-symmetry displacements of Sn (≈0.4 Å) and such a set of locally correlated structures is termed local disorder. Moreover, the anharmonicity of this local disorder induces an ultrafast atomic displacement within 100 fs, indicating the signature of probable THz Einstein oscillators. The identified local disorder and local anharmonicity suggest a glass-like thermal transport channel, which updates the fundamental insight into the long-debated ultralow thermal conductivity of SnSe. The method of revealing the 3D local disorder and the locally correlated interactions by ultrafast structural dynamics will inspire broad interest in the construction of structure-property relationships in material science.

Effects of Pd atom vibration in the Sr-Te octahedral interstitial space in Zintl compound SrPdTe on lattice anharmonicity and thermoelectric properties.

Based on first-principles calculations, the current study deeply explores the thermoelectric properties of the Zintl compound SrPdTe. We found that the anharmonic vibration of Pd atoms plays an important role in the quartic anharmonic effect and the temperature dependence of the thermal conductivity. In the crystalline structure, Sr atoms form octahedra with eight surrounding Te atoms, while Pd atoms are located in the gaps between the octahedra. This structure makes the strong atomic mean square displacement of Pd atoms the main factor leading to the ultralow thermal conductivity. The study also reveals the effects of phonon frequency renormalization and four-phonon scattering on heat transfer performance. Even considering the spin-orbit coupling effect, multiple secondary valence band tops maintain the power factor of the material at high temperatures, providing a potential opportunity for achieving excellent thermoelectric performance.

Laser direct overall water splitting for H2 and H2O2 production.

Hydrogen (H2) and hydrogen peroxide (H2O2) play crucial roles as energy carriers and raw materials for industrial production. However, the current techniques for H2 and H2O2 production rely on complex catalysts and involve multiple intermediate steps. In this study, we present a straightforward, environmentally friendly, and highly efficient laser-induced conversion method for overall water splitting to simultaneously generate H2 and H2O2 at ambient conditions without any catalysts. The laser direct overall water splitting approach achieves an impressive light-to-hydrogen energy conversion efficiency of 2.1%, with H2 production rates of 2.2 mmol/h and H2O2 production rates of 65 µM/h in a limited reaction area (1 mm2) within a short real reaction time (0.36 ms/h). Furthermore, we elucidate the underlying physics and chemistry behind the laser-induced water splitting to produce H2 and H2O2. The laser-induced cavitation bubbles create an optimal microenvironment for water-splitting reactions because of the transient high temperatures (104 K) surpassing the chemical barrier required. Additionally, their rapid cooling rate (1010 K/s) hinders reverse reactions and facilitates H2O2 retention. Finally, upon bubble collapse, H2 is released while H2O2 remains dissolved in the water. Moreover, a preliminary amplification experiment demonstrates the potential industrial applications of this laser chemistry. These findings highlight that laser-based production of H2 and H2O2 from water holds promise as a straightforward, environmentally friendly, and efficient approach on an industrial scale beyond conventional chemical catalysis.

Solid-state high harmonic spectroscopy for all-optical band structure probing of high-pressure quantum states.

High pressure has triggered various novel states/properties in condensed matter, as the most representative and dramatic example being near-room-temperature superconductivity in highly pressured hydrides (~200 GPa). However, the mechanism of superconductivity is not confirmed, due to the lacking of effective approach to probe the electronic band structure under such high pressures. Here, we theoretically propose that the band structure and electron-phonon coupling (EPC) of high-pressure quantum states can be probed by solid-state high harmonic generation (sHHG). This strategy is investigated in high-pressure Im-3m H3S by the state-of-the-art first-principles time-dependent density-functional theory simulations, where the sHHG is revealed to be strongly dependent on the electronic structures and EPC. The dispersion of multiple bands near the Fermi level is effectively retrieved along different momentum directions. Our study provides unique insights into the potential all-optical route for band structure and EPC probing of high-pressure quantum states, which is expected to be helpful for the experimental exploration of high-pressure superconductivity in the future.

MiR-17-5p-engineered sEVs Encapsulated in GelMA Hydrogel Facilitated Diabetic Wound Healing by Targeting PTEN and p21.

Delayed wound healing is a major complication of diabetes, and is associated with impaired cellular functions. Current treatments are unsatisfactory. Based on the previous reports on microRNA expression in small extracellular vesicles (sEVs), miR-17-5p-engineered sEVs (sEVs17-OE) and encapsulated them in gelatin methacryloyl (GelMA) hydrogel for diabetic wounds treatment are fabricated. SEVs17-OE are successfully fabricated with a 16-fold increase in miR-17-5p expression. SEVs17-OE inhibited senescence and promoted the proliferation, migration, and tube formation of high glucose-induced human umbilical vein endothelial cells (HG-HUVECs). Additionally, sEVs17-OE also performs a promotive effect on high glucose-induced human dermal fibroblasts (HG-HDFs). Mechanism analysis showed the expressions of p21 and phosphatase and tensin homolog (PTEN), as the target genes of miR-17-5p, are downregulated significantly by sEVs17-OE. Accordingly, the downstream genes and pathways of p21 and PTEN, are activated. Next, sEVs17-OE are loaded in GelMA hydrogel to fabricate a novel bioactive wound dressing and to evaluate their effects on diabetic wound healing. Gel-sEVs17-OE effectively accelerated wound healing by promoting angiogenesis and collagen deposition. The cellular mechanism may be associated with local cell proliferation. Therefore, a novel bioactive wound dressing by loading sEVs17-OE in GelMA hydrogel, offering an option for chronic wound management is successfully fabricated.

Evaluation of the Robustness Verification of Downstream Production Process for Inactivated SARS-CoV-2 Vaccine and Different Chromatography Medium Purification Effects.

BACKGROUND: Large-scale vaccine production requires downstream processing that focuses on robustness, efficiency, and cost-effectiveness. METHODS: To assess the robustness of the current vaccine production process, three batches of COVID-19 Omicron BA.1 strain hydrolytic concentrated solutions were selected. Four gel filtration chromatography media (Chromstar 6FF, Singarose FF, Bestarose 6B, and Focurose 6FF) and four ion exchange chromatography media (Maxtar Q, Q Singarose, Diamond Q, and Q Focurose) were used to evaluate their impact on vaccine purification. The quality of the vaccine was assessed by analyzing total protein content, antigen content, residual Vero cell DNA, residual Vero cell protein, and residual bovine serum albumin (BSA). Antigen recovery rate and specific activity were also calculated. Statistical analysis was conducted to evaluate process robustness and the purification effects of the chromatography media. RESULTS: The statistical analysis revealed no significant differences in antigen recovery (p = 0.10), Vero HCP residue (p = 0.59), Vero DNA residue (p = 0.28), and BSA residue (p = 0.97) among the three batches of hydrolytic concentrated solutions processed according to the current method. However, a significant difference (p < 0.001) was observed in antigen content. CONCLUSIONS: The study demonstrated the remarkable robustness of the current downstream process for producing WIBP-CorV vaccines. This process can adapt to different batches of hydrolytic concentrated solutions and various chromatography media. The research is crucial for the production of inactivated SARS-CoV-2 vaccines and provides a potential template for purifying other viruses.

MiR-141-3p-Functionalized Exosomes Loaded in Dissolvable Microneedle Arrays for Hypertrophic Scar Treatment.

Hypertrophic scar (HS) is a common fibroproliferative disease caused by abnormal wound healing after deep skin injury. However, the existing approaches have unsatisfactory therapeutic effects, which promote the exploration of newer and more effective strategies. MiRNA-modified functional exosomes delivered by dissolvable microneedle arrays (DMNAs) are expected to provide new hope for HS treatment. In this study, a miRNA, miR-141-3p, which is downregulated in skin scar tissues and in hypertrophic scar fibroblasts (HSFs), is identified. MiR-141-3p mimics inhibit the proliferation, migration, and myofibroblast transdifferentiation of HSFs in vitro by targeting TGF-ß2 to suppress the TGF-ß2/Smad pathway. Subsequently, the engineered exosomes encapsulating miR-141-3p (miR-141-3pOE -Exos) are isolated from adipose-derived mesenchymal stem cells transfected with Lv-miR-141-3p. MiR-141-3pOE -Exos show the same inhibitive effects as miR-141-3p mimics on the pathological behaviors of HSFs in vitro. The DMNAs for sustained release of miR-141-3pOE -Exos are further fabricated in vivo. MiR-141OE -Exos@DMNAs effectively decrease the thickness of HS and improve fibroblast distribution and collagen fiber arrangement, and downregulate the expression of α-SMA, COL-1, FN, TGF-ß2, and p-Smad2/3 in the HS tissue. Overall, a promising, effective, and convenient exosome@DMNA-based miRNA delivery strategy for HS treatment is provided.

Anomalous Water Wetting on a Hydrophilic Substrate under a High Electric Field.

Macroscopically, the traditional Young-Lippmann equation is used to describe the water contact angle under a weak electric field. Here we report a new wetting mechanism of deionized water under a strong electric field that defies the conventional Young-Lippmann equation. The contact angle of the deionized water droplet on a model hexagonal lattice with a different initial wettability is extensively modulated by the vertical electric field. The cosine of water contact angle on a hydrophilic substrate displays an anomalous linear relationship with the field, in contrast to the hydrophobic case, which shows an inverse parabolic relationship. Such anomalous wetting is verified by experimental measurements of water droplets on a pyroelectric substrate. Moreover, we identify that this anomaly arises from the linear modulation of the solid-liquid interfacial tension of hydrophilic substrates by the electric field. Our findings provide atomistic insight into the fundamental laws and new phenomena of water-surface interactions under extreme electric fields.

Downregulation of pro-surfactant protein B contributes to the recurrence of early-stage non-small cell lung cancer by activating PGK1-mediated Akt signaling.

Recurrence is one of the main causes of treatment failure in early-stage non-small cell lung cancer (NSCLC). However, there are no predictors of the recurrence of early-stage NSCLC, and the molecular mechanism of its recurrence is not clear. In this study, we used clinical sample analysis to demonstrate that low levels of expression of precursor surfactant protein B (pro-SFTPB) in primary NSCLC tissue compared to their adjacent tissues are closely correlated with recurrence and poor prognosis in early-stage NSCLC patients. In vitro and in vivo experiments showed that downregulation of pro-SFTPB expression activates the Akt pathway by upregulating PGK1, which promotes metastasis and tumorigenicity in NSCLC cells. We then demonstrated that pro-SFTPB suppresses the formation of the ADRM1/hRpn2/UCH37 complex by binding to ADRM1, which inhibits PGK1 deubiquitination, thus accelerating ubiquitin-mediated PGK1 degradation. In summary, our findings indicate that low expression of pro-SFTPB in primary NSCLC compared to their adjacent tissue has potential as a predictor of recurrence and poor prognosis in early-stage NSCLC. Mechanistically, downregulation of pro-SFTPB attenuates inhibition of ADRM1-deubiquitinated PGK1, resulting in elevated levels of PGK1 protein; this activates the Akt pathway, ultimately leading to the progression of early-stage NSCLC.

Unraveling Hidden Charge Density Wave Phases in 1T-TiSe_{2}.

The unexpected chiral order observed in 1T-TiSe_{2} represents an exciting area to explore chirality in condensed matter, while its microscopic mechanism remains elusive. Here, we have identified three metastable collective modes-the so-called single-q modes-in single layer TiSe_{2}, which originate from the unstable phonon eigenvectors at the zone boundary and break the threefold rotational symmetry. We show that polarized laser pulse is a unique and efficient tool to reconstruct the transient potential energy surface, so as to drive phase transitions between these states. By designing sequent layers with chiral stacking order, we propose a practical means to realize chiral charge density waves in 1T-TiSe_{2}. Further, the constructed chiral structure is predicted to exhibit circular dichroism as observed in recent experiments. These facts strongly indicate the chirality transfer from photons to the electron subsystem, meanwhile being strongly coupled to the lattice degree of freedom. Our work provides new insights into understanding and modulating chirality in quantum materials that we hope will spark further experimental investigation.

Molecular Orbital Insights into Plasmon-Induced Methane Photolysis.

As a promising way to reduce the temperature for conventional thermolysis, plasmon-induced photocatalysis has been utilized for the dehydrogenation of methane. Here we probe the microscopic dynamic mechanism for plasmon-induced methane dissociation over a tetrahedral Ag20 nanoparticle with molecular orbital insights using time-dependent density functional theory. We ingeniously built the relationship between the chemical bonds and molecular orbitals via Hellmann-Feynman forces. The time- and energy-resolved photocarrier analysis shows that the indirect hot hole transfer from the Ag nanoparticle to methane dominates the photoreaction at low laser intensity, due to the strong hybridization of the Ag nanoparticle and CH4 orbitals, while indirect and direct charge transfer coexist to facilitate methane dissociation in intense laser fields. Our findings can be used to design novel methane photocatalysts and highlight the broad prospects of the molecular orbital approach for adsorbate-substrate systems.

A novel mRNA rabies vaccine as a promising candidate for rabies post-exposure prophylaxis protects animals from different rabies viruses.

Rabies, caused by the rabies virus (RABV), is the most fatal zoonotic disease. It is a neglected tropical disease which remains a major public health problem, causing approximately 59,000 deaths worldwide annually. Despite the existence of effective vaccines, the high incidence of human rabies is mainly linked to tedious vaccine immunisation procedures and the overall high cost of post-exposure prophylaxis. Therefore, it is necessary to develop an effective vaccine that has a simple procedure and is affordable to prevent rabies infection in humans. RABV belongs to the genus Lyssavirus and family Rhabdoviridae. Previous phylogenetic analyses have identified seven major clades of RABV in China (China I-VII), confirmed by analysing nucleotide sequences from both the G and N proteins. This study evaluated the immunogenicity and protective capacity of SYS6008, an mRNA rabies vaccine expressing rabies virus glycoprotein, in mice and cynomolgus macaques. We demonstrated that SYS6008 induced sufficient levels of rabies neutralising antibody (RVNA) in mice. In addition, SYS6008 elicited strong and durable RVNA responses in vaccinated cynomolgus macaques. In the pre-exposure prophylaxis murine model, one or two injections of SYS6008 at 1/10 or 1/30 of dosage provided protection against a challenge with a 30-fold LD50 of rabies virus (China I and II clades). We also demonstrated that in the post-exposure prophylaxis murine model, which was exposed to lethal rabies virus (China I-VII clades) before vaccination, one or two injections of SYS6008 at both 1/10 and 1/30 dosages provided better protection against rabies virus challenge than the immunization by five injections of commercial vaccines at the same dosage. In addition, we proved that SYS6008-induced RVNAs could neutralise RABV from the China I-VII clades. Finally, 1/10 of the dosage of SYS6008 was able to stimulate significant RABV-G specificity in the T cell response. Furthermore, we found that SYS6008 induced high cellular immunity, including RABV-G-specific T cell responses and memory B cells. Our results imply that the SYS6008 rabies vaccine, with a much simpler vaccination procedure, better immunogenicity, and enhanced protective capacity, could be a candidate vaccine for post-exposure prophylaxis of rabies infections.