Effects of Intermittent Calorie Restriction in Nondiabetic Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND & AIMS: We compared the effects of a 12-week intermittent calorie restriction (ICR) and standard-of-care (SOC) diet on liver fat content (LFC) in metabolic dysfunction-associated steatotic liver disease patients. METHODS: This randomized controlled trial included patients with magnetic resonance imaging-proton density fat fraction ≥8%. Patients were randomly assigned to the ICR (5:2 diet) or SOC (80% of the recommended calorie intake) groups and stratified according to the body mass index (≥25 or <25 kg/m2). The primary outcome was the proportion of patients who achieved a relative LFC reduction as measured by magnetic resonance imaging-proton density fat fraction ≥30%. RESULTS: Seventy-two participants underwent randomization (36 patients with and 36 without obesity), and 63 (34 patients with and 29 without obesity) completed the trial. At week 12, a higher proportion of patients in the ICR arm achieved a relative LFC reduction of ≥30% compared with the SOC arm (72.2% vs 44.4%; P = .033), which was more prominent in the group with obesity (61.1% vs 27.7%; P = .033) than in the group without obesity (83.3% vs 61.1%; P = .352). The relative weight reduction was insignificant between the ICR and SOC arms (-5.3% vs -4.2%; P = .273); however, it was higher in the ICR arm compared with the SOC arm (-5.5% vs -2.9%; P = .039) in the group with obesity. Changes in fibrosis, muscle and fat mass, and liver enzyme levels were similar between the 2 groups (all P > .05). CONCLUSIONS: The ICR diet reduced LFC more effectively than SOC in patients with metabolic dysfunction-associated steatotic liver disease, particularly in patients with obesity. Additional studies are warranted in larger and more diverse cohorts. CLINICALTRIALS: gov, Number: NCT05309642.

A humanized ACE2 mouse model recapitulating age- and sex-dependent immunopathogenesis of COVID-19.

In the ongoing battle against coronavirus disease 2019 (COVID-19), understanding its pathogenesis and developing effective treatments remain critical challenges. The creation of animal models that closely replicate human infection stands as a critical step forward in this research. Here, we present a genetically engineered mouse model with specifically-humanized knock-in ACE2 (hiACE2) receptors. This model, featuring nine specific amino acid substitutions for enhanced interaction with the viral spike protein, enables efficient severe acute respiratory syndrome coronavirus 2 replication in respiratory organs without detectable infection in the central nervous system. Moreover, it mirrors the age- and sex-specific patterns of morbidity and mortality, as well as the immunopathological features observed in human COVID-19 cases. Our findings further demonstrate that the depletion of eosinophils significantly reduces morbidity and mortality, depending on the infecting viral dose and the sex of the host. This reduction is potentially achieved by decreasing the pathogenic contribution of eosinophil-mediated inflammation, which is strongly correlated with neutrophil activity in human patients. This underscores the model's utility in studying the immunopathological aspects of COVID-19 and represents a significant advancement in COVID-19 modeling. It offers a valuable tool for testing vaccines and therapeutics, enhancing our understanding of the disease mechanisms and potentially guiding more targeted and effective treatments.

Impact of Anti-PEG IgM Induced via the Topical Application of a Cosmetic Product Containing PEG Derivatives on the Antitumor Effects of PEGylated Liposomal Antitumor Drug Formulations in Mice.

Poly(ethylene glycol) (PEG) is used in many common products, such as cosmetics. PEG, however, is also used to covalently conjugate drug molecules, proteins, or nanocarriers, which is termed PEGylation, to serve as a shield against the natural immune system of the human body. Repeated administration of some PEGylated products, however, is known to induce anti-PEG antibodies. In addition, preexisting anti-PEG antibodies are now being detected in healthy individuals who have never received PEGylated therapeutics. Both treatment-induced and preexisting anti-PEG antibodies alter the pharmacokinetic properties, which can result in a subsequent reduction in the therapeutic efficacy of administered PEGylated therapeutics through the so-called accelerated blood clearance (ABC) phenomenon. Moreover, these anti-PEG antibodies are widely reported to be related to severe hypersensitivity reactions following the administration of PEGylated therapeutics, including COVID-19 vaccines. We recently reported that the topical application of a cosmetic product containing PEG derivatives induced anti-PEG immunoglobulin M (IgM) in a mouse model. Our finding indicates that the PEG derivatives in cosmetic products could be a major cause of the preexistence of anti-PEG antibodies in healthy individuals. In this study, therefore, the pharmacokinetics and therapeutic effects of Doxil (doxorubicin hydrochloride-loaded PEGylated liposomes) and oxaliplatin-loaded PEGylated liposomes (Liposomal l-OHP) were studied in mice. The anti-PEG IgM antibodies induced by the topical application of cosmetic products obviously accelerated the blood clearance of both PEGylated liposomal formulations. Moreover, in C26 tumor-bearing mice, the tumor growth suppressive effects of both Doxil and Liposomal l-OHP were significantly attenuated in the presence of anti-PEG IgM antibodies induced by the topical application of cosmetic products. These results confirm that the topical application of a cosmetic product containing PEG derivatives could produce preexisting anti-PEG antibodies that then affect the therapeutic efficacy of subsequent doses of PEGylated therapeutics.

HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes.

Enveloped viruses that rely on a low pH-dependent step for entry initiate infection by fusing with acidic endosomes, whereas the entry sites for pH-independent viruses, such as HIV-1, have not been defined. These viruses have long been assumed to fuse directly with the plasma membrane. Here we used population-based measurements of the viral content delivery into the cytosol and time-resolved imaging of single viruses to demonstrate that complete HIV-1 fusion occurred in endosomes. In contrast, viral fusion with the plasma membrane did not progress beyond the lipid mixing step. HIV-1 underwent receptor-mediated internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. We also show that, strikingly, endosomal fusion is sensitive to a dynamin inhibitor, dynasore. These findings imply that HIV-1 infects cells via endocytosis and envelope glycoprotein- and dynamin-dependent fusion with intracellular compartments.

Association of local steroid injection as a risk factor for electrocoagulation syndrome after esophageal endoscopic submucosal dissection.

BACKGROUND: Postendoscopic submucosal dissection electrocoagulation syndrome (PEECS) is commonly observed after performing endoscopic submucosal dissection (ESD) for esophageal neoplasia. However, data on the incidence and risk factors for PEECS in the esophagus are lacking due to an unclear definition of PEECS and varied clinical settings. Therefore, we aimed to determine the risk factors for PEECS in patients undergoing ESD for esophageal neoplasia. METHODS: We retrospectively reviewed data of relevant clinical and endoscopy-specific parameters from 202 consecutive patients with esophageal neoplasias (139 carcinomas and 63 dysplasias) who underwent ESD under general anesthesia. Esophageal PEECS was defined by satisfying at least two of the following criteria: fever ≥ 37.8 °C, leukocytosis ≥ 10,800/mm3, and localized chest pain ≥ 5/10 points as assessed on a numeric rating scale within 24 h after ESD. Significant factors associated with PEECS were determined by regression analysis. RESULTS: PEECS was recorded in 98 of 202 (48.5%) patients. Patients with PEECS exhibited a larger tumor size (25.0 vs. 17.0 mm, P = 0.002), longer procedure (40.0 vs. 29.5 min, P = 0.021) and hemostasis times (5.0 vs. 3.5 min, P = 0.004), required greater submucosal injection volume (60.0 mL vs. 50.0 mL, P = 0.030), and had a lower rate of local steroid injection (4.1% vs. 12.5%, P = 0.029) than those without PEECS. Multivariate regression analysis revealed tumor size ≥ 17 mm (P = 0.047), procedure time ≥ 33 min (P = 0.027), and hemostasis time ≥ 5 min (P = 0.007) as risk factors for PEECS. In addition, local steroid injection was a significant negatively associated factor (P = 0.001). CONCLUSIONS: Patients with a large tumor, prolonged procedure and hemostasis times are at a high risk of PEECS occurrence. Further, local steroid injection is a negatively associated factor.

Individual characteristics and environmental factors influencing preschoolers' emotional eating.

Emotional eating, which refers to eating in response to emotional states, is prevalent in early childhood. Executive function (EF) and sleep problems are related to preschoolers' self-regulatory abilities during the day and night and have been reported to be associated with their emotional eating. These associations can be stronger in emotionally stressful situations, such as controlling feeding practices. This study explored the role of preschoolers' EF and sleep problems as child characteristics, as well as maternal feeding practices as environmental factors influencing emotional eating during the preschool period. Participants included 363 Korean mothers with preschoolers aged 3- to 5-years old (190 boys, 173 girls). Mothers reported on their own feeding practices, and preschoolers' EF, sleep problems, and emotional eating. Results indicated that preschoolers' EF was negatively associated with emotional over- and undereating, and this association was stronger when mothers applied more pressure to eat. Maternal monitoring had a similar effect, with emotional overeating exerting a greater impact with low levels of maternal monitoring. Finally, maternal pressure to eat moderated the influence of preschoolers' sleep problems on emotional overeating, with higher pressure to eat predicting a stronger relationship between sleep problems and emotional overeating. These findings suggest that maternal feeding practices, which are relatively modifiable, should be considered an important element in intervention programs aimed at preventing emotional eating in preschool children.

Discordant clinical features of identical hypertrophic cardiomyopathy twins.

Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle, which affects ∼1 in 500 individuals and is characterized by increased left ventricular wall thickness. While HCM is caused by pathogenic variants in any one of eight sarcomere protein genes, clinical expression varies considerably, even among patients with the same pathogenic variant. To determine whether background genetic variation or environmental factors drive these differences, we studied disease progression in 11 pairs of monozygotic HCM twins. The twin pairs were followed for 5 to 14 y, and left ventricular wall thickness, left atrial diameter, and left ventricular ejection fraction were collected from echocardiograms at various time points. All nine twin pairs with sarcomere protein gene variants and two with unknown disease etiologies had discordant morphologic features of the heart, demonstrating the influence of nonhereditable factors on clinical expression of HCM. Whole genome sequencing analysis of the six monozygotic twins with discordant HCM phenotypes did not reveal notable somatic genetic variants that might explain their clinical differences. Discordant cardiac morphology of identical twins highlights a significant role for epigenetics and environment in HCM disease progression.

Factors associated with age-related changes in oral diadochokinesis and masticatory function in healthy old adults.

BACKGROUND: This cross-sectional study aimed to identify factors associated with age-related changes in masticatory performance (MP) and oral diadochokinesis (ODK) and to provide normal values in healthy old adults for the diagnosis of oral frailty. METHODS: A total of 385 participants were divided into three age groups (Gr1-3): 20-64 years, 65-74 years, and ≥ 75 years. To investigate tongue-lip motor function, ODK was assessed as the number of repetitions of the monosyllables /pa/ta/ka/. Four questionnaires were used to assess subjective masticatory ability, cognitive ability, and psychological status. MP, bite force, and occlusal area were tested to assess dynamic objective masticatory function, and the number of remaining teeth and functional tooth pairs were determined to assess static objective masticatory function. Handgrip strength (HG), oral dryness, and tongue pressure (TP) were assessed to identify influencing factors. Intergroup differences were evaluated by ANOVA and the Kruskal‒Wallis test, and correlations between ODK and orofacial factors were evaluated. RESULTS: This study revealed significant age-related declines in TP, HG, and ODK, especially after 65 years of age. Factors affecting MP were posterior teeth, the Eichner index, bite force, occluding area, the Korean Mini-Mental State Examination (KMMSE) score, and ODK. Each ODK syllable was associated with different factors, but common factors associated with ODK were MP, HG, and PHQ-9 score. For the syllables /pa/ta/, the Eichner Index, TP, and oral dryness were also associated. For the syllable /ka/ in Gr3, MP, TP, HG, oral dryness, and the KMMSE score were associated. CONCLUSIONS: These results could provide practical guidelines for oral rehabilitation in old adults and contribute to improving the understanding of age-related changes in oral function and the multidimensional nature of masticatory dynamics.

Spotted fever rickettsia-induced microvascular endothelial barrier dysfunction is delayed by the calcium channel blocker benidipine.

The tick-borne bacterium Rickettsia parkeri is an obligate intracellular pathogen that belongs to spotted fever group rickettsia (SFGR). The SFG pathogens are characterized by their ability to infect and rapidly proliferate inside host vascular endothelial cells that eventually result in impairment of vascular endothelium barrier functions. Benidipine, a wide range dihydropyridine calcium channel blocker, is used to prevent and treat cardiovascular diseases. In this study, we tested whether benidipine has protective effects against rickettsia-induced microvascular endothelial cell barrier dysfunction in vitro. We utilized an in vitro vascular model consisting of transformed human brain microvascular endothelial cells (tHBMECs) and continuously monitored transendothelial electric resistance (TEER) across the cell monolayer. We found that during the late stages of infection when we observed TEER decrease and when there was a gradual increase of the cytoplasmic [Ca2+], benidipine prevented these rickettsia-induced effects. In contrast, nifedipine, another cardiovascular dihydropyridine channel blocker specific for L-type Ca2+ channels, did not prevent R. parkeri-induced drop of TEER. Additionally, neither drug was bactericidal. These data suggest that growth of R. parkeri inside endothelial cells is associated with impairment of endothelial cell monolayer integrity due to Ca2+ flooding through specific, benidipine-sensitive T- or N/Q-type Ca2+ channels but not through nifedipine-sensitive L-type Ca2+ channels. Further study will be required to discern the exact nature of the Ca2+ channels and Ca2+ transporting system(s) involved, any contributions of the pathogen toward this process, as well as the suitability of benidipine and new dihydropyridine derivatives as complimentary therapeutic drugs against Rickettsia-induced vascular failure.

Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7.

Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma that is etiologically linked to Kaposi's sarcoma-associated herpesvirus (KSHV). Despite standard multi-chemotherapy treatment, PEL continues to cause high mortality. Thus, new strategies to control PEL are needed urgently. Here, we show that a phosphodegron motif within the KSHV protein, latency-associated nuclear antigen (LANA), specifically interacts with E3 ubiquitin ligase FBW7, thereby competitively inhibiting the binding of the anti-apoptotic protein MCL-1 to FBW7. Consequently, LANA-FBW7 interaction enhances the stability of MCL-1 by preventing its proteasome-mediated degradation, which inhibits caspase-3-mediated apoptosis in PEL cells. Importantly, MCL-1 inhibitors markedly suppress colony formation on soft agar and tumor growth of KSHV+PEL/BCBL-1 in a xenograft mouse model. These results strongly support the conclusion that high levels of MCL-1 expression enable the oncogenesis of PEL cells and thus, MCL-1 could be a potential drug target for KSHV-associated PEL. This work also unravels a mechanism by which an oncogenic virus perturbs a key component of the ubiquitination pathway to induce tumorigenesis.

A natural variation in the RNA polymerase of severe fever with thrombocytopenia syndrome virus enhances viral replication and in vivo virulence.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with high mortality in Eastern Asia. The disease is caused by the SFTS virus (SFTSV), also known as Dabie bandavirus, which has a segmented RNA genome consisting of L, M, and S segments. Previous studies have suggested differential viral virulence depending on the genotypes of SFTSV; however, the critical viral factor involved in the differential viral virulence is unknown. Here, we found a significant difference in viral replication in vitro and virulence in vivo between two Korean isolates belonging to the F and B genotypes, respectively. By generating viral reassortants using the two viral strains, we demonstrated that the L segment, which encodes viral RNA-dependent RNA polymerase (RdRp), is responsible for the enhanced viral replication and virulence. Comparison of amino acid sequences and viral replication rates revealed a point variation, E251K, on the surface of RdRp to be the most significant determinant for the enhanced viral replication rate and in vivo virulence. The effect of the variation was further confirmed using recombinant SFTSV generated by reverse genetic engineering. Therefore, our results indicate that natural variations affecting the viral replicase activity could significantly contribute to the viral virulence of SFTSV.

Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency.

[Figure: see text].

Liver-Dependent Lung Remodeling during Systemic Inflammation Shapes Responses to Secondary Infection.

Systemic duress, such as that elicited by sepsis, burns, or trauma, predisposes patients to secondary pneumonia, demanding better understanding of host pathways influencing this deleterious connection. These pre-existing circumstances are capable of triggering the hepatic acute-phase response (APR), which we previously demonstrated is essential for limiting susceptibility to secondary lung infections. To identify potential mechanisms underlying protection afforded by the lung-liver axis, our studies aimed to evaluate liver-dependent lung reprogramming when a systemic inflammatory challenge precedes pneumonia. Wild-type mice and APR-deficient littermate mice with hepatocyte-specific deletion of STAT3 (hepSTAT3-/-), a transcription factor necessary for full APR initiation, were challenged i.p. with LPS to induce endotoxemia. After 18 h, pneumonia was induced by intratracheal Escherichia coli instillation. Endotoxemia elicited significant transcriptional alterations in the lungs of wild-type and hepSTAT3-/- mice, with nearly 2000 differentially expressed genes between genotypes. The gene signatures revealed exaggerated immune activity in the lungs of hepSTAT3-/- mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. Proteomics revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. These results indicate that after systemic inflammation, liver acute-phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the established vulnerability of hepSTAT3-/- mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs.

Risk factors associated with recurrence of gastric hyperplastic polyps: a single-center, long-term, retrospective cohort study.

BACKGROUND: The likelihood of recurrence of gastric hyperplastic polyps (GHPs) following endoscopic resection and the need for long-term follow-up remain unknown. We, therefore, aimed to investigate the factors associated with the recurrence and cumulative incidence of GHPs over a 10-year period. METHODS: Between May 1995 and December 2020, 1,018 GHPs > 1 cm were endoscopically resected from 869 patients. Medical records of these patients were retrospectively reviewed and their clinical features and outcomes were assessed. Groups of GHPs with recurrence and those without recurrence group were compared, and univariate and multivariable analyses were performed to identify the potential risk factors for GHP recurrence. RESULTS: A total of 104 (12.0%) patients who underwent endoscopic removal of GHPs experienced recurrence. Compared to patients without recurrent GHPs, those with recurrent GHPs showed considerably larger median polyp size (28 mm vs. 14 mm, P < 0.001), a higher proportion of multiple polyps (41.3% vs. 29.3%, P = 0.020), polyps with lobulation (63.5% vs. 40.3%, P = 0.001), and exudate (63.5% vs. 46.8%, P = 0.001). Compared to the local recurrence (n = 52) group, the metachronous recurrence (n = 52) group had larger median polyp size (20 mm vs. 16 mm, P = 0.006) as well as higher rates of polyp lobulation (86.5% vs. 40.4%, P < 0.001) and exudate (82.7% vs. 44.4%, P = 0.001). After primary GHP excision, the cumulative incidence of recurrence was 7.2%, 12.7%, and 19.6% at 2 years, 5 years, and 10 years, respectively. CONCLUSION: The incidence of GHP recurrence following endoscopic excision increased as the follow-up period increased, especially in patients whose GHPs were large-sized, multiple, or characterized by surface exudates/lobulations.

Upper Gastrointestinal Bleeding Due to a Left Gastric Artery Pseudoaneurysm: A Case Series.

BACKGROUND: Left gastric artery (LGA) pseudoaneurysm presenting with upper gastrointestinal (UGI) bleeding is rare but fatal, unless treated. AIMS: We aimed to describe the clinical and endoscopic features of patients with UGI bleeding due to LGA pseudoaneurysms. METHODS: We performed a computerized search of our hospital's de-identified clinical data warehouse to identify patients with UGI bleeding due to an LGA pseudoaneurysm between 2000 and 2020. Patients' electronic medical records and data on esophagogastroduodenoscopy and digital subtraction angiography were reviewed retrospectively. RESULTS: Of 26 patients with an LGA pseudoaneurysm, six patients had UGI bleeding related to an LGA pseudoaneurysm. No patients had previous vascular diseases or pancreatitis. One patient had liver cirrhosis and a history of radiofrequency ablation for hepatocellular carcinoma, one had colon cancer, two had undergone abdominal surgeries, one had received chemoradiotherapy for renal cell carcinoma, and one had no intraabdominal diseases. Symptoms were hematemesis in two, hematochezia in the other two, and melena in the remaining two patients. Esophagogastroduodenoscopy showed a pulsating bulge in the ulcer in two and a large Dieulafoy's lesion-like structure in four patients. All patients achieved hemostasis by angioembolization. CONCLUSION: LGA pseudoaneurysm should be suspected in UGI bleeding if a large Dieulafoy's lesion-like structure or a pulsating bulge in the ulcer is found at the lesser curvature of the gastric body on endoscopy and if the patient has any intra-abdominal inflammatory disease.

Comparison of endoscopic submucosal dissection and surgery for early gastric cancer that is not indicated for endoscopic resection in elderly patients.

BACKGROUND: Endoscopic submucosal dissection (ESD) is sometimes performed for early gastric cancer (EGC) which is not indicated for endoscopic resection (ER) in elderly patients considering old age and comorbidities. We aimed to compare outcomes between ESD and surgery in elderly patients with EGC that is not indicated for ER. METHODS: Elderly patients aged ≥ 75 years who underwent either ESD or surgery for EGC which was not indicated for ER between 2005 and 2015 were retrospectively investigated. RESULTS: Among a total of 294 patients, 59 (20.1%) and 235 (79.9%) patients underwent ESD and surgery as the initial treatment, respectively. The ESD group had smaller size of tumors (25 vs. 30 mm, p = .001) and higher rate of differentiated-type cancer than the surgery group had (88.1% vs. 60.9%, p = 0.001). With a median observation period of 91.8 months (range 11.6-198.1 months), 141 (48.0%) patients died: 25 (42.4%) and 116 (49.4%) patients in the ESD group and the surgery group, respectively. Overall survival and disease-free survival between the two groups had no significant differences (p = 0.982. p = 0.155, respectively). CONCLUSIONS: ESD may be an alternative option for EGC which is not indicated for ER in elderly patients aged ≥ 75 years, considering old age and comorbidity.

Cancer therapeutics based on diverse energy sources.

Light-based phototherapy has been developed for cancer treatment owing to its non-invasiveness and spatiotemporal control. Despite the unique merits of phototherapy, one critical disadvantage of light is its limited penetration depth, which restricts its application in cancer treatment. Although many researchers have developed various strategies to deliver light into deep-seated tumors with two-photon and near-infrared light irradiation, phototherapy encounters the peculiar limitations of light. In addition, high oxygen dependency is another limitation of photodynamic therapy to treat hypoxic tumors. To overcome the drawbacks of conventional treatments, various energy sources have been developed for cancer treatment. Generally, most energy sources, such as ultrasound, chemiluminescence, radiation, microwave, electricity, and magnetic field, are relatively free from the restraint of penetration depth. Combining other strategies or therapies with other energy-source-based therapies improves the strength and compensates for the weakness. This tutorial review focuses on recent advances in the diverse energy sources utilized in cancer treatment and their future perspectives.

Genetics of cancer therapy-associated cardiotoxicity.

As the number of cancer survivors has increased significantly over the last decades due to aging of population and development of effective cancer therapies, side effects from cancer therapies have been increasingly recognized. High-dose anthracyclines, immunotherapies, and concurrent radiation, as well as traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidemia, and obesity increase risks for unintended cardiovascular toxicity. However, these factors do not fully explain why only a subset of patients develop adverse cardiovascular sequelae from cancer therapies. Recent studies demonstrate that genetics play a substantial role in susceptibility to development of cardiovascular toxicities from cancer therapies. Common single nucleotide polymorphisms in multiple genes involved in various cellular pathways including membrane transport, stress response, and sarcomeres are recognized to increase risks for these toxicities. Pathogenic variants in the genes encoding proteins that comprise sarcomeres also contribute to cardiomyopathy following cancer therapies. Furthermore, genetic manipulations of model systems indicate mechanisms by which cardiotoxicities emerge following cancer immunomodulatory therapies. Continued efforts are needed to enable insights into cardiovascular responsiveness to these multi-targeted therapies, improve risk stratification of patients, and enable therapeutic interventions that limit these unintended adverse consequences from life-saving cancer treatments.

Imitation encourages empathic capacity toward other individuals with physical disabilities.

Many people have difficulty empathizing with others who have dissimilar characteristics, such as physical disabilities. We hypothesized that people with no disabilities imitating the movements of individuals with disabilities could improve the empathic capacity toward their difficulties. To evaluate this hypothesis, we used functional magnetic resonance imaging to measure the neural activity patterns of 26 healthy participants while they felt the difficulties of individuals with hemiplegia by adopting their perspective. The participants initially either imitated or observed hemiplegic hand movements shown in video clips. Subsequently, the videos were rewatched and their difficulties were rated. Analysis of the subjective rating scores indicated that after imitating the hemiplegic movements, the participants felt into the difficulties of hemiplegia better than if they simply observed them. The cross-validation approach of multivoxel pattern analyses demonstrated that the information regarding the effect of imitation on empathizing with the difficulties was represented in specific activation patterns of brain regions involved in the mirror neuron system and cognitive empathy by comparing to other conditions that did not contain the information. The cross-classification approach detected distinct activation patterns in the brain regions involved in affective and cognitive empathy, commonly while imitating the hemiplegic movements and subsequently feeling them. This indicated that the common representation related to these two types of empathy existed between imitating and feeling the hemiplegic movements. Furthermore, representational similarity analysis revealed that activity patterns in the anterior cingulate cortex linked to affective empathy tuned to the subjective assessment of hemiplegic movements. Our findings indicate that imitating the movements of individuals with hemiplegia triggered the affective empathic response and improved the cognitive empathic response toward them. The affective empathic response also linked the subjective assessment to the difficulties of hemiplegia, which was especially modulated by the experience of imitation. Imitating the movements of individuals with disabilities likely encourages empathic capacity from both affective and cognitive aspects, resulting in people with no disabilities precisely feeling what they are feeling.

Manipulating Nanoparticle Aggregates Regulates Receptor-Ligand Binding in Macrophages.

The receptor-ligand interactions in cells are dynamically regulated by modulation of the ligand accessibility. In this study, we utilize size-tunable magnetic nanoparticle aggregates ordered at both nanometer and atomic scales. We flexibly anchor magnetic nanoparticle aggregates of tunable sizes over the cell-adhesive RGD ligand (Arg-Gly-Asp)-active material surface while maintaining the density of dispersed ligands accessible to macrophages at constant. Lowering the accessible ligand dispersity by increasing the aggregate size at constant accessible ligand density facilitates the binding of integrin receptors to the accessible ligands, which promotes the adhesion of macrophages. In high ligand dispersity, distant magnetic manipulation to lift the aggregates (which increases ligand accessibility) stimulates the binding of integrin receptors to the accessible ligands available under the aggregates to augment macrophage adhesion-mediated pro-healing polarization both in vitro and in vivo. In low ligand dispersity, distant control to drop the aggregates (which decreases ligand accessibility) repels integrin receptors away from the aggregates, thereby suppressing integrin receptor-ligand binding and macrophage adhesion, which promotes inflammatory polarization. Here, we present "accessible ligand dispersity" as a novel fundamental parameter that regulates receptor-ligand binding, which can be reversibly manipulated by increasing and decreasing the ligand accessibility. Limitless tuning of nanoparticle aggregate dimensions and morphology can offer further insight into the regulation of receptor-ligand binding in host cells.