Tuning instability in suspended monolayer 2D materials.

Monolayer two-dimensional (2D) materials possess excellent in-plane mechanical strength yet extremely low bending stiffness, making them particularly susceptible to instability, which is anticipated to have a substantial impact on their physical functionalities such as 2D-based Micro/Nanoelectromechanical systems (M/NEMS), nanochannels, and proton transport membrane. In this work, we achieve quantitatively tuning instability in suspended 2D materials including monolayer graphene and MoS2 by employing a push-to-shear strategy. We comprehensively examine the dynamic wrinkling-splitting-smoothing process and find that monolayer 2D materials experience stepwise instabilities along with different recovery processes. These stepwise instabilities are governed by the materials' geometry, pretension, and the elastic nonlinearity. We attribute the different instability and recovery paths to the local stress redistribution in monolayer 2D materials. The tunable instability behavior of suspended monolayer 2D materials not only allows measuring their bending stiffness but also opens up new opportunities for programming the nanoscale instability pattern and even physical properties of atomically thin films.

Strain Engineering of Twisted Bilayer Graphene: The Rise of Strain-Twistronics.

The layer-by-layer stacked van der Waals structures (termed vdW hetero/homostructures) offer a new paradigm for materials design-their physical properties can be tuned by the vertical stacking sequence as well as by adding a mechanical twist, stretch, and hydrostatic pressure to the atomic structure. In particular, simple twisting and stacking of two layers of graphene can form a uniform and ordered Moiré superlattice, which can effectively modulate the electrons of graphene layers and lead to the discovery of unconventional superconductivity and strong correlations. However, the twist angle of twisted bilayer graphene (tBLG) is almost unchangeable once the interlayer stacking is determined, while applying mechanical elastic strain provides an alternative way to deeply regulate the electronic structure by controlling the lattice spacing and symmetry. In this review, diverse experimental advances are introduced in straining tBLG by in-plane and out-of-plane modes, followed by the characterizations and calculations toward quantitatively tuning the strain-engineered electronic structures. It is further discussed that the structural relaxation in strained Moiré superlattice and its influence on electronic structures. Finally, the conclusion entails prospects for opportunities of strained twisted 2D materials, discussions on existing challenges, and an outlook on the intriguing emerging field, namely "strain-twistronics".

Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.

Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied.

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. Objective: To investigate the potential therapeutic benefit of sildenafil on AD. Methods: We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. Results: We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. Conclusions: These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

CCR5 regulates Aß1-42-induced learning and memory deficits in mice.

C-C chemokine receptor 5 (CCR5) is a chemokine receptor involved in immune responses and a co-receptor for HIV infection. Recently, CCR5 has also been reported to play a role in synaptic plasticity, learning and memory, and cognitive deficits associated with normal aging, traumatic brain injury (TBI), and HIV-associated neurocognitive disorder (HAND). In contrast, the role of CCR5 in cognitive deficits associated with other disorders, including Alzheimer's disease (AD), is much less understood. Studies have reported an increase in expression of CCR5 or its ligands in both AD patients and AD rodent models, suggesting a correlation between AD and CCR5 expression. However, whether blocking CCR5 in specific brain regions, such as the hippocampus, could improve memory deficits in AD mouse models is unknown. To study the potential causal role of CCR5 in cognitive deficits in AD, we injected soluble Aß1-42 or a control (Aß42-1) oligomers in the dorsal CA1 region of the hippocampus and found that Aß1-42 injection resulted in severe memory impairment in the object place recognition (OPR) and novel object recognition (NOR) tests. Aß1-42 injection caused an increase in Ccr5, Ccl3, and Ccl4 in the dorsal hippocampus, and the expression levels of CCR5 and its ligands remained elevated at 2 weeks after Aß1-42 injection. Knocking down Ccr5 in the CA1 region of dorsal hippocampus reversed the increase in microglia number and size in dorsal CA1 and rescued memory deficits. These results indicate that CCR5 plays an important role in modulating Aß1-42-induced learning and memory deficits, and suggest that CCR5 antagonists may serve as a potential treatment to improve cognitive deficits associated with AD.

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. RESULTS: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.

Enhancement of the viability of T cells electroporated with DNA via osmotic dampening of the DNA-sensing cGAS-STING pathway.

Viral delivery of DNA for the targeted reprogramming of human T cells can lead to random genomic integration, and electroporation is inefficient and can be toxic. Here we show that electroporation-induced toxicity in primary human T cells is mediated by the cytosolic pathway cGAS-STING (cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase-stimulator of interferon genes). We also show that an isotonic buffer, identified by screening electroporation conditions, that reduces cGAS-STING surveillance allowed for the production of chimaeric antigen receptor (CAR) T cells with up to 20-fold higher CAR T cell numbers than standard electroporation and with higher antitumour activity in vivo than lentivirally generated CAR T cells. The osmotic pressure of the electroporation buffer dampened cGAS-DNA interactions, affecting the production of the STING activator 2'3'-cGAMP. The buffer also led to superior efficiencies in the transfection of therapeutically relevant primary T cells and human haematopoietic stem cells. Our findings may facilitate the optimization of electroporation-mediated DNA delivery for the production of genome-engineered T cells.

In Situ TEM Characterization and Modulation for Phase Engineering of Nanomaterials.

Solid-state phase transformation is an intriguing phenomenon in crystalline or noncrystalline solids due to the distinct physical and chemical properties that can be obtained and modified by phase engineering. Compared to bulk solids, nanomaterials exhibit enhanced capability for phase engineering due to their small sizes and high surface-to-volume ratios, facilitating various emerging applications. To establish a comprehensive atomistic understanding of phase engineering, in situ transmission electron microscopy (TEM) techniques have emerged as powerful tools, providing unprecedented atomic-resolution imaging, multiple characterization and stimulation mechanisms, and real-time integrations with various external fields. In this Review, we present a comprehensive overview of recent advances in in situ TEM studies to characterize and modulate nanomaterials for phase transformations under different stimuli, including mechanical, thermal, electrical, environmental, optical, and magnetic factors. We briefly introduce crystalline structures and polymorphism and then summarize phase stability and phase transformation models. The advanced experimental setups of in situ techniques are outlined and the advantages of in situ TEM phase engineering are highlighted, as demonstrated via several representative examples. Besides, the distinctive properties that can be obtained from in situ phase engineering are presented. Finally, current challenges and future research opportunities, along with their potential applications, are suggested.

Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs.

Reactivating silenced γ-globin expression through the disruption of repressive regulatory domains offers a therapeutic strategy for treating ß-hemoglobinopathies. Here, we used transformer base editor (tBE), a recently developed cytosine base editor with no detectable off-target mutations, to disrupt transcription-factor-binding motifs in hematopoietic stem cells. By performing functional screening of six motifs with tBE, we found that directly disrupting the BCL11A-binding motif in HBG1/2 promoters triggered the highest γ-globin expression. Via a side-by-side comparison with other clinical and preclinical strategies using Cas9 nuclease or conventional BEs (ABE8e and hA3A-BE3), we found that tBE-mediated disruption of the BCL11A-binding motif at the HBG1/2 promoters triggered the highest fetal hemoglobin in healthy and ß-thalassemia patient hematopoietic stem/progenitor cells while exhibiting no detectable DNA or RNA off-target mutations. Durable therapeutic editing by tBE persisted in repopulating hematopoietic stem cells, demonstrating that tBE-mediated editing in HBG1/2 promoters is a safe and effective strategy for treating ß-hemoglobinopathies.

Genome-wide DNA methylation analysis of Astragalus and Danshen on the intervention of myofibroblast activation in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial lung disease of unknown etiology, is characterized by continuous damage to alveolar epithelial cells, abnormal repair of alveolar tissue, and alveolar wall scar formation. Currently, the recommended treatment for IPF in Western medicine is relatively limited. In contrast, traditional Chinese medicine and compound prescriptions show advantages in the diagnosis and treatment of IPF, which can be attributed to their multi-channel and multi-target characteristics and minimal side-effects. The purpose of this study was to further corroborate the effectiveness and significance of the traditional Chinese medications Astragalus and Danshen in IPF treatment. METHODS: We performed whole-genome methylation analysis on nine rat lung tissue samples to determine the epigenetic variation between IPF and non-fibrotic lungs using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and quantitative reverse transcription polymerase chain reactions. RESULTS: We identified differentially methylated regions and 105 associated key functional genes in samples related to IPF and Chinese medicine treatment. Based on the methylation levels and gene expression profiles between the Chinese medicine intervention and pulmonary fibrosis model groups, we speculated that Astragalus and Salvia miltiorrhiza (traditionally known as Danshen) act on the Isl1, forkhead box O3, and Sonic hedgehog genes via regulation at transcriptional and epigenetic levels during IPF. CONCLUSIONS: These findings provide novel insights into the epigenetic regulation of IPF, indicate the effectiveness of Astragalus and Danshen in treating IPF, and suggest several promising therapeutic targets for preventing and treating IPF.

Ductile amorphous boron nitride microribbons.

The broad applications of ceramic materials in functional devices are often limited by their intrinsic brittleness. Amorphous boron nitride (a-BN), as a promising ceramic has shown high thermal stability and excellent dielectric properties that can be applied to microfabricated aerogel and nano dielectric layers, while its mechanical properties at small scales are yet to be studied. Here we report synthesized a-BN microribbons can have a uniform elongation at a breaking strain of more than 50% upon tension, exhibiting outstanding ductility. Such a-BN microribbons with lengths ranging from tens to hundreds of micro-meters were prepared via the small molecule precursors sol-gel method. Through in situ uniaxial tensile measurements, we demonstrated that a-BN microribbons also display a surprising flaw-tolerance behaviour. Combining high-resolution atomic characterization with molecular dynamics simulations, we reveal that the large tensile plasticity of a-BN originates from the topological deformation induced multiple energy-dissipation mechanisms including unfolding and reorientation of local curly h-BN layers and their interlayer debonding, slippage as well as the intralayer tearing. Our findings provide new insights to develop ductile amorphous covalent-bonded materials for emerging applications.

Transcutaneous electrical acupoint stimulation in adult patients receiving gastrectomy/colorectal resection: A randomized controlled trial.

BACKGROUND: Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery. The effects of transcutaneous electrical acupoint stimulation (TEAS) remain unclear. AIM: To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection. METHODS: Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive: (1) TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery, plus two 30-min daily sessions for 3 consecutive days after surgery (perioperative TEAS group); (2) Preoperative and intraoperative TEAS only; (3) Preoperative and postoperative TEAS only; or (4) Sham stimulation. The primary outcome was the time from the end of surgery to the first bowel sound. RESULTS: In total, 441 patients were randomized; 405 patients (58.4 ± 10.2 years of age; 247 males) received the planned surgery. The time to the first bowel sounds did not differ among the four groups (P = 0.90; log-rank test). On postoperative day 1, the rest pain scores differed significantly among the four groups (P = 0.04; Kruskal-Wallis test). Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group (1.4 ± 1.2) than in the sham stimulation group (1.7 ± 1.1; P = 0.04). Surgical complications did not differ among the four groups. CONCLUSION: TEAS provided analgesic effects in adult patients undergoing major abdominal surgery, and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients.

Network pharmacology and molecular docking to explore the pharmacological mechanism of Yifei Tongluo granules in treating idiopathic pulmonary fibrosis: A review.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that leads to progressive dyspnea and dry cough, with extracellular matrix deposition as the main pathological feature. Yifei Tongluo granules (YTG) are a traditional Chinese medicine formula that could nourish Qi-Yin, clear phlegm, and invigorate blood circulation. In this research, network pharmacology and molecular docking were used to elucidate the potential mechanism of YTG for treating IPF. A total of 278 biologically active compounds were included in YTG, and 16 compounds were selected for pharmacological analysis and molecular docking through "drugs-compounds-intersecting targets of YTG and IPF" network construction. Protein-protein interaction network was constructed using 330 YTG-IPF intersecting targets. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. A total of 10 core targets were screened by protein-protein interaction, and molecular docking was used to further validate the binding ability of the compounds to the core targets. The network pharmacology and molecular docking results showed that Danshenol A, isorhamnetin, Ginsenoside-Rh4, quercetin, and kaempferol might be the main active compounds in the treatment of IPF by YTG, whereas MAPK1, MAPK3, EGFR, and SRC are the core targets while PI3K/AKT pathway and MAPK pathway are the main signaling pathways through which YTG regulates relevant biological processes to intervene in IPF. This study shows that YTG can treat IPF by inhibiting the epithelial-mesenchymal transit process, fibroblast proliferation, fibroblast-to-myofibroblast conversion, myofibroblast anti-apoptosis, collagen expression, and other mechanisms.YTG can be widely used as an adjuvant therapy for IPF in clinical practice, and this study provides the basis for subsequent experimental studies.

Dual-Affinity Graphene Sheets for High-Resolution Cryo-Electron Microscopy.

With the development of cryo-electron microscopy (cryo-EM), high-resolution structures of macromolecules can be reconstructed by the single particle method efficiently. However, challenges may still persist during the specimen preparation stage. Specifically, proteins tend to adsorb at the air-water interface and exhibit a preferred orientation in vitreous ice. To overcome these challenges, we have explored dual-affinity graphene (DAG) modified with two different affinity ligands as a supporting material for cryo-EM sample preparation. The ligands can bind to distinct sites on the corresponding tagged particles, which in turn generates various orientation distributions of particles and prevents the adsorption of protein particles onto the air-water interface. As expected, the DAG exhibited high binding specificity and affinity to target macromolecules, resulting in more balanced particle Euler angular distributions compared to single functionalized graphene on two different protein cases, including the SARS -CoV-2 spike glycoprotein. We anticipate that the DAG grids will enable facile and efficient three-dimensional (3D) reconstruction for cryo-EM structural determination, providing a robust and general technique for future studies.

Effect of a group-based acceptance and commitment therapy (ACT) intervention on self-esteem and psychological flexibility in patients with schizophrenia in remission.

The present study explored whether acceptance and commitment therapy (ACT), a cognitive behavioral therapy approach, could improve the symptoms of schizophrenia spectrum disorders among patients with schizophrenia in remission. A pre- and post-treatment design with two evaluation time points was employed. Sixty outpatients with schizophrenia in remission were randomly divided into two groups: the ACT plus treatment as usual (ACT+TAU) and treatment as usual (TAU) groups. The ACT+TAU group participated in 10 group-based ACT interventions and TAU in the hospital, and the TAU group only received TAU interventions. General psycho-pathological symptoms, self-esteem, and psychological flexibility were assessed before intervention (baseline; pre-test) and after intervention (five weeks; post-test). Results indicated that, compared to the TAU group, the ACT+TAU group exhibited a more significant improvement in general psychopathological symptoms, self-esteem, cognitive fusion, and acceptance and action at post-test. ACT intervention could effectively decrease the general psycho-pathological symptoms and increase self-esteem level and psychological flexibility in people with schizophrenia in remission.

Performance of heart rate adjusted heart rate variability for risk stratification of sudden cardiac death.

PURPOSE: As a non-invasive tool for the assessment of cardiovascular autonomic function, the predictive value of heart rate variability (HRV) for sudden cardiac death (SCD) risk stratification remains unclear. In this study, we investigated the performance of the individualized heart rate (HR) adjusted HRV (HRVI) for SCD risk stratification in subjects with diverse risks. METHODS: A total of 11 commonly used HRV metrics were analyzed in 192 subjects, including 88 healthy controls (low risk group), 82 hypertrophic cardiomyopathy (HCM) patients (medium risk group), and 22 SCD victims (high risk group). The relationship between HRV metrics and HR was examined with long-term and short-term analysis. The performance HRVI was evaluated by area under the receiver operating characteristic curve (AUC) and covariance of variation (CV). RESULTS: Most of the HRV metrics were exponentially decayed with the increase of HR, while the exponential power coefficients were significantly different among groups. The HRVI metrics discriminated low, medium and high risk subjects with a median AUC of 0.72[0.11], which was considerably higher than that of the traditional long-term (0.63[0.04]) and short-term (0.58[0.05]) HRV without adjustment. The average CV of the HRVI metrics was also significantly lower than traditional short-term HRV metrics (0.09 ± 0.02 vs. 0.24 ± 0.13, p < 0.01). CONCLUSIONS: Subjects with diverse risks of SCD had similar exponential decay relationship between HRV metrics and HR, but with different decaying rates. HRVI provides reliable and robust estimation for risk stratification of SCD.