The wavelength-selective, reversible photocontrol over various molecular processes in parallel remains an unsolved challenge. Overlapping ultraviolet-visible spectra of frequently employed ...photoswitches have prevented the development of orthogonally responsive systems, analogous to those that rely on wavelength-selective cleavage of photo-removable protecting groups. Here we report the orthogonal and reversible control of two distinct types of photoswitches in one solution, that is, a donor-acceptor Stenhouse adduct (DASA) and an azobenzene. The control is achieved by using three different wavelengths of irradiation and a thermal relaxation process. The reported combination tolerates a broad variety of differently substituted photoswitches. The presented system is also extended to an intramolecular combination of photoresponsive units. A model application for an intramolecular combination of switches is presented, in which the DASA component acts as a phase-transfer tag, while the azobenzene moiety independently controls the binding to α-cyclodextrin.
Abstract Following global brain ischemia and reperfusion, it is well-established that neurons undergo a translation arrest that is reversible in surviving neurons, but irreversible in vulnerable ...neurons. We previously showed a correlation between translation arrest in reperfused neurons and the presence of granular mRNA-containing structures we termed “mRNA granules.” Here we further characterized the mRNA granules in reperfused neurons by performing colocalization studies using fluorescent in situ hybridization for poly(A) mRNAs and immunofluorescence histochemistry for markers of organelles and mRNA-binding proteins. There was no colocalization between the mRNA granules and markers of endoplasmic reticulum, cis- or trans-Golgi apparatus, mitochondria, microtubules, intermediate filaments, 60S ribosomal subunits, or the HuR ligands APRIL and pp32. The mRNA granules colocalized with the neuronal marker NeuN regardless of the relative vulnerability of the neuron type. RNA immunoprecipitation of HuR from the cytoplasmic fraction of 8 h reperfused forebrains selectively isolated hsp70 mRNA suggesting the mRNA granules are soluble structures. Together, these results rule out several organelle systems and a known HuR pathway as being directly involved in mRNA granule function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective
To provide updated guidelines for pharmacologic management of juvenile idiopathic arthritis (JIA), focusing on treatment of oligoarthritis, temporomandibular joint (TMJ) arthritis, and ...systemic JIA with and without macrophage activation syndrome. Recommendations regarding tapering and discontinuing treatment in inactive systemic JIA are also provided.
Methods
We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.
Results
Similar to those published in 2019, these JIA recommendations are based on clinical phenotypes of JIA, rather than a specific classification schema. This guideline provides recommendations for initial and subsequent treatment of JIA with oligoarthritis, TMJ arthritis, and systemic JIA as well as for tapering and discontinuing treatment in subjects with inactive systemic JIA. Other aspects of disease management, including factors that influence treatment choice and medication tapering, are discussed. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional.
Conclusion
This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis. It serves as a tool to support clinicians, patients, and caregivers in decision‐making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision‐making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically ...active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light‐controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E‐Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.
The state of the art of rational design in photopharmacology is analyzed with a focus on E‐Z molecular photoswitches and on computer‐aided approaches. By meticulously examining the design strategies of photopharmacology through the lens of medicinal chemistry, this review identifies existing trends and novel opportunities for the development of photoswitchable ligands.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
The intersection of granulomatosis and autoinflammatory disease is a rare occurrence that can be generally subdivided into purely granulomatous phenotypes and disease spectra that are ...inclusive of granulomatous features. NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-related disease, which includes Blau syndrome and early-onset sarcoidosis, is the prototypic example of granulomatous inflammation in the context of monogenic autoinflammation. Granulomatous inflammation has also been observed in two related autoinflammatory diseases caused by mutations in PLCG2 (phospholipase Cγ2). More recently, mutations in LACC1 (laccase domain-containing protein 1) have been identified as the cause of a monogenic form of systemic juvenile idiopathic arthritis, which does not itself manifest granulomatous inflammation, but the same LACC1 mutations have also been shown to cause an early-onset, familial form of a well-known granulomatous condition, Crohn’s disease (CD). Rare genetic variants of PLCG2 have also been shown to cause a monogenic form of CD, and moreover common variants of all three of these genes have been implicated in polygenic forms of CD. Additionally, common variants of NOD2 and LACC1 have been implicated in susceptibility to leprosy, a granulomatous infection. Although no specific mechanistic link exists between these three genes, they form an intriguing web of susceptibility to both monogenic and polygenic autoinflammatory and granulomatous phenotypes.
The development of novel transition metal carbides for improved hard coating technologies requires a detailed understanding of the factors influencing their stability and mechanical performance. To ...this end, we carried out first principles calculations based on density functional theory to tabulate the electronic structures, formation energies, and phonon dispersion curves of 3d transition metal carbides adopting zincblende, rocksalt, and cesium chloride structures. By analyzing the corresponding results, we outline a theoretical framework that describes how valence electron concentration and bonding configuration control the stability of these compounds. Many early transition metal carbides are predicted to be stable in the rocksalt and zincblende structures, enabled by filled bonding states, whereas the cesium chloride structure shows persistent instability. For compounds that are predicted to be stable, mechanical properties were investigated through calculation of elastic tensors, from which observable properties including Vicker’s hardness and ductility were derived. A robust mechanical performance is shown to be correlated with complete filling of bonding orbitals as illustrated for rocksalt TiC and VC, which have calculated hardnesses of 25.66 and 22.63 GPa respectively. However, enhanced ductility and toughness can be achieved by allowing partial occupation of the antibonding states as in CrC, which has a relatively low Pugh’s ratio of 0.51.
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•Early 3d transition metal carbides show robust stability and high hardness.•Complete filling of bonding orbitals is crucial to maintain stability.•Partial antibonding contributes to decreased hardness but enhanced ductility.•Overoccupied antibonding orbitals cause instabilities in the rocksalt structure.•Jahn-Teller distortions cause instabilities in the zincblende structure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Most stellar remnants so far have been found in binary systems, where they interact with matter from their companions. Isolated neutron stars and black holes are difficult to find as they are dark, ...yet they are predicted to exist in our Galaxy in vast numbers. We explored the OGLE-III data base of 150 million objects observed in years 2001–2009 and found 59 microlensing events exhibiting a parallax effect due to the Earth's motion around the Sun. Combining parallax and brightness measurements from microlensing light curves with expected proper motions in the Milky Way, we identified 13 microlensing events which are consistent with having a white dwarf, neutron star or a black hole lens and we estimated their masses and distances. The most massive of our black hole candidates has 9.3 M⊙ and is at a distance of 2.4 kpc. The distribution of masses of our candidates indicates a continuum in mass distribution with no mass gap between neutron stars and black holes. We also present predictions on how such events will be observed by the astrometric Gaia mission.
Abstract
Most of studied social interactions arise from dyadic relations. An exception is Heider Balance Theory that postulates the existence of triad dynamics, which however has been elusive to ...observe. Here, we discover a sufficient condition for the Heider dynamics observability: assigning the edge signs according to multiple opinions of connected agents. Using longitudinal records of university student mutual contacts and opinions, we create a coevolving network on which we introduce models of student interactions. These models account for: multiple topics of individual student opinions, influence of such opinions on dyadic relations, and influence of triadic relations on opinions. We show that the triadic influence is empirically measurable for static and dynamic observables when signs of edges are defined by multidimensional differences between opinions on all topics. Yet, when these signs are defined by a difference between opinions on each topic separately, the triadic interactions’ influence is indistinguishable from noise.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A straightforward synthesis of azobenzenes with bathochromically‐shifted absorption bands is presented. It employs an ortho‐lithiation of aromatic substrates, followed by a coupling reaction with ...aryldiazonium salts. The products are obtained with good to excellent yields after simple purification. Moreover, with the presented methodology, a structurally diverse panel of different azobenzenes, including unsymmetric tetra‐ortho‐substituted ones, can be readily obtained, which paves the way for future development of red‐light‐addressable azobenzene derivatives for in vivo application.
Red‐shifted tetra‐ortho‐substituted azobenzenes were synthesized in a rapid manner with high functional group tolerance (see picture). The privileged tetra‐ortho‐methoxy, ‐chloro, and ‐fluoro azobenzenes become readily accessible, which paves the way for future applications of red‐shifted azobenzenes in material and biological sciences.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The endo-lysosomal pathway is essential for intracellular transport and the degradation of extracellular cargo. The relationship between three populations of endo-lysosomal vesicles--Rab7-positive, ...LAMP1-positive, and both Rab7- and LAMP1-postive--was probed with fluorescence microscopy and single particle tracking. Of specific interest was determining if these vesicles were intermediate or terminal vesicles in the transport of extracellular cargo. We find that the major organelle in the endo-lysosomal pathway, both in terms of population and cargo transport, is positive for Rab7 and LAMP1. Dextran, a fluid phase cargo, shifts from localization within all three populations of vesicles at 30 minutes and 1 hour to primarily LAMP1- and Rab7/LAMP1-vesicles at longer times. This demonstrates that LAMP1- and Rab7/LAMP1-vesicles are terminal vesicles in the endo-lysosomal pathway. We tested two possible mechanisms for this distribution of cargo, delivery to mannose 6-phosphate receptor (M6PR)-negative vesicles and the fusion dynamics of individual vesicles. We find no correlation with M6PR but do find that Rab7-vesicles undergo significantly fewer fusion events than LAMP1- or Rab7/LAMP1-vesicles suggesting that the distribution of fluid phase cargo is driven by vesicle dynamics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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