Effects of the Biomimetic Microstructure in Electrospun Fiber Sutures and Mechanical Tension on Tissue Repair.

Electrospun microfibers, designed to emulate the extracellular matrix (ECM), play a crucial role in regulating the cellular microenvironment for tissue repair. Understanding their mechanical influence and inherent biological interactions at the ECM interface, however, remains a complex challenge. This study delves into the role of mechanical cues in tissue repair by fabricating Col/PLCL microfibers with varying chemical compositions and alignments that mimic the structure of the ECM. Furthermore, we optimized these microfibers to create the Col/PLCL@PDO aligned suture, with a specific emphasis on mechanical tension in tissue repair. The result reveals that within fibers of identical chemical composition, fibroblast proliferation is more pronounced in aligned fibers than in unaligned ones. Moreover, cells on aligned fibers exhibit an increased aspect ratio. In vivo experiments demonstrated that as the tension increased to a certain level, cell proliferation augmented, cells assumed more elongated morphologies with distinct protrusions, and there was an elevated secretion of collagen III and tension suture, facilitating soft tissue repair. This research illuminates the structural and mechanical dynamics of electrospun fiber scaffolds; it will provide crucial insights for the advancement of precise and controllable tissue engineering materials.

Stretchable, Transparent, and Ultra-Broadband Terahertz Shielding Thin Films Based on Wrinkled MXene Architectures.

With the increasing demand for terahertz (THz) technology in security inspection, medical imaging, and flexible electronics, there is a significant need for stretchable and transparent THz electromagnetic interference (EMI) shielding materials. Existing EMI shielding materials, like opaque metals and carbon-based films, face challenges in achieving both high transparency and high shielding efficiency (SE). Here, a wrinkled structure strategy was proposed to construct ultra-thin, stretchable, and transparent terahertz shielding MXene films, which possesses both isotropous wrinkles (height about 50 nm) and periodic wrinkles (height about 500 nm). Compared to flat film, the wrinkled MXene film (8 nm) demonstrates a remarkable 36.5% increase in SE within the THz band. The wrinkled MXene film exhibits an EMI SE of 21.1 dB at the thickness of 100 nm, and an average EMI SE/t of 700 dB µm-1 over the 0.1-10 THz. Theoretical calculations suggest that the wrinkled structure enhances the film's conductivity and surface plasmon resonances, resulting in an improved THz wave absorption. Additionally, the wrinkled structure enhances the MXene films' stretchability and stability. After bending and stretching (at 30% strain) cycles, the average THz transmittance of the wrinkled film is only 0.5% and 2.4%, respectively. The outstanding performances of the wrinkled MXene film make it a promising THz electromagnetic shielding materials for future smart windows and wearable electronics.

Tunnel-Oriented VO2 (B) Cathode for High-Rate Aqueous Zinc-Ion Batteries.

Tunnel-type vanadium oxides are promising cathodes for aqueous zinc ion batteries. However, unlike layer-type cathodes with adjustable layer distances, enhancing ion-transport kinetics in tunnels characterized by fixed sizes poses a considerable challenge. This study highlights that the macroscopic arrangement of the electrode crucially determines tunnel orientation, thereby influencing ion transport. By changing the material morphology, the tunnel orientation can be optimized to facilitate rapid ion diffusion. In a proof-of-concept demonstration, it is revealed that (00l) facets-dominated VO2 (B) nanobelts with dispersive morphology (VO2-D) tend to adopt a stacking pattern with directional ion transport along the c-axis on the electrode and guarantee fast ion diffusion. Compared with the aggregated sample (VO2-A) that tends to random arrangement on the electrode with isotropic and slow ion transfer behavior, the electrode featuring dispersive (00l) facets-dominated VO2 (B) nanobelts displays directional and fast ion diffusion behavior, thus exhibits an ultrahigh-rate performance (420.8 and 344.8 mAh g-1 at 0.1 and 10 A g-1, respectively) and long cycling stability (84.3% capacity retention under 5000 cycles at 10 A g-1). The results suggest that simultaneous manipulation of exposed crystal facet and morphology-related electrode arrangement should be promising for boosting the ion-transport kinetics in tunnel-type vanadium oxide cathodes.

Converting Commercial Zn Foils into Single (002)-Textured Zn with Millimeter-Sized Grains for Highly Reversible Aqueous Zinc Batteries.

Rechargeable aqueous zinc batteries are promising but hindered by unfavorable dendrite growth and side reactions on zinc anodes. In this study, we demonstrate a fast melting-solidification approach for effectively converting commercial Zn foils into single (002)-textured Zn featuring millimeter-sized grains. The melting process eliminates initial texture, residual stress, and grain size variations in diverse commercial Zn foils, guaranteeing the uniformity of commercial Zn foils into single (002)-textured Zn. The single (002)-texture ensures large-scale epitaxial and dense Zn deposition, while the reduction in grain boundaries significantly minimizes intergranular reactions. These features enable large grain single (002)-textured Zn shows planar and dense Zn deposition under harsh conditions (100 mA cm-2, 100 mAh cm-2), impressive reversibility in Zn||Zn symmetric cell (3280 h under 1 mA cm-2, 830 h under 10 mAh cm-2), and long cycling stability over 180 h with a high depth of discharge value of 75 %. This study successfully addresses the issue of uncontrollable texture formation in Zn foils following routine annealing treatments with temperatures below the Zn melting point. The findings of this study establish a highly efficient strategy for fabricating highly reversible single (002)-textured Zn anodes.

Flexible, Transparent and Conductive Metal Mesh Films with Ultra-High FoM for Stretchable Heating and Electromagnetic Interference Shielding.

Despite the growing demand for transparent conductive films in smart and wearable electronics for electromagnetic interference (EMI) shielding, achieving a flexible EMI shielding film, while maintaining a high transmittance remains a significant challenge. Herein, a flexible, transparent, and conductive copper (Cu) metal mesh film for EMI shielding is fabricated by self-forming crackle template method and electroplating technique. The Cu mesh film shows an ultra-low sheet resistance (0.18 Ω â–¡-1), high transmittance (85.8%@550 nm), and ultra-high figure of merit (> 13,000). It also has satisfactory stretchability and mechanical stability, with a resistance increases of only 1.3% after 1,000 bending cycles. As a stretchable heater (ε > 30%), the saturation temperature of the film can reach over 110 °C within 60 s at 1.00 V applied voltage. Moreover, the metal mesh film exhibits outstanding average EMI shielding effectiveness of 40.4 dB in the X-band at the thickness of 2.5 µm. As a demonstration, it is used as a transparent window for shielding the wireless communication electromagnetic waves. Therefore, the flexible and transparent conductive Cu mesh film proposed in this work provides a promising candidate for the next-generation EMI shielding applications.

CDK2 inhibition disorders centrosome stoichiometry and alters cellular outcomes in aneuploid cancer cells.

Cyclin-dependent Kinase 2 (CDK2) inhibition prevents supernumerary centrosome clustering. This causes multipolarity, anaphase catastrophe and apoptotic death of aneuploid cancers. This study elucidated how CDK2 antagonism affected centrosome stoichiometry. Focused ion beam scanning electron microscopy (FIB-SEM) and immunofluorescent imaging were used. Studies interrogated multipolar mitosis after pharmacologic or genetic repression of CDK2. CDK2/9 antagonism with CYC065 (Fadraciclib)-treatment disordered centrosome stoichiometry in aneuploid cancer cells, preventing centrosome clustering. This caused ring-like chromosomes or multipolar cancer cells to form before onset of cell death. Intriguingly, CDK2 inhibition caused a statistically significant increase in single centrioles rather than intact centrosomes with two centrioles in cancer cells having chromosome rings or multipolarity. Statistically significant alterations in centrosome stoichiometry were undetected in other mitotic cancer cells. To confirm this pharmacodynamic effect, CDK2 but not CDK9 siRNA-mediated knockdown augmented cancer cells with chromosome ring or multipolarity formation. Notably, engineered gain of CDK2, but not CDK9 expression, reversed emergence of cancer cells with chromosome rings or multipolarity, despite CYC065-treatment. In marked contrast, CDK2 inhibition of primary human alveolar epithelial cells did not confer statistically significant increases of cells with ring-like chromosomes or multipolarity. Hence, CDK2 antagonism caused differential effects in malignant versus normal alveolar epithelial cells. Translational relevance was confirmed by CYC065-treatment of syngeneic lung cancers in mice. Mitotic figures in tumors exhibited chromosome rings or multipolarity. Thus, CDK2 inhibition preferentially disorders centrosome stoichiometry in cancer cells. Engaging this disruption is a strategy to explore against aneuploid cancers in future clinical trials.

A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment.

All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA's anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA's anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice-a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.

Flexible, Transparent, and Wafer-Scale Artificial Synapse Array Based on TiOx /Ti3 C2 Tx Film for Neuromorphic Computing.

A high-density neuromorphic computing memristor array based on 2D materials paves the way for next-generation information-processing components and in-memory computing systems. However, the traditional 2D-materials-based memristor devices suffer from poor flexibility and opacity, which hinders the application of memristors in flexible electronics. Here, a flexible artificial synapse array based on TiOx /Ti3 C2 Tx film is fabricated by a convenient and energy-efficient solution-processing technique, which realizes high transmittance (≈90%) and oxidation resistance (>30 days). The TiOx /Ti3 C2 Tx memristor shows low device-to-device variability, long memory retention and endurance, a high ON/OFF ratio, and fundamental synaptic behavior. Furthermore, satisfactory flexibility (R = 1.0 mm) and mechanical endurance (104 bending cycles) of the TiOx /Ti3 C2 Tx memristor are achieved, which is superior to other film memristors prepared by chemical vapor deposition. In addition, high-precision (>96.44%) MNIST handwritten digits recognition classification simulation indicates that the TiOx /Ti3 C2 Tx artificial synapse array holds promise for future neuromorphic computing applications, and provides excellent high-density neuron circuits for new flexible intelligent electronic equipment.

Protein circuit design using de novo proteins.

Protein-based biological circuits enable customized control of cellular functions, and de novo protein design enables circuit functionalities that are not possible by repurposing natural proteins. Here, I highlight recent progress in protein circuit design, including CHOMP, developed by Gao et al., and SPOC, developed by Fink et al.

Bridging sheet size controls densification of MXene films for robust electromagnetic interference shielding.

Numerous voids among the incompact layer-structure of MXene films result in their low ambient stability and poor innate conductivity for electromagnetic interference (EMI) shielding. Herein, we report a bridging-sheet-size-controlled densification process of MXene films by applying graphene oxide (GO) as a bridging agent. Specifically, the sheet size of GO is tailored to quantify a negative correlation of sheet size with densification for directing the preparation of most compact MXene-GO films. Benefiting from the shortest electron-transport-distance in the most compact structure, the conductivity of the MXene-GO film achieves 1.7 times (∼1.6 × 105 S/m) that of MXene film. The EMI shielding performance (5.2 × 106 dB/m) reaches the record-value among reported MXene films at 10 µm-scale thickness. Moreover, the compact structure boosts the ambient stability of MXene-GO films where the conductivity and EMI shielding performance remain 88.7% and 90.0% after 15 days, respectively. The findings rationale the structure-activity relationship of compact MXene films for flexible electronics.

Interpreting Neural Networks for Biological Sequences by Learning Stochastic Masks.

Sequence-based neural networks can learn to make accurate predictions from large biological datasets, but model interpretation remains challenging. Many existing feature attribution methods are optimized for continuous rather than discrete input patterns and assess individual feature importance in isolation, making them ill-suited for interpreting non-linear interactions in molecular sequences. Building on work in computer vision and natural language processing, we developed an approach based on deep learning - Scrambler networks - wherein the most salient sequence positions are identified with learned input masks. Scramblers learn to predict Position-Specific Scoring Matrices (PSSMs) where unimportant nucleotides or residues are scrambled by raising their entropy. We apply Scramblers to interpret the effects of genetic variants, uncover non-linear interactions between cis-regulatory elements, explain binding specificity for protein-protein interactions, and identify structural determinants of de novo designed proteins. We show that Scramblers enable efficient attribution across large datasets and result in high-quality explanations, often outperforming state-of-the-art methods.

Optimization of Site Selection for Emergency Medical Facilities considering the SEIR Model.

Since the outbreak of COVID-19, the rapid construction and operation of Wuhan Vulcan Mountain Hospital and Raytheon Hospital have attracted positive responses from local and international observers. At the same time, it has also highlighted the urgency for the construction of emergency medical facilities for public health emergencies. Before construction, the practical location of medical facilities is the basis for improving the city's emergency management ability. Based on the classic susceptible, exposed, infected, and recovered (SEIR) epidemic model and epidemic data in Guangzhou, we established a multi-stage time-delay SEIR epidemic model that is suitable for epidemic research in Guangzhou. According to the results of the model, the five areas with the highest number of infected patients were identified, which included Baiyun District, Panyu District, Haizhu District, Tianhe District, and Zengcheng District. We then centralized infected individuals at five demand points. Based on the distribution of these points and by combining the characteristics of the emergency medical facilities, we built and solved the set covering location decision model, and considered the economy, society, and environment as the starting points to optimize the site location. Finally, based on simulations, we concluded that appropriate site selection can increase the time required to reach the maximum number of patients and reduce the proportion of infected and exposed people by 11.3% and 1.11%, respectively. This is indicative of the effectiveness of the site selection model and the rational selection of facility points in this study. It solves the optimization problem of the location decision of emergency medical facilities for public health emergencies in China, and also provides some valuable references for site selection decisions of emergency medical facilities in other areas.

CT-707 overcomes hypoxia-mediated sorafenib resistance in Hepatocellular carcinoma by inhibiting YAP signaling.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome. MATERIALS AND METHODS: The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia. RESULTS: Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC. CONCLUSIONS: Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients.

Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis.

Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced lung cancer growth, wound-healing, migration, and invasion versus controls (P < .001) and markedly decreased murine lung cancer metastases (P < .001). Reverse Phase Protein Arrays (RPPAs) in shRNA knock-down lung cancer cells showed that 14-3-3ζ protein was regulated by loss of USP18. ISG15 complexed with 14-3-3ζ protein reducing its stability. Survival in lung adenocarcinomas (P < .0015) and other cancers was linked to elevated 14-3-3ζ expression as assessed by The Cancer Genome Atlas (TCGA). The findings were confirmed and extended using 14-3-3ζ immunohistochemical assays of human lung cancer arrays and syngeneic murine lung cancer metastasis models. A direct 14-3-3ζ role in controlling lung cancer metastasis came from engineered 14-3-3ζ knock-down in lung cancer cell lines and 14-3-3ζ rescue experiments that reversed migration and invasion inhibition. Findings presented here revealed that USP18 controlled metastasis by regulating 14-3-3ζ expression. These data provide a strong rationale for developing a USP18 inhibitor to combat metastases.

Programmable protein circuit design.

A fundamental challenge in synthetic biology is to create molecular circuits that can program complex cellular functions. Because proteins can bind, cleave, and chemically modify one another and interface directly and rapidly with endogenous pathways, they could extend the capabilities of synthetic circuits beyond what is possible with gene regulation alone. However, the very diversity that makes proteins so powerful also complicates efforts to harness them as well-controlled synthetic circuit components. Recent work has begun to address this challenge, focusing on principles such as orthogonality and composability that permit construction of diverse circuit-level functions from a limited set of engineered protein components. These approaches are now enabling the engineering of circuits that can sense, transmit, and process information; dynamically control cellular behaviors; and enable new therapeutic strategies, establishing a powerful paradigm for programming biology.

The Ubiquitin-Specific Peptidase USP18 Promotes Lipolysis, Fatty Acid Oxidation, and Lung Cancer Growth.

Ubiquitin specific peptidase 18 (USP18), previously known as UBP43, is the IFN-stimulated gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate proteins. This study reports that USP18-null mice (vs. wild-type mice) exhibited lower lipolysis rates, altered fat to body weight ratios, and cold sensitivity. USP18 is a regulator of lipid and fatty acid metabolism. Prior work established that USP18 promotes lung tumorigenesis. We sought to learn whether this occurs through altered lipid and fatty acid metabolism. Loss of USP18 repressed adipose triglyceride lipase (ATGL) expression; gain of USP18 expression upregulated ATGL in lung cancer cells. The E1-like ubiquitin activating enzyme promoted ISG15 conjugation of ATGL and destabilization. Immunoprecipitation assays confirmed that ISG15 covalently conjugates to ATGL. Protein expression of thermogenic regulators was examined in brown fat of USP18-null versus wild-type mice. Uncoupling protein 1 (UCP1) was repressed in USP18-null fat. Gain of USP18 expression augmented UCP1 protein via reduced ubiquitination. Gain of UCP1 expression in lung cancer cell lines enhanced cellular proliferation. UCP1 knockdown inhibited proliferation. Beta-hydroxybutyrate colorimetric assays performed after gain of UCP1 expression revealed increased cellular fatty acid beta-oxidation, augmenting fatty acid beta-oxidation in Seahorse assays. Combined USP18, ATGL, and UCP1 profiles were interrogated in The Cancer Genome Atlas. Intriguingly, lung cancers with increased USP18, ATGL, and UCP1 expression had an unfavorable survival. These findings reveal that USP18 is a pharmacologic target that controls fatty acid metabolism. IMPLICATIONS: USP18 is an antineoplastic target that affects lung cancer fatty acid metabolism.

A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers.

Cyclin-dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically tractable antineoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Antineoplastic activity was studied in preclinical models. CYC065 treatment augmented anaphase catastrophe in diverse cancers including lymphoma, lung, colon, and pancreatic cancers, despite KRAS oncoprotein expression. Anaphase catastrophe was a broadly active antineoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase and Src phosphorylation that regulate metastasis were each repressed by CYC065 treatment. Intriguingly, CYC065 treatment decreased lung cancer metastases in in vivo murine models. CYC065 treatment also significantly reduced the rate of lung cancer growth in syngeneic murine and patient-derived xenograft (PDX) models independent of KRAS oncoprotein expression. Immunohistochemistry analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 antitumor response. Phospho-histone H3 staining detected anaphase catastrophe in CYC065-treated PDXs. Thus, induced anaphase catastrophe after CYC065 treatment can combat aneuploid cancers despite KRAS oncoprotein expression. These findings should guide future trials of this novel CDK2/9 inhibitor in the cancer clinic.

Modulating mechanical stability of heterodimerization between engineered orthogonal helical domains.

Mechanically stable specific heterodimerization between small protein domains have a wide scope of applications, from using as a molecular anchorage in single-molecule force spectroscopy studies of protein mechanics, to serving as force-bearing protein linker for modulation of mechanotransduction of cells, and potentially acting as a molecular crosslinker for functional materials. Here, we explore the possibility to develop heterodimerization system with a range of mechanical stability from a set of recently engineered helix-heterotetramers whose mechanical properties have yet to be characterized. We demonstrate this possibility using two randomly chosen helix-heterotetramers, showing that their mechanical properties can be modulated by changing the stretching geometry and the number of interacting helices. These helix-heterotetramers and their derivatives are sufficiently stable over physiological temperature range. Using it as mechanically stable anchorage, we demonstrate the applications in single-molecule manipulation studies of the temperature dependent unfolding and refolding of a titin immunoglobulin domain and α-actinin spectrin repeats.

De novo design of protein logic gates.

The design of modular protein logic for regulating protein function at the posttranscriptional level is a challenge for synthetic biology. Here, we describe the design of two-input AND, OR, NAND, NOR, XNOR, and NOT gates built from de novo-designed proteins. These gates regulate the association of arbitrary protein units ranging from split enzymes to transcriptional machinery in vitro, in yeast and in primary human T cells, where they control the expression of the TIM3 gene related to T cell exhaustion. Designed binding interaction cooperativity, confirmed by native mass spectrometry, makes the gates largely insensitive to stoichiometric imbalances in the inputs, and the modularity of the approach enables ready extension to three-input OR, AND, and disjunctive normal form gates. The modularity and cooperativity of the control elements, coupled with the ability to de novo design an essentially unlimited number of protein components, should enable the design of sophisticated posttranslational control logic over a wide range of biological functions.