Tumor-targeted and stimulus-responsive polymeric prodrug nanoparticles to enhance the anticancer therapeutic efficacy of doxorubicin.

Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H2O2)-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H2O2, characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H2O2. In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent.

Fusion Length Requiring Spinopelvic Fixation in Lumbosacral Fusion with Anterior Column Support at L5-S1: Assessment of Fusion Status Using Computed Tomography.

Background: The lumbosacral (LS) junction has a higher nonunion rate than other lumbar segments, especially in long-level fusion. Nonunion at L5-S1 would result in low back pain, spinal imbalance, and poor surgical outcomes. Although anterior column support at L5-S1 has been recommended to prevent nonunion in long-level LS fusion, fusion length requiring additional spinopelvic fixation (SPF) in LS fusion with anterior column support at L5-S1 has not been evaluated thoroughly. This study aimed to determine the number of fused levels requiring SPF in LS fusion with anterior column support at L5-S1 by assessing the interbody fusion status using computed tomography (CT) depending on the fusion length. Methods: Patients who underwent instrumented LS fusion with L5-S1 interbody fusion without additional augmentation and CT > 1 year postoperatively were included. The fusion rates were assessed based on the number of fused segments. Patients were divided into two groups depending on the L5-S1 interbody fusion status: those with union vs. those with nonunion. Binary logistic regression analyses were performed to identify risk factors for LS junctional nonunion. Results: Fusion rates of L5-S1 interbody fusion were 94.9%, 90.3%, 80.0%, 50.0%, 52.6%, and 43.5% for fusion of 1, 2, 3, 4, 5, and ≥ 6 levels, respectively. The number of spinal levels fused ≥ 4 (p < 0.001), low preoperative bone mineral density (BMD; adjusted odds ratio [aOR], 0.667; p = 0.035), and postoperative pelvic incidence (PI) - lumbar lordosis (LL) mismatch (aOR, 1.034; p = 0.040) were identified as significant risk factors for nonunion of L5-S1 interbody fusion according to the multivariate logistic regression analysis. Conclusions: Exhibiting ≥ 4 fused spinal levels, low preoperative BMD, and large postoperative PI-LL mismatch were identified as independent risk factors for nonunion of anterior column support at L5-S1 in LS fusion without additional fixation. Therefore, SPF should be considered in LS fusion extending to or above L2 to prevent LS junctional nonunion.

Generality-Driven Catalyst Development: A Universal Catalyst for Enantioselective Nitroalkene Reduction.

Cracking the selectivity-generality paradox is among the most pressing challenges in asymmetric catalysis. This obstacle prevents the immediate and successful translation of new methods to diverse small molecules. This is particularly rate-limiting for therapeutic development, where availability and structural diversity are often critical components of successful campaigns. Here we describe the union of generality-driven enantioselective catalysis and the preparation of diverse peptidomimetics. A single new organocatalyst provides high selectivity and substrate generality that is matched only by a combination of metal and organocatalysts. Within organocatalysis, this discovery breaks a 16-year monolithic paradigm, uncovering a powerful new scaffold for enantioselective reduction with behavior that suggests the recognition of a nitroethylene minimal catalaphile.

Gender diversity at spine surgery academic conferences: a 15-year investigation.

BACKGROUND CONTEXT: Enhancing gender diversity at academic conferences is critical for advancing women's representation and career trajectories in spine surgery. PURPOSE: To discover trends in women's representation at major spine conferences over a 15-year period. STUDY DESIGN/SETTING: Conference records from the 2007-2021 annual meetings of the Congress of Neurological Surgeons, North American Spine Society, and Scoliosis Research Society (SRS). PATIENT SAMPLE: Authors of spine-related presentations. OUTCOME MEASURES: Authorship by gender. METHODS: Retrospective bibliometric analysis with univariate and multivariate modeling to identify trends and predictors of gender diversity. RESULTS: Among 8,948 presentations, 750 (8.4%) had female first authors and 618 (6.9%) had female senior authors. There was no change in rates of female first authorship (p=.41) or senior authorship (p=.88) over time. The strongest predictors of female first authorship were having a female senior author (OR 7.32, p<.001), and delivering presentations at SRS (OR 1.95, p=.001). Factors negatively associated with female first authorship included poster format (OR 0.82, p=.039) and conference location in the United States/Canada (OR 0.76, p=.045). Similar trends were encountered for senior authorship. Productivity per senior author was similar between genders (p=.160); whereas a gender gap in productivity per first author during 2007 to 2011 (p=.020) equalized by 2017 to 2021 (p=.300). Among the 10 most productive authors of each gender, male authors delivered more presentations, but all authors shared similar format, content, and location. CONCLUSIONS: Women's representation in spine-related presentations did not increase at three major conferences over a 15-year period. Our findings regarding the positive effects of female mentorship, and international or virtual venues merit further investigation to address the gender gap. The upstream pipeline of recruiting women into academic spine surgery also needs to be addressed.

Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer.

Homodimeric class 1 cytokine receptors include the erythropoietin (EPOR), thrombopoietin (TPOR), granulocyte colony-stimulating factor 3 (CSF3R), growth hormone (GHR), and prolactin receptors (PRLR). These cell-surface single-pass transmembrane (TM) glycoproteins regulate cell growth, proliferation, and differentiation and induce oncogenesis. An active TM signaling complex consists of a receptor homodimer, one or two ligands bound to the receptor extracellular domains, and two molecules of Janus Kinase 2 (JAK2) constitutively associated with the receptor intracellular domains. Although crystal structures of soluble extracellular domains with ligands have been obtained for all of the receptors except TPOR, little is known about the structure and dynamics of the complete TM complexes that activate the downstream JAK-STAT signaling pathway. Three-dimensional models of five human receptor complexes with cytokines and JAK2 were generated here by using AlphaFold Multimer. Given the large size of the complexes (from 3220 to 4074 residues), the modeling required a stepwise assembly from smaller parts, with selection and validation of the models through comparisons with published experimental data. The modeling of active and inactive complexes supports a general activation mechanism that involves ligand binding to a monomeric receptor followed by receptor dimerization and rotational movement of the receptor TM α-helices, causing proximity, dimerization, and activation of associated JAK2 subunits. The binding mode of two eltrombopag molecules to the TM α-helices of the active TPOR dimer was proposed. The models also help elucidate the molecular basis of oncogenic mutations that may involve a noncanonical activation route. Models equilibrated in explicit lipids of the plasma membrane are publicly available.

Structural modeling of cytokine-receptor-JAK2 signaling complexes using AlphaFold Multimer.

Homodimeric class 1 cytokine receptors include the erythropoietin (EPOR), thrombopoietin (TPOR), granulocyte colony-stimulating factor 3 (CSF3R), growth hormone (GHR), and prolactin receptors (PRLR). They are cell-surface single-pass transmembrane (TM) glycoproteins that regulate cell growth, proliferation, and differentiation and induce oncogenesis. An active TM signaling complex consists of a receptor homodimer, one or two ligands bound to the receptor extracellular domains and two molecules of Janus Kinase 2 (JAK2) constitutively associated with the receptor intracellular domains. Although crystal structures of soluble extracellular domains with ligands have been obtained for all the receptors except TPOR, little is known about the structure and dynamics of the complete TM complexes that activate the downstream JAK-STAT signaling pathway. Three-dimensional models of five human receptor complexes with cytokines and JAK2 were generated using AlphaFold Multimer. Given the large size of the complexes (from 3220 to 4074 residues), the modeling required a stepwise assembly from smaller parts with selection and validation of the models through comparisons with published experimental data. The modeling of active and inactive complexes supports a general activation mechanism that involves ligand binding to a monomeric receptor followed by receptor dimerization and rotational movement of the receptor TM α-helices causing proximity, dimerization, and activation of associated JAK2 subunits. The binding mode of two eltrombopag molecules to TM α-helices of the active TPOR dimer was proposed. The models also help elucidating the molecular basis of oncogenic mutations that may involve non-canonical activation route. Models equilibrated in explicit lipids of the plasma membrane are publicly available.

The Anti-Inflammatory and Skin Barrier Function Recovery Effects of Schisandra chinensis in Mice with Atopic Dermatitis.

Background and Objectives: The fruit of Schisandra chinensis (Turcz.) Baill. is widely used medicinally to treat coughs, asthma, exhaustion, eczema, and pruritus in Northeast Asian countries, including Korea, China, and Japan. This study was designed to investigate the effects of S. chinensis on dermatitis in mice with calcipotriol (MC-903)-induced atopic dermatitis (AD), and its effects on skin barrier dysfunction was also investigated. Materials and Methods: The inhibitory effects of an ethanolic extract of S. chinensis (EESC) on skin lesions, water content, water-holding capacity (WHC), histopathological abnormalities, and inflammatory cytokine and chemokine levels were evaluated in mice with AD induced by MC903. Results: Topical EESC ameliorated skin lesions, reduced skin water content, and increased MC903-induced WHC. EESC also prevented MC-903-induced histopathological abnormalities such as epidermal disruption, hyperkeratosis, spongiotic changes, and immune cell infiltration in inflamed tissue. Moreover, topical EESC reduced MC-903-induced levels of pro-inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-4, IL-6, IL-8, monocyte chemotactic protein (MCP)-1, and thymic stromal lymphopoietin (TSLP). Furthermore, unlike dexamethasone, EESC did not reduce the spleen/body weight ratio. Conclusions: These results suggest that S. chinensis can be used as an alternative to external corticosteroids and that its anti-inflammatory and skin barrier dysfunction-restoring effects are related to the downregulation of pro-inflammatory cytokines and chemokines, such as TNF-α, IL-4, IL-6, IL-8, and TSLP.

Label-free adaptive optics single-molecule localization microscopy for whole zebrafish.

Specimen-induced aberration has been a major factor limiting the imaging depth of single-molecule localization microscopy (SMLM). Here, we report the application of label-free wavefront sensing adaptive optics to SMLM for deep-tissue super-resolution imaging. The proposed system measures complex tissue aberrations from intrinsic reflectance rather than fluorescence emission and physically corrects the wavefront distortion more than three-fold stronger than the previous limit. This enables us to resolve sub-diffraction morphologies of cilia and oligodendrocytes in whole zebrafish as well as dendritic spines in thick mouse brain tissues at the depth of up to 102 µm with localization number enhancement by up to 37 times and localization precision comparable to aberration-free samples. The proposed approach can expand the application range of SMLM to whole zebrafish that cause the loss of localization number owing to severe tissue aberrations.

CHARMM-GUI PDB Manipulator: Various PDB Structural Modifications for Biomolecular Modeling and Simulation.

Molecular modeling and simulation play important roles in biomedical research as they provide molecular-level insight into the underlying mechanisms of biological functions that are difficult to elucidate only with experiments. CHARMM-GUI (https://charmm-gui.org) is a web-based cyberinfrastructure that is widely used to generate various molecular simulation system and input files and thus facilitates and standardizes the usage of common and advanced simulation techniques. In particular, PDB Manipulator provides various chemical modification options as the starting point for most input generation modules in CHARMM-GUI. Here, we discuss recent additions to PDB Manipulator, such as non-standard amino acids/RNA substitutions, ubiquitylation and SUMOylation, Lys/Arg post-translational modifications, lipidation, peptide stapling, and improved parameterization options of small molecules. These additional features are expected to make complex PDB modifications easy for biomolecular modeling and simulation.

Role of Klotho and N-acetylcysteine in Oxidative Stress Associated with the Vitrification of Ovarian Tissue Cytoprotective Function of Klotho in Cryopreservation.

BACKGROUND: Cryopreservation can cause mechanical and chemical stress, ultimately leading to the formation of reactive oxygen species (ROS) and oxidative stress. ROS inhibits the expression of antioxidant enzymes in cells, resulting in increased DNA fragmentation and apoptosis. In this paper, we used a vitrification method that has the advantage of producing less ice crystal formation, cost-effectiveness, and time efficiency during cryopreservation. The objective of this paper is to evaluate the degree of protection of ovarian tissue against oxidative stress when N-acetylcysteine (NAC) and Klotho proteins are treated in the vitrification process of ovarian tissue.  METHODS: The control group and the cryopreservation groups were randomly assigned, and treated NAC, Klotho, or the combination (NAC + Klotho). The cell morphological change, DNA damage, senescence, and apoptosis of each group after the freeze-thaw process were compared using transmission electron microscopy, immunohistochemistry, and western blot analysis. RESULTS: Both NAC and Klotho were found to be more effective at protecting against DNA damage than the control; however, DNA damage was greater in the NAC + Klotho group than in the group treated with NAC and Klotho, respectively. DNA damage and cellular senescence were also reduced during the vitrification process when cells were treated with NAC, Klotho, or the combination (NAC + Klotho). NAC increased apoptosis during cryopreservation, whereas Klotho inhibited apoptosis and NAC-induced apoptosis. CONCLUSION: This study highlights Klotho's benefits in inhibiting DNA damage, cell senescence, and apoptosis, including NAC-induced apoptosis, despite its unclear role in vitrification.

Cs2Ln3CuS8 (Ln = La-Nd, Sm-Tb): Synthesis, Crystal Structure, and Magnetic and Optical Properties.

This work reports the preparation of new quaternary sulfides Cs2Ln3CuS8 (Ln = La-Nd, Sm-Tb), their original crystal and electronic structures, and their magnetic properties. The sulfides were prepared using a reactive flux method from mixtures of Ln2S3 (EuS), Cs2S6, Cu2S, and S. They crystallize in a new type of structure (C2/m space group) and exhibit a layer-like crystal structure, which is a hybrid of those of the ACe2CuS6 series (A = Cs, K) and that of K2CeCu2S4. The values of the optical band gap calculated by the Kubelka-Munk equation are in the range of 1.2-2.62 eV depending on the nature of the Ln ion. The Cs2Gd3CuS8 compound displays relatively great magnetic refrigerating properties at cryogenic temperature with the mass entropy change (-ΔSM) reaching 19.5 J kg-1 K-1 at 3.5 K for ΔH = 5 T.

Exploring objective factors to predict successful outcomes after laparoscopic Nissen fundoplication.

BACKGROUND: Currently, the reported parameters that predict the resolution of symptoms after surgery are largely subjective and unreliable. Considering that fundoplication rebuilds the structural integrity of the lower esophageal sphincter (LES), the authors focused on searching for objective and quantitative predictors for the resolution of symptoms based on the anatomical issues and whether an antireflux barrier can be well established or not. MATERIALS AND METHODS: The authors reviewed the prospectively collected data of 266 patients with gastroesophageal reflux disease (GERD) who had undergone laparoscopic Nissen fundoplication (LNF). All patients were diagnosed with GERD using preoperative esophagogastroduodenoscopy, 24-h ambulatory esophageal pH monitoring, and high-resolution esophageal manometry. The patients received GERD symptom surveys using the validated Korean Antireflux Surgery Group questionnaire twice: preoperatively and 3 months after the surgery. RESULTS: After excluding patients with insufficient follow-up data, 152 patients were included in the analysis. Multivariate logistic regression analyses revealed that a longer length of the LES and lower BMI determined better resolution of typical symptoms after LNF (all P <0.05). Regarding atypical symptoms, higher resting pressure of LES and DeMeester score greater than or equal to 14.7 were associated with better resolution after the surgery (all P <0.05). After LNF, typical symptoms improved in 34 out of 37 patients (91.9%) with a length of LES >greater than .05 cm, BMI less than 23.67 kg/m 2 , and atypical symptoms were resolved in 16 out of 19 patients (84.2%) with resting pressure of LES greater than or equal to 19.65 mm Hg, DeMeester score greater than or equal to 14.7. CONCLUSION: These results show that the preoperative length and resting pressure of LES is important in the objective prediction of symptom improvement after LNF.

Tumor-targeted redox-regulating and antiangiogenic phototherapeutics nanoassemblies for self-boosting phototherapy.

Cancer cells are equipped with abundant antioxidants such as glutathione (GSH) that eliminate reactive oxygen species (ROS) to deteriorate the therapeutic efficacy of photodynamic therapy (PDT). Another challenge in PDT is circumventing PDT-induced hypoxic condition that provokes upregulation of pro-angiogenic factor such as vascular endothelial growth factor (VEGF). It is therefore reasonable to expect that therapeutic outcomes of PDT could be maximized by concurrent delivery of photosensitizers with GSH depleting agents and VEGF suppressors. To achieve cooperative therapeutic actions of PDT with in situ GSH depletion and VEGF suppression, we developed tumor targeted redox-regulating and antiangiogenic phototherapeutic nanoassemblies (tRAPs) composed of self-assembling disulfide-bridged borylbenzyl carbonate (ssBR), photosensitizer (IR780) and tumor targeting gelatin. As a framework of tRAPs, ssBR was rationally designed to form nanoconstructs that serve as photosensitizer carriers with intrinsic GSH depleting- and VEGF suppressing ability. tRAPs effectively depleted intracellular GSH to render cancer cells more vulnerable to ROS and also provoked immunogenic cell death (ICD) of cancer cells upon near infrared (NIR) laser irradiation. In mouse xenograft models, tRAPs preferentially accumulated in tumors and dramatically eradicated tumors with laser irradiation. The design rationale of tRAPs provides a simple and versatile strategy to develop self-boosting phototherapeutic agents with great potential in targeted cancer therapy.

A Comparative Analysis of Bi-Portal Endoscopic Spine Surgery and Unilateral Laminotomy for Bilateral Decompression in Multilevel Lumbar Stenosis Patients.

The clinical and radiological results before and after surgery were compared and analyzed for patients with multilevel lumbar stenosis who underwent bi-portal endoscopic spine surgery (BESS) and microscopic unilateral laminotomy for bilateral decompression (ULBD). We retrospectively identified 47 and 49 patients who underwent BESS and microscopic ULBD, respectively, who were diagnosed with multi-level lumbar stenosis. Clinical outcomes were evaluated using the visual analog scale score for both back and leg pain, and medication (pregabalin) use and Oswestry Disability Index (ODI) scores for overall treatment outcomes were used pre-operatively and at the final follow-up. Radiological outcomes were evaluated as the percentage of dura expansion volume, and percentage preservation of both facets and both lateral recess angles. The follow-up period of patients was about 17.04 months in the BESS group and about 16.90 months in the microscopic ULBD group. The back and leg visual analog scale (VAS) scores and average pregabalin use decreased more significantly in the BESS group than in the microscopic ULBD group (each p-value 0.0443, <0.001, 0.0378). All radiological outcomes were significantly higher in the BESS group than in the ULBD group. The change in ODI in two-level spinal stenosis showed a significantly higher value in the BESS group compared to the microscopic ULBD group (p-value 0.0335). Multilevel decompression with the BESS technique in multiple spinal stenosis is an adequate technique as it shows better clinical and radiological results than microscopic ULBD during a short-term follow-up period.

Peptoniphilus gorbachii alleviates collagen-induced arthritis in mice by improving intestinal homeostasis and immune regulation.

Introduction: The intricate connection between gut microbiota and rheumatoid arthritis (RA) pathogenesis has gained prominence, although the specific microbial species contributing to RA development remain largely unknown. Recent studies have sought to comprehensively explore alterations in the human microbiome, focusing on identifying disease-related microbial species through blood analysis. Consequently, this study aimed to identify RA-associated microbial species using a serum microbial array system and to investigate the efficacy and underlying mechanisms of potential microbial species for RA treatment. Methods: Serum immunoglobulin M levels against 384 intestinal microbial species were assessed using a microbial microarray in patients with RA and healthy individuals. We investigated the therapeutic potential of the identified microbial candidate regarding arthritis development, immune responses, gut barrier function, and gut microbiome using a collagen-induced arthritis (CIA) mouse model. Results: Our findings revealed significant alterations in antibody levels against 36 microbial species in patients with RA compared to healthy individuals. Notably, the antibody levels against Peptoniphilus gorbachii (PG) were decreased in patients with RA and exhibited an inverse correlation with RA disease activity. In vitro experiments demonstrated that PG produced acetate and butyrate, while exhibiting anti-inflammatory properties. In CIA mice, PG administration suppressed arthritis symptoms, reduced the accumulation of inflammatory monocytes in the mesenteric lymph nodes, and downregulated gene expression of pro-inflammatory cytokines in the ileum. Additionally, PG supplementation restored intestinal barrier integrity and partially resolved gut microbial dysbiosis in CIA mice. The fecal microbiota in PG-treated mice corresponded to improved intestinal barrier integrity and reduced inflammatory responses. Conclusion: This study highlights the potential of serum-based detection of anti-microbial antibodies to identify microbial targets at the species level for RA treatment. Moreover, our findings suggest that PG, identified through the microbial microarray analysis, holds therapeutic potential for RA by restoring intestinal barrier integrity and suppressing the immunologic response associated with RA.

Changes in retro-odontoid mass after upper cervical spine surgery.

A non-neoplastic mass posterior to the dens is termed a retro-odontoid mass (R-OM). This retrospective study evaluated radiographic and clinical outcomes and R-OM changes after upper cervical spine surgery. This study included 69 patients who underwent upper cervical spine surgery, including atlantoaxial fusion, occipitocervical fusion, or decompression. All patients underwent preoperative magnetic resonance imaging (MRI). Six-month follow-up MRI examinations were performed in 30 patients who had preoperative R-OMs. Radiographic outcomes of the anterior and posterior atlantodental intervals were measured using X-rays and computed tomography. The R-OM and space available for the cord (SAC) were measured using MRI. Clinical outcomes were evaluated using neck and arm pain visual analog scales, the Japanese Orthopedic Association score, the neck disability index, and the patient-reported subjective improvement rate. The anterior atlantodental interval decreased, while the posterior atlantodental interval and SAC increased postoperatively. Among the clinical outcomes, the neck and arm pain and the neck disability index decreased postoperatively, while the Japanese Orthopedic Association score increased. All clinical and radiographic outcomes improved postoperatively. The R-OM either decreased in size or disappeared after fusion surgery in all cases, except in one patient who underwent decompression surgery. In conclusion, stabilization through fusion surgery is essential for treating R-OM.

Lumbar Spinal Stenosis: Review Update 2022.

Patients with lumbar spinal stenosis (LSS) may experience neuropathic symptoms, such as back pain, radiating pain, and neurogenic claudication. Although the long-term outcomes of both nonsurgical and surgical treatments are similar, surgery may provide shortterm benefits, including improved symptoms and lower risk of falling. Decompression is mainly used for surgical treatment, and depending on the decompression degree and associated instability, combination therapy may be given. Minimally invasive surgery has been demonstrated to produce excellent results in the treatment of LSS. Thus, an approach aimed at understanding the overall pathophysiology and treatment methods of LSS is expected to have a better therapeutic effect.

Recent advances in optical imaging through deep tissue: imaging probes and techniques.

Optical imaging has been essential for scientific observations to date, however its biomedical applications has been restricted due to its poor penetration through tissues. In living tissue, signal attenuation and limited imaging depth caused by the wave distortion occur because of scattering and absorption of light by various molecules including hemoglobin, pigments, and water. To overcome this, methodologies have been proposed in the various fields, which can be mainly categorized into two stategies: developing new imaging probes and optical techniques. For example, imaging probes with long wavelength like NIR-II region are advantageous in tissue penetration. Bioluminescence and chemiluminescence can generate light without excitation, minimizing background signals. Afterglow imaging also has high a signal-to-background ratio because excitation light is off during imaging. Methodologies of adaptive optics (AO) and studies of complex media have been established and have produced various techniques such as direct wavefront sensing to rapidly measure and correct the wave distortion and indirect wavefront sensing involving modal and zonal methods to correct complex aberrations. Matrix-based approaches have been used to correct the high-order optical modes by numerical post-processing without any hardware feedback. These newly developed imaging probes and optical techniques enable successful optical imaging through deep tissue. In this review, we discuss recent advances for multi-scale optical imaging within deep tissue, which can provide reseachers multi-disciplinary understanding and broad perspectives in diverse fields including biophotonics for the purpose of translational medicine and convergence science. Methodologies for multi-scale optical imaging within deep tissues are discussed in diverse fields including biophotonics for the purpose of translational medicine and convergence science. Recent imaging probes have tried deep tissue imaging by NIR-II imaging, bioluminescence, chemiluminescence, and afterglow imaging. Optical techniques including direct/indirect and coherence-gated wavefront sensing also can increase imaging depth.

CHARMM-GUI Enhanced Sampler for various collective variables and enhanced sampling methods.

Enhanced sampling methodologies modifying underlying Hamiltonians can be used for the systems with a rugged potential energy surface that makes it hard to observe convergence using conventional unbiased molecular dynamics (MD) simulations. We present CHARMM-GUI Enhanced Sampler, a web-based tool to prepare various enhanced sampling simulations inputs with user-selected collective variables (CVs). Enhanced Sampler provides inputs for the following nine methods: accelerated MD, Gaussian accelerated MD, conformational flooding, metadynamics, adaptive biasing force, steered MD, temperature replica exchange MD, replica exchange solute tempering 2, and replica exchange umbrella sampling for the method-implemented MD packages including AMBER, CHARMM, GENESIS, GROMACS, NAMD, and OpenMM. Users only need to select a group of atoms via intuitive web-implementation in order to define commonly used nine CVs of interest: center of mass based distance, angle, dihedral, root-mean-square-distance, radius of gyration, distance projected on axis, two types of angles projected on axis, and coordination numbers. The enhanced sampling methods are tested with several biological systems to illustrate their efficiency over conventional MD. Enhanced Sampler with carefully optimized system-dependent parameters will help users to get meaningful results from their enhanced sampling simulations.

Chiral exceptional point in transformation cavity.

Unlike the ideal circular whispering gallery cavities, those without mirror symmetry intrinsically support resonant modes exhibiting chirality which indicates an imbalance between clockwise and counterclockwise wave components. In extreme cases, nearly degenerate pairs of copropagating modes can be found around the chiral exceptional points (EPs) in parameter spaces. The chiral EPs have been studied in various schemes; however, most attention has been focused on the cases with piecewise constant or periodic refractive index profiles. In this Letter, we report the formation of a chiral EP in a gradient-index cavity designed by conformal transformation optics. Here, the mirror symmetry of the cavity is broken solely by its gradient index profile, and the parameter space is constructed with coordinate transformation parameters. We unveil the chirality, nonorthogonality, and complex-square-root topology near the chiral EP, which can be explained by the non-Hermitian model Hamiltonian.