Estimation of the proximal temperature rise of an excited upconversion particle by detecting the wavefront of emission.

Monitoring the temperature distribution within a local environment at the micro and nanoscale is vital as many processes are solely thermal. Various thermometric techniques have been explored in the community, and out of these, fluorescent nano/micro particle-based mechanisms are accepted widely (fluorescence intensity ratio (FIR) techniques, where the ratio of populations in two consecutive energy levels is compared with Boltzmann distribution). We describe a new technique to account for the temperature rise near an illuminated upconverting particle (UCP) using wavefront imaging, which is more sensitive than the conventional thermometric techniques on the microscale. We rely on a thermo-optical phase microscopic technique by reconstructing the wavefront of emission from an upconverting particle using a Shack-Hartmann wavefront sensor. The wavefront maps the local phase distribution, which is an indicator of the surroundings' optical parameters, particularly the suspended medium's temperature-induced refractive index in the presence of convection currents. We describe how these extracted phase values can provide information about the optical heating due to the particle and hence its local environment along the direction of the emission. Our findings demonstrate the detection of a minimum temperature rise of 0.23 K, while the FIR methods indicate a minimum of 0.3 K rise. This technique is used to study the temperature increase in the backscattered direction for an upconverting particle illuminated on pump resonance. We also estimate the Soret coefficient for an upconverting particle optically trapped on pump resonance and experiencing anisotropic heating across the body.

Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in Candida albicans.

Azoles are the main antifungal agents employed in clinical practice to treat invasive candidiasis. Nonetheless, their efficacy is limited by fungal resistance mechanisms, mainly the overexpression of efflux pumps. Consequently, candidiasis has a worrisome death rate of 75%. One potential strategy to overcome efflux-mediated resistance is to inhibit this process. Ailanthus altissima is a Chinese tree that produces several active substances, including altissimacoumarin D. Due to the low yield of its extraction and the need to search for new drugs to treat candidiasis, this study aimed to synthesize altissimacoumarin D and its analogues, as well as evaluating their ability to reverse the resistance phenotype of Candida albicans. Coumarin isofraxidin was prepared via total synthesis through a solvent-free Knoevenagel condensation as the key step. Isofraxidin and other commercially available coumarins were alkylated with prenyl or geranyl groups to yield the natural product altissimacoumarin D and seven analogues. The antifungal activity of the coumarins and their ability to reverse the fungal resistance phenotype were assessed using microbroth methodologies. Toxicity was evaluated using erythrocytes and an in silico prediction. All compounds improved the antifungal activity of fluconazole by inhibiting efflux pumps, and ACS47 and ACS50 were the most active. None of the coumarins were toxic to erythrocytes. In silico predictions indicate that ACS47 and ACS50 may be safe for human use. ACS47 and ACS50 are promising candidates when used as adjuvants in the antifungal therapy against C. albicans-resistant strains.

Acute Respiratory Infection Incidence and Outpatient Antibiotic Prescription Patterns in People With or Without Human Immunodeficiency Virus Infection: A Virtual Cohort Study.

Background: Inappropriate antibiotic use in acute respiratory infections (ARIs) is a major public health concern; however, data for people with human immunodeficiency virus (PWH) are limited. Methods: The HIV Virtual Cohort Study is a retrospective cohort of adult Department of Defense beneficiaries. Male PWH cases (n = 2413) were matched 1:2 to controls without HIV (n = 4826) by age, gender, race/ethnicity, and beneficiary status. Acute respiratory infection encounters between 2016 and 2020 and corresponding antibiotic prescriptions were characterized as always, sometimes, or never appropriate based on International Classification of Diseases, Tenth Revision coding. Incidence of ARI encounters and antibiotic appropriateness were compared between PWH and controls. Subgroup analyses were assessed by CD4 count and viral load suppression on antiretroviral therapy. Results: Mean rates of ARI encounters were similar for PWH (1066 per 1000 person-years) and controls (1010 per 1000 person-years); however, the rate was double among PWH without viral load (VL) suppression (2018 per 1000 person-years). Antibiotics were prescribed in 26% of encounters among PWH compared to 34% for controls (P ≤ .01); antibiotic use was "never" appropriate in 38% of encounters with PWH and 36% in controls. Compared to controls, PWH received more sulfonamides (5.5% vs 2.7%; P = .001), and variation existed among HIV subgroups in the prescription of sulfonamides, fluoroquinolones, and ß-lactams. Discussion: Acute respiratory infection encounters were similar for PWH and those without HIV; however, PWH with lower CD4 counts and/or nonsuppressed VL had more frequent ARI visits. Inappropriate antibiotic use for ARIs was high in both populations, and focused interventions to improve antibiotic appropriateness for prescribers caring for PWH should be pursued.

Failure of diltiazem to prevent 1:1 conduction of atrial flutter: a case report.

BACKGROUND: Atrial flutter with 1:1 conduction to the ventricles is a dangerous cardiac arrhythmia. Contemporary guidelines recommend atrioventricular nodal blocking agents should be co-administered with class 1C anti-arrhythmics, as prophylaxis against 1:1 flutter. No guidance is provided on the type or strength of atrioventricular nodal blockade required, and in practice, these agents are frequently prescribed at low dose, or even omitted, due to their side effect profile. CASE PRESENTATION: A 62 year old Caucasian man with a history of paroxysmal atrial fibrillation treated with flecainide, presented with atrial flutter with 1:1 conduction to the ventricles and was cardioverted. Diltiazem was added to prevent this complication and he again presented with atrial flutter with 1:1 conduction to the ventricles, despite prophylaxis with coadministration of diltiazem. CONCLUSIONS: This case report demonstrates failure of diltiazem to prevent 1:1 flutter in a patient chronically treated with flecainide for paroxysmal atrial fibrillation.

Acute Ostracism-Related Pain Sensitization in the Context of Accumulated Lifetime Experiences of Ostracism.

Ostracism (ie, being ignored/excluded) is a form of social adversity that powerfully impacts health and well-being. While laboratory research indicates that experimentally manipulated experiences of ostracism impact pain, findings have been mixed. Prior investigations have not considered moderating or main effects of individual histories of ostracism, and have been limited in the scope of their pain testing. In this study, participants without current pain reported lifetime experiences of ostracism prior to a laboratory visit where they were randomized to experience either a single episode of ostracism (ie, acute ostracism) or control condition that was immediately followed by quantitative sensory testing. Results indicate that the experimental effect of a single episode of ostracism on pain ratings, after-sensations, and temporal summation of pain is moderated by lifetime ostracism; no main effects were found. For individuals with histories of more lifetime ostracism, encountering a single episode of ostracism led to greater pain sensitization relative to the control condition, whereas no experimental effect was observed for individuals with little lifetime exposure to ostracism. These findings indicate that acute experiences of ostracism may be accompanied by periods of hyperalgesia for people who are chronically ostracized, implicating ostracism as a potential social moderator of pain sensitization. People who are stigmatized may therefore experience enhanced pain burden with repeated and accumulating experiences of ostracism. PERSPECTIVE: Results suggest that in the context of accumulated lifetime experiences of ostracism, single experiences of ostracism evoke central sensitization. In this way, ostracism may function to trigger central sensitization and shape socially- and societally-determined patterns of pain burden and disparity.

Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells.

Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.

Synthesis, Characterization, and Physicochemical Studies Of Orientation-Controlled Multi-Arm PEG Zn(II)/Mg(II) (Aza)Phthalocyanines.

Tuning the amphiphilicity of (aza)phthalocyanine hydrophobic cores by introducing multiple polyethylene glycol (PEG) moieties with controlled orientations of their (non)peripheral positions is an innovative approach to fabricating water-soluble macrocyclic materials. Although many water-soluble PEGylated macrocycles have been produced in this way, the ability to generate substances with PEG tails oriented outward from the macrocyclic plane in order to obtain non-aggregated, water soluble forms remains a challenge. In this study, we resolved this issue by developing a methods for the synthesis of four new dual directional PEG containing Zn(II)/Mg(II) amphiphiles (ZnPc-PEG, MgPc-PEG, ZnAzaPc-PEG and MgAzaPc-PEG). In addition, the non-aggregating behaviour, and photophysical and photochemical properties of these PEG-complexes were elucidated.

Interaction of molecular nitrogen with vanadium oxide in the absence and presence of water vapor at room temperature: Near-ambient pressure XPS.

Interactions of N2 at oxide surfaces are important for understanding electrocatalytic nitrogen reduction reaction (NRR) mechanisms. Interactions of N2 at the polycrystalline vanadium oxide/vapor interface were monitored at room temperature and total pressures up to 10-1 Torr using Near-Ambient Pressure X-ray Photoelectron Spectroscopy (NAP-XPS). The oxide film was predominantly V(IV), with V(III) and V(V) components. XPS spectra were acquired in environments of both pure N2 and equal pressures of N2 and H2O vapor. In pure N2, broad, partially resolved N1s features were observed at binding energies of 401.0 and 398.7 eV, with a relative intensity of ∼3:1, respectively. These features remained upon subsequent pumpdown to 10-9 Torr. The observed maximum N surface coverage was ∼1.5 × 1013 cm-2-a fraction of a monolayer. In the presence of equal pressures of H2O, the adsorbed N intensity at 10-1 Torr is ∼25% of that observed in the absence of H2O. The formation of molecularly adsorbed H2O was also observed. Density functional theory-based calculations suggest favorable absorption energies for N2 bonding to both V(IV) and V(III) cation sites but less so for V(V) sites. Hartree-Fock-based cluster calculations for N2-V end-on adsorption show that experimental XPS doublet features are consistent with the calculated shake-up and normal, final ionic configurations for N2 end-on bonding to V(III) sites but not V(IV) sites. The XPS spectra of vanadium oxide transferred in situ between electrochemical and UHV environments indicate that the oxide surfaces studied here are stable upon exposure to the electrolyte under NRR-relevant conditions.

Growth vector elaboration of fragments: regioselective functionalization of 5-hydroxy-6-azaindazole and 3-hydroxy-2,6-naphthyridine.

This article discusses the reactivity of 6-azaindazole (1) and 2,6-naphthyridine (2), proposed to be "heteroaromatic rings of the future," which would be useful for fragment-based drug discovery (FBDD) campaigns, developing growth vectors for fragment elaboration by selectively functionalizing different positions on the rings. The pyridone oxygens and pyrazole nitrogen can be functionalized selectively. Arylation at the α-carbon of the pyridone moiety was achieved by a transition metal-free radical cross-coupling using aryl hydrazines. This method proceeded under mild conditions without the need for protection of the hydroxypyridine. Additionally, we developed a method for the regioselective C-3 functionalization of heterocycle 1via N-sulfonamide rearrangement. This method involved a novel regioselective base-mediated N-C migration of the N-1 sulfonamide to yield the C-3 sulfone. This procedure is also applicable for indazole C-3 functionalization and mechanistic studies of the rearrangement suggest that an intermolecular process is involved. These reactions enable the fragment elaboration of heterocycles 1 and 2 in several growth vectors to facilitate their use in FBDD.

Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis.

By limiting the nitrogen source to glutamic acid, we isolated cyclic peptides from Euglena gracilis containing asparagine and non-proteinogenic amino acids. Structure elucidation was accomplished through spectroscopic methods, mass spectrometry and chemical degradation. The euglenatides potently inhibit pathogenic fungi and cancer cell lines e.g., euglenatide B exhibiting IC50 values of 4.3 µM in Aspergillus fumigatus and 0.29 µM in MCF-7 breast cancer cells. In an unprecedented convergence of non-ribosomal peptide synthetase and polyketide synthase assembly-line biosynthesis between unicellular species and the metazoan kingdom, euglenatides bear resemblance to nemamides from Caenorhabditis elegans and inhibited both producing organisms E. gracilis and C. elegans. By molecular network analysis, we detected over forty euglenatide-like metabolites in E. gracilis, E. sanguinea and E. mutabilis, suggesting an important biological role for these natural products.

Synthesis of [1-8-NαC]-zanriorb A1, alanine-containing analogues, and their cytotoxic and anti-inflammatory activity.

The synthesis of the orbitide[1-8-NαC]-zanriorb A1, isolated from the medicinal plant Zanthoxylum riedelianum, was investigated by solution-phase macrocyclization of a linear peptide and on-resin solid-phase macrocyclization with an acylsulfonamide safety-catch linker. The solution-phase route produced a mixture of proline rotamers, and the main component was assigned as the trans, cis rotamer, identical to the natural product. The on-resin cyclization was less successful, producing mainly a linear peptide, and minor cyclic products as rotameric mixtures. Although the natural product was reported to be significantly cytotoxic against Jurkat leukemia T cells, our synthetic peptides were inactive, suggesting the presence of other rotamers or impurities in the naturally isolated material. Additional analogues of zanriorb A1 were synthesized in which proline and glycine residues were replaced with alanine. While these analogues were not cytotoxic, several of them inhibited the production of nitric oxide in lipopolysaccharide (LPS)-stimulated macrophages. The most active compound, cyclic[Ala5,6,8 ]-zanriorb A1 had an IC50 of 22 µM and was more potent compared with the standard NG-monomethyl-l-arginine acetate (L-NMMA) with an IC50 of 98 µM, indicating their strong anti-inflammatory potential.

Vomiting, electrolyte disturbance, and medications; the perfect storm for acquired long QT syndrome and cardiac arrest: a case report.

BACKGROUND: Acquired long QT syndrome is an important and preventable cause of cardiac arrest. Certain medications and electrolyte disturbance are common contributors, and often coexist. In this case, we report five contributors to cardiac arrest. CASE PRESENTATION: This case is of a 51-year-old Caucasian female patient who presented with vomiting associated with hypokalemia and hypomagnesemia. She subsequently received ondansetron and metoclopramide, on the background of chronic treatment with fluoxetine. She then suffered an in-hospital monitored cardiac arrest, with features of long QT and torsades de pointes retrospectively noted on her prearrest electrocardiogram. She was diagnosed with acquired long QT syndrome, and her QT interval later normalized after removal of offending causes. CONCLUSIONS: This case highlights the importance of proper consideration prior to prescribing QT prolonging medications, especially in patients who have other risk factors for prolonged QT, such as electrolyte disturbances and pretreatment with QT prolonging medications.

Analyses on the distribution and influence of higher-order aberrations both clinically and experimentally among varied refractive errors.

PURPOSE: The aim of this work is to determine and compare the distribution and influence of higher-order aberrations (HOAs) both clinically and experimentally between different refractive errors. METHODS: Commercially available Shack-Hartmann aberrometer was employed to measure the HOA clinically in human eyes. Experimentally, HOA was measured in a model eye by simulating various refractive errors by constructing an aberrometer based on the same Shack Hartmann principle. One-way analyses of variance and simple regression were employed to analyze the distribution and influence of HOA among various refractive errors. RESULTS: A total of 100 eyes were clinically measured for aberrations, of which 35, 50, and 15 eyes were emmetropes, myopes, and hyperopes, respectively. Out of the total root mean square (RMS) value, the HOAs found in the human eyes were 23%, 7%, and 26% and in the model eye, it was 20%, 8%, and 10% between emmetropes, myopes, and hyperopes, respectively. The mean higher-order RMS was almost similar between the groups and among various refractive errors. There was no statistical significance between the individual Zernikes except for the coma in both human and model eyes. CONCLUSION: The mean HOA is similar amidst the different refractive errors. The presence of 23% HOA in emmetropes signifies that larger part of the human eye is capable of complying with HOA without compromising the image quality. This work signifies that HOA does not play an important role in image clarity for human eyes with regular refractive surface unlike irregular refractive surfaces.

From Hit Seeking to Magic Bullets: The Successful Union of Epigenetic and Fragment Based Drug Discovery (EPIDD + FBDD).

We review progress in the application of fragment-based drug discovery (FBDD) to epigenetic drug discovery (EPIDD) targeted at epigenetic writer and eraser enzymes as well as reader domains over the last 15 years. The greatest successes to date are in prospecting for bromodomain binding ligands. From a diverse array of fragment hits, multiple potent and selective compounds ensued, including the oncology clinical candidates mivebresib, ABBV-744, pelabresib, and PLX51107.

Factors associated with erectile dysfunction diagnosis in men with HIV infection: a case-control study.

OBJECTIVES: HIV infection is associated with increased risk of erectile dysfunction (ED); however, factors associated with ED remain unclear. We evaluated the prevalence of ED among men living with HIV and factors associated with ED diagnosis in the US Military HIV Natural History Study (NHS). METHODS: A retrospective cohort study evaluated participants in the NHS, a cohort of HIV-positive active duty members and beneficiaries with HIV infection. Men with a diagnosis of ED after HIV diagnosis were included. Cohort controls without ED diagnosis were matched 2:1 by age at HIV diagnosis and duration of follow-up. Multivariate logistic regression models were used to identify factors associated with ED. RESULTS: A total of 543 of 5682 male participants (9.6% prevalence) had a diagnosis of ED, of whom 488 were included in the analysis. The median (interquartile range, IQR) age at ED diagnosis was 43 (37.0-49.0) years and the time from HIV diagnosis to antiretroviral therapy (ART) start was longer for cases (5.0 years, IQR: 2.0-9.0) than for controls (3.0 years, 1.0-6.0; P < 0.01). Cases had higher proportions of multiple comorbid conditions, including depression (33.4% vs. 21.7%), tobacco use (19.7% vs. 9.0%) and sleep apnoea (14.8% vs. 4.2%) compared with controls (P < 0.01 for all). Logistic regression showed increased odds of ED for delayed ART initiation > 4 years [odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.56-2.71], protease inhibitor use ≥ 1 year (OR = 1.81, 95% CI: 1.38-2.38) and sleep apnoea (OR = 2.60, 95% CI: 1.68-4.01). CONCLUSIONS: Erectile dysfunction was common in men with HIV and associated factors included both HIV-related and traditional factors.

Synthesis of Carboxamide-Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia.

Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.

Insights into the Structure-Activity Relationship of Glycosides as Positive Allosteric Modulators Acting on P2X7 Receptors.

P2X7 is an important ligand-gated ion channel expressed in multiple immune cell populations. This study aimed to investigate the chemical requirements of triterpenoid glycosides within a new binding pocket to characterize the structure-activity relationship. A set of glycosides were screened for positive modulator activity at human P2X7 using a YO-PRO-1 dye uptake assay in HEK-293 cells stably expressing the wild-type human P2X7 variant (HEK-hP2X7 cells). The highest positive modulator activity was with ginsenoside-compound K (CK), containing a monosaccharide (glucose) attached at carbon-20. Ginsenoside-20(S)-Rg3, containing a disaccharide group (glucose-glucose) at carbon-3, displayed positive modulator activity with a reduced EC50 for ATP and increased maximal response at human P2X7. The epimer 20(R)-Rg3 was inactive. A similar stereo-specific pattern was observed for 20(S)-Rh2. Ginsenoside-F1, highly similar to ginsenoside-CK but containing a single additional hydroxyl group, was also inactive at P2X7. Computational docking suggests hydrophobic residues in the pocket are involved in steric discrimination between triterpenoids, whereas the position and identity of the carbohydrate group are important for positive modulator activity at human P2X7. Ginsenosides containing monosaccharide attachments perform better than di- or trisaccharide glycosides. Additional modifications to the triterpenoid scaffold at carbon-6 are not tolerated. Gypenosides from plant sources other than Panax ginseng (gypenoside XVII, gypenoside XLIX, stevenleaf) can also act as positive allosteric modulators of P2X7. We also investigated the effect of positive allosteric modulators on endogenous P2X7 in THP-1 monocytes and confirmed our findings in a calcium response assay. A cell viability assay showed potentiation of ATP-induced cell death with ginsenoside-CK in THP-1 and HEK-hP2X7 cells. SIGNIFICANCE STATEMENT: Ginsenosides are active as positive allosteric modulators at P2X7, and this study determines the chemical features important for mediating this effect. The position and identity of the sugar group is important for activity, as is the position of a number of hydroxyl groups on the triterpenoid scaffold. Diastereomers of ginsenoside-Rg3 and ginsenoside-Rh2 demonstrate the importance of the location of hydroxyl groups relative to the hydrophobic face of the predicted binding pocket.

Two-hit wonders: The expanding universe of multitargeting epigenetic agents.

Multitargeting involves the application of molecules that are deliberately intended to bind to two or more unrelated cellular targets with high affinity. In epigenetic chemical biology and drug discovery, the rational design of multitargeting agents has evolved to a sophisticated level, and there are now five examples that have reached clinical trials. This review covers recent developments in the field and future prospects.

Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.

It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.