12 research outputs found
Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function
A wide variety of phytochemicals are consumed for their perceived health benefits. Many of these phytochemicals have been found to alter numerous cell functions, but the mechanisms underlying their biological activity tend to be poorly understood. Phenolic phytochemicals are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examined five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochemicals alters lipid bilayer properties and the function of diverse membrane proteins. Molecular dynamics simulations show that these phytochemicals modify bilayer properties by localizing to the bilayer/solution interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochemicals, consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochemicals are due to cell membrane perturbations, rather than specific protein binding
Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force.
A clinician-reported outcome (ClinRO) assessment is a type of clinical outcome assessment (COA). ClinRO assessments, like all COAs (patient-reported, observer-reported, or performance outcome assessments), are used to 1) measure patients’ health status and 2) define end points that can be interpreted as treatment benefits of medical interventions on how patients feel, function, or survive in clinical trials. Like other COAs, ClinRO assessments can be influenced by human choices, judgment, or motivation. A ClinRO assessment is conducted and reported by a trained health care professional and requires specialized professional training to evaluate the patient’s health status. This is the second of two reports by the ISPOR Clinical Outcomes Assessment—Emerging Good Practices for Outcomes Research Task Force. The first report provided an overview of COAs including definitions important for an understanding of COA measurement practices. This report focuses specifically on issues related to ClinRO assessments. In this report, we define three types of ClinRO assessments (readings, ratings, and clinician global assessments) and describe emerging good measurement practices in their development and evaluation. The good measurement practices include 1) defining the context of use; 2) identifying the concept of interest measured; 3) defining the intended treatment benefit on how patients feel, function, or survive reflected by the ClinRO assessment and evaluating the relationship between that intended treatment benefit and the concept of interest; 4) documenting content validity; 5) evaluating other measurement properties once content validity is established (including intra- and inter-rater reliability); 6) defining study objectives and end point(s) objectives, and defining study end points and placing study end points within the hierarchy of end points; 7) establishing interpretability in trial results; and 8) evaluating operational considerations for the implementation of ClinRO assessments used as end points in clinical trials. Applying good measurement practices to ClinRO assessment development and evaluation will lead to more efficient and accurate measurement of treatment effects. This is important beyond regulatory approval in that it provides evidence for the uptake of new interventions into clinical practice and provides justification to payers for reimbursement on the basis of the clearly demonstrated added value of the new intervention
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Tertiary lymphoid structures sustain cutaneous B cell activity in hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a chronic skin condition affecting approximately 1% of the US population. HS skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu, the biology and the contribution of these cells in HS pathogenesis are unclear. We aimed to investigate the dynamics and microenvironmental interactions of B cells within cutaneous HS lesions. Combining histological analysis, single-cell RNA sequencing, and spatial transcriptomics profiling of HS lesions, we defined the tissue microenvironment relative to B cell activity within this disease. Our findings identified tertiary lymphoid structures (TLSs) within HS lesions and described organized interactions among T cells, B cells, antigen-presenting cells, and skin stroma. We found evidence that B cells within HS TLSs actively underwent maturation, including participation in germinal center reactions and class switch recombination. Moreover, skin stroma and accumulating T cells were primed to support the formation of TLSs and facilitate B cell recruitment during HS. Our data definitively demonstrated the presence of TLSs in lesional HS skin and point to ongoing cutaneous B cell maturation through class switch recombination and affinity maturation during disease progression in this inflamed nonlymphoid tissue
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Phytochemicals perturb membranes and promiscuously alter protein function.
A wide variety of phytochemicals are consumed for their perceived health benefits. Many of these phytochemicals have been found to alter numerous cell functions, but the mechanisms underlying their biological activity tend to be poorly understood. Phenolic phytochemicals are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examined five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochemicals alters lipid bilayer properties and the function of diverse membrane proteins. Molecular dynamics simulations show that these phytochemicals modify bilayer properties by localizing to the bilayer/solution interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochemicals, consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochemicals are due to cell membrane perturbations, rather than specific protein binding
Characterization of berkelium(III) dipicolinate and borate compounds in solution and the solid state
Electronic Structure and Properties of Berkelium Iodates
The
reaction of <sup>249</sup>BkÂ(OH)<sub>4</sub> with iodate under
hydrothermal conditions results in the formation of BkÂ(IO<sub>3</sub>)<sub>3</sub> as the major product with trace amounts of BkÂ(IO<sub>3</sub>)<sub>4</sub> also crystallizing from the reaction mixture.
The structure of BkÂ(IO<sub>3</sub>)<sub>3</sub> consists of nine-coordinate
Bk<sup>III</sup> cations that are bridged by iodate anions to yield
layers that are isomorphous with those found for Am<sup>III</sup>,
Cf<sup>III</sup>, and with lanthanides that possess similar ionic
radii. BkÂ(IO<sub>3</sub>)<sub>4</sub> was expected to adopt the same
structure as MÂ(IO<sub>3</sub>)<sub>4</sub> (M = Ce, Np, Pu), but instead
parallels the structural chemistry of the smaller Zr<sup>IV</sup> cation.
Bk<sup>III</sup>–O and Bk<sup>IV</sup>–O bond lengths
are shorter than anticipated and provide further support for a postcurium
break in the actinide series. Photoluminescence and absorption spectra
collected from single crystals of BkÂ(IO<sub>3</sub>)<sub>4</sub> show
evidence for doping with Bk<sup>III</sup> in these crystals. In addition
to luminescence from Bk<sup>III</sup> in the BkÂ(IO<sub>3</sub>)<sub>4</sub> crystals, a broad-band absorption feature is initially present
that is similar to features observed in systems with intervalence
charge transfer. However, the high-specific activity of <sup>249</sup>Bk (<i>t</i><sub>1/2</sub> = 320 d) causes oxidation of
Bk<sup>III</sup> and only Bk<sup>IV</sup> is present after a few days
with concomitant loss of both the Bk<sup>III</sup> luminescence and
the broadband feature. The electronic structure of BkÂ(IO<sub>3</sub>)<sub>3</sub> and BkÂ(IO<sub>3</sub>)<sub>4</sub> were examined using
a range of computational methods that include density functional theory
both on clusters and on periodic structures, relativistic <i>ab initio</i> wave function calculations that incorporate spin–orbit
coupling (CASSCF), and by a full-model Hamiltonian with spin–orbit
coupling and Slater–Condon parameters (CONDON). Some of these
methods provide evidence for an asymmetric ground state present in
Bk<sup>IV</sup> that does not strictly adhere to Russel–Saunders
coupling and Hund’s Rule even though it possesses a half-filled
5<i>f</i> <sup>7</sup> shell. Multiple factors contribute
to the asymmetry that include 5<i>f</i> electrons being
present in microstates that are not solely spin up, spin–orbit
coupling induced mixing of low-lying excited states with the ground
state, and covalency in the Bk<sup>IV</sup>–O bonds that distributes
the 5<i>f</i> electrons onto the ligands. These factors
are absent or diminished in other <i>f</i><sup>7</sup> ions
such as Gd<sup>III</sup> or Cm<sup>III</sup>