Self-Assembly of Uniaxial Fullerene Supramolecules Aligned within Carbon Nanotube Fibers.

The conductivity and strength of carbon nanotube (CNT) wires currently rival those of existing engineering materials; fullerene-based materials have not progressed similarly, despite their exciting transport properties such as superconductivity. This communication reveals a new mechanically robust wire of mutually aligned fullerene supramolecules self-assembled between CNT bundles, where the fullerene supramolecular internal crystal structure and outer surface are aligned and dispersed with the CNT bundles. The crystallinity, crystal dimensions, and other structural features of the fullerene supramolecular network are impacted by a number of important production processes such as fullerene concentration and postprocess annealing. The crystal spacing of the CNTs and fullerenes is not altered, suggesting that they are not exerting significant internal pressure on each other. In low concentrations, the addition of networked fullerenes makes the CNT wire mechanically stronger. More importantly, novel mutually aligned and networked fullerene supramolecules are now in a bulk self-supporting architecture.

Six-Month Deep Vein Thrombosis Outcomes by Chronicity: Analysis of the Real-World ClotTriever Outcomes Registry.

PURPOSE: To analyze the first 250 patients from the prospective, multicenter, industry-sponsored ClotTriever Outcomes (CLOUT) registry, assessing the safety and effectiveness of mechanical thrombectomy for acute, subacute, and chronic deep vein thrombosis (DVT). MATERIALS AND METHODS: Real-world patients with lower extremity DVT were treated with the ClotTriever System (Inari Medical, Irvine, California). Adjuvant venoplasty, stent placement, or both were performed at the physician's discretion. Thrombus chronicity was determined by visual inspection of removed thrombus, categorizing patients into acute, subacute, and chronic subgroups. Serious adverse events (SAEs) were assessed through 30 days. Clinical and quality-of-life (QoL) outcomes are reported through 6 months. RESULTS: Thrombus chronicity was designated for 244 of the 250 patients (acute, 32.8%; subacute, 34.8%; chronic, 32.4%) encompassing 254 treated limbs. Complete or near-complete (≥75%) thrombus removal was achieved in 90.8%, 81.9%, and 83.8% of the limbs with acute, subacute, and chronic thrombus, respectively. No fibrinolytics were administered, and 243 (99.6%) procedures were single sessions. One (0.4%) patient in the subacute group experienced a device-related SAE, a fatal pulmonary embolism. On comparing baseline and 6-month data, improvements were demonstrated in median Villalta scores (acute, from 10 to 1; subacute, from 9 to 1; chronic, from 10 to 3; for all, P < .0001) and mean EuroQol group 5-dimension (EQ-5D) self-report questionnaire scores (acute, 0.58 to 0.89; subacute, 0.65 to 0.87; chronic, 0.58 to 0.88; for all, P < .0001). There were no significant differences in outcomes across the subgroups. CONCLUSIONS: Mechanical thrombectomy using the ClotTriever System with adjunctive venoplasty and stent placement is safe and similarly effective for acute, subacute, and chronic DVT.

Cryo-FIB for TEM investigation of soft matter and beam sensitive energy materials.

Primarily driven by structural biology, the rapid advances in cryogenic electron microscopy techniques are now being adopted and applied by materials scientists. Samples that inherently have electron transparency can be rapidly frozen (vitrified) in amorphous ice and imaged directly on a cryogenic transmission electron microscopy (cryo-TEM), however this is not the case for many important materials systems, which can consist of layered structures, embedded architectures, or be contained within a device. Cryogenic focused ion beam (cryo-FIB) lift-out procedures have recently been developed to extract intact regions and interfaces of interest, that can then be thinned to electron transparency and transferred to the cryo-TEM for characterization. Several detailed studies have been reported demonstrating the cryo-FIB lift-out procedure, however due to its relative infancy in materials science improvements are still required to ensure the technique becomes more accessible and routinely successful. Here, we review recent results on the preparation of cryo-TEM lamellae using cryo-FIB and show that the technique is broadly applicable to a range of soft matter and beam sensitive energy materials. We then present a tutorial that can guide the materials scientist through the cryo-FIB lift-out process, highlighting recent methodological advances that address the most common failure points of the technique, such as needle attachment, lift-out and transfer, and final thinning.

Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr-/-) mice were crossed with the KrasG12D/+; Trp53R172H/+; Ptf1aCre/+ (KPC) model of metastatic PDA. Ddr1-/-; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1-/-; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1-/- mice were crossed with the KrasG12D/+; Ptf1aCre/+ neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1-/- models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1-/- animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.

Discovery of N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of µ-opioid receptor antagonists.

Gastrointestinal dysfunction as a consequence of the use of opioid analgesics is of significant clinical concern. First generation drugs to treat these opioid-induced side-effects were limited by their negative impact on opioid receptor agonist-induced analgesia. Second generation therapies target a localized, peripherally-restricted, non-CNS penetrant drug distribution of opioid receptor antagonists. Herein we describe the discovery of the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of µ-opioid receptor antagonists. This report highlights the discovery of the key µ-opioid receptor antagonist pharmacophore and the optimization of in vitro metabolic stability through the application of a phenol bioisostere. The compounds 27a and 31a with the most attractive in vitro profile, formed the basis for the application of Theravance Biopharma's multivalent approach to drug discovery to afford the clinical compound axelopran (TD-1211), targeted for the treatment of opioid-induced constipation.

A comparison of pediatric and adult CT organ dose estimation methods.

BACKGROUND: Computed Tomography (CT) contributes up to 50% of the medical exposure to the United States population. Children are considered to be at higher risk of developing radiation-induced tumors due to the young age of exposure and increased tissue radiosensitivity. Organ dose estimation is essential for pediatric and adult patient cancer risk assessment. The objective of this study is to validate the VirtualDose software in comparison to currently available software and methods for pediatric and adult CT organ dose estimation. METHODS: Five age groups of pediatric patients and adult patients were simulated by three organ dose estimators. Head, chest, abdomen-pelvis, and chest-abdomen-pelvis CT scans were simulated, and doses to organs both inside and outside the scan range were compared. For adults, VirtualDose was compared against ImPACT and CT-Expo. For pediatric patients, VirtualDose was compared to CT-Expo and compared to size-based methods from literature. Pediatric to adult effective dose ratios were also calculated with VirtualDose, and were compared with the ranges of effective dose ratios provided in ImPACT. RESULTS: In-field organs see less than 60% difference in dose between dose estimators. For organs outside scan range or distributed organs, a five times' difference can occur. VirtualDose agrees with the size-based methods within 20% difference for the organs investigated. Between VirtualDose and ImPACT, the pediatric to adult ratios for effective dose are compared, and less than 21% difference is observed for chest scan while more than 40% difference is observed for head-neck scan and abdomen-pelvis scan. For pediatric patients, 2 cm scan range change can lead to a five times dose difference in partially scanned organs. CONCLUSIONS: VirtualDose is validated against CT-Expo and ImPACT with relatively small discrepancies in dose for organs inside scan range, while large discrepancies in dose are observed for organs outside scan range. Patient-specific organ dose estimation is possible using the size-based methods, and VirtualDose agrees with size-based method for the organs investigated. Careful range selection for CT protocols is necessary for organ dose optimization for pediatric and adult patients.

Composition and transstadial retention of the salivary glands in Ornithodoros hermsi (Acari: Argasidae).

Following several days of blood feeding by larval and nymphal ixodid (hard) ticks, the salivary glands degenerate and are completely replaced in the next life stage. Yet, what happens during the molt of immature argasid (soft) ticks after their rapid and small bloodmeal has remained a mystery. Multiple studies of nymphal Ornithodoros hermsi Wheeler (Acari: Argasidae) ticks infected with the relapsing fever spirochete Borrelia hermsii suggested the salivary glands in these ticks may not disintegrate after feeding. Therefore, cohorts of second-stage O. hermsi nymphs were fed and examined daily after the bloodmeal by fresh dissections and weekly by histological cross-sections of the entire tick. The composition of the salivary glands was typical for argasid ticks in having agranular (Type I) and granular (Type II) acini, the latter being surrounded by a myo-epithelial sheath. In all 197 ticks examined from 1 to 63 days after feeding, morphologically intact salivary glands were present. During apolysis, 5 ticks had extralimital clusters of granular acini adhering to otherwise intact glands. Our observations demonstrate that the salivary glands of nymphal O. hermsi do not disintegrate after feeding and new acini are produced during the molt for incorporation into the existing glands. Cumulatively, these findings suggest a fundamental difference in the transstadial development of argasid and ixodid ticks.

ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency.

Triose phosphate isomerase (TPI) is responsible for the interconversion of dihydroxyacetone phosphate to glyceraldehyde-3-phosphate in glycolysis. Point mutations in this gene are associated with a glycolytic enzymopathy called TPI deficiency. This study utilizes a Drosophila melanogaster model of TPI deficiency; TPI(sugarkill) is a mutant allele with a missense mutation (M80T) that causes phenotypes similar to human TPI deficiency. In this study, the redox status of TPI(sugarkill) flies was examined and manipulated to provide insight into the pathogenesis of this disease. Our data show that TPI(sugarkill) animals exhibit higher levels of the oxidized forms of NAD(+), NADP(+) and glutathione in an age-dependent manner. Additionally, we demonstrate that mitochondrial redox state is significantly more oxidized in TPI(sugarkill) animals. We hypothesized that TPI(sugarkill) animals may be more sensitive to oxidative stress and that this may underlie the progressive nature of disease pathogenesis. The effect of oxidizing and reducing stressors on behavioral phenotypes of the TPI(sugarkill) animals was tested. As predicted, oxidative stress worsened these phenotypes. Importantly, we discovered that reducing stress improved the behavioral and longevity phenotypes of the mutant organism without having an effect on TPI(sugarkill) protein levels. Overall, these data suggest that reduced activity of TPI leads to an oxidized redox state in these mutants and that the alleviation of this stress using reducing compounds can improve the mutant phenotypes.

Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.

The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.

A multivalent approach towards linked dual-pharmacology prostaglandin F receptor agonist/carbonic anhydrase-II inhibitors for the treatment of glaucoma.

Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.

A reliable emergency logistics network for COVID-19 considering the uncertain time-varying demands.

The evolving COVID-19 epidemic pose significant threats and challenges to emergency response operations. This paper focuses on designing an emergency logistic network, including the deployment of emergency facilities and the allocation of supplies to satisfy the time-varying demands. A Demand prediction-Network optimization-Decision adjustment framework is proposed for the emergency logistic network design. We first present an improved short-term epidemic model to predict the evolutionary trajectory of the epidemic. Then, considering the uncertainty of the estimated demands, we construct a capacitated multi-period, multi-echelon facility deployment and resource allocation robust optimization model to improve the reliability of the decisions. To address the conservativeness of robust solutions during the evolution of the epidemic, an uncertainty budget adjustment strategy is proposed and integrated into the rolling horizon optimization approach. The results of the case study show that (i) the short-term prediction method has higher accuracy and the accuracy increases with the amount of observed data; (ii) considering the demand uncertainty, the proposed robust optimization model combined with uncertainty budget adjustment strategy can improve the performance of the emergency logistic network; (iii) the proposed solution method is more efficient than its benchmark, especially for large-scale cases. Moreover, some managerial insights related to the emergency logistics network design problem are presented.

Dynamic Electrode-Electrolyte Intermixing in Solid-State Sodium Nano-Batteries.

Nanostructured solid-state batteries (SSBs) are poised to meet the demands of next-generation energy storage technologies by realizing performance competitive to their liquid-based counterparts while simultaneously offering improved safety and expanded form factors. Atomic layer deposition (ALD) is among the tools essential to fabricate nanostructured devices with challenging aspect ratios. Here, we report the fabrication and electrochemical testing of the first nanoscale sodium all-solid-state battery (SSB) using ALD to deposit both the V2O5 cathode and NaPON solid electrolyte followed by evaporation of a thin-film Na metal anode. NaPON exhibits remarkable stability against evaporated Na metal, showing no electrolyte breakdown or significant interphase formation in the voltage range of 0.05-6.0 V vs Na/Na+. Electrochemical analysis of the SSB suggests intermixing of the NaPON/V2O5 layers during fabrication, which we investigate in three ways: in situ spectroscopic ellipsometry, time-resolved X-ray photoelectron spectroscopy (XPS) depth profiling, and cross-sectional cryo-scanning transmission electron microscopy (cryo-STEM) coupled with electron energy loss spectroscopy (EELS). We characterize the interfacial reaction during the ALD NaPON deposition on V2O5 to be twofold: (1) reduction of V2O5 to VO2 and (2) Na+ insertion into VO2 to form NaxVO2. Despite the intermixing of NaPON-V2O5, we demonstrate that NaPON-coated V2O5 electrodes display enhanced electrochemical cycling stability in liquid-electrolyte coin cells through the formation of a stable electrolyte interphase. In all-SSBs, the Na metal evaporation process is found to intensify the intermixing reaction, resulting in the irreversible formation of mixed interphases between discrete battery layers. Despite this graded composition, the SSB can operate for over 100 charge-discharge cycles at room temperature and represents the first demonstration of a functional thin-film solid-state sodium-ion battery.

Organ doses for reference pediatric and adolescent patients undergoing computed tomography estimated by Monte Carlo simulation.

PURPOSE: To establish an organ dose database for pediatric and adolescent reference individuals undergoing computed tomography (CT) examinations by using Monte Carlo simulation. The data will permit rapid estimates of organ and effective doses for patients of different age, gender, examination type, and CT scanner model. METHODS: The Monte Carlo simulation model of a Siemens Sensation 16 CT scanner previously published was employed as a base CT scanner model. A set of absorbed doses for 33 organs∕tissues normalized to the product of 100 mAs and CTDI(vol) (mGy∕100 mAs mGy) was established by coupling the CT scanner model with age-dependent reference pediatric hybrid phantoms. A series of single axial scans from the top of head to the feet of the phantoms was performed at a slice thickness of 10 mm, and at tube potentials of 80, 100, and 120 kVp. Using the established CTDI(vol)- and 100 mAs-normalized dose matrix, organ doses for different pediatric phantoms undergoing head, chest, abdomen-pelvis, and chest-abdomen-pelvis (CAP) scans with the Siemens Sensation 16 scanner were estimated and analyzed. The results were then compared with the values obtained from three independent published methods: CT-Expo software, organ dose for abdominal CT scan derived empirically from patient abdominal circumference, and effective dose per dose-length product (DLP). RESULTS: Organ and effective doses were calculated and normalized to 100 mAs and CTDI(vol) for different CT examinations. At the same technical setting, dose to the organs, which were entirely included in the CT beam coverage, were higher by from 40 to 80% for newborn phantoms compared to those of 15-year phantoms. An increase of tube potential from 80 to 120 kVp resulted in 2.5-2.9-fold greater brain dose for head scans. The results from this study were compared with three different published studies and∕or techniques. First, organ doses were compared to those given by CT-Expo which revealed dose differences up to several-fold when organs were partially included in the scan coverage. Second, selected organ doses from our calculations agreed to within 20% of values derived from empirical formulae based upon measured patient abdominal circumference. Third, the existing DLP-to-effective dose conversion coefficients tended to be smaller than values given in the present study for all examinations except head scans. CONCLUSIONS: A comprehensive organ∕effective dose database was established to readily calculate doses for given patients undergoing different CT examinations. The comparisons of our results with the existing studies highlight that use of hybrid phantoms with realistic anatomy is important to improve the accuracy of CT organ dosimetry. The comprehensive pediatric dose data developed here are the first organ-specific pediatric CT scan database based on the realistic pediatric hybrid phantoms which are compliant with the reference data from the International Commission on Radiological Protection (ICRP). The organ dose database is being coupled with an adult organ dose database recently published as part of the development of a user-friendly computer program enabling rapid estimates of organ and effective dose doses for patients of any age, gender, examination types, and CT scanner model.

Discovery, oral pharmacokinetics and in vivo efficacy of velusetrag, a highly selective 5-HT(4) receptor agonist that has achieved proof-of-concept in patients with chronic idiopathic constipation.

Utilization of Theravance's multivalent approach to drug discovery towards 5-HT(4) receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation.

Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: clinical compound TD-2749.

Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.

Whither the virtuous cycle? Past and future trends in black-white inequality in educational attainment.

The inequality in the relative years of education between blacks and whites has diminished dramatically over the 20th century. One possible explanation for this convergence is a virtuous cycle of parents passing on educational advantage, from one generation to the next, leading to an overall educational upgrading. In this paper we test the virtuous cycle hypothesis by estimating the three way interaction of cohort, race, and family background. We find that the convergence in educational attainment between blacks and whites over the past century was driven by processes unrelated to family background.

Persistent fibrosis and decreased cardiac function following cardiac injury in the Ctenopharyngodon idella (grass carp).

Following the discovery of heart regeneration in zebrafish, several more species within the Cyprinidae family have been found to have the same capability, suggesting heart regeneration may be conserved within this family. Although gonad regeneration has been observed in grass carp (Ctenopharyngodon idella), one of the largest cyprinid fish, the species' response to cardiac injury has not been characterized. Surprisingly, we found cardiomyocytes do not repopulate the injured region following cryoinjury to the ventricle, instead exhibiting unresolved fibrosis and decreased cardiac function that persists for the 8-week duration of this study. Additionally, fibroblasts are likely depleted following injury, a phenomenon not previously described in any cardiac model. The data collected in this study indicate that heart regeneration is unlikely in grass carp (C. idella). It is possible that not all members of the Cyprinidae family possesses regenerative capability observed in zebrafish. Further study of these phenomenon may reveal the underlying differences between regeneration versus unresolved fibrosis in heart disease.