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CONTEXT: We demonstrate that the minimum of the reaction force curve of a diatomic or polyatomic molecule undergoing bond dissociation is significant in several respects. As has been pointed out in the past, it is the point at which the force opposing dissociation is strongest. It marks the boundary between the primarily structural stage of a bond dissociation (stretching) and the transition region between the stretched bond and independent atoms. We now show that the reaction force minimum is also where the kinetic and potential energy curves tend to change direction abruptly. At this point, the total energy E(R) has increased by about 27% of the dissociation energy, for both diatomic and polyatomic molecules. METHODS: Dissociation curves are analyzed at the UHF/daug-cc-pV5Z level of theory using Gaussian 16.
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BACKGROUND: Statins are widely used in coronary and peripheral arterial disease, but their impact on patency of stents placed for peripheral arterial disease is not well-studied. The purpose of this study was to evaluate femoropopliteal stent primary patency according to statin intensity at the time of stent placement and compare this effect to other covariates that may influence stent patency. MATERIALS AND METHODS: A retrospective review identified 278 discrete femoropopliteal stent constructs placed in 216 patients over a 10-year period; Rutherford categories were 2 (3.6%), 3 (12.9%), 4 (21.2%), 5 (49.6%), and 6 (12.6%). Stent locations were common femoral (1.8%), common femoral/superficial femoral (0.7%), superficial femoral (50.7%), superficial femoral/popliteal (32.7%) and popliteal (14.0%) arteries; 63.3% of stents were paclitaxel-eluting. Primary patency of each stent construct was determined with duplex ultrasound, angiography, or computed tomographic angiography. Greater than 50% restenosis or stent occlusion was considered loss of patency. Cox proportional hazard and Kaplan-Meier modeling were used to assess the effect of statin use and additional covariates on stent patency. RESULTS: Patients on any statin at the time of stent placement were half as likely to undergo loss of primary unassisted patency as patients on no statin therapy (hazard ratio, 0.53; 95% confidence interval, 0.19-0.87; P = .004). Moderate/high intensity statin therapy conferred 17 additional months of median stent patency compared to the no statin group. Antiplatelet therapy, anticoagulant therapy, drug-eluting stents (versus bare metal or covered stents), and Rutherford class were not predictive of stent patency (P = 0.52, 0.85, 0.58, and 0.82, respectively). CONCLUSION: Use of statin therapy at the time of femoropopliteal stent placement was the most predictive examined variable influencing primary unassisted patency.
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A new clear-cut strategy for fusing N-heterocyclic and carbon-pure systems is introduced en route to a versatile platform of multi-purpose tetrapyrrolic chromophores. In particular, three novel C-C bond-fused porphyrin-hexabenzocoronene (HBC) conjugates were synthesized under oxidative cyclodehydrogenation conditions, starting from tailor-made nickel porphyrin precursors. The fusion of the individual aromatic systems via 5-membered rings led to highly soluble π-extended porphyrins in excellent yields. The resulting porphyrin-HBC conjugates exhibit absorption cross-sections that are of interdisciplinary interest in the ever-growing field of organic photovoltaics and near-infrared (NIR) dyes. Quantum chemical calculations show that the newly formed 5-membered rings induce biradicaloid character in the porphyrin core, which has a strong impact on excited state lifetimes. This is confirmed by a thorough optoelectronic and time-resolved characterization in order to understand these unique features better. Broadened absorption characteristics go hand-in-hand with short-lived excited states with up to six orders of magnitude faster decay rates.
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This article describes the Cell Maps for Artificial Intelligence (CM4AI) project and its goals, methods, standards, current datasets, software tools , status, and future directions. CM4AI is the Functional Genomics Data Generation Project in the U.S. National Institute of Health's (NIH) Bridge2AI program. Its overarching mission is to produce ethical, AI-ready datasets of cell architecture, inferred from multimodal data collected for human cell lines, to enable transformative biomedical AI research.
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The craft of tuning optical properties is well-established for crystalline inorganic and hybrid solids. However, a far greater challenge is to tune the optical properties of organic materials systematically by design. We now introduce a synthesis concept that enables us to alter the optical properties of crystalline covalent organic frameworks (COFs) systematically using isomeric structures of thienothiophene-based building blocks (T23/32T) combined with a variety of tetratopic aromatic amines, e.g., the Wurster moiety (W-NH2). This concept is demonstrated for the synthesis of COFs in bulk and film forms and provides highly crystalline and porous isomeric COFs featuring predesigned photophysical properties. The band gap of the framework can be tuned continuously and precisely by chemically doping the pristine W23TT COF with its related constitutional isomer building block. Density-functional theory investigations of COF model compounds indicate that the extent of π-conjugation is among the key characteristics enabling the band-gap engineering.
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The maximum rate at which animals take up oxygen from their environment (MO2,max) is a crucial aspect of their physiology and ecology. In fishes, MO2,max is commonly quantified by measuring oxygen uptake either during incremental swimming tests or during recovery from an exhaustive chase. In this Commentary, we compile recent studies that apply both techniques to the same fish and show that the two methods typically yield different mean estimates of MO2,max for a group of individuals. Furthermore, within a group of fish, estimates of MO2,max determined during swimming are poorly correlated with estimates determined during recovery from chasing (i.e. an individual's MO2,max is not repeatable across methods). One explanation for the lack of agreement is that these methods measure different physiological states, each with their own behavioural, anatomical and biochemical determinants. We propose that these methods are not directly interchangeable but, rather, each is suited to address different questions in fish biology. We suggest that researchers select the method that reflects the biological contexts of their study, and we advocate for the use of accurate terminology that acknowledges the technique used to elevate MO2 (e.g. peak MO2,swim or peak MO2,recovery). If the study's objective is to estimate the 'true' MO2,max of an individual or species, we recommend that pilot studies compare methods, preferably using repeated-measures designs. We hope that these recommendations contribute new insights into the causes and consequences of variation in MO2,max within and among fish species.
Subject(s)
Fishes , Oxygen Consumption , Swimming , Animals , Swimming/physiology , Fishes/physiology , Fishes/metabolism , Oxygen Consumption/physiology , Oxygen/metabolismABSTRACT
Two isomeric pentacene dimers, each linked by a diamantane spacer, have been synthesized. These dimers are designed to provide experimental evidence to support quantum mechanical calculations, which predict the substitution pattern on the carbon-rich diethynyldiamantane spacer to be decisive in controlling the interpentacene coupling. Intramolecular singlet fission (i-SF) serves as a probe for the existence and strength of the electronic coupling between the two pentacenes, with transient absorption spectroscopy as the method of choice to characterize i-SF. 4,9-Substitution of diamantane provides a pentacene dimer (4,9-dimer) in which the two chromophores are completely decoupled and that, following photoexcitation, deactivates to the ground state analogous to a monomeric pentacene chromophore. Conversely, 1,6-substitution provides a pentacene dimer (1,6-dimer) that exhibits sufficiently strong coupling to drive i-SF, resulting in correlated triplet M(T1T1) yields close to unity and free triplet (T1 + T1) yields of ca. 50%. Thus, the diamantane spacer effectively switches "on" or "off" the coupling between the chromophores, based on the substitution pattern. The binary control of diamantane contrasts other known molecular spacers designed only to modulate the coupling strength between two pentacenes.
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The physiological processes underlying the post-prandial rise in metabolic rate, most commonly known as the 'specific dynamic action' (SDA), remain debated and controversial. This Commentary examines the SDA response from two opposing hypotheses: (i) the classic interpretation, where the SDA represents the energy cost of digestion, versus (ii) the alternative view that much of the SDA represents the energy cost of growth. The traditional viewpoint implies that individuals with a reduced SDA should grow faster given the same caloric intake, but experimental evidence for this effect remains scarce and inconclusive. Alternatively, we suggest that the SDA reflects an organism's efficacy in allocating the ingested food to growth, emphasising the role of post-absorptive processes, particularly protein synthesis. Although both viewpoints recognise the trade-offs in energy allocation and the dynamic nature of energy distribution among physiological processes, we argue that equating the SDA with 'the energy cost of digestion' oversimplifies the complexities of energy use in relation to the SDA and growth. In many instances, a reduced SDA may reflect diminished nutrient absorption (e.g. due to lower digestive efficiency) rather than increased 'free' energy available for somatic growth. Considering these perspectives, we summarise evidence both for and against the opposing hypotheses with a focus on ectothermic vertebrates. We conclude by presenting a number of future directions for experiments that may clarify what the SDA is, and what it is not.
Subject(s)
Energy Intake , Postprandial Period , Humans , Animals , Postprandial Period/physiology , Oxygen Consumption , Digestion/physiology , Energy Metabolism/physiologyABSTRACT
Free-energy profiles for the activation/deactivation of the ß2-adrenergic receptor (ADRB2) with neutral antagonist and inverse agonist ligands have been determined with well-tempered multiple-walker (MW) metadynamics simulations. The inverse agonists carazolol and ICI118551 clearly favor single inactive conformational minima in both the binary and ternary ligand-receptor-G-protein complexes, in accord with the inverse-agonist activity of the ligands. The behavior of neutral antagonists is more complex, as they seem also to affect the recruitment of the G-protein. The results are analyzed in terms of the conformational states of the well-known microswitches that have been proposed as indicators of receptor activity.
Subject(s)
Drug Inverse Agonism , Receptors, Adrenergic, beta-2 , Receptors, Adrenergic, beta-2/metabolism , GTP-Binding Proteins/metabolism , LigandsABSTRACT
PURPOSE: To determine safety and effectiveness of percutaneous interventions performed by interventional radiologists at a single institution over 2 decades in patients with dialysis access steal syndrome (DASS). MATERIALS AND METHODS: A retrospective review of fistulograms from 2001 to 2021 (N = 11,658) was performed. In total, 286 fistulograms in 212 patients with surgically created dialysis accesses met inclusion criterion of fistulography for suspected DASS. Chart review collected data regarding patient demographics, comorbidities, access characteristics, fistulography findings, intervention(s) performed, and outcomes. Procedures with and without DASS intervention were compared. Odds ratios (ORs), adjusted for age, sex, comorbidities, access characteristics, and multiple within-patient events, were calculated using logistic regression to determine associations between steal intervention status and outcome variables: (a) major adverse events, (b) access preservation, and (c) follow-up surgery. A percutaneously treatable cause of DASS was present in 128 cases (45%). Treatment of DASS lesions was performed in 118 cases. Fifteen embolizations were also performed in patients without DASS lesions. RESULTS: Technical success of DASS interventions, defined by the Society of Interventional Radiology (SIR) reporting standards, was 94%; 54% of interventions resulted in DASS symptom improvement at a median follow-up of 15 days. Patients with steal intervention had 60% lower odds of follow-up surgery (OR, 0.4; P = .007). There was no difference in major adverse events (P = .98) or access preservation (P = .13) between groups. CONCLUSIONS: In this retrospective cohort study, approximately half of DASS fistulograms revealed a percutaneously treatable cause of steal. Over half of DASS interventions resulted in symptomatic relief. Percutaneous intervention was associated with lower odds of follow-up surgery without compromising access preservation.
Subject(s)
Arteriovenous Shunt, Surgical , Vascular Diseases , Humans , Renal Dialysis/adverse effects , Arteriovenous Shunt, Surgical/adverse effects , Arteriovenous Shunt, Surgical/methods , Retrospective Studies , Ischemia/diagnostic imaging , Ischemia/etiology , Ischemia/therapy , Treatment Outcome , Vascular Diseases/etiology , SyndromeABSTRACT
PURPOSE: To assess the outcome and safety of radiofrequency (RF) wire recanalization in patients with end-stage renal disease (ESRD) and chronic central venous occlusions (CVO). MATERIALS AND METHODS: A retrospective review of ESRD patients who underwent RF-wire recanalization of symptomatic chronic thoracic CVO from January 2017 to August 2022 yielded 20 patients who underwent 21 procedures. All patients had undergone at least one prior unsuccessful attempt at central venous recanalization using conventional catheter-based techniques. Technical success was defined by the ability to cross the CVO using RF-wire recanalization enabling endovascular treatment. Access circuit patency was evaluated based on follow-up imaging and symptomatic improvement. RESULTS: Radiofrequency wire recanalization was successful in 17/21 procedures (81%) with all patients (100%) reporting resolution of arm ± facial swelling. Three major complications occurred (14%): two hemothoraces and one hemopericardium. Medial stent diameter was 13 mm (range, 9-14 mm). Mean duration of hospital stay was 2 days ± 3 days. Mean procedure time was 158 ± 46 min with a mean fluoroscopy time of 31.7 ± 16.3 min. Primary unassisted patency at 6 and 12 months was 94 ± 6% and 85 ± 10%, respectively. Additional interventions resulted in significantly increased stent graft patency (P = 0.006). CONCLUSION: Radiofrequency wire-enabled recanalization of CVO in symptomatic dialysis patients has a high rate of technical success with resolution of arm and facial swelling and resumed use of the ipsilateral dialysis access. Although a superior safety profile was seen than with needle-based techniques such as sharp recanalization, major complications were not infrequent indicating that this RF-wire procedure should be performed in centers equipped to manage central venous perforations.
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PURPOSE: To examine the effect of end-stage renal disease (ESRD) on the likelihood of major adverse limb events (MALEs) in patients with Rutherford Category 4-6 critical limb ischemia (CLI) who underwent percutaneous vascular intervention (PVI). MATERIALS AND METHODS: Two contemporaneous cohorts of patients who underwent PVI for symptomatic CLI from 2012 to 2022, differing in ESRD status, were matched using propensity score methods. This database identified 628 patients who underwent 1,297 lower extremity revascularization procedures; propensity score matching yielded 147 patients (180 limbs, 90 limbs in each group). Kaplan-Meier and Cox proportional hazard analyses were used to assess the effect of ESRD status on MALEs, stratified into major amputation (further stratified into above-knee amputation and below-knee amputation [BKA]) and reintervention (PVI or bypass). RESULTS: After PVI, 31.3% of patients in the matched cohorts experienced a MALE (45.7% ESRD vs 18.2% non-ESRD), and 15.6% experienced a major amputation (27.1% ESRD vs 5.2% non-ESRD). Cox proportional hazards analysis revealed that ESRD was an independent predictor of MALE (hazard ratio [HR], 3.15; 95% CI, 1.58-6.29; P = .001), major amputation (HR, 7.00; 95% CI, 2.06-23.79; P = .002), and BKA (HR, 7.56; 95% CI, 1.71-33.50; P = .008). CONCLUSIONS: ESRD is strongly predictive of MALE and major amputation risk, specifically BKA, in patients undergoing PVI for Rutherford Category 4-6 CLI. These patients warrant closer follow-up, and new methods may become necessary to predict and further reduce their amputation risk.
Subject(s)
Kidney Failure, Chronic , Peripheral Arterial Disease , Male , Humans , Risk Factors , Risk Assessment , Treatment Outcome , Limb Salvage , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/therapy , Lower Extremity/blood supply , Ischemia/diagnostic imaging , Ischemia/surgery , Peripheral Arterial Disease/diagnostic imaging , Peripheral Arterial Disease/surgery , Retrospective StudiesABSTRACT
Triplet dynamics in singlet fission depend strongly on the strength of the electronic coupling. Covalent systems in solution offer precise control over such couplings. Nonetheless, efficient free triplet generation remains elusive in most systems, as the intermediate triplet pair 1 (T1 T1 ) is prone to triplet-triplet annihilation due to its spatial confinement. In the solid state, entropically driven triplet diffusion assists in the spatial separation of triplets, resulting in higher yields of free triplets. Control over electronic coupling in the solid state is, however, challenging given its sensitivity to molecular packing. We have thus developed a hexameric system (HexPnc) to enable solid-state-like triplet diffusion at the molecular scale. This system is realized by covalently tethering three pentacene dimers to a central subphthalocyanine scaffold. Transient absorption spectroscopy, complemented by theoretical structural optimizations and steady-state spectroscopy, reveals that triplet diffusion is indeed facilitated due to intramolecular cluster formation. The yield of free triplets in HexPnc is increased by a factor of up to 14 compared to the corresponding dimeric reference (DiPnc). Thus, HexPnc establishes crucial design aspects for achieving efficient triplet dissociation in strongly coupled systems by providing avenues for diffusive separation of 1 (T1 T1 ), while, concomitantly, retaining strong interchromophore coupling which preserves rapid formation of 1 (T1 T1 ).
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A metadynamics protocol is presented to characterize the binding and unbinding of peptide ligands to class A G-protein-coupled receptors (GPCRs). The protocol expands on the one previously presented for binding and unbinding small-molecule ligands to class A GPCRs and accounts for the more demanding nature of the peptide binding-unbinding process. It applies to almost all class A GPCRs. Exemplary simulations are described for subtypes Y1R, Y2R, and Y4R of the neuropeptide Y receptor family, vasopressin binding to the vasopressin V2 receptor (V2R), and oxytocin binding to the oxytocin receptor (OTR). Binding free energies and the positions of alternative binding sites are presented and, where possible, compared with the experiment.
Subject(s)
Receptors, G-Protein-Coupled , Vasopressins , Receptors, G-Protein-Coupled/chemistry , Vasopressins/metabolism , Receptors, Oxytocin/chemistry , Receptors, Oxytocin/metabolism , Oxytocin/metabolism , Binding Sites , LigandsABSTRACT
Fish tend to grow faster as the climate warms but attain a smaller adult body size following an earlier age at sexual maturation. Despite the apparent ubiquity of this phenomenon, termed the temperature-size rule (TSR), heated scientific debates have revealed a poor understanding of the underlying mechanisms. At the centre of these debates are prominent but marginally tested hypotheses which implicate some form of 'oxygen limitation' as the proximate cause. Here, we test the role of oxygen limitation in the TSR by rearing juvenile Galaxias maculatus for a full year in current-day (15°C) and forecasted (20°C) summer temperatures while providing half of each temperature group with supplemental oxygen (hyperoxia). True to the TSR, fish in the warm treatments grew faster and reached sexual maturation earlier than their cooler conspecifics. Yet, despite supplemental oxygen significantly increasing maximum oxygen uptake rate, our findings contradict leading hypotheses by showing that the average size at sexual maturation and the adult body size did not differ between normoxia and hyperoxia groups. We did, however, discover that hyperoxia extended the reproductive window, independent of fish size and temperature. We conclude that the intense resource investment in reproduction could expose a bottleneck where oxygen becomes a limiting factor.
Subject(s)
Hyperoxia , Animals , Oxygen , Oxygen Consumption , Fishes , Temperature , ReproductionABSTRACT
Inversion barriers ΔG for planar chiral phosphine-alkene and sulfonamide-alkene hybrid ligands based on phenyl-dibenz[b,f]azepine have been determined by density-functional theory calculations. Analysis of the structural and electronic characteristics of the minima and transition states explains the magnitudes of ΔG and the geometrical changes during the inversion process. The steric repulsion caused by bulky substituents attached to the azepine nitrogen atom has a pronounced effect on the ΔG value, explaining, inter alia, the stereochemical stability of the P- and S-alkene ligands when compared to the fluxional parent compound where X = H.
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We use enhanced-sampling simulations with an effective collective variable to study the activation of the ß2-adrenergic receptor in the presence of ligands with different efficacy. The free-energy profiles are computed for the ligand-free (apo) receptor and binary (apo-receptor + G-protein α-subunit and receptor + ligand) and ternary complexes. The results are not only compatible with available experiments but also allow unprecedented structural insight into the nature of GPCR conformations along the activation pathway and their role in the activation mechanism. In particular, the simulations reveal an unexpected mode of action of partial agonists such as salmeterol and salbutamol that arises already in the binary complex without the G-protein. Specific differences in the polar interactions with residues in TM5, which are required to stabilize an optimal TM6 conformation that facilitates G-protein binding and receptor activation, play a major role in differentiating them from full agonists.
Subject(s)
Receptors, Adrenergic, beta-2 , Signal Transduction , Ligands , Protein Conformation , Receptors, Adrenergic, beta-2/chemistry , Albuterol/pharmacology , Albuterol/chemistry , GTP-Binding Proteins/metabolismABSTRACT
Through comprehensive photo-assays, this study investigates the reaction coordinate governing the interconversion between quadricyclane (QC) and norbornadiene (NBD) upon photo-irradiation up to a wavelength of 550 nm. To harness this spectroscopic range for energy release, we link the NBD-core with a highly electron-accepting perylenediimide (PDI) with broad absorption, achieving strong electronic coupling between them. We detail the successful synthesis and present extensive DFT calculations to determine the amount of stored energy. By means of transient absorption spectroscopy, an oxidative electron transfer is observed during the QC-to-NBD isomerization following the initial PDI photoexcitation. This charge-separated state is key to triggering the back-isomerization with visible light excitation.