Both natural enzymatic systems and synthetic porous material catalysts utilize well-defined and uniform channels to dictate reaction selectivities on the basis of size or shape. Mimicry of this ...design element in homogeneous systems is generally difficult owing to the flexibility inherent in most small molecular species. Herein, we report the synthesis of a tripodal ligand scaffold that orients a narrow and rigid cavity atop accessible metal coordination space. The permanent void is formed through a macrocyclization reaction whereby the 3,5-dihydroxyphenyl arms are covalently linked through methylene bridges. Deprotonative metallation leads to anionic and coordinatively unsaturated complexes of divalent cobalt, nickel, and zinc. An analogous series of trigonal monopyramidal complexes bearing a nonmacrocyclized variant of the tripodal ligand are also reported. Physical characterization of the coordination complexes has been carried out using multiple spectroscopic techniques (NMR, EPR, and UV–vis), cyclic voltammetry, and X-ray diffraction. Complexes of the macrocyclized LOCH2O3– ligand retain a rigid cavity upon metallation, with this cavity guarding the entrance to the open axial coordination site. Through a combination of spectroscopic and computational studies, it is shown that acetonitrile entry into the void is sterically precluded, disrupting anticipated coordination at the intracavity site.
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IJS, KILJ, NUK, PNG, UL, UM
We previously used a pulse-based
assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here we advanced this model ...system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both
and
we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.
Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically ...been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that ...cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%.
CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period.
A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%.
The difference in peak Vo2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048).
CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
► Dynamic respiratory sinus arrhythmia (RSA) change during anger-induction predicted children's self-control of aggression. ► Effective regulation of anger was reflected in stronger initial RSA ...suppression, followed by RSA augmentation or recovery. ► Interactions between children's anger-prone temperament and parenting predicted parasympathetic regulation of anger.
This study examined the moderating effects of child temperament on the association between maternal socialization and 4–6-year-old children's dynamic respiratory sinus arrhythmia (RSA) change in response to anger-themed emotional materials (N=180). We used latent growth curve modeling to explore adaptive patterns of dynamic RSA change in response to anger. Greater change in RSA during anger-induction, characterized by more initial RSA suppression and a subsequent return to baseline, was related to children's better regulation of aggression. For anger-themed materials, low levels of authoritarian parenting predicted more RSA suppression and recovery for more anger-prone children, whereas more authoritative parenting predicted more RSA suppression and recovery for less anger-prone children. These findings suggest that children's adaptive patterns of dynamic RSA change can be characterized by latent growth curve modeling, and that these patterns may be differentially shaped by parent socialization experiences as a function of child temperament.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
EQUiPPED is a multicomponent quality improvement initiative combining education, electronic clinical decision support, and individual provider feedback to influence prescribing and improve medication ...safety for older adults. The objective here was to evaluate the effectiveness and sustainability of EQUiPPED to reduce the use of potentially inappropriate medications (PIMs), as defined by the American Geriatrics Society 2012 Beers Criteria, prescribed to older Veterans at the time of emergency department (ED) discharge. This evaluation represents a pre‐ and post‐intervention comparison of PIM prescriptions at 4 urban Veteran Affairs (VA) Medical Center EDs. Poisson regression was used to compare the number of PIMs prescribed to Veterans 65 years or older discharged from the ED for at least 6 months prior to the first EQUiPPED intervention at each site and for at least 12 months following the final EQUiPPED intervention. The implementation timeline varied by site depending on local resources. All 4 sites showed a significant and sustained reduction in use of PIMs. The proportion of PIMs at site one decreased from 11.9% (SD 1.8) pre‐EQUiPPED to 5.1% (SD 1.4) post‐EQUiPPED (P < .0001); site 2 from 8.2% (SD 0.8) pre to 4.5% (SD 1.0) post (P < .0001); site 3 from 8.9% (SD 1.9) pre to 6.1% (SD 1.7) post (P = .0007); and site 4 from 7.4% (SD 1.7) pre to 5.7% (SD 0.8) post (P = .04). These results suggest a multicomponent program to influence provider prescribing behavior leads to safer prescribing for older adults discharged from the ED and is sustainable across multiple VA ED sites.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Atmospheric deposition of trace elements and isotopes (TEI) is an important source of trace metals to the open ocean, impacting TEI budgets and distributions, stimulating oceanic primary ...productivity, and influencing biological community structure and function. Thus, accurate sampling of aerosol TEIs is a vital component of ongoing GEOTRACES cruises, and standardized aerosol TEI sampling and analysis procedures allow the comparison of data from different sites and investigators. Here, we report the results of an aerosol analysis intercalibration study by seventeen laboratories for select GEOTRACES‐relevant aerosol species (Al, Fe, Ti, V, Zn, Pb, Hg, NO3−, and SO42−) for samples collected in September 2008. The collection equipment and filter substrates are appropriate for the GEOTRACES program, as evidenced by low blanks and detection limits relative to analyte concentrations. Analysis of bulk aerosol sample replicates were in better agreement when the processing protocol was constrained (± 9% RSD or better on replicate analyses by a single lab, n = 7) than when it was not (generally 20% RSD or worse among laboratories using different methodologies), suggesting that the observed variability was mainly due to methodological differences rather than sample heterogeneity. Much greater variability was observed for fractional solubility of aerosol trace elements and major anions, due to differing extraction methods. Accuracy is difficult to establish without an SRM representative of aerosols, and we are developing an SRM for this purpose. Based on these findings, we provide recommendations for the GEOTRACES program to establish consistent and reliable procedures for the collection and analysis of aerosol samples.
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BFBNIB, FZAB, GIS, IJS, KILJ, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background Semiconstrained total elbow arthroplasty is used to improve elbow function and reduce pain. Although effective, high complication rates exist, with the polyethylene bushing especially ...susceptible to failure. The Discovery Elbow System (Biomet Inc, Warsaw, IN, USA) contains a spherical bearing designed to minimize polyethylene wear. This prospective, multicenter clinical study investigated the 4-year (mean) outcomes of this elbow. Methods From 2002 to 2009, 92 patients (71 women, 21 men; mean age, 63.9 years; range, 33.4-88.7 years) received 99 Discovery elbows at 4 centers. The study cohort was limited to 46 elbows with complete preoperative and minimum 2-year clinical (modified American Shoulder and Elbow Surgeons elbow score) and radiographic follow-up. Results Mean follow-up was 4.1 years (range, 2-5.9 years). All American Shoulder and Elbow Surgeons elbow score components improved significantly ( P < .001). Mean flexion-extension arcs increased from 81° to 121° and pronation-supination arcs from 134° to 163° ( P < .001). Loose locking screws in 2 elbows (first-generation screws), a loose polyethylene bearing in 1 (history of falls), and a condyle/bearing in 1 (deep infection) were exchanged. Among the 46 elbows, gross survivorship was humeral/ulnar components, 100%; condyles, 97.8%; bearings, 95.7%; and screws, 95.7%. One humeral component (2.2%) was radiographically loose but not revised. An additional elbow (elbow 47) that did not meet the criteria for inclusion (<2 years of follow-up) was revised due to a loose humeral component and was reported separately. Conclusion The Discovery elbow increased function and decreased pain with high survivorship at a mean of 4.1 years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Parental supportiveness and protective overcontrol and preschoolers' parasympathetic regulation were examined as predictors of temperamental inhibition, social wariness, and internalizing problems. ...Lower baseline vagal tone and weaker vagal suppression were expected to mark poorer dispositional self-regulatory capacity, leaving children more susceptible to the influence of parental socialization. Less supportive mothers had preschoolers with more internalizing problems. One interaction between baseline vagal tone and maternal protective overcontrol, predicting social wariness, conformed to the moderation hypothesis. Conversely, vagal suppression moderated several links between paternal socialization and children's anxious difficulties in the expected pattern. There were more links between mothers' self-reported parenting and child outcomes than were noted for direct observations of maternal behavior, whereas the opposite tended to be true for fathers.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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