FGFR2-fusions define a clinically actionable molecular subset of pancreatic cancer.

Genomic alterations in fibroblast growth factor receptor (FGFR) genes are present in a small number of metastatic pancreatic ductal adenocarcinomas (PDAC) and may represent an emerging subgroup of patients likely to benefit from FGFR targeted therapies. Here we present four FGFR2 fusion-positive metastatic PDAC patients who exhibited durable responses or disease control to FGFR kinase inhibitors. Utilizing our custom FGFR focused cell-free DNA assay, FGFR-Dx, we serially monitored variant allele fractions of FGFR2 fusions during FGFR inhibitor treatment and observed dynamic changes correlating with clinical responses. Genomic analysis of 30,229 comprehensively profiled pancreatic cancers revealed FGFR1-3 fusions in 245 cases, an incidence of 0.81%. FGFR fusions were generally mutually exclusive from other known oncogenes. Our findings provide clinical evidence for identifying and treating FGFR2 fusion-positive PDAC patients with FGFR targeted therapy.

Effectiveness and safety of botulinum toxin type A combined with blepharoplasty in treating sagging skin around the eyes.

Objective: Researchers looked into the safety and effectiveness of blepharoplasty in conjunction with botulinum toxin type A for the treatment of periocular skin laxity. Methods: 92 patients who received treatment at our institution for periocular skin laxity were chosen as research subjects. Their admission time ranged from May 2020 to December 2022. Using various therapy modalities, the patients were split into two groups: an observational team (n = 46) and a controlling team (n = 46). They were respectively given blepharoplasty treatment intervention and botulinum toxin type A combined with blepharoplasty treatment intervention. Eyelid bags, crow's feet, skin radiance and aesthetic results, quality of life were analyzed before and after the intervention, and physician and patient' satisfaction with the results were compared. Results: 95.65 % was the effective rate of the observed group, which was 71.74 % compared with the control group, and significantly increased (P < 0.05). After interference, the score, aesthetic effect and quality of life grade of skin gloss, crow's feet and eyelid bags were significantly higher in the observation group than in the control group (P < 0.05). The complication rate in the observation group was 6.52 % was significantly higher than 30.43 % in the control group (P < 0.05). The patient satisfaction of the observation group was 93.48 %, significantly greater than the control group 69.57 % (P < 0.05); the customer satisfaction of the observation group was 95.65 %, which was significantly higher than the control group 82.61 % (P < 0.05). Conclusion: The combination of type A botulinum toxin and eye bag plastic surgery has a good effect on improving skin laxity around the eyes. It can significantly reduce eyelid bags and crow's feet, improve skin gloss, increase aesthetic effects, and comprehensively restore vitality to aged eye skin, improve life quality, and have high doctor-client contentment and safety.

Adverse Weather Optical Flow: Cumulative Homogeneous-Heterogeneous Adaptation.

Optical flow has made great progress in clean scenes, while suffers degradation under adverse weather due to the violation of the brightness constancy and gradient continuity assumptions of optical flow. Typically, existing methods mainly adopt domain adaptation to transfer motion knowledge from clean to degraded domain through one-stage adaptation. However, this direct adaptation is ineffective, since there exists a large gap due to adverse weather and scene style between clean and real degraded domains. Moreover, even within the degraded domain itself, static weather (e.g., fog) and dynamic weather (e.g., rain) have different impacts on optical flow. To address above issues, we explore synthetic degraded domain as an intermediate bridge between clean and real degraded domains, and propose a cumulative homogeneous-heterogeneous adaptation framework for real adverse weather optical flow. Specifically, for clean-degraded transfer, our key insight is that static weather possesses the depth-association homogeneous feature which does not change the intrinsic motion of the scene, while dynamic weather additionally introduces the heterogeneous feature which results in a significant boundary discrepancy in warp errors between clean and degraded domains. For synthetic-real transfer, we figure out that cost volume correlation shares a similar statistical histogram between synthetic and real degraded domains, benefiting to holistically aligning the homogeneous correlation distribution for synthetic-real knowledge distillation. Under this unified framework, the proposed method can progressively and explicitly transfer knowledge from clean scenes to real adverse weather. In addition, we further collect a real adverse weather dataset with manually annotated optical flow labels and perform extensive experiments to verify the superiority of the proposed method. Both the code and the dataset will be available at https://github.com/hyzhouboy/CH2DA-Flow.

Current landscape of mRNA technologies and delivery systems for new modality therapeutics.

Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases.

PIAS1 S510G variant acts as a genetic modifier of spinocerebellar ataxia type 3 by selectively impairing mutant ataxin-3 proteostasis.

Dysregulated protein homeostasis, characterized by abnormal protein accumulation and aggregation, is a key contributor to the progression of neurodegenerative disorders such as Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Previous studies have identified PIAS1 gene variants in patients with late-onset SCA3 and Huntington's disease. This study aims to elucidate the role of PIAS1 and its S510G variant in modulating the pathogenic mechanisms of SCA3. Through in vitro biochemical analyses and in vivo assays, we demonstrate that PIAS1 stabilizes both wild-type and mutant ataxin-3 (ATXN3). The PIAS1 S510G variant, however, selectively reduces the stability and SUMOylation of mutant ATXN3, thereby decreasing its aggregation and toxicity while maintaining the stability of wild-type ATXN3. This effect is mediated by a weakened interaction with the SUMO-conjugating enzyme UBC9 in the presence of mutant ATXN3. In Drosophila models, downregulation of dPIAS1 resulted in reduced levels of mutant ATXN3 and alleviated associated phenotypes, including retinal degeneration and motor dysfunction. Our findings suggest that the PIAS1 S510G variant acts as a genetic modifier of SCA3, highlighting the potential of targeting SUMOylation as a therapeutic strategy for this disease.

Acupuncture and Acupoints for Managing Pediatric Cerebral Palsy: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Acupuncture is frequently used to manage pediatric cerebral palsy (CP), yet updated evidence is needed to guide future research and clinical practice. METHODS: Seven databases were searched from 1994 to 26 June 2023. Randomized controlled trials (RCTs) involving body, scalp, or ear acupuncture for managing CP, excluding acupoint injection, catgut embedding, electro-acupuncture, or laser acupuncture, were included. RESULTS: Twenty RCTs with 1797 participants were analyzed. Acupuncture groups had better improvements in gross motor function measure (GMFM) scores by 5% (mean difference: 5.93, 95% CI: 3.67-8.19, p < 0.001, I2 = 57%); a 16% higher probability to yield prominent improvement in effectiveness rate (ER) (risk ratio: 1.16, 95% CI: 1.08-1.25, p < 0.001, I2 = 0%); and better outcomes in the Modified Ashworth Scale (MAS) (standardized mean difference [SMD]: 0.3, 95%, CI: 0.11-0.49, p < 0.001, I2 = 0%), the Berg Balance Scale (BBS) (SMD: 2.48; 95% CI: 2.00-2.97, p < 0.001, I2 = 72%) and ADL (SMD: 1.66; 95% CI: 1.23-2.08, p < 0.001, I2 = 91%). Studies with eight core acupoints identified from all ninety-five acupoints had better ER. CONCLUSIONS: Acupuncture, especially using core acupoints, may be effective for managing symptoms in children with CP.

An Evaluation of Skin and Immunological Responses after Using a Novel Cross-Linked Porcine-Based Dermal Injectable Collagen with Lidocaine for Nasolabial Fold Correction.

Background: Hypersensitivity to the new dermal injectable porcine-based collagen with lidocaine featuring a novel cross-linking technology (test filler) for nasolabial fold correction was compared to the commercially available traditional cross-linked dermal injectable porcine-based collagen with lidocaine (control filler). Methods: Recruited participants (n = 279) received a single 0.1 mL intradermal injection of either test filler or control filler in the left forearm as a screening skin allergy test. Injection sites were assessed clinically at 24 h post-implant. Treatment was given to 252 successfully screened participants, and injection sites were monitored for 21 days. Immunological examinations were performed at screening and then at 4 and 24 weeks post-treatment. Observations for adverse events continued until the 52nd week. Results: Intradermal allergy testing results were negative for all the test recipients (0/124) and positive for two control recipients (2/132, 1.5%). Most of the participants exhibited no changes in serum immunoglobulin (IgG, IgM) and complement (C3, C4) levels. No serious adverse events related to the device were recorded. Most adverse events were common complications of dermal filler treatment and were related to the injection site. Most adverse effects were resolved or under control by 52 weeks. Conclusions: Hypersensitivity reactions with the test filler were lower than those with the control filler, validating the safe use of test filler for nasolabial fold correction without the need for pretreatment skin testing.

A Simple, Fast, and Reliable Method for the Identification of Candida albicans.

Background: Candida is one of the common pathogens in nosocomial infections. Culture is the gold standard for diagnosing candidemia. Candida albicans is identified via the germ tube test, which uses serum as the culture medium, which is costly and time-consuming. This study was conducted to evaluate and compare a relatively simple, fast, and reliable method for the detection of Candida albicans. Methods: We conducted this randomized case study at Taipei City Hospital (TCH) from January 2023 to August 2023, with a total of 30 specimen culture reports collected and confirmed to be cases of Candida albicans infection. A germ tube test was performed in a 37°C water bath using serum, plasma, and safe plasma products (Fresh Frozen Plasma, FFP). Further, the same procedures were repeated with the addition of 22% bovine serum albumin (BSA) to the identification/culture. Results: By adding BSA, more than 50% of the budding phenomenon was observed in 40 minutes, which shortened the diagnosis time compared with the traditional method (2-3 hours). Using BSA can shorten the identification time for early clinical medication and improve the quality of medical care. Conclusion: Using safer plasma products for germ tube test of candidiasis not only reduced the risk of infection for medical technicians but could also replace the serum used in traditional methods to increase convenience and save time. This study proposed BSA as a germ tube induction medium enhancer, which reduced the culture time, thereby enabling quicker diagnosis of C. albicans infections.

Nonlinear response of very high frequency contour mode resonators.

We explore the source of nonlinearities in Aluminum Nitride (AlN) Contour Mode Resonators (CMRs) operating in the Very High Frequency (VHF) range. We demonstrate that the red-shift of the resonance frequency found in VHF CMRs when the input RF power increases is due to nonlinear stiffness appearing from self-heating, and variable damping due to geometric nonlinearities. Moreover, we find a linear relationship between the variable damping coefficient and the resonator quality factor (Q). Such nonlinear mechanisms are modeled using a spring-mass-damper physical system and, in the electrical domain, a modified Butterworth-Van Dyke (MBVD) circuit where the nonlinear stiffness and variable damping are captured by a charge-dependent motional capacitor and a charge-dependent motional resistor, respectively. Detailed guidelines are provided to accurately analyze nonlinear CMRs using full-wave numerical simulations based on a finite-element method. Such simulations allow us to isolate the influence of each independent nonlinear mechanism and establish a relation between variable damping and geometric nonlinearities. Circuit and full-wave numerical simulations are in good agreement with measured data from fabricated 225 MHz CMRs exhibiting different Q. Finally, we exploit nonlinearities in high-Q CMRs to generate frequency combs at the MHz range opening the door to new exciting applications in telecommunication and sensing.

A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease.

Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD ,estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks treatment with standard of care plus subcutaneous cotadutide up-titrated to100, 300, or 600 µg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once-weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m2, geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 µg (-43.9% [95%confidence interval -54.7 to -30.6]) and 600 µg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 µg were comparable to semaglutide. Thus, our study shows that in patients with T2Dand CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study.

Glucosamine inhibits myoblast proliferation and differentiation, and stimulates myotube atrophy through distinct signal pathways.

Glucosamine (GlcN) is one of the dietary supplements used in the treatment of osteoarthritis. Endogenously, GlcN is synthesized from glucose through the hexosamine pathway. In addition to ameliorating arthritis, several biological functions of GlcN have been reported, including insulin resistance in skeletal muscle. However, the regulatory role of GlcN in skeletal muscle development is not clear. We therefore investigated the effect of GlcN on myoblast proliferation, differentiation, and myotube development and their underlying mechanisms in C2C12 cells. Myoblast proliferation was measured by MTT assay. The expressions of MyoD, myogenin (MyoG), and myosin heavy chain (MyHC) were identified as determinants of myoblast differentiation. Expressions of atrogin-1 and muscle RING-finger protein-1 (MuRF-1) were identified as markers of myotube atrophy. The results show that treatment with GlcN significantly reduced myoblast proliferation and phosphorylation of Stat3 and S6K. These findings suggest that GlcN can inhibit growth of myoblasts through inhibiting phosphorylation of Stat3 and S6K. In addition, GlcN significantly suppressed the expression of MyoD, MyoG, and MyHC, as well as myotube formation. Pretreatment of C2C12 myoblast cells with ER stress inhibitors significantly blocked GlcN-inhibited MyHC expression and myotube formation. It can be concluded that GlcN suppressed myogenic differentiation via a pathway that involved ER stress. Moreover, GlcN decreased myotube diameter and expression of MyHC, as well as increased MuRF-1 in C2C12 myotubes. Meanwhile, GlcN also reduced the expressions of phosphorylated Akt and mTOR were stimulated after GlcN treatment in C2C12 myotubes. Thus, GlcN induced skeletal muscle atrophy by inhibiting the protein synthesis pathway. Chronic GlcN infusion also caused skeletal muscle atrophy in mice. In conclusion, GlcN regulated important stages of skeletal muscle development through different signaling pathways.

Surgical strategy and long-term outcomes of dissected carotid artery with false lumen thrombus in acute type A aortic dissection.

Background: Optimal management of involved common carotid artery (CCA) with false-lumen thrombus remains unclear in aortic dissection patients. We aim to investigate outcomes and compare different surgical strategies. Methods: This is a retrospective cohort study and the institutional database of acute type A aortic dissection was reviewed. The patients with CCA involvement and extended false-lumen thrombus were enrolled and grouped according to the management of CCA: extra-thoracic carotid artery replacement (CAR) and reconstruction in situ (RIS). Multivariate logistic regression analysis was used to investigate the effect of management on neurological outcomes. Kaplan-Meier method was used for survival analysis and log-rank test was used to compare the difference on survival rate. Results: From March 2011 to December 2019, 68 patients were enrolled (24 in the CAR group and 44 in the RIS group). The overall operative mortality was 7.4% (5 patients) and 21 patients had the incidence of postoperative neurological deficit was (30.9%). The rates of main postoperative complications were similar between the two groups. Twenty-five (56.8%) patients in the RIS group had residual false-lumen thrombus at discharge. In multivariate analysis, CAR was the only independent protective factor of postoperative neurological deficit [odds ratio (OR) =0.03, 95% confidence interval (CI): 0.0-0.61, P=0.02] and age was the only risk factor (OR =1.34, 95% CI: 1.11-1.62, P=0.002). The median follow-up time was 40 (interquartile range, 24-69) months and some of the patients received imaging follow-up. The overall survival rates at 5 and 10 years were 95.8%, and 95.8% in the CAR group and 84.1%, and 76.4% in the RIS group, with no significant difference (P=0.22). No cerebrovascular accident and reintervention occurred and 20 (90.9%) patients with residual false-lumen thrombus had reabsorption of thrombus during the follow-up period. Conclusions: CAR was a thorough technique and could protect patients from postoperative neurological deficit than RIS. Patients in either group could have a satisfying long-term prognosis after surviving from perioperative period. Most patients had reabsorption of residual false-lumen thrombus after anticoagulant therapy.

Diversifying Policies with Non-Markov Dispersion to Expand the Solution Space.

Policy diversity, encompassing the variety of policies an agent can adopt, enhances reinforcement learning (RL) success by fostering more robust, adaptable, and innovative problem-solving in the environment. The environment in which standard RL operates is usually modeled with a Markov Decision Process (MDP) as the theoretical foundation. However, in many real-world scenarios, the rewards depend on an agent's history of states and actions leading to a non-MDP. Under the premise of policy diffusion initialization, non-MDPs may have unstructured expanding solution space due to varying historical information and temporal dependencies. This results in solutions having non-equivalent closed forms in non-MDPs. In this paper, deriving diverse solutions for non-MDPs requires policies to break through the boundaries of the current solution space through gradual dispersion. The goal is to expand the solution space, thereby obtaining more diverse policies. Specifically, we first model the sequences of states and actions by a transformer-based method to learn policy embeddings for dispersion in the solution space, since the transformer has advantages in handling sequential data and capturing long-range dependencies for non-MDP. Then, we stack the policy embeddings to construct a dispersion matrix as the policy diversity measure to induce the policy dispersion in the solution space and obtain a set of diverse policies. Finally, we prove that if the dispersion matrix is positive definite, the dispersed embeddings can effectively enlarge the disagreements across policies, yielding a diverse expression for the original policy embedding distribution. Experimental results of both non-MDP and MDP environments show that this dispersion scheme can obtain more expressive diverse policies via expanding the solution space, showing more robust performance than the recent learning baselines.

Nonconjugated Polyurethane Derivatives with Aggregation-Induced Luminochromism for Multicolor and White Photoluminescent Films.

A simple and effective strategy to obtain solid-state multicolor emitting materials is a particularly attractive topic. Nonconventional/nonconjugated polymers are receiving widespread attention because of their advantages of rich structural diversity, low cost, and good processability. However, it is difficult to control the molecular conformation or to obtain the crystal structure of amorphous molecules, which means it is a challenge to obtain nontraditional polymeric materials with multicolor emission. In this work, a polyurethane derivative (PUH) with red-shifted emission was synthesized by a simple one-pot polymerization reaction. By exploiting the aggregation-induced luminochromism of PUH, a series of plastic films with tunable emission from blue to orange, and white-light emission, was obtained by doping different amounts of PUH into poly(methyl methacrylate) (PMMA), thereby changing the aggregation degree of PUH. This work demonstrates the excellent promise of polyurethane derivatives for the simple fabrication of large-scale flexible luminescent films.

Analytic validation of an FGFR -focused cell-free DNA liquid biopsy assay (FGFR-Dx).

Commercial liquid biopsy assays are routinely used by oncologists to monitor disease response and resistance to therapy. Additionally, in cases where tumor tissue is not available, clinicians may rely on cell-free DNA (cfDNA) testing as a surrogate for comprehensive tumor testing. While some gene rearrangements are well detected, current commercial liquid biopsy assays exhibit low sensitivity for fibroblast growth factor receptor ( FGFR ) rearrangements. FGFRs are altered in ∼2.5% of all cancers, including FGFR2 rearrangements in 10% of intrahepatic cholangiocarcinoma and FGFR3 point mutations and rearrangements in 10-15% of urothelial carcinoma. Therefore, we developed and analytically validated FGFR-Dx, an FGFR -focused cfDNA assay with improved sensitivity for FGFR rearrangements. FGFR-Dx comprehensively targets the introns in FGFR1-3 previously shown to be involved in gene fusions as well as all coding exons. Custom FGFR synthetic reference standards representing both single nucleotide variants (SNVs) and gene rearrangements were utilized at a range of variant frequencies and revealed a detection limit of 0.5% with sensitivities of 97.2% and 92.9% for SNVs and rearrangements, respectively. Furthermore, FGFR-Dx detected rearrangements and identified the intronic breakpoints from cfDNA collected from 13 of 15 patients with known FGFR fusions.

Rational design of Au-Bi bimetallic nanozyme for NIR-II laser mediated multifunctional combined tumor therapy.

To maximize the therapeutic effects and minimize the adverse effects of synergistic tumor therapies, a multifunctional nanozyme Au-Bi/ZIF-8@DOX@HA (ABZ@DOX@HA) was designed and synthesized through the Au and Bi bimetallic doping of ZIF-8, loading of the DOX, and modifying with hyaluronic acid (HA). The ABZ@DOX@HA nanoparticles (NPs) could simulate the enzymatic activities of glucose oxidase (GOx) and peroxidase (POD). Upon irradiated by near-infrared region (NIR-II) laser, the strong synergism of the photothermal abilities of the loaded Au and Bi nanodots accelerated the collapse of the ABZ structure at the tumor site considerably and released Au, Bi nanodots and DOX. The results in vitro and in vivo proved that ABZ@DOX@HA nanozyme could effectively exert the combined tumor therapy of starvation treatment, photothermal therapy (PTT), chemodynamic therapy (CDT) and chemotherapy. The current research provides a new strategy to address the inherent challenges of easy clearance and short blood circulation of small-sized NPs during the treatment of tumors with nanomedicine, as well as the aggregation and oxidation of inorganic nanodots.

SpatialCTD: A Large-Scale Tumor Microenvironment Spatial Transcriptomic Dataset to Evaluate Cell Type Deconvolution for Immuno-Oncology.

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at a multicellular resolution that is more cost-effective. The task of cell type deconvolution has been introduced to disentangle discrete cell types from such multicellular spots. However, existing benchmark datasets for cell type deconvolution are either generated from simulation or limited in scale, predominantly encompassing data on mice and are not designed for human immuno-oncology. To overcome these limitations and promote comprehensive investigation of cell type deconvolution for human immuno-oncology, we introduce a large-scale spatial transcriptomic deconvolution benchmark dataset named SpatialCTD, encompassing 1.8 million cells and 12,900 pseudo spots from the human tumor microenvironment across the lung, kidney, and liver. In addition, SpatialCTD provides more realistic reference than those generated from single-cell RNA sequencing (scRNA-seq) data for most reference-based deconvolution methods. To utilize the location-aware SpatialCTD reference, we propose a graph neural network-based deconvolution method (i.e., GNNDeconvolver). Extensive experiments show that GNNDeconvolver often outperforms existing state-of-the-art methods by a substantial margin, without requiring scRNA-seq data. To enable comprehensive evaluations of spatial transcriptomics data from flexible protocols, we provide an online tool capable of converting spatial transcriptomic data from various platforms (e.g., 10× Visium, MERFISH, and sci-Space) into pseudo spots, featuring adjustable spot size. The SpatialCTD dataset and GNNDeconvolver implementation are available at https://github.com/OmicsML/SpatialCTD, and the online converter tool can be accessed at https://omicsml.github.io/SpatialCTD/.

Aldosterone, mitochondria and regulation of cardiovascular metabolic disease.

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.

Condensate interfacial forces reposition DNA loci and probe chromatin viscoelasticity.

Biomolecular condensates assemble in living cells through phase separation and related phase transitions. An underappreciated feature of these dynamic molecular assemblies is that they form interfaces with other cellular structures, including membranes, cytoskeleton, DNA and RNA, and other membraneless compartments. These interfaces are expected to give rise to capillary forces, but there are few ways of quantifying and harnessing these forces in living cells. Here, we introduce viscoelastic chromatin tethering and organization (VECTOR), which uses light-inducible biomolecular condensates to generate capillary forces at targeted DNA loci. VECTOR can be utilized to programmably reposition genomic loci on a timescale of seconds to minutes, quantitatively revealing local heterogeneity in the viscoelastic material properties of chromatin. These synthetic condensates are built from components that naturally form liquid-like structures in living cells, highlighting the potential role for native condensates to generate forces and do work to reorganize the genome and impact chromatin architecture.