Motility induced phase separation of deformable cells.

Using a multi-phase field model, we examine how particle deformability, which is a proxy for cell stiffness, affects motility induced phase separation (MIPS). We show that purely repulsive deformable, i.e., squishy, cells phase separate more effectively than their rigid counterparts. This can be understood as due to the fact that deformability increases the effective duration of collisions. In addition, the dense regions become increasingly disordered as deformability increases. Our results contextualize the applicability of MIPS to biological systems and have implications for how cells in biological systems may self-organize.

Can machine learning 'transform' peptides/peptidomimetics into small molecules? A case study with ghrelin receptor ligands.

There has been considerable interest in transforming peptides into small molecules as peptide-based molecules often present poorer bioavailability and lower metabolic stability. Our studies looked into building machine learning (ML) models to investigate if ML is able to identify the 'bioactive' features of peptides and use the features to accurately discriminate between binding and non-binding small molecules. The ghrelin receptor (GR), a receptor that is implicated in various diseases, was used as an example to demonstrate whether ML models derived from a peptide library can be used to predict small molecule binders. ML models based on three different algorithms, namely random forest, support vector machine, and extreme gradient boosting, were built based on a carefully curated dataset of peptide/peptidomimetic and small molecule GR ligands. The results indicated that ML models trained with a dataset exclusively composed of peptides/peptidomimetics provide limited predictive power for small molecules, but that ML models trained with a diverse dataset composed of an array of both peptides/peptidomimetics and small molecules displayed exceptional results in terms of accuracy and false rates. The diversified models can accurately differentiate the binding small molecules from non-binding small molecules using an external validation set with new small molecules that we synthesized previously. Structural features that are the most critical contributors to binding activity were extracted and are remarkably consistent with the crystallography and mutagenesis studies.

Local Yield and Compliance in Active Cell Monolayers.

The rheology of biological tissue plays an important role in many processes, from organ formation to cancer invasion. Here, we use a multiphase field model of motile cells to simulate active microrheology within a tissue monolayer. When unperturbed, the tissue exhibits a transition between a solidlike state and a fluidlike state tuned by cell motility and deformability-the ratio of the energetic costs of steric cell-cell repulsion and cell-edge tension. When perturbed, solid tissues exhibit local yield-stress behavior, with a threshold force for the onset of motion of a probe particle that vanishes upon approaching the solid-to-liquid transition. This onset of motion is qualitatively different in the low and high deformability regimes. At high deformability, the tissue is amorphous when solid, it responds compliantly to deformations, and the probe transition to motion is smooth. At low deformability, the monolayer is more ordered translationally and stiffer, and the onset of motion appears discontinuous. Our results suggest that cellular or nanoparticle transport in different types of tissues can be fundamentally different and point to ways in which it can be controlled.

DNA Methylation Analysis of Imprinted Genes in the Cortex and Hippocampus of Cross-Fostered Mice Selectively Bred for Increased Voluntary Wheel-Running.

We have previously shown that high runner (HR) mice (from a line genetically selected for increased wheel-running behavior) have distinct, genetically based, neurobiological phenotypes as compared with non-selected control (C) mice. However, developmental programming effects during early life, including maternal care and parent-of-origin-dependent expression of imprinted genes, can also contribute to variation in physical activity. Here, we used cross-fostering to address two questions. First, do HR mice have altered DNA methylation profiles of imprinted genes in the brain compared to C mice? Second, does maternal upbringing further modify the DNA methylation status of these imprinted genes? To address these questions, we cross-fostered all offspring at birth to create four experimental groups: C pups to other C dams, HR pups to other HR dams, C pups to HR dams, and HR pups to C dams. Bisulfite sequencing of 16 imprinted genes in the cortex and hippocampus revealed that the HR line had altered DNA methylation patterns of the paternally imprinted genes, Rasgrf1 and Zdbf2, as compared with the C line. Both fostering between the HR and C lines and sex modified the DNA methylation profiles for the paternally expressed genes Mest, Peg3, Igf2, Snrpn, and Impact. Ig-DMR, a gene with multiple paternal and maternal imprinted clusters, was also affected by maternal upbringing and sex. Our results suggest that differential methylation patterns of imprinted genes in the brain could contribute to evolutionary increases in wheel-running behavior and are also dependent on maternal upbringing and sex.

Contemporary Incidence of Medical Inoperability in Clinical Stage I Endometrial Cancer.

BACKGROUND: Minimally invasive surgical (MIS) staging is the standard treatment approach for clinical stage I endometrial cancer. Historical rates of inoperability in endometrial cancer are approximately 10%. Given surgical and medical advancements against increasing population obesity, we aimed to describe a contemporary incidence of medical inoperability in clinical stage I endometrial cancer. PATIENTS AND METHODS: Patients diagnosed with clinical stage I endometrial cancer of any histology from April 2014 to December 2018 were included in this retrospective cohort study. The primary outcome, medical inoperability, was defined as (1) patients deemed inoperable by a gynecologic oncologist at initial consultation, (2) patients deemed inoperable during preoperative clearance, or (3) an aborted hysterectomy. Fisher's exact or χ2, and Student's t-test or Wilcoxon rank sum test were used, as appropriate, for data analysis. Multivariable logistic regression was also employed. RESULTS: Overall, 767 patients were included, of which 4.6% (35/767) were determined to be inoperable. The inoperable group had a higher body mass index (52.7 vs. 33.9, p < 0.001), and increased rates of diabetes (62.8%, 22/35 vs. 27.1%, 199/732, p < 0.001), coronary artery disease (31.4%, 11/35 vs. 7.1%, 52/732, p < 0.001), and hypertension (94.3%, 33/35 vs. 70.2%, 514/732, p < 0.001). Of those with attempted surgical staging, hysterectomy was aborted intraoperatively in 0.68% (5/737). The overall complication rate was 11.6% (86/737). CONCLUSIONS: With maximal surgical effort and MIS, hysterectomy is possible in > 95% of patients with newly diagnosed endometrial cancer treated at a high-volume center. Complication rates were comparable to other trials evaluating the safety of MIS staging for endometrial cancer.

The development of modulators for lysophosphatidic acid receptors: A comprehensive review.

Lysophosphatidic acids (LPAs) are bioactive phospholipids implicated in a wide range of cellular activities that regulate a diverse array of biological functions. They recognize two types of G protein-coupled receptors (LPARs): LPA1-3 receptors and LPA4-6 receptors that belong to the endothelial gene (EDG) family and non-endothelial gene family, respectively. In recent years, the LPA signaling pathway has captured an increasing amount of attention because of its involvement in various diseases, such as idiopathic pulmonary fibrosis, cancers, cardiovascular diseases and neuropathic pain, making it a promising target for drug development. While no drugs targeting LPARs have been approved by the FDA thus far, at least three antagonists have entered phase Ⅱ clinical trials for idiopathic pulmonary fibrosis (BMS-986020 and BMS-986278) and systemic sclerosis (SAR100842), and one radioligand (BMT-136088/18F-BMS-986327) has entered phase Ⅰ clinical trials for positron emission tomography (PET) imaging of idiopathic pulmonary fibrosis. This article provides an extensive review on the current status of ligand development targeting LPA receptors to modulate LPA signaling and their therapeutic potential in various diseases.

Entanglement Kinetics in Polymer Melts Are Chemically Specific.

We investigate the universality of entanglement kinetics in polymer melts. We compare predictions of a recently developed constitutive equation for disentanglement to molecular dynamics simulations of both united-atom polyethylene and Kremer-Grest models for polymers in shear and extensional flow. We confirm that entanglements recover on the retraction time scale, rather than the reptation time scale. We find that the convective constraint release parameter ß is independent of molecular weight, but that it increases with the ratio of Kuhn length bK to packing length p as ß âˆ¼ (bK/p)α, with an exponent α = 1.9, which may suggest that disentanglement rate correlates with an increase in the tube diameter. These results may help shed light on which polymers are more likely to undergo shear banding.

Lysophosphatidic Acid Receptor 1 (LPA1) Antagonists as Potential Migrastatics for Triple Negative Breast Cancer.

Metastasis is responsible for about 90 % of cancer deaths. Anti-metastatic drugs, termed as migrastatics, offer a distinctive therapeutic approach to address cancer migration and invasion. However, therapeutic exploitation of metastasis-specific targets remains limited, and the effective prevention and suppression of metastatic cancer continue to be elusive. Lysophosphatidic acid receptor 1 (LPA1) is activated by an endogenous lipid molecule LPA, leading to a diverse array of cellular activities. Previous studies have shown that the LPA/LPA1 axis supports the progression of metastasis for many types of cancer. In this study, we report the synthesis and biological evaluation of fluorine-containing triazole derivatives as potent LPA1 antagonists, offering potential as migrastatic drugs for triple negative breast cancer (TNBC). In particular, compound 12 f, the most potent and highly selective in this series with an IC50 value of 16.0 nM in the cAMP assay and 18.4 nM in the calcium mobilization assay, inhibited cell survival, migration, and invasion in the TNBC cell line. Interestingly, the compound did not induce apoptosis in TNBC cells and demonstrated no cytotoxic effects. These results highlight the potential of LPA1 as a migrastatic target. Consequently, the LPA1 antagonists developed in this study hold promise as potential migrastatic candidates for TNBC.

An Overview of Adolescent Psychostimulant Use.

Adolescence marks a period of significant neural maturation and development of lifelong habits, including the potential use of recreational psychostimulant drugs. Increased prevalence of drug adulteration and fatalities related to drug overdose pose new challenges for individuals who use drugs recreationally. As the prevalence of recreational psychostimulant use drastically increases during young adulthood, pediatric and adolescent health care providers can play a crucial role in the lifelong well-being of their patients by identifying those with risk factors for consequences associated with substance use at an early age. This article discusses the epidemiology, pharmacology, clinical manifestations, complications, and common methods of use for three types of psychostimulant drugs-amphetamines, methamphetamine, and 3,4-Methylenedioxymethamphetamine. This article aims to provide pediatric and adolescent health care providers with practical knowledge to effectively perform substance use screening, brief intervention, and referral to treatment with the goal of reducing drug-related morbidity and mortality among the adolescent age group. [Pediatr Ann. 2023;52(5):170-e177.].

Limited progress in nutrient pollution in the U.S. caused by spatially persistent nutrient sources.

Human agriculture, wastewater, and use of fossil fuels have saturated ecosystems with nitrogen and phosphorus, threatening biodiversity and human water security at a global scale. Despite efforts to reduce nutrient pollution, carbon and nutrient concentrations have increased or remained high in many regions. Here, we applied a new ecohydrological framework to ~12,000 water samples collected by the U.S. Environmental Protection Agency from streams and lakes across the contiguous U.S. to identify spatial and temporal patterns in nutrient concentrations and leverage (an indicator of flux). For the contiguous U.S. and within ecoregions, we quantified trends for sites sampled repeatedly from 2000 to 2019, the persistence of spatial patterns over that period, and the patch size of nutrient sources and sinks. While we observed various temporal trends across ecoregions, the spatial patterns of nutrient and carbon concentrations in streams were persistent across and within ecoregions, potentially because of historical nutrient legacies, consistent nutrient sources, and inherent differences in nutrient removal capacity for various ecosystems. Watersheds showed strong critical source area dynamics in that 2-8% of the land area accounted for 75% of the estimated flux. Variability in nutrient contribution was greatest in catchments smaller than 250 km2 for most parameters. An ensemble of four machine learning models confirmed previously observed relationships between nutrient concentrations and a combination of land use and land cover, demonstrating how human activity and inherent nutrient removal capacity interactively determine nutrient balance. These findings suggest that targeted nutrient interventions in a small portion of the landscape could substantially improve water quality at continental scales. We recommend a dual approach of first prioritizing the reduction of nutrient inputs in catchments that exert disproportionate influence on downstream water chemistry, and second, enhancing nutrient removal capacity by restoring hydrological connectivity both laterally and vertically in stream networks.

Leader cells in collective chemotaxis: Optimality and trade-offs.

Clusters of cells can work together in order to follow a signal gradient, chemotaxing even when single cells do not. Cells in different regions of collectively migrating neural crest streams show different gene expression profiles, suggesting that cells may specialize to leader and follower roles. We use a minimal mathematical model to understand when this specialization is advantageous. In our model, leader cells sense the gradient with an accuracy that depends on the kinetics of ligand-receptor binding, while follower cells follow the cluster's direction with a finite error. Intuitively, specialization into leaders and followers should be optimal when a few cells have more information than the rest of the cluster, such as in the presence of a sharp transition in chemoattractant concentration. We do find this-but also find that high levels of specialization can be optimal in the opposite limit of very shallow gradients. We also predict that the best location for leaders may not be at the front of the cluster. In following leaders, clusters may have to choose between speed and flexibility. Clusters with only a few leaders can take orders of magnitude more time to reorient than all-leader clusters.

Capnocytophaga bacteremia precipitating severe thrombocytopenia and preterm labor in an asplenic host.

Capnocytophaga species are gram-negative bacilli that inhabit mammalian oral surfaces and can cause opportunistic infection, especially in asplenic patients. The species Capnocytophaga canimorsus is particularly associated with dog bites and is known to cause endocarditis, meningitis, and sepsis in the general population. In pregnant patients, infections tied to Capnocytophaga species from human flora have been associated with preterm labor, chorioamnionitis, and neonatal septicemia. There is little known about the effects of zoonotically-acquired Capnocytophaga infection in pregnant patients. In this case report, we present a patient with Capnocytophaga bacteremia acquired after a dog bite associated with profound thrombocytopenia and preterm labor. Dog bites are common in the United States, and we present basic recommendations for management of dog bites in pregnant patients in order to avoid morbidity associated with delay in time to antibiotic treatment of infection as described in this case.

Intrapartum Group B Streptococcus Antibiotic Prophylaxis in Penicillin Allergic Pregnant Women.

Objectives To estimate the prevalence of and identify modifiable risk factors for alternative antibiotics for group B Streptococcus (GBS) prophylaxis in penicillin-allergic women. Methods Retrospective cohort study of pregnant women within a health care network from January 1, 2014, to December 31, 2017. Included women were GBS colonized, delivered at ≥ 37 weeks' gestation, and reported penicillin/cephalosporin allergy. The primary outcome was the use of alternate antibiotics GBS prophylaxis, defined per Centers for Disease Control and Prevention guidelines as antibiotics other than penicillin, ampicillin, or cefazolin. Results We identified 190 GBS-colonized pregnant women self-reporting a penicillin/cephalosporin allergy; 5% reported anaphylaxis, 44% high-risk symptoms (isolated hives, shortness of breath, swelling, or vomiting), and 51% low-risk symptoms (isolated rash, itching, or nausea). Two-thirds (63%) had alternative antibiotic prophylaxis. In adjusted analyses, nonwhite race (adjusted odds ratio [aOR]: 2.42; 95% confidence interval [CI]: 1.19-4.94) and high-risk allergic reaction (aOR: 2.42; 95% CI: 1.30-4.49) were associated with higher odds of alternative antibiotics prophylaxis compared with low-risk allergic reaction. Low-risk allergic reaction group was less likely to receive alternative antibiotic prophylaxis (aOR: 0.36; 95 CI%: 0.19-0.66). Conclusion Alternative antibiotic use for GBS prophylaxis is frequent with penicillin/cephalosporin allergies. Efforts to confirm allergy and perform penicillin hypersensitivity testing may increase compliance with guidelines for antibiotic administration.