This paper reports a room temperature visible light photocatalyzed method for the C–H amination of arenes and heteroarenes. A key enabling advance in this work is the design of N-acyloxyphthalimides ...as precursors to nitrogen-based radical intermediates for these transformations. A broad substrate scope is presented, including the selective meta-amination of pyridine derivatives. A radical aromatic substitution mechanism is proposed.
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IJS, KILJ, NUK, PNG, UL, UM
Dynamic phototuning of 3D hydrogel stiffness Stowers, Ryan S.; Allen, Shane C.; Suggs, Laura J.
Proceedings of the National Academy of Sciences,
02/2015, Volume:
112, Issue:
7
Journal Article
Peer reviewed
Open access
Significance Extracellular matrix (ECM) stiffness is an influential factor in many biological processes. Temporal changes in ECM stiffness are observed in cancer, cardiovascular disease, and wound ...healing, and are likely involved in disease progression. However, no cell culture systems exist to appropriately model temporal changes in ECM stiffness to determine the biological relevance and mechanisms involved. Here, we present a 3D hydrogel cell culture system in which the matrix stiffness can be tuned by light. Our approach offers both spatial and temporal control of stiffness, is compatible with cell culture, and can be used transdermally for in vivo applications. This system is amenable to many applications to investigate the influence of matrix stiffness on cell behavior and fate.
Hydrogels are widely used as in vitro culture models to mimic 3D cellular microenvironments. The stiffness of the extracellular matrix is known to influence cell phenotype, inspiring work toward unraveling the role of stiffness on cell behavior using hydrogels. However, in many biological processes such as embryonic development, wound healing, and tumorigenesis, the microenvironment is highly dynamic, leading to changes in matrix stiffness over a broad range of timescales. To recapitulate dynamic microenvironments, a hydrogel with temporally tunable stiffness is needed. Here, we present a system in which alginate gel stiffness can be temporally modulated by light-triggered release of calcium or a chelator from liposomes. Others have shown softening via photodegradation or stiffening via secondary cross-linking; however, our system is capable of both dynamic stiffening and softening. Dynamic modulation of stiffness can be induced at least 14 d after gelation and can be spatially controlled to produce gradients and patterns. We use this system to investigate the regulation of fibroblast morphology by stiffness in both nondegradable gels and gels with degradable elements. Interestingly, stiffening inhibits fibroblast spreading through either mesenchymal or amoeboid migration modes. We demonstrate this technology can be translated in vivo by using deeply penetrating near-infrared light for transdermal stiffness modulation, enabling external control of gel stiffness. Temporal modulation of hydrogel stiffness is a powerful tool that will enable investigation of the role that dynamic microenvironments play in biological processes both in vitro and in well-controlled in vivo experiments.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
In the mid-twentieth century, growing North American textile and ready-to-wear industries vigorously appropriated Native American aesthetics to cultivate a commercial and design identity apart from ...Europe. Most studies of the circulation of Indigenous idioms in these industries focus on Southwestern or South Pacific regionalisms, and scholarship on studio and commercial fabric and fashion design from the Northwest Coast in the twentieth century is limited. This paper contributes by raising Indigenous and non-Indigenous use of Northwest Coast design forms during the politically turbulent 1940s–1960s and analyzing the impact of this aesthetic vocabulary within broader North American textiles and fashion. Throughout, I engage with the approaches of critical fashion theory and multiple modernisms, considering the frictions of property and power relations within settler-colonial states, then and now. Drawing from study of objects, periodicals, and archival materials as well as first-person perspectives, I contextualize these representations within entangled art, museum, and design worlds in the Northwest Coast, New York City, and the Southwest. My examination illustrates that Northwest Coast artists and art ideas asserted a peripheral but locatable role in mid-century textiles and fashion, facilitating the development of today’s robust Indigenous fashion network on the Northwest Coast and its cultural politics.
Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single‐cell approaches ...to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single‐cell microglia transcriptomes. We discovered microglial co‐expression network modules associated with age, sex, and APOE‐ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single‐cell transcriptomes revealed significant overlap between age‐associated module genes and both pro‐inflammatory and disease‐associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta‐analyses with published bulk and single‐cell microglial datasets further supported our findings. Thus, these data represent a well‐characterized human microglial transcriptome resource and highlight age, sex, and APOE‐related microglial immunometabolism perturbations with potential relevance in neurodegeneration.
Using bulk and single‐cell approaches, we identified microglial subclusters enriched for different biological functions. Activated microglia were more abundant with aging and lipid localization genes were upregulated. In APOE‐ε4 carriers, homeostatic microglia were reduced along with downregulation of carbohydrate metabolism genes, whereas cholesterol absorption genes were unregulated in macrophages and activated microglia.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The persistence of drug resistant cell populations following chemotherapeutic treatment is a significant challenge in the clinical management of cancer. Resistant subpopulations arise via both cell ...intrinsic and extrinsic mechanisms. Extrinsic factors in the microenvironment, including neighboring cells, glycosaminoglycans, and fibrous proteins impact therapy response. Elevated levels of extracellular fibrous proteins are associated with tumor progression and cause the surrounding tissue to stiffen through changes in structure and composition of the extracellular matrix (ECM). We sought to determine how this progressively stiffening microenvironment affects the sensitivity of breast cancer cells to chemotherapeutic treatment. MDA-MB-231 triple negative breast carcinoma cells cultured in a 3D alginate-based hydrogel system displayed a stiffness-dependent response to the chemotherapeutic doxorubicin. MCF7 breast carcinoma cells cultured in the same conditions did not exhibit this stiffness-dependent resistance to the drug. This differential therapeutic response was coordinated with nuclear translocation of YAP, a marker of mesenchymal differentiation. The stiffness-dependent response was lost when cells were transferred from 3D to monolayer cultures, suggesting that endpoint ECM conditions largely govern the response to doxorubicin. To further examine this response, we utilized a platform capable of dynamic ECM stiffness modulation to allow for a change in matrix stiffness over time. We found that MDA-MB-231 cells have a stiffness-dependent resistance to doxorubicin and that duration of exposure to ECM stiffness is sufficient to modulate this response. These results indicate the need for additional tools to integrate mechanical stiffness with therapeutic response and inform decisions for more effective use of chemotherapeutics in the clinic.
Major gaps exist in the routine initiation and dose up-titration of guideline-directed medical therapies (GDMT) for patients with heart failure with reduced ejection fraction. Without novel ...approaches to improve prescribing, the cumulative benefits of heart failure with reduced ejection fraction treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients.
The EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction) trial randomized patients with heart failure with reduced ejection fraction from a diverse health system to usual care versus patient activation tools-a 3-minute video and 1-page checklist-delivered electronically 1 week before, 3 days before, and 24 hours before a cardiology clinic visit. The tools encouraged patients to work collaboratively with their clinicians to "make one positive change" in heart failure with reduced ejection fraction prescribing. The primary endpoint was the percentage of patients with GDMT medication initiations and dose intensifications from immediately preceding the cardiology clinic visit to 30 days after, compared with usual care during the same period.
EPIC-HF enrolled 306 patients, 290 of whom attended a clinic visit during the study period: 145 were sent the patient activation tools and 145 were controls. The median age of patients was 65 years; 29% were female, 11% were Black, 7% were Hispanic, and the median ejection fraction was 32%. Preclinic data revealed significant GDMT opportunities, with no patients on target doses of β-blocker, sacubitril/valsartan, and mineralocorticoid receptor antagonists. From immediately preceding the cardiology clinic visit to 30 days after, 49.0% in the intervention and 29.7% in the control experienced an initiation or intensification of their GDMT (
=0.001). The majority of these changes were made at the clinician encounter itself and involved dose uptitrations. There were no deaths and no significant differences in hospitalization or emergency department visits at 30 days between groups.
A patient activation tool delivered electronically before a cardiology clinic visit improved clinician intensification of GDMT. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03334188.
The binding of carboxylate- and acetylacetonate-linked chromophores to homodisperse polyoxotitanate nanoclusters with 17 Ti atoms or more are surveyed and found to be limited to chelate-bidentate and ...the bridging modes, the former being dominant for the acetylacetonate-linked chromophores, the latter for the carboxylate linkers. Chromophores with acetylacetonate linking groups invariably bind in the chelate mode, whereas carboxylic acid terminated chromophores more frequently are observed to have the bridging mode, with the exception of three cases in which a strong electron-donating substituent is present on two different sensitizers. The calculations for isonicotinateand nitrophenylacetylacetonate functionalized Ti17 clusters show the observed binding modes to correspond to the lower energy functionalized clusters, but do not predict the difference between the cinnamic acid and dimethylaminocinnamic acid binding to Ti17, which are bridging and chelate respectively. Both binding modes were never observed to occur for a single chromophore, even when synthetic conditions were varied. Density of state calculations show broadening and splitting of the chromophore LUMO on complexation due to interaction with the cluster’s conduction band, as well as frequent penetration of sensitizer orbitals into the bandgap of the functionalized nanoparticle.
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IJS, KILJ, NUK, PNG, UL, UM
Aim
More than ever, ecologists seek to understand how species are distributed and have assembled into communities using the “filtering framework”. This framework is based on the hypothesis that local ...assemblages result from a series of abiotic and biotic filters applied to regional species pools and that these filters leave predictable signals in observed diversity patterns. In theory, statistical comparisons of expected and observed patterns enable data‐driven tests of assembly processes. However, so far this framework has fallen short in delivering generalizable conclusions, challenging whether (and how) diversity patterns can be used to characterize and understand underlying assembly processes better.
Methods
By synthesizing the previously raised critiques and suggested solutions in a comprehensive way, we identify 10 pitfalls that can lead to flawed interpretations of α‐diversity patterns, summarize solutions developed to circumvent these pitfalls and provide general guidelines.
Results
We find that most issues arise from an overly simplistic view of potential processes that influence diversity patterns, which is often motivated by practical constraints on study design, focal scale and methodology. We outline solutions for each pitfall, such as methods spanning over spatial, environmental or phylogenetic scales, and suggest guidelines for best scientific practices in community ecology. Among key future challenges are the integration of mechanistic modelling and multi‐trophic interactions.
Main conclusions
Our conclusion is that the filtering framework still holds promise, but only if researchers successfully navigate major pitfalls, foster the integration of mechanistic modelling and multi‐trophic interactions and directly account for uncertainty in their conclusions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
There has been a dramatic rise in opioid abuse, and diversion of excess, unused prescriptions is a major contributor. We assess the impact of implementing a new standardized pain care bundle to ...reduce postoperative opioids in outpatient general surgical procedures.
This study was designed to demonstrate non-inferiority for the primary end point: patient-reported average pain in the first 7 postoperative days. We prospectively evaluated 224 patients who underwent laparoscopic cholecystectomy or open hernia repair (inguinal, umbilical) pre-intervention to 192 patients post-intervention. We implemented a multimodal intra- and postoperative analgesic bundle, including promoting co-analgesia, opioid-reduced prescriptions, and patient education designed to clarify patient expectations. Patients completed a brief pain inventory at their first postoperative visit. Groups were compared using chi-square test, Mann-Whitney U test, and independent samples t-test, where appropriate.
No difference was seen in average postoperative pain scores in the pre- vs post-intervention groups (2.3 vs 2.1 of 10; p = 0.12). The reported quality of pain control improved post-intervention (good/very good pain control in 69% vs 85%; p < 0.001). The median total morphine equivalents for prescriptions filled in the post-intervention group were significantly less (100; interquartile range 75 to 116 pre-intervention vs 50; interquartile range 50 to 50 post-intervention; p < 0.001). Only 78 of 172 (45%) patients filled their opioid prescription in the post-intervention group (p < 0.001), with no significant difference in prescription renewals (3.5% pre-intervention vs 2.6% post-intervention; p = 0.62).
For outpatient open hernia repair and cholecystectomy, a standardized pain care bundle decreased opioid prescribing significantly and frequently eliminated opioid use, while adequately treating postoperative pain and improving patient satisfaction.
Thiopurines (eg, 6-mercaptopurine MP) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited ...NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15-guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15−/− mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15−/− mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15−/− mice also showed excessive accumulation of a thiopurine active metabolite (ie, DNA-incorporated thioguanine nucleotides DNA-TG) in an MP dose–dependent fashion, as a plausible cause of increased toxicity. MP dose reduction effectively normalized systemic exposure to DNA-TG in Nudt15−/− mice and largely eliminated Nudt15 deficiency–mediated toxicity. In 95 children with acute lymphoblastic leukemia, MP dose adjustment also directly led to alteration in DNA-TG levels, the effects of which were proportional to the degree of NUDT15 deficiency. Using leukemia-bearing mice with concordant Nudt15 genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in Nudt15−/− mice receiving a reduced MP dose compared with Nudt15+/+ counterparts exposed to a standard dose. In conclusion, we demonstrated that NUDT15 genotype–guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.
•We established a Nudt15 knockout mouse model with which to evaluate individualized thiopurine therapy.•Preemptive NUDT15 genotype–guided thiopurine dosing can effectively prevent drug toxicity without compromising antileukemic efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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