We investigate the confinement-induced formation and stability of helix morphologies in lamella-forming AB diblock copolymers via large-scale, particle-based, single-chain-in-mean-field simulations. ...Such helix structures are rarely observed in bulk or thin films. Structure formation is induced by quenching incompatibility, χN, from a disordered morphology. If the surfaces of the cylindrical confinement do not prefer one component over the other, we observe that stacked lamellae, with their normals along the cylinder axis, are the preferred morphology. Kinetically, this morphology initially forms close to the cylinder surface, whereas the spontaneous, spinodal microphase separation in the cylinder’s interior gives rise to a microemulsion-like morphology, riddled with defects and no directional order. Subsequently, the ordered morphology on the cylinder surface progresses inward, pervading the entire volume. In case that the cylindrical pore is only partially filled, the additional confinement along the cylinder axis generally gives rise to incommensurability between the equilibrium spacing of stacked lamellae and the cylinder height. To accommodate this mismatch, the lamella normals will tilt away from the cylinder axis and generate helices of lamellae on the surface of the cylinder. Again, this order progresses from the cylinder surface inward, generating a chiral morphology. Because the spacing between the internal AB interfaces decreases upon approaching the helix center, the concomitant stress results in a decrease in the number of lamellae and the formation of unique dislocation defects. This type of chiral defect morphology is reproducibly formed by the kinetics of structure formation in partly filled cylindrical pores with nonpreferential surfaces and may find applications in photonic applications.
Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262
...parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target-inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the
resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.
Although clinical trials of autologous whole bone marrow for cardiac repair demonstrate promising results, many practical and mechanistic issues regarding this therapy remain highly controversial. ...Here, we report the results of a randomized study of bone-marrow-derived mesenchymal stem cells, administered to pigs, which offer several new insights regarding cellular cardio-myoplasty. First, cells were safely injected by using a percutaneous-injection catheter 3 d after myocardial infarction. Second, cellular transplantation resulted in long-term engraftment, profound reduction in scar formation, and near-normalization of cardiac function. Third, transplanted cells were preprepared from an allogeneic donor and were not rejected, a major practical advance for widespread application of this therapy. Together, these findings demonstrate that the direct injection of cellular grafts into damaged myocardium is safe and effective in the periinfarct period. The direct delivery of cells to necrotic myocardium offers a valuable alternative to intracoronary cell injections, and the use of allogeneic mesenchymal stem cells provides a valuable strategy for cardiac regenerative therapy that avoids the need for preparing autologous cells from the recipient.
Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. ...Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano3,2-dthiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.
The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in ...PI3K-dependent suppression, we compared the transcriptome of WT and p110δ(D910A) Tregs. Among the genes that were differentially expressed was the gene for the transmembrane cyclic ADP ribose hydrolase CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3(+)CD25(+)CD4(+) T cells originating in the thymus and on Tregs in the spleen. CD38(high) WT Tregs showed superior suppressive activity to CD38(low) Tregs, which failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38(+/-) mice were unimpaired despite lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110δ(D910A) mice can in part be explained by the failure of CD38(high) cells to develop.
Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic ...progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4
T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.
Local probes of the electronic ground state are essential for understanding hydrogen bonding in aqueous environments. When tuned to the dissociative core-excited state at the O1s pre-edge of water, ...resonant inelastic X-ray scattering back to the electronic ground state exhibits a long vibrational progression due to ultrafast nuclear dynamics. We show how the coherent evolution of the OH bonds around the core-excited oxygen provides access to high vibrational levels in liquid water. The OH bonds stretch into the long-range part of the potential energy curve, which makes the X-ray probe more sensitive than infra-red spectroscopy to the local environment. We exploit this property to effectively probe hydrogen bond strength via the distribution of intramolecular OH potentials derived from measurements. In contrast, the dynamical splitting in the spectral feature of the lowest valence-excited state arises from the short-range part of the OH potential curve and is rather insensitive to hydrogen bonding.
Surgical options for cartilage resurfacing may be significantly improved by advances and application of biomaterials that direct tissue repair. A poly(ethylene glycol) diacrylate (PEGDA) hydrogel was ...designed to support cartilage matrix production, with easy surgical application. A model in vitro system demonstrated deposition of cartilage-specific extracellular matrix in the hydrogel biomaterial and stimulation of adjacent cartilage tissue development by mesenchymal stem cells. For translation to the joint environment, a chondroitin sulfate adhesive was applied to covalently bond and adhere the hydrogel to cartilage and bone tissue in articular defects. After preclinical testing in a caprine model, a pilot clinical study was initiated where the biomaterials system was combined with standard microfracture surgery in 15 patients with focal cartilage defects on the medial femoral condyle. Control patients were treated with microfracture alone. Magnetic resonance imaging showed that treated patients achieved significantly higher levels of tissue fill compared to controls. Magnetic resonance spin-spin relaxation times (T(2)) showed decreasing water content and increased tissue organization over time. Treated patients had less pain compared with controls, whereas knee function International Knee Documentation Committee (IKDC) scores increased to similar levels between the groups over the 6 months evaluated. No major adverse events were observed over the study period. With further clinical testing, this practical biomaterials strategy has the potential to improve the treatment of articular cartilage defects.
Efforts to track the severity and public health impact of coronavirus disease 2019 (COVID-19) in the United States have been hampered by state-level differences in diagnostic test availability, ...differing strategies for prioritization of individuals for testing, and delays between testing and reporting. Evaluating unexplained increases in deaths due to all causes or attributed to nonspecific outcomes, such as pneumonia and influenza, can provide a more complete picture of the burden of COVID-19.
To estimate the burden of all deaths related to COVID-19 in the United States from March to May 2020.
This observational study evaluated the numbers of US deaths from any cause and deaths from pneumonia, influenza, and/or COVID-19 from March 1 through May 30, 2020, using public data of the entire US population from the National Center for Health Statistics (NCHS). These numbers were compared with those from the same period of previous years. All data analyzed were accessed on June 12, 2020.
Increases in weekly deaths due to any cause or deaths due to pneumonia/influenza/COVID-19 above a baseline, which was adjusted for time of year, influenza activity, and reporting delays. These estimates were compared with reported deaths attributed to COVID-19 and with testing data.
There were approximately 781 000 total deaths in the United States from March 1 to May 30, 2020, representing 122 300 (95% prediction interval, 116 800-127 000) more deaths than would typically be expected at that time of year. There were 95 235 reported deaths officially attributed to COVID-19 from March 1 to May 30, 2020. The number of excess all-cause deaths was 28% higher than the official tally of COVID-19-reported deaths during that period. In several states, these deaths occurred before increases in the availability of COVID-19 diagnostic tests and were not counted in official COVID-19 death records. There was substantial variability between states in the difference between official COVID-19 deaths and the estimated burden of excess deaths.
Excess deaths provide an estimate of the full COVID-19 burden and indicate that official tallies likely undercount deaths due to the virus. The mortality burden and the completeness of the tallies vary markedly between states.
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