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The breasts undergo marked physiologic changes during lactation that can make conventional imaging evaluation with mammography and US challenging. MRI can be a valuable diagnostic aid to differentiate physiologic and benign processes from malignancy in patients who are lactating. In addition, MRI may allow more accurate delineation of disease involvement than does conventional imaging and assists in locoregional staging, screening of the contralateral breast, assessment of response to neoadjuvant chemotherapy, and surgical planning. Although the American College of Radiology recommends against patients undergoing contrast-enhanced MRI during pregnancy because of fetal safety concerns, contrast-enhanced MRI is safe during lactation. As more women delay childbearing, the incidence of pregnancy-associated breast cancer (PABC) and breast cancer in lactating women beyond the 1st year after pregnancy is increasing. Thus, MRI is increasingly being performed in lactating women for diagnostic evaluation and screening of patients at high risk. PABC is associated with a worse prognosis than that of non-PABCs, with delays in diagnosis contributing to an increased likelihood of advanced-stage disease at diagnosis. Familiarity with the MRI features of the lactating breast and the appearance of various pathologic conditions is essential to avoid diagnostic pitfalls and prevent delays in cancer diagnosis and treatment. The authors review clinical indications for breast MRI during lactation, describe characteristic features of the lactating breast at MRI, and compare MRI features of a spectrum of benign and malignant breast abnormalities. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Chikarmane in this issue.

The spatial organization of molecules in a cell is essential for their functions. While current methods focus on discerning tissue architecture, cell-cell interactions, and spatial expression patterns, they are limited to the multicellular scale. We present Bento, a Python toolkit that takes advantage of single-molecule information to enable spatial analysis at the subcellular scale. Bento ingests molecular coordinates and segmentation boundaries to perform three analyses: defining subcellular domains, annotating localization patterns, and quantifying gene-gene colocalization. We demonstrate MERFISH, seqFISH + , Molecular Cartography, and Xenium datasets. Bento is part of the open-source Scverse ecosystem, enabling integration with other single-cell analysis tools.

In the eye, the isomerization of all-trans-retinal to 11-cis-retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential trans-cis isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure-activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were tested in vitro and in vivo for RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties.

Today, the high concentrations of copper found in water resources result in an urgent problem to solve since human health and aquatic ecosystems have been affected. Functionalized crosslinked polyketone resins (XLPK) have demonstrated high performance for the uptake of heavy metals in water solutions. In addition, its green chemical synthesis makes these resins very attractive as sorbents for metal ions contained in wastewater. XLPK are not soluble in aqueous media and do not require any catalyst, solvent, or harsh conditions to carry out the uptake process. In this paper, a series of functionalized XLPK with pending amino-derivatives namely; butylamine (BA), amino 2-propanol (A2P), 4-(aminomethyl) benzoic acid (HAMC), 6-aminohexanoic acid (PAMBA), and 1,2 diamino propane (DAP) directly attached to the pyrrole backbone of the polymers and crosslinked by di-amine derivatives was investigated using Density Functional Theory (DFT) calculations. Our computational analysis revealed that dipole-dipole interactions played a crucial role in enhancing the adsorption of Cu2+ ions onto XLPKs. The negatively charged ketone moieties and functional groups within XLPKs were identified as key adsorption sites for the selective binding of Cu2+ ions. Additionally, we found that XLPKs exhibited strong electrostatic interactions primarily through the –NH2 and –C=O groups. Evaluation of the adsorption energies in XLPK-Cu(II) complexes showed that the DAP-Cu(II) complex exhibited the highest stability, attributed to strong Cu(II)-N binding facilitated by the amino moiety (–NH2). The remaining XLPKs displayed binding modes involving oxygen atoms (Cu(II)-O) within the ketone moieties in the polymer backbone. Furthermore, the complexation and thermochemical analysis emphasized the role of the coordinator atom (N or O) and the coordinating environment, in which higher entropic effects involved in the adsorption of Cu2+ ions onto XLPKs describes a lower spontaneity of the adsorption process. The adsorption reactions were favored at lower temperatures and higher pressures. These findings provide valuable insights into the reactivity and adsorption mechanisms of functionalized and crosslinked polyketones for Cu2+ uptake, facilitating the design of high-performance polymeric resins for water treatment applications. [ABSTRACT FROM AUTHOR]

Recycling of all-trans-retinal to 11-cis-retinal through the visual cycle is a fundamental metabolic pathway in the eye. A potent retinoid isomerase (RPE65) inhibitor, (R)-emixustat, has been developed and tested in several clinical trials; however, it has not received regulatory approval for use in any specific retinopathy. Rapid clearance of this drug presents challenges to maintaining concentrations in eyes within a therapeutic window. To address this pharmacokinetic inadequacy, we rationally designed and synthesized a series of emixustat derivatives with strategically placed fluorine and deuterium atoms to slow down the key metabolic transformations known for emixustat. Crystal structures and quantum chemical analysis of RPE65 in complex with the most potent emixustat derivatives revealed the structural and electronic bases for how fluoro substituents can be favorably accommodated within the active site pocket of RPE65. We found a close (∼3.0 Å) F-π interaction that is predicted to contribute ∼2.4 kcal/mol to the overall binding energy.

Myocardial infarction (MI) and osteoporotic fracture are leading causes of morbidity and mortality, and epidemiological evidence linking their incidence suggests possible crosstalk. MI can exacerbate atherosclerosis through the sympathetic nervous system (SNS) activation and β3 adrenoreceptor-mediated release of hematopoietic stem cells, leading to monocytosis. We hypothesized that this same pathway initiates systemic bone loss following MI, since osteoclasts differentiate from monocytes. In this study, MI was created with left anterior descending artery ligation in 12-week-old male mice (n = 24) randomized to β3 -adrenergic receptor (AR) antagonist (SR 59230A) treatment or no treatment for 10 days postoperatively. Additional mice (n = 21, treated and untreated) served as unoperated controls. Bone mineral density (BMD), bone mineral content (BMC), and body composition were quantified at baseline and 10 days post-MI using dual-energy x-ray absorptiometry; circulating monocyte levels were quantified and the L5 vertebral body and femur were analyzed with microcomputed tomography 10 days post-MI. We found that MI led to circulating monocyte levels increases, BMD and BMC decreases at the femur and lumbar spine in MI mice (-6.9% femur BMD, -3.5% lumbar BMD), and trabecular bone volume decreases in MI mice compared with control mice. β3 -AR antagonist treatment appeared to diminish the bone loss response (-5.3% femur BMD, -1.2% lumbar BMD), though these results were somewhat inconsistent. Clinical significance: These results suggest that MI leads to systemic bone loss, but that the SNS may not be a primary modulator of this response; bone loss and increased fracture risk may be important clinical comorbidities following MI or other ischemic injuries.

The discovery of how a photon is converted into a chemical signal is one of the most important achievements in the field of vision. A key molecule in this process is the visual chromophore retinal. Several eye diseases are attributed to the abnormal metabolism of retinal in the retina and the retinal pigment epithelium. Also, the accumulation of two toxic retinal derivatives, N-retinylidene-N-retinylethanolamine and the retinal dimer, can damage the retina leading to blindness. RPE65 (Retinal pigment epithelium-specific 65 kDa protein) is one of the central enzymes that regulates the metabolism of retinal and the formation of its toxic metabolites. Its inhibition might decrease the rate of the retinas degeneration by limiting the amount of retinal and its toxic byproducts. Two RPE65 inhibitors, (R)-emixustat and (R)-MB001, were recently developed for this purpose.

PurposeExtracellular accumulation of all-trans-retinaldehyde (atRAL), a highly reactive visual cycle intermediate, is toxic to cells of the outer retina and contributes to retinal and macular degenerations. However, the contribution of atRAL to retinal capillary function has not been studied. We hypothesized that atRAL released from the outer retina can contribute to retinal vascular permeability. We, therefore, tested the contribution of atRAL to retinal ischemia-reperfusion (IR)-induced vascular permeability.MethodsIR was induced in mice by transient increase in intraocular pressure followed by natural reperfusion. The visual cycle was ablated in the Lrat-/- mice, reduced by dark adaptation or the use of the RPE65 inhibitor and atRAL scavenger emixustat. Accumulation of FITC-BSA was used to assess vascular permeability and DNA fragmentation quantified cell death after IR. Primary bovine retinal endothelial cell (BREC) culture was used to measure the direct effects of atRAL on endothelial permeability and cell death.ResultsInhibition of the visual cycle by Lrat-/-, dark adaptation, or with emixustat, all reduced approximately half of IR induced vascular permeability at 48 hours. An increase in BREC permeability with atRAL coincided with lactate dehydrogenase (LDH) release, a measure of cell death. Both permeability and toxicity were blocked by emixustat.ConclusionsOuter retinal pathology may contribute to vascular permeability by release of atRAL, which can act directly on vascular endothelial cells to alter barrier properties and induce cell death. These studies may have implications for a variety of blinding eye diseases that include outer retinal damage and retinal vascular permeability.

Visual function in vertebrates critically depends on the continuous regeneration of visual pigments in rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase in the pigment epithelium that regenerates rhodopsin during the rod visual cycle; however, its contribution to the regeneration of cone pigments remains obscure. In this study, we use potent and selective RPE65 inhibitors in rod- and cone-dominant animal models to discern the role of this enzyme in cone-mediated vision. We confirm that retinylamine and emixustat-family compounds selectively inhibit RPE65 over DES1, the putative retinoid isomerase of the intraretinal visual cycle. In vivo and ex vivo electroretinography experiments in Gnat1-/- mice demonstrate that acute administration of RPE65 inhibitors after a bleach suppresses the late, slow phase of cone dark adaptation without affecting the initial rapid portion, which reflects intraretinal visual cycle function. Acute administration of these compounds does not affect the light sensitivity of cone photoreceptors in mice during extended exposure to background light, but does slow all phases of subsequent dark recovery. We also show that cone function is only partially suppressed in cone-dominant ground squirrels and wild-type mice by multiday administration of an RPE65 inhibitor despite profound blockade of RPE65 activity. Complementary experiments in these animal models using the DES1 inhibitor fenretinide show more modest effects on cone recovery. Collectively, these studies demonstrate a role for continuous RPE65 activity in mammalian cone pigment regeneration and provide further evidence for RPE65-independent regeneration mechanisms.

A new electrochemical selective annulative amino-ketalization and amino-oxygenation of 1,6-enynes with disulfonimides and alcohols is reported, producing a series of functionalized benzofurans under catalyst- and oxidant-free conditions. The annulative aminoketalization proceeds with simple short-chain alcohols such as methanol, ethanol and n-propanol as O-nucleophilic reagents, while the reaction occurs in the annulative aminooxygenation direction in the presence of water and large steric sec-butyl alcohol (SBA). [ABSTRACT FROM AUTHOR]

In previous studies, the β-blocker carvedilol inhibited EGF-induced epidermal cell transformation and chemical carcinogen-induced mouse skin hyperplasia. As exposure to ultraviolet (UV) radiation leads to skin cancer, the present study examined whether carvedilol can prevent UV-induced carcinogenesis. Carvedilol absorbs UV like a sunscreen; thus, to separate pharmacological from sunscreen effects, 4-hydroxycarbazole (4-OHC), which absorbs UV to the same degree as carvedilol, served as control. JB6 P+ cells, an established epidermal model for studying tumor promotion, were used for evaluating the effect of carvedilol on UV-induced neoplastic transformation. Both carvedilol and 4-OHC (1 mM) blocked transformation induced by chronic UV (15 mJ/cm(2)) exposure for eight weeks. However, EGF-mediated transformation was only inhibited by carvedilol but not by 4-OHC. Carvedilol (1 and 5 mM), but not 4-OHC, attenuated UV-induced AP-1 and NF-kB luciferase reporter activity, suggesting a potential anti-inflammatory activity. In a single dose UV (200 mJ/cm(2)) induced skin inflammation mouse model, carvedilol (10 mM), applied topically after UV exposure, reduced skin hyperplasia and the levels of cyclobutane pyrimidine dimers, IL-1β, IL-6, and COX-2 in skin. In SKH-1 mice exposed to gradually increasing levels of UV (50-150 mJ/cm(2)) three times a week for 25 weeks, topical administration of carvedilol (10 mM) after UV exposure increased tumor latency compared with control (week 18 vs. 15), decreased incidence and multiplicity of squamous cell carcinomas, while 4-OHC had no effect.  These data suggest that carvedilol has a novel chemopreventive activity and topical carvedilol following UV exposure may be repurposed for preventing skin inflammation and cancer.

The present work involves experimental and computational investigations into the density of pure and mixed states of ethanolamine (ET) and 2-amino-2-methyl-1-propanol (AMP) under a pressure of 1 atm and temperatures ranging from 293.15 K to 333.15 K The density data were used to derive the excess molar volume, thermal expansion coefficient, and isothermal coefficient of pressure excess molar enthalpy. The Redlich-Kister equation was employed to calculate the excess molar and its accompanying coefficients. In the gas phase, density functional theory (DFT) was utilized to explore the most stable structures of ET … ET, AMP … AMP, and the ET … AMP mixture. Molecular dynamics simulation (MD) was used to calculate the structural properties of these mixtures in the liquid phase. Radial distribution function (RDFs) combined distribution function (CDF) and spatial distribution function (SDF) in different mole fractions calculated in the liquid phase. The intramolecular and intermolecular interactions of ethanolamine and AMP were obtained using the radial distribution function in different molar fractions. It was found that the ethanolamine molecule has a greater tendency to form intramolecular hydrogen bonds, while the AMP molecule has a greater tendency to form intermolecular hydrogen bonds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Toehold-mediated strand displacement (TMSD) reaction, one of the DNA nanotechnologies, has great potential as s biological programmable platform in the cellular environment. Various artificial nucleic acids have been developed to improve stability and affinity for biological applications. However, the lack of understanding of the kinetics of TMSD reaction among artificial nucleic acids has limited their applications. We herein systematically characterized the kinetics of TMSD reactions with acyclic xeno nucleic acids (XNAs): serinol nucleic acid (SNA), acyclic D-threoninol nucleic acid (D-aTNA), and acyclic L-threoninol nucleic acid (L-aTNA). We found that the strand displacement reactions by D-aTNA and by L-aTNA were highly dependent on temperature. D-aTNA and L-aTNA systems were orthogonal to each other, and chirality of the input can be switched by using SNA as an interface. We also applied TMSD reactions of XNAs to a seesaw gate amplification system which utilizes the orthogonality. This work will contribute to the developments of thermoresponsive and bioorthogonal nucleic acid circuits., (© 2024 Wiley-VCH GmbH.)

Contemporary discussion of the baroreflex includes the efferent vascular-sympathetic and cardiovagal arms. Since sympathetic postganglionic neurons also innervate the left ventricle (LV), it is often assumed that the LV produces a sympathetically mediated increase in contractility during baroreceptor unloading, but this has not been characterized using a load-independent index of contractility. We aimed to determine 1 ) whether LV contractility increases in response to baroreceptor unloading and 2 ) whether such increases are mediated via the sympathetic or parasympathetic arm of the autonomic nervous system. Ten male Wistar rats were anesthetized (urethane) and instrumented with arterial and LV pressure-volume catheters to measure mean arterial pressure (MAP) and load-independent LV contractility [maximal rate of increase in pressure adjusted to end-diastolic volume (PAdP/d t max )], respectively. Rats were placed in a servo-controlled lower-body negative pressure (LBNP) chamber to reduce MAP by 10% for 60 s to mechanically unload baroreceptors under control conditions. LBNP was repeated in each animal following infusions of cardiac autonomic blockers using esmolol (sympathetic), atropine (parasympathetic), and esmolol + atropine. Under control conditions, PAdP/d t max increased during baroreceptor unloading (26 ± 6 vs. 31 ± 9 mmHg·s -1 ·μL -1 , P = 0.031). During esmolol, there was no increase in LV contractility during baroreceptor unloading (11 ± 2 vs. 12 ± 2, P = 0.125); however, during atropine, there was an increase in LV contractility during baroreceptor unloading (26 ± 6 vs. 31 ± 9, P = 0.019). During combined esmolol and atropine, there was a small increase in contractility versus control (13 ± 3 vs. 15 ± 4, P = 0.046). Our results demonstrate that, in anesthetized rats, LV contractility increases in response to baroreceptor unloading, which is largely sympathetically mediated. NEW & NOTEWORTHY This study empirically demonstrates a sympathetically mediated increase in LV contractility in response to baroreceptor unloading using a load-independent index of cardiac contractility in the anesthetized rat.

New series of bis(amino-1,2,4-triazoles ‏) 5a–f were prepared by the reaction of bis(chloro) diamides 3a–d with 5-substituted-4-amino-1,2,4-triazoles-3-thiole (4a–c). Reaction of bis(amino) triazoles 5a–d with the appropriate aldehydes afforded the corresponding Schiff bases 7a–d in good yields. Similarly, cyclocondansation of bis(amino) triazoles 5a–d with 1,3-bis(2-formyphenoxy)-2-propanol furnished the desired lariat macrocycles 12a–d. The antimicrobial activities of the prepared bis(amines) 5a–c, e–g, Schiff bases 7a–d, 11a–b and lariat macrocycles 12a,c,d were evaluated against series of selected microorganisms. Some of the prepared derivatives showed good antimicrobial activity against gram positive bacteria and gram negative bacteria. The MIC values for some of the tested compound were investigated. [ABSTRACT FROM AUTHOR]