Engineering artificial non-coding RNAs for targeted protein degradation.

Targeted protein degradation has become a notable drug development strategy, but its application has been limited by the dependence on protein-based chimeras with restricted genetic manipulation capabilities. The use of long non-coding RNAs (lncRNAs) has emerged as a viable alternative, offering interactions with cellular proteins to modulate pathways and enhance degradation capabilities. Here we introduce a strategy employing artificial lncRNAs (alncRNAs) for precise targeted protein degradation. By integrating RNA aptamers and sequences from the lncRNA HOTAIR, our alncRNAs specifically target and facilitate the ubiquitination and degradation of oncogenic transcription factors and tumor-related proteins, such as c-MYC, NF-κB, ETS-1, KRAS and EGFR. These alncRNAs show potential in reducing malignant phenotypes in cells, both in vitro and in vivo, offering advantages in efficiency, adaptability and versatility. This research enhances knowledge of lncRNA-driven protein degradation and presents an effective method for targeted therapies.

Enhancement of protein translation by CRISPR/dCasRx coupled with SINEB2 repeat of noncoding RNAs.

The use of new long noncoding RNAs (lncRNAs) as biotechnological or therapeutic tools is still in its infancy, despite recent efforts to uncover their involvement in various biological processes including mRNA translation. An important question is whether lncRNA functional elements can be used to target translation of mRNAs of interest by incorporating the RNA-targeting CRISPR tools. The CRISPR/dCasRx-SINEB2 technology was developed in this research by coupling the sgRNA of a catalytically inactive Type VI-D Cas13 enzyme (CasRx) to an integrated SINEB2 domain of uchl1 lncRNA that promotes the translation of targeted mRNA. It has been demonstrated to be effective and adaptable in selectively increasing the expression of a variety of exogenous and endogenous proteins with a variety of functions with minimal off-target effects. dCasRx-SINEB2 is currently the sole CRISPR-related technique for translational control of gene expression, and works just as well or even better than the traditional RNAe tool under comparable conditions. Additionally, human cancer cells can be prevented from proliferating and migrating both in vitro and in vivo by dCasRx-SINEB2-targeted mRNA translation of transcripts encoding for antitumor proteins, including PTEN and P53. The present study provides an innovative protein enhancement method that will have several applications in biopharmaceuticals production and cancer research.

Association of sex hormones with non-alcoholic fatty liver disease: An observational and Mendelian randomization study.

BACKGROUND AND AIMS: Sex-specific associations of sex hormone-binding globulin (SHBG) and bioavailable testosterone (BAT) with NAFLD remain indeterminate. We aimed to explore observational and genetically determined relationships between each hormone and NAFLD. METHODS: We included 187 395 men and 170 193 women from the UK Biobank. Linear and nonlinear Cox regression models and Mendelian randomization (MR) analysis were used to test the associations. RESULTS: During 12.49 years of follow-up, 2209 male and 1886 female NAFLD cases were documented. Elevated SHBG levels were linearly associated with a lower risk of NAFLD in women (HR (95% CI), .71 (.63, .79)), but not in men (a "U" shape, pnon-linear < .001). Higher BAT levels were associated with a lower NAFLD risk in men (HR (95% CI), .81 (.71, .93)) but a higher risk in women (HR (95% CI): 1.25 (1.15, 1.36)). Genetically determined SHBG and BAT levels were linearly associated with NAFLD risk in women (OR (95% CI): .57 (.38, .87) and 2.21 (1.41, 3.26) respectively); in men, an "L-shaped" MR association between SHBG levels and NAFLD risk was found (pnon-linear = .016). The bidirectional MR analysis further revealed the effect of NAFLD on SHBG and BAT levels in both sexes. CONCLUSIONS: Consistently, linear associations of lower SHBG and higher BAT levels with increased NAFLD risk were both conventionally and genetically found in women, while in men, SHBG acts in a nonlinear manner. In addition, NAFLD may affect SHBG and BAT levels.

Combined piezoelectricity, valley splitting and Dzyaloshinskii-Moriya interaction in Janus GdXY (X, Y = Cl, Br, I) magnetic semiconductors.

Janus materials, as a family of multifunctional materials with broken mirror symmetry, have played a great role in piezoelectric, valley-related, and Rashba spin-orbit coupling (SOC) applications. Using first-principles calculations, it is predicted that monolayer 2H-GdXY (X, Y = Cl, Br, I) will combine giant piezoelectricity, intrinsic valley splitting and a strong Dzyaloshinskii-Moriya interaction (DMI), resulting from the intrinsic electric polarization, spontaneous spin polarization and strong spin-orbit coupling. Opposite Berry curvatures and unequal Hall conductivities at the K- and K'-valleys of monolayer GdXY are promising for storing information through the anomalous valley Hall effect (AVHE). Through construction of the spin Hamiltonian and micromagnetic model, we obtained the primary magnetic parameters of monolayer GdXY as a function of the biaxial strain. Due to the dimensionless parameter κ having strong tunability, monolayer GdClBr is promising to host isolated skyrmions. The present results are expected to enable the application of Janus materials in piezoelectricity, spin- and valley-tronics and the formation of chiral magnetic structures.

Hexagonal Single-Crystal CoS Nanosheets: Controllable Synthesis and Tunable Oxygen Evolution Performance.

Cobalt-based sulfides with variable valence states and unique physical and chemical properties have shown great potential as oxygen evolution reaction (OER) catalysts for electrochemical water-splitting reactions. However, poor morphological characteristics and a small specific surface area limit its further application. Here, hexagonal single-crystal two-dimensional (2D) CoS nanosheets with different thicknesses are successfully prepared by an atmospheric-pressure chemical vapor deposition method. Because of the advantages of the 2D structure, more exposed catalytic active sites, better reactant adsorption ability, accelerated electron transfer, and enhanced electrical conductivities can be achieved from the thinnest 5 nm CoS nanosheets (CoS-5), significantly improving OER performance. The electrochemical tests manifest that CoS-5 show an overpotential of 290 mV at 10 mA cm-2 and a Tafel slope of 65.6 mV dec-1 in the OER in an alkaline solution, superior to those for other thicknesses of CoS, bulk CoS, and RuO2. For the mechanistic investigation, the lowest charge transfer resistance (Rct) and the highest double-layer capacitance (Cdl) were obtained for CoS-5, demonstrating the faster OER kinetics and the larger active area. Density functional theory calculations further reveal the enhanced density of states around the Fermi level and higher H2O molecule adsorption energy for thinner CoS nanosheets, promoting its intrinsic catalytic activity. Moreover, the two-electrode system with CoS-5 as the anode and Pt/C as the cathode requires only 1.56 V to attain 10 mA cm-2 in the overall water-splitting reaction. We believe that this study will provide a fresh view for thickness-dependent catalytic performance and offers a new material for the study of electronic and energy devices.

Cell-free DNA: A Neglected Source for Antibiotic Resistance Genes Spreading from WWTPs.

Cell-associated ARGs in wastewater treatment plants (WWTPs) has been concerned, however, cell-free ARGs in WWTPs was rarely studied. In this study, the abundances of four representative ARGs, sulII, tetC, blaPSE-1, and ermB, in a large municipal WWTP were investigated in both cell-associated and cell-free fractions. Cell-associated ARGs was the dominant ARGs fraction in the raw wastewater. After biological treatment, sludge settling, membrane filtration, and disinfection, cell-associated ARGs were substantially reduced, though the ratios of ARG/16S rRNA gene were increased with disinfection. Cell-free ARGs persisted in the WWTP with a removal of 0.36 log to 2.68 logs, which was much lower than the removal of cell-associated ARGs (3.21 logs to 4.14 logs). Therefore, the abundance ratio of cell-free ARGs to cell-associated ARGs increased from 0.04-1.59% to 2.00-1895.08% along the treatment processes. After 25-day-storage, cell-free ARGs in both biological effluent and disinfection effluent increased by 0.14 log to 1.99 logs and 0.12 log to 1.77 logs respectively, reflecting the persistence and low decay rate of cell-free ARGs in the discharge water. Therefore, cell-free ARGs might be a kind of important but previously neglected pollutant from WWTPs, which added potential risks to the effluent receiving environments.

Is fusion superior to non-fusion for the treatment of thoracolumbar burst fracture? A systematic review and meta-analysis.

OBJECTIVE: The purpose of this meta-analysis was to compare the efficacy and safety between patients with thoracolumbar burst fracture who underwent posterior fixation alone (non-fusion) and supplemented with fusion. METHODS: A comprehensive search of related literature was performed in PubMed, Embase and the Cochrane library. Clinical outcomes (LBOS and VAS), surgical outcomes (operation time, blood loss, hospital stay and perioperative complications), and radiographic outcomes (kyphotic angle, decreased vertebral body height and segmental motion) were assessed in the meta-analysis. Data analysis was conducted with RevMan 5.3 software. RESULTS: Five RCTs and three retrospective studies including a total of 445 cases were identified. We found that there was no significant difference in terms of LBOS, VAS, implant-related complications, kyphotic and VBH parameters. However, there was a significant difference regarding blood loss, operation time, segmental motion and donor site pain between fusion and non-fusion. CONCLUSION: This meta-analysis demonstrated that posterior fixation alone could achieve satisfactory clinical and radiological results in treating thoracolumbar burst fracture. Moreover, posterior fixation without fusion was superior to additional fusion with less blood loss, shorter operation time, better segmental motion and lower donor site pain.

Global burden of metabolic dysfunction-associated steatotic liver disease attributable to high fasting plasma glucose in 204 countries and territories from 1990 to 2021.

Metabolic dysfunction-associated steatotic liver disease (MASLD) brings heavy clinical and economic burdens to patients worldwide. High fasting plasma glucose (HFPG) was proven to be an important modifiable risk factor. However, the global burden distribution of HFPG-attributable MASLD has not been fully studied. This study aimed to describe the epidemiological distribution and trends of the burden of HFPG-attributable MASLD worldwide. The data source was the 2021 Global Burden of Disease Study. Descriptive statistics were mainly conducted using disability-adjusted life years (DALYs) and deaths of HFPG-attributable MASLD from 1990 to 2021, as well as their age-standardized rates (ASRs) and population-attributable fractions. Subgroup analyses were conducted by region, age group, and sex. We found that 213.48 thousand DALYs and 10.02 thousand deaths in MASLD were attributable to HFPG worldwide in 2021, with an increase of 2.96 and 3.32 times compared with 1990, respectively. Over the past 32 years, age-standardized DALY rates (ASDRs) have fluctuated upward, reaching 2.45 per 100,000 people in 2021, with an increase of 81.21%. The ASDRs continued to rise in low, low-middle, and high social demographic index (SDI) regions, fluctuated upward at high levels in middle SDI regions, and were relatively low in high-middle SDI regions. People aged 50-69 accounted for the largest proportion of DALYs, while people over 70 had the largest increase of 3.73 times. Men had higher ASDRs, and the sex difference has been gradually expanding over the past 32 years, peaking at the age of 45-49. In conclusion, the burden of HFPG-attributable MASLD has continued to increase globally, with differences in geographical area, age, and sex distribution. HFPG, as a modifiable risk factor, should be given more importance. The implementation of targeted health intervention strategies is recommended for each country based on trends in the burden of HFPG-attributable MASLD.

Cardiac resident macrophages: The core of cardiac immune homeostasis.

Cardiac resident macrophages (CRMs) are essential in maintaining the balance of the immune homeostasis in the heart. One of the main factors in the progression of cardiovascular diseases, such as myocarditis, myocardial infarction(MI), and heart failure(HF), is the imbalance in the regulatory mechanisms of CRMs. Recent studies have reported novel heterogeneity and spatiotemporal complexity of CRMs, and their role in maintaining cardiac immune homeostasis and treating cardiovascular diseases. In this review, we focus on the functions of CRMs, including immune surveillance, immune phagocytosis, and immune metabolism, and explore the impact of CRM's homeostasis imbalance on cardiac injury and cardiac repair. We also discuss the therapeutic approaches linked to CRMs. The immunomodulatory strategies targeting CRMs may be a therapeutic approach for the treatment of cardiovascular disease.

Primordial Drivers of Diabetes Heart Disease: Comprehensive Insights into Insulin Resistance.

Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and myocardium, which indirectly cause cardiac hypertrophy and ventricular remodeling, participating in the pathogenesis of DHD. Meanwhile, hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance can directly impair the metabolism and function of the heart. Targeting insulin resistance is a potential therapeutic strategy for the prevention of DHD. Currently, the role of insulin resistance in the pathogenic development of DHD is still under active research, as the pathological roles involved are complex and not yet fully understood, and the related therapeutic approaches are not well developed. In this review, we describe insulin resistance and add recent advances in the major pathological and physiological changes and underlying mechanisms by which insulin resistance leads to myocardial remodeling and dysfunction in the diabetic heart, including exosomal dysfunction, ferroptosis, and epigenetic factors. In addition, we discuss potential therapeutic approaches to improve insulin resistance and accelerate the development of cardiovascular protection drugs.

A wide landscape of morbidity and mortality risk associated with marital status in 0.5 million Chinese men and women: a prospective cohort study.

Background: A comprehensive depiction of long-term health impacts of marital status is lacking. Methods: Sex-stratified phenome-wide association analyses (PheWAS) of marital status (living with vs. without a spouse) were performed using baseline (2004-2008) and follow-up information (ICD10-coded events till Dec 31, 2017) from the China Kadoorie Biobank (CKB). We estimated adjusted hazard ratios (aHRs) to evaluate the associations of marital status with morbidity risks of phenome-wide significant diseases or sex-specific top-10 death causes in China documented in 2017. Additionally, the association between marital status and mortality risks among participants with major chronic diseases at baseline was assessed. Findings: During up to 11.1 years of the median follow-up period, 1,946,380 incident health events were recorded among 210,202 men and 302,521 women aged 30-79. Marital status was found to have phenome-wide significant associations with thirteen diseases among men (p < 9.92 × 10-5) and nine diseases among women (p < 9.33 × 10-5), respectively. After adjusting for all disease-specific covariates in the final model, participants living without a spouse showed increased risks of schizophrenia, schizotypal and delusional disorders (aHR [95% CI]: 2.55, [1.83-3.56] for men; 1.49, [1.13-1.97] for women) compared with their counterparts. Additional higher risks in overall mental and behavioural disorder (1.31, 1.13-1.53), cardiovascular disease (1.07, 1.04-1.10) and cancer (1.06, 1.00-1.12) were only observed among men without a spouse, whereas women living without a spouse were at lower risks of developing genitourinary diseases (0.89, 0.85-0.93) and injury & poisoning (0.93, 0.88-0.97). Among 282,810 participants with major chronic diseases at baseline, 39,166 deaths were recorded. Increased mortality risks for those without a spouse were observed in 12 of 21 diseases among male patients and one of 23 among female patients. For patients with any self-reported disease at baseline, compared with those living with a spouse, the aHRs (95% CIs) of mortality risk were 1.29 (1.24-1.34) and 1.04 (1.00-1.07) among men and women without a spouse (pinteraction<0.0001), respectively. Interpretation: Long-term associations of marital status with morbidity and mortality risks are diverse among middle-aged Chinese adults, and the adverse impacts due to living without a spouse are more profound among men. Marital status may be an influential factor for health needs. Funding: The National Natural Science Foundation of China, the Kadoorie Charitable Foundation, the National Key R&D Program of China, the Chinese Ministry of Science and Technology, and the UK Wellcome Trust.

Conventional ultrasonography enabled with augmented reality needle guidance for percutaneous kidney access: An innovative methodologies randomized controlled trial.

IMPORTANCE: Successful needle puncture of the renal collecting system is a critical but difficult procedure in percutaneous nephrolithotomy (PCNL). Although fluoroscopy and ultrasound are the standard imaging techniques to guide puncture during PCNL, both have known limitations. OBJECTIVE: To assess the feasibility and safety of a new navigation system for needle puncture in ultrasound-guided PCNL. DESIGN: This study employed a single-center randomized controlled trial (RCT) design to assess the feasibility and safety of a new navigation system for needle puncture in ultrasound-guided PCNL. Conducted between May 2021 and November 2021, the trial utilized computer-generated random numbers for participant allocation to control for selection bias. SETTING: The trial was executed at the *********, which serves as an academic medical center. PARTICIPANTS: All patients who met the inclusion criteria were randomly divided into two groups, with 29 patients in each group. One group underwent PCNL procedures using the new navigation system, while the control group underwent standard ultrasound-guided PCNL procedures. Included patients had renal pelvis or caliceal calculi larger than 2.0 cm in diameter or had multiple or staghorn stones. The puncture procedure was performed with the support of real-time ultrasound imaging and visual guidance displayed on the screen. MAIN OUTCOMES AND MEASURES: The primary outcome was system feasibility and puncture success rate. Secondary outcomes included puncture time, total surgical time, number of attempts, post-procedure complications, and one-year and three-year stone recurrence rates. Stone clearance was defined by postoperative CT. Descriptive statistics summarized patient demographics, stone size, and location. Independent samples t-tests analyzed puncture time and total surgical time. Chi-square or Fisher's exact tests compared stone clearance, complications, socioeconomic status, renal hydronephrosis, stone location, race, and medical history. Linear regression examined the correlation between BMI and puncture time. Significance was set at P<0.05. RESULTS: For all 58 patients undergoing PCNL, needle punctures of the renal collecting system were completed with a success rate of 100%. The average time from planning the puncture protocol to successful puncture was significantly shorter in the AcuSee guidance system group (3.12 min, range 0.2-6.88 min) compared to the standard ultrasound-guided group (7.58 min, range 5.41-10.68 min), representing a reduction of approximately 59%. The total surgical time was also shorter in the AcuSee group for patients with no and mild hydronephrosis (P<0.05). Complication rates were lower in the AcuSee group, with no major complications observed. However, 3 patients in the standard ultrasound-guided group have adverse effects after the PCNL procedure. The one-year stone recurrence rate was significantly lower in the AcuSee group (3.4%) compared to the standard group (24.1%), and the three-year recurrence rate was also lower (6.9% vs. 41.4%). Patient-specific factors such as BMI, renal morphology, and prior surgical history did not significantly affect the performance of the AcuSee system. CONCLUSIONS AND RELEVANCE: We report the first clinical application of a new navigation system for needle puncture in ultrasound-guided PCNL. It has been demonstrated that it is feasible and safe compared to the standard ultrasound-guided group in percutaneous renal puncture. This technology provides intuitive and easy-to-use visual guidance, which may facilitate safe, accurate and fast needle puncture of the kidney.

Enhanced RNA knockdown efficiency with engineered fusion guide RNAs that function with both CRISPR-CasRx and hammerhead ribozyme.

BACKGROUND: CRISPR-Cas13 is a newly emerging RNA knockdown technology that is comparable to RNAi. Among all members of Cas13, CasRx degrades RNA in human cells with high precision and effectiveness. However, it remains unclear whether the efficiency of this technology can be further improved and applied to gene therapy. RESULTS: In this study, we fuse CasRx crRNA with an antisense ribozyme to construct a synthetic fusion guide RNA that can interact with both CasRx protein and ribozyme and tested the ability of this approach in RNA knockdown and cancer gene therapy. We show that the CasRx-crRNA-ribozyme system (CCRS) is more efficient for RNA knockdown of mRNAs and non-coding RNAs than conventional methods, including CasRx, shRNA, and ribozyme. In particular, CCRS is more effective than wild-type CasRx when targeting multiple transcripts simultaneously. We next use bladder cancer as a model to evaluate the anticancer effects of CCRS targeting multiple genes in vitro and in vivo. CCRS shows a higher anticancer effect than conventional methods, consistent with the gene knockdown results. CONCLUSIONS: Thus, our study demonstrates that CCRS expands the design ideas and RNA knockdown capabilities of Cas13 technology and has the potential to be used in disease treatment.

Comparative Study on Physical Activity in Diabetic and Non-Diabetic Individuals and Influential Factors - China, 2020-2021.

What is already known about this topic?: The majority of Chinese patients with diabetes failed to achieve the level of physical activity recommended by clinical guidelines. What is added by this report?: The prevalence of low-level physical activity was found to be greater in individuals diagnosed with diabetes. It was observed that patients with a protracted duration of diabetes demonstrated a propensity to participate in lower levels of physical activity compared to those with a shorter disease trajectory. The likelihood of engaging in low-level physical activity associated with diabetes was higher in rural inhabitants, those with medium-tier education, employed individuals, and individuals who had longer sleep durations. What are the implications for public health practice?: Developing strategies and interventions to encourage greater involvement of Chinese diabetic patients in physical activity is essential. However, these strategies must take population characteristics into account.

Factors Affecting the Breastfeeding Duration of Infants and Young Children in China: A Cross-Sectional Study.

OBJECTIVE: To investigate the factors affecting the duration of continuous breastfeeding of infants within 2 years of age, and to explore intervention strategies that may promote breastfeeding duration in China. METHOD: A self-made electronic questionnaire was used to investigate the breastfeeding duration of infants, and the influencing factors were collected from three levels of individual, family, and social support. The Kruskal-Wallis rank sum test and the multivariable ordinal logistic regression model were used for data analysis. Subgroup analysis was carried out according to region and parity. RESULTS: A total of 1001 valid samples from 26 provinces across the country were obtained. Among them, 9.9% breastfed for less than 6 months, 38.6% for 6 to 12 months, 31.8% for 12 to 18 months, 6.7% for 18 to 24 months, and 13.1% for more than 24 months. Barriers to sustained breastfeeding included the mother's age at birth being over 31, education level below junior high, cesarean delivery, and the baby's first nipple sucking at 2 to 24 h after birth. Factors that promote continued breastfeeding included freelancer or full-time mother, high breastfeeding knowledge score, supporting breastfeeding, baby with low birth weight, first bottle feeding at 4 months and later, first supplementary food at over 6 months old, high family income, the mother's family and friends supporting breastfeeding, breastfeeding support conditions after returning to work, etc. Conclusion: The breastfeeding duration in China is generally short, and the proportion of mothers breastfeeding until the age of 2 years and above, recommended by WHO, is very low. Multiple factors at the individual, family, and social support levels influence the duration of breastfeeding. It is suggested to improve the current situation by strengthening health education, improving system security, and enhancing social support.

Hypertension Promotes the Proliferation and Migration of ccRCC Cells by Downregulation of TIMP3 in Tumor Endothelial Cells through the miR-21-5p/TGFBR2/P38/EGR1 Axis.

Recent studies have demonstrated that hypertension correlates with tumorigenesis and prognosis of clear-cell renal cell carcinoma (ccRCC); however, the underlying molecular mechanisms remain unclear. By analyzing bulk and single-cell RNA sequencing data and experimental examining of surgical excised ccRCC samples, we found that tissue inhibitors of metalloproteinases 3 (TIMP3), a pivotal paracrine factor in suppressing tumor progression, was significantly reduced in the tumor endothelial cells of patients with hypertensive ccRCC. Besides, in tumor xenograft of NCG mouse model, compared with saline normotensive group the expression of TIMP3 was significantly decreased in the angiotensin II-induced hypertension group. Treating human umbilical vein endothelial cells (HUVEC) with the plasma of patients with hypertensive ccRCC and miR-21-5p, elevated in the plasma of patients with hypertensive ccRCC, reduced the expression of TIMP3 compared with normotensive and control littermates. We also found that the inhibition of TIMP3 expression by miR-21-5p was not through directly targeting at 3'UTR of TIMP3 but through suppressing the expression of TGFß receptor 2 (TGFBR2). In addition, the knockout of TGFBR2 reduced TIMP3 expression in HUVECs through P38/EGR1 (early growth response protein 1) signaling axis. Moreover, via coculture of ccRCC cell lines with HUVECs and mouse tumor xenograft model, we discovered that the TIMP3 could suppress the proliferation and migration of ccRCC. IMPLICATIONS: Overall, our findings shed new light on the role of hypertension in promoting the progression of ccRCC and provide a potential therapeutic target for patients with ccRCC with hypertension.

The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics.

Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies.

CRISPR signal conductor 2.0 for redirecting cellular information flow.

A key challenge in designing intelligent artificial gene circuits is generating flexible connections between arbitrary components and directly coupling them with endogenous signaling pathways. The CRISPR signal conductor based on conditionally inducible artificial transcriptional regulators can link classic cellular protein signals with targeted gene expression, but there are still problems with multiple signal processing and gene delivery. With the discovery and characterization of new Cas systems and long noncoding RNA (lncRNA) functional motifs, and because of the compatibility of guide RNA with noncoding RNA elements at multiple sites, it is increasingly possible to solve these problems. In this study, we developed CRISPR signal conductor version 2.0 by integrating various lncRNA functional motifs into different parts of the crRNA in the CRISPR-dCasΦ system. This system can directly regulate the expression of target genes by recruiting cellular endogenous transcription factors and efficiently sense a variety of protein signals that are not detected by a classical synthetic system. The new system solved the problems of background leakage and insensitive signaling responses and enabled the construction of logic gates with as many as six input signals, which can be used to specifically target cancer cells. By rewiring endogenous signaling networks, we further demonstrated the effectiveness and biosafety of this system for in vivo cancer gene therapy.

Phase-Controllable Chemical Vapor Deposition Synthesis of Atomically Thin MoTe2.

Two-dimensional (2D) molybdenum telluride (MoTe2) is attracting increasing attention for its potential applications in electronic, optoelectronic, photonic and catalytic fields, owing to the unique band structures of both stable 2H phase and 1T' phase. However, the direct growth of high-quality atomically thin MoTe2 with the controllable proportion of 2H and 1T' phase seems hard due to easy phase transformation since the potential barrier between the two phases is extremely small. Herein, we report a strategy of the phase-controllable chemical vapor deposition (CVD) synthesis for few-layer (<3 layer) MoTe2. Besides, a new understanding of the phase-controllable growth mechanism is presented based on a combination of experimental results and DFT calculations. The lattice distortion caused by Te vacancies or structural strain might make 1T'-MoTe2 more stable. The conditions for 2H to 1T' phase conversion are determined to be the following: Te monovacancies exceeding 4% or Te divacancies exceeding 8%, or lattice strain beyond 6%. In contrast, sufficient Te supply and appropriate tellurization velocity are essential to obtaining the prevailing 2H-MoTe2. Our work provides a novel perspective on the preparation of 2D transition metal chalcogenides (TMDs) with the controllable proportion of 2H and 1T' phase and paves the way to their subsequent potential application of these hybrid phases.

From Iron Metabolism to Ferroptosis: Pathologic Changes in Coronary Heart Disease.

Coronary heart disease (CHD) is closely related to oxidative stress and inflammatory response and is the most common cardiovascular disease (CVD). Iron is an essential mineral that participates in many physiological and biochemical reactions in the human body. Meanwhile, on the negative side, iron has an active redox capacity, which leads to the accumulation of reactive oxygen species (ROS) and lipid peroxidation. There is growing evidence that disordered iron metabolism is involved in CHD's pathological progression. And the result of disordered iron metabolism is associated with iron overload-induced programmed cell death, often called ferroptosis. That features iron-dependent lipid peroxidation. Ferroptosis may play a crucial role in the development of CHD, and targeting ferroptosis may be a promising option for treating CHD. Here, we review the mechanisms of iron metabolism in cardiomyocytes (CMs) and explain the correlation between iron metabolism and ferroptosis. Meanwhile, we highlight the specific roles of iron metabolism and ferroptosis in the main pathological progression of CHD.