Deepening insights into cholinergic agents for intraocular pressure reduction: systems genetics, molecular modeling, and in vivo perspectives.

Parasympathetic activation in the anterior eye segment regulates various physiological functions. This process, mediated by muscarinic acetylcholine receptors, also impacts intraocular pressure (IOP) through the trabecular meshwork. While FDA-approved M3 muscarinic receptor (M3R) agonists exist for IOP reduction, their systemic cholinergic adverse effects pose limitations in clinical use. Therefore, advancing our understanding of the cholinergic system in the anterior segment of the eye is crucial for developing additional IOP-reducing agents with improved safety profiles. Systems genetics analyses were utilized to explore correlations between IOP and the five major muscarinic receptor subtypes. Molecular docking and dynamics simulations were applied to human M3R homology model using a comprehensive set of human M3R ligands and 1,667 FDA-approved or investigational drugs. Lead compounds from the modeling studies were then tested for their IOP-lowering abilities in mice. Systems genetics analyses unveiled positive correlations in mRNA expressions among the five major muscarinic receptor subtypes, with a negative correlation observed only in M3R with IOP. Through modeling studies, rivastigmine and edrophonium emerged as the most optimally suited cholinergic drugs for reducing IOP via a potentially distinct mechanism from pilocarpine or physostigmine. Subsequent animal studies confirmed comparable IOP reductions among rivastigmine, edrophonium, and pilocarpine, with longer durations of action for rivastigmine and edrophonium. Mild cholinergic adverse effects were observed with pilocarpine and rivastigmine but absent with edrophonium. These findings advance ocular therapeutics, suggesting a more nuanced role of the parasympathetic system in the anterior eye segment for reducing IOP than previously thought.

Evaluation of Pregabalin bioadhesive multilayered microemulsion IOP-lowering eye drops.

In spite of available treatment options, glaucoma continues to be a leading cause of irreversible blindness in the world. Current glaucoma medications have multiple limitations including: lack of sustained action; requirement for multiple dosing per day, ocular irritation and limited options for drugs with different mechanisms of action. Previously, we demonstrated that pregabalin, a drug with high affinity and selectivity for CACNA2D1, lowered IOP in a dose-dependent manner. The current study was designed to evaluate pregabalin microemulsion eye drops and to estimate its efficacy in humans using in silico methods. Molecular docking studies of pregabalin against CACNA2D1 of mouse, rabbit, and human were performed. Pregabalin microemulsion eye drops were characterized using multiple in vivo studies and its stability was evaluated over one year at different storage conditions. Molecular docking analyses and QSPR of pregabalin confirmed its suitability as a new IOP-lowering medication that functions using a new mechanism of action by binding to CACNA2D1 in all species evaluated. Because of its prolonged corneal residence time and corneal penetration enhancement, a single topical application of pregabalin ME can provide an extended IOP reduction of more than day in different animal models. Repeated daily dosing for 2 months confirms the lack of any tachyphylactic effect, which is a common drawback among marketed IOP-lowering medications. In addition, pregabalin microemulsion demonstrated good physical stability for one year, and chemical stability for 3-6 months if stored below 25 °C. Collectively, these outcomes greatly support the use of pregabalin eye drops as once daily IOP-lowering therapy for glaucoma management.

Cryo-EM structure of orf virus scaffolding protein orfv075.

Capsid-like poxvirus scaffold proteins self-assemble into semi-regular lattice that govern the formation of spherical immature virus particles. The scaffolding is a critical step in virus morphogenesis as exemplified by the drug rifampicin that impairs the recruitment of scaffold onto the viral membrane in vaccinia virus (VACV). Here we report cryo-electron microscopy structure of scaffolding protein Orfv075 of orf virus (ORFV) that causes smallpox-like diseases in sheep, goats and occasionally humans via zoonotic infection. We demonstrate that the regions that are involved in intertrimeric interactions for scaffold assembly are largely conserved in comparison to its VACV orthologue protein D13 whose intermediate assembly structures have been previously characterized. By contrast, less conserved regions are located away from these interfaces, indicating both viruses share similar assembly mechanisms. We also show that the phenylalanine-rich binding site of rifampicin in D13 is conserved in Orfv075, and molecular docking simulation confirms similar binding modes. Our study provides structural basis of scaffolding protein as a target for anti-poxvirus treatment across wide range of poxvirus genera.

How good are collimated Gaussian beams produced with engineered diffusers?

Collimating a Gaussian beam from an uncollimated laser source has been achieved via the deployment of engineered diffusers (EDs)-also referred to as light shaping diffusers. When compared to conventional pinhole-based optical collimation systems, this method of beam collimation ensures high optical transmission efficiency at the expense of the introduction of additional speckle and a resulting reduction in spatial coherence. Despite a lower collimation quality, these ED-produced collimated beams are attractive and promising in terms of their deployment in various benchtop or tabletop systems that involve shorter beam propagation distances of up to a few meters while requiring a high optical power throughput. This paper aims to further the understanding of collimation quality and propagation properties of ED-produced Gaussian collimated beams via carefully designed experiments and accompanying analysis. We measure and document the beam divergence, Rayleigh distance, and M 2 factor, as well as evolution of the wavefront radius of curvature (RoC), of these ED-generated beams over a few meters of propagation-a propagation distance which encapsulates a vast majority of optical systems. We further investigate the changes in the beam profile with the addition of a laser speckle reducer (SR) and compare the ED-produced beams with a near-ideal collimated beam produced with spatial filtering systems.

Measuring the radius of curvature of spherical surfaces with actively tunable Fizeau and Twyman-Green interferometers.

Accurate and repeatable measurement of the radius of curvature (RoC) of spherical sample surfaces is of great importance in optics. This importance lies in the ubiquitous use of spherical optical elements such as curved mirrors and lenses. Due to a high measurement sensitivity, interferometric techniques are often deployed for accurate characterization of the sample surface RoC. One method by which a typical commercial Fizeau or Twyman-Green (TG) interferometer measures surface RoC is via scanning between two principal retroreflective optical configurations-namely, the confocal and catseye configurations. Switching between these two configurations is typically achieved by moving an optical head along the axis of the propagating laser beam and the RoC is estimated by measuring the magnitude of mechanical motion to switch between the two principal configurations. In this paper, we propose a motion-free catseye/confocal-imaging-based sample RoC measurement system. The necessity of bulk motion to switch between the two configurations is circumvented via the use of an actively controlled varifocal lens. We demonstrate the usefulness of the proposed innovation in RoC measurements with either the TG or the Fizeau interferometer. Furthermore, we convert a commercial motion-based Zygo RoC measurement system into a motion-free one by introducing a tunable lens inside the apparatus and using it to accurately characterize the RoC of different test samples. We also compute the wavefront aberrations for all spherical sample surfaces from the recorded measurement data.

Free-standing two-dimensional ferro-ionic memristor.

Two-dimensional (2D) ferroelectric materials have emerged as significant platforms for multi-functional three-dimensional (3D) integrated electronic devices. Among 2D ferroelectric materials, ferro-ionic CuInP2S6 has the potential to achieve the versatile advances in neuromorphic computing systems due to its phase tunability and ferro-ionic characteristics. As CuInP2S6 exhibits a ferroelectric phase with insulating properties at room temperature, the external temperature and electrical field should be required to activate the ferro-ionic conduction. Nevertheless, such external conditions inevitably facilitate stochastic ionic conduction, which completely limits the practical applications of 2D ferro-ionic materials. Herein, free-standing 2D ferroelectric heterostructure is mechanically manipulated for nano-confined conductive filaments growth in free-standing 2D ferro-ionic memristor. The ultra-high mechanical bending is selectively facilitated at the free-standing area to spatially activate the ferro-ionic conduction, which allows the deterministic local positioning of Cu+ ion transport. According to the local flexoelectric engineering, 5.76×102-fold increased maximum current is observed within vertical shear strain 720 nN, which is theoretically supported by the 3D flexoelectric simulation. In conclusion, we envision that our universal free-standing platform can provide the extendable geometric solution for ultra-efficient self-powered system and reliable neuromorphic device.

Ultrastable 3D Heterogeneous Integration via N-Heterocyclic Carbene Self-Assembled Nanolayers.

The commercialization of 3D heterogeneous integration through hybrid bonding has accelerated, and accordingly, Cu-polymer bonding has gained significant attention as a means of overcoming the limitations of conventional Cu-SiO2 hybrid bonding, offering high compatibility with other fabrication processes. Polymers offer robust bonding strength and a low dielectric constant, enabling high-speed signal transmission with high reliability, but suffer from low thermomechanical stability. Thermomechanical stability of polymers was not achieved previously because of thermal degradation and unstable anchoring. To overcome these limitations, wafer-scale Cu-polymer bonding via N-heterocyclic carbene (NHC) nanolayers was presented for 3D heterogeneous integration, affording ultrastable packing density, crystallinity, and thermal properties. NHC nanolayers were deposited on copper electrodes via electrochemical deposition, and wafer-scale 3D heterogeneous integration was achieved by adhesive bonding at 170 °C for 1 min. Ultrastable conductivity and thermomechanical properties were observed by the spatial mapping of conductivity, work function, and force-distance curves. With regard to the characterization of NHC nanolayers, low-temperature bonding, robust corrosion inhibition, enhanced electrical conductivity, back-end-of-line process compatibility, and fabrication process reduction, NHC Cu/polymer bonding provides versatile advances in 3D heterogeneous integration, indicating that NHC Cu/polymer bonding can be utilized as a platform for future 3D vertical chip architectures.

Numerical investigation of the effect of air layer on drag reduction in channel flow over a superhydrophobic surface.

This study investigates the effects of an air layer on drag reduction and turbulence dynamics in channel flow over a superhydrophobic surface (SHS). Employing the OpenFOAM platform, direct numerical simulation was conducted to investigate turbulent channel flow with an air layer over an SHS. The simulations, which take into account the interaction between water and air, analyze various parameters such as velocity distribution, drag reduction (DR), Reynolds stress, turbulent kinetic energy (TKE), and coherent structures near the water-air interface. The presence of an air layer significantly alters the velocity distribution, leading to higher velocities at the interface compared to simulations without the air layer. Notably, the thickness of the air layer emerges as an important factor, with larger thicknesses resulting in increased velocities and drag reduction. This study underscores the substantial impact of the air layer on TKE near the superhydrophobic surface, emphasizing its role in understanding and optimizing drag reduction. Furthermore, the nonlinear relationship between slip velocity, Q contours, and coherent structures near the SHS are investigated.

The dispensability of VH-VL pairing and the indispensability of VL domain integrity in the IgG1 secretion process.

Introduction: The CH1 domain of IgG antibodies controls assembly and secretion, mediated by the molecular chaperone BiP via the endoplasmic reticulum protein quality control (ERQC) mechanism. However, it is not clear whether the variable domains are necessary for this process. Methods: Here, we generated IgG1 antibodies in which the V domain (VH and/or VL) was either removed or replaced, and then assessed expression, assembly, and secretion in HEK293 cells. Results: All Ig variants formed a covalent linkage between the Cγ1 and Cκ, were successfully secreted in an assembled form. Replacement of the cognate Vκ with a non-secretory pseudo Vκ (ψVκ) hindered secretion of individual or assembled secretion of neither heavy chains (HCs) nor light chains (LCs). The ψLC (ψVκ-Cκ) exhibited a less folded structure compared to the wild type (wt) LC, as evidenced by enhanced stable binding to the molecular chaperone BiP and susceptibility to proteolytic degradation. Molecular dynamics simulation demonstrated dramatic alterations in overall structure of ψFab (Fd-ψLC) from wt Fab. Discussion: These findings suggest that V domains do not initiate HC:LC assembly and secretion; instead, the critical factor governing IgG assembly and secretion is the CH-CL pairing. Additionally, the structural integrity of the VL domain is crucial for IgG secretion. These data offer valuable insight into the design of bioactive molecules based on an IgG backbone.

Diagnosis of Unruptured Intracranial Aneurysms Using Proton-Density Magnetic Resonance Angiography: A Comparison With High-Resolution Time-of-Flight Magnetic Resonance Angiography.

OBJECTIVE: Differentiating intracranial aneurysms from normal variants using CT angiography (CTA) or MR angiography (MRA) poses significant challenges. This study aimed to evaluate the efficacy of proton-density MRA (PD-MRA) compared to high-resolution time-of-flight MRA (HR-MRA) in diagnosing aneurysms among patients with indeterminate findings on conventional CTA or MRA. MATERIALS AND METHODS: In this retrospective analysis, we included patients who underwent both PD-MRA and HR-MRA from August 2020 to July 2022 to assess lesions deemed indeterminate on prior conventional CTA or MRA examinations. Three experienced neuroradiologists independently reviewed the lesions using HR-MRA and PD-MRA with reconstructed voxel sizes of 0.253 mm3 or 0.23 mm3, respectively. A neurointerventionist established the gold standard with digital subtraction angiography. We compared the performance of HR-MRA, PD-MRA (0.253-mm3 voxel), and PD-MRA (0.23-mm3 voxel) in diagnosing aneurysms, both per lesion and per patient. The Fleiss kappa statistic was used to calculate inter-reader agreement. RESULTS: The study involved 109 patients (average age 57.4 ± 11.0 years; male:female ratio, 11:98) with 141 indeterminate lesions. Of these, 78 lesions (55.3%) in 69 patients were confirmed as aneurysms by the reference standard. PD-MRA (0.253-mm3 voxel) exhibited significantly higher per-lesion diagnostic performance compared to HR-MRA across all three readers: sensitivity ranged from 87.2%-91.0% versus 66.7%-70.5%; specificity from 93.7%-96.8% versus 58.7%-68.3%; and accuracy from 90.8%-92.9% versus 63.8%-69.5% (P ≤ 0.003). Furthermore, PD-MRA (0.253-mm3 voxel) demonstrated significantly superior per-patient specificity and accuracy compared to HR-MRA across all evaluators (P ≤ 0.013). The diagnostic accuracy of PD-MRA (0.23-mm3 voxel) surpassed that of HR-MRA and was comparable to PD-MRA (0.253-mm3 voxel). The kappa values for inter-reader agreements were significantly higher in PD-MRA (0.820-0.938) than in HR-MRA (0.447-0.510). CONCLUSION: PD-MRA outperformed HR-MRA in diagnostic accuracy and demonstrated almost perfect inter-reader consistency in identifying intracranial aneurysms among patients with lesions initially indeterminate on CTA or MRA.

High-Throughput Roll-to-Roll Processed Large-Area Perovskite Solar Cells Using Rapid Radiation Annealing Technique.

The development of a stable roll-to-roll (R2R) process for flexible large-area perovskite solar cells (PSCs) and modules is a pressing challenge. In this study, we introduced a new R2R PSC manufacturing system that employs a two-step deposition method for coating perovskite and uses intensive pulsed light (IPL) for annealing. This system has successfully fabricated small-sized cells and the first-ever large-sized, R2R-processed flexible modules. A key focus of our work was to accelerate the conversion of PbI2 to perovskite. To this end, we utilized IPL annealing and incorporated additives into the PbI2 layer. With these modifications, the R2R-processed perovskite films achieved a power conversion efficiency (PCE) of 16.87%, representing the highest reported value for R2R two-step processed PSCs. However, these cells exhibited hysteresis in reverse and forward PCE measurements. To address this, we introduced a dual-annealing process consisting of IPL followed by a 2-min thermal heating step. This approach successfully reduced hysteresis, resulting in low-hysteresis, R2R-processed flexible PSCs. Moreover, we fabricated large-scale flexible modules (10 × 10 cm2) with a PCE of 11.25% using the dual-annealing system, marking a significant milestone in this field.

Magnetite particles accelerate methanogenic degradation of highly concentrated acetic acid in anaerobic digestion process.

The anaerobic digestion (AD) process has become significant for its capability to convert organic wastewater into biogas, a valuable energy source. Excessive acetic acid accumulation in the anaerobic digester can inhibit methanogens, ultimately leading to the deterioration of process performance. Herein, the effect of magnetite particles (MP) as an enhancer on the methanogenic degradation of highly-concentrated acetate (6 g COD/L) was examined through long-term sequential AD batch tests. Bioreactors with (AM) and without (AO) MP were compared. AO experienced inhibition and its methane production rate (qm) converged to 0.45 L CH4/g VSS/d after 10 sequential batches (AO10, the 10th batch in a series of the sequential batch tests conducted using bioreactors without MP addition). In contrast, AM achieved 3-425% higher qm through the sequential batches, indicating that MP could counteract the inhibition caused by the highly-concentrated acetate. MP addition to inhibited bioreactors (AO10) successfully restored them, achieving qm of 1.53 L CH4/g VSS/d, 3.4 times increase from AO10 after 8 days lag time, validating its potential as a recovery strategy for inhibited digesters with acetate accumulation. AM exhibited higher microbial populations (1.8-3.8 times) and intracellular activity (9.3 times) compared to AO. MP enriched Methanosaeta, Peptoclostridium, Paraclostridium, OPB41, and genes related to direct interspecies electron transfer and acetate oxidation, potentially driving the improvement of qm through MP-mediated methanogenesis. These findings demonstrated the potential of MP supplementation as an effective strategy to accelerate acetate-utilizing methanogenesis and restore an inhibited anaerobic digester with high acetate accumulation.

Expression of Immunoglobulin G4 in Eosinophilic Esophagitis.

Background: Eosinophilic esophagitis (EoE) is a disease that has been subcategorized into two endoscopic phenotypes: inflammatory and fibrostenotic. Moreover, studies have shown a link between EoE and immunoglobulin G4 (IgG4), a subclass of the immunoglobulin G (IgG) antibody. In this study, we aimed to evaluate the relationship between histologic IgG4 expression and endoscopic phenotypes in patients with EoE. Methods: This case-control study included patients diagnosed with EoE (n = 19) and patients with non-obstructive dysphagia without abnormal findings as controls (NOD; n = 12). The EoE group was further divided into three subgroups based on endoscopic phenotype: inflammatory, fibrostenotic, or combined. Retrospective examination of endoscopic findings and pathological slides was performed to analyze IgG4 staining. Results: Histological analysis revealed a significant difference in IgG4 cell count (15.00 vs. 0.58, p = 0.003) and eosinophil cell count (84.67 vs. 0.08, p < 0.001) between the EoE and NOD groups. Symptom manifestation and blood test results were similar across all three endoscopic EoE phenotypes. However, histological analysis revealed a significant difference in IgG4 cell count between the inflammatory, fibrostenotic, and combined phenotypes (4.13 vs. 17.6 vs. 59.7, p = 0.030). Conclusions: IgG4 expression was higher in EoE patients than in those with NOD, the highest being in the combined phenotype subgroup. These findings emphasize the important role of endoscopic and histological examination in diagnosing EoE and the need for further research in this area.

Orbital-Selective Mott Transition Effects and Nontrivial Topology of Iron Chalcogenide.

The iron-based superconductor FeSe_{1-x}Te_{x} has recently gained significant attention as a host of two distinct physical phenomena: (i) Majorana zero modes that can serve as potential topologically protected qubits, and (ii) a realization of the orbital-selective Mott transition. In this Letter, we connect these two phenomena and provide new insights into the interplay between strong electronic correlations and nontrivial topology in FeSe_{1-x}Te_{x}. Using linearized quasiparticle self-consistent GW plus dynamical mean-field theory, we show that the topologically protected Dirac surface state has substantial Fe(d_{xy}) character. The proximity to the orbital-selective Mott transition plays a dual role: it facilitates the appearance of the topological surface state by bringing the Dirac cone close to the chemical potential but destroys the Z_{2} topological superconductivity when the system is too close to the orbital-selective Mott phase. We derive a reduced effective Hamiltonian that describes the topological band. Its parameters capture all the chemical trends found in the first principles calculation. Our findings provide a framework for further study of the interplay between strong electronic correlations and nontrivial topology in other iron-based superconductors.

Identification of differentially expressed mRNA/lncRNA modules in acutely regorafenib-treated sorafenib-resistant Huh7 hepatocellular carcinoma cells.

The multikinase inhibitor sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but many patients become sorafenib-resistant (SR). This study investigated the efficacy of another kinase inhibitor, regorafenib (Rego), as a second-line treatment. We produced SR HCC cells, wherein the PI3K-Akt, TNF, cAMP, and TGF-beta signaling pathways were affected. Acute Rego treatment of these cells reversed the expression of genes involved in TGF-beta signaling but further increased the expression of genes involved in PI3K-Akt signaling. Additionally, Rego reversed the expression of genes involved in nucleosome assembly and epigenetic gene expression. Weighted gene co-expression network analysis (WGCNA) revealed four differentially expressed long non-coding RNA (DElncRNA) modules that were associated with the effectiveness of Rego on SR cells. Eleven putative DElncRNAs with distinct expression patterns were identified. We associated each module with DEmRNAs of the same pattern, thus obtaining DElncRNA/DEmRNA co-expression modules. We discuss the potential significance of each module. These findings provide insights and resources for further investigation into the potential mechanisms underlying the response of SR HCC cells to Rego.

Impaired Glymphatic Flow on Diffusion Tensor MRI as a Marker of Neurodegeneration in Alzheimer's Disease: Correlation with Gray Matter Volume Loss and Cognitive Decline Independent of Cerebral Amyloid Deposition.

Background: Impaired glymphatic flow on the Alzheimer's disease (AD) spectrum may be evaluated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Objective: We aimed to validate impaired glymphatic flow and explore its association with gray matter volume, cognitive status, and cerebral amyloid deposition on the AD spectrum. Methods: 80 participants (mean age, 76.9±8.5 years; 57 women) with AD (n = 65) and cognitively normal (CN) (n = 15) who underwent 3T brain MRI including DTI and/or amyloid PET were included. After adjusting for age, sex, apolipoprotein E status, and burden of white matter hyperintensities, the ALPS-index was compared according to the AD spectrum. The association between the ALPS-index and gray matter volume, cognitive status, and quantitative amyloid from PET was assessed. Results: The ALPS-index in the AD was significantly lower (mean, 1.476; 95% CI, 1.395-1.556) than in the CN (1.784;1.615-1.952; p = 0.026). Volumes of the entorhinal cortex, hippocampus, temporal pole, and primary motor cortex showed significant associations with the ALPS-index (all, p < 0.05). There was a positive correlation between the ALPS-index and MMSE score (partial r = 0.435; p < 0.001), but there was no significant correlation between the ALPS-index and amyloid SUVRs (all, p > 0.05). Conclusions: Decreased glymphatic flow measured by DTI-ALPS in AD may serve as a marker of neurodegeneration correlating with structural atrophy and cognitive decline.

Advances in algal lipid metabolism and their use to improve oil content.

Microalgae are eukaryotic photosynthetic micro-organisms that convert CO2 into carbohydrates, lipids, and other valuable metabolites. They are considered promising chassis for the production of various bioproducts, including fatty acid-derived biofuels. However, algae-based biofuels are not yet commercially available, mainly because of their low yields and high production cost. Optimizing strains to improve lipid productivity using the principles of synthetic biology should help move forward. This necessitates developments in the following areas: (1) identification of molecular bricks (enzymes, transcription factors, regulatory proteins etc.); (2) development of genetic tools; and (3) availability of high-throughput phenotyping methods. Here, we highlight the most recent developments in some of these areas and provide examples of the use of genome editing tools to improve oil content.

Control of Meniscus Formation Using an Electrohydrodynamics Module in Roll-to-Roll Systems for the Stable Coating of Functional Layers.

In fabricating functional layers, including thin-film transistors and conductive electrodes, using roll-to-roll (R2R) processing on polymer-based PET film, the instability of the slot-die coating meniscus under a high-speed web impedes functional layer formation with the desired thickness and width. The thickness profiles of the functional layers significantly impact the performance of the final products. In this study, we introduce an electrohydrodynamic (EHD)-based voltage application module to a slot-die coater to ensure the uniformity of the cross-machine direction (CMD) thickness profile within the functional layer and enable a stable, high-speed R2R process. The module can effectively control the spreadability of the meniscus by utilizing variations in the surface tension of the ink. The effectiveness of the EHD module was experimentally verified by applying a high voltage to a slot-die coater while keeping other process variables constant. As the applied voltage increases, the CMD thickness deviation reduces by 64.5%, and the production rate significantly increases (up to 300%), owing to the formation of a stable coated layer. The introduction of the EHD-based application module to the slot-die coater effectively controlled the spreadability of the meniscus, producing large-area functional layers.

Advances in single-cell omics and multiomics for high-resolution molecular profiling.

Single-cell omics technologies have revolutionized molecular profiling by providing high-resolution insights into cellular heterogeneity and complexity. Traditional bulk omics approaches average signals from heterogeneous cell populations, thereby obscuring important cellular nuances. Single-cell omics studies enable the analysis of individual cells and reveal diverse cell types, dynamic cellular states, and rare cell populations. These techniques offer unprecedented resolution and sensitivity, enabling researchers to unravel the molecular landscape of individual cells. Furthermore, the integration of multimodal omics data within a single cell provides a comprehensive and holistic view of cellular processes. By combining multiple omics dimensions, multimodal omics approaches can facilitate the elucidation of complex cellular interactions, regulatory networks, and molecular mechanisms. This integrative approach enhances our understanding of cellular systems, from development to disease. This review provides an overview of the recent advances in single-cell and multimodal omics for high-resolution molecular profiling. We discuss the principles and methodologies for representatives of each omics method, highlighting the strengths and limitations of the different techniques. In addition, we present case studies demonstrating the applications of single-cell and multimodal omics in various fields, including developmental biology, neurobiology, cancer research, immunology, and precision medicine.

Utilizing systems genetics to enhance understanding into molecular targets of skin cancer.

Despite progress made with immune checkpoint inhibitors and targeted therapies, skin cancer remains a significant public health concern in the United States. The intricacies of the disease, encompassing genetics, immune responses, and external factors, call for a comprehensive approach. Techniques in systems genetics, including transcriptional correlation analysis, functional pathway enrichment analysis, and protein-protein interaction network analysis, prove valuable in deciphering intricate molecular mechanisms and identifying potential diagnostic and therapeutic targets for skin cancer. Recent studies demonstrate the efficacy of these techniques in uncovering molecular processes and pinpointing diagnostic markers for various skin cancer types, highlighting the potential of systems genetics in advancing innovative therapies. While certain limitations exist, such as generalizability and contextualization of external factors, the ongoing progress in AI technologies provides hope in overcoming these challenges. By providing protocols and a practical example involving Braf, we aim to inspire early-career experimental dermatologists to adopt these tools and seamlessly integrate these techniques into their skin cancer research, positioning them at the forefront of innovative approaches in combating this devastating disease.