University at Buffalo, The State University of New York
Recent publications
Objective: This study examines the knowledge and confidence of college healthcare providers in discussing vaping with their college student populations. Methods: This is a mixed-methods descriptive study using a sequential-explanatory approach, consisting of a cross-sectional, online survey followed by qualitative interviews. Survey data was collected from 50 college health providers located at 26 colleges in the 64-campus State University of New York system. Targeted semi-structured interviews (N = 11) were conducted by telephone with providers who completed the survey. Results: Despite high reported levels of knowledge and confidence, few providers had participated in educational activities relative to vaping. There was evidence of misinformation about e-cigarettes, and they did not know what product (nicotine/cannabis) students typically vape. Conclusions: Findings indicate a potential disconnect between providers' perceived and actual knowledge of college student vaping and demonstrate areas of opportunity to assist college health providers in comprehensively addressing vaping with their college student populations. Innovation: College health providers played a key role in lowering rates of combustible cigarette smoking, but little is known about how they are now are communicating with college students about e-cigarette and cannabis vaping. This paper examines college health providers' knowledge, confidence, and training needs relative to vaping communications.
The problem of robust hypothesis testing is studied, where under the null and the alternative hypotheses, the data-generating distributions are assumed to be in some uncertainty sets, and the goal is to design a test that performs well under the worst-case distributions over the uncertainty sets. In this paper, uncertainty sets are constructed in a data-driven manner using kernel method, i.e., they are centered around empirical distributions of training samples from the null and alternative hypotheses, respectively; and are constrained via the distance between kernel mean embeddings of distributions in the reproducing kernel Hilbert space, i.e., maximum mean discrepancy (MMD). The Bayesian setting and the Neyman-Pearson setting are investigated. For the Bayesian setting where the goal is to minimize the worst-case error probability, an optimal test is firstly obtained when the alphabet is finite. When the alphabet is infinite, a tractable approximation is proposed to quantify the worst-case average error probability, and a kernel smoothing method is further applied to design test that generalizes to unseen samples. A direct robust kernel test is also proposed and proved to be exponentially consistent. For the Neyman-Pearson setting, where the goal is to minimize the worst-case probability of miss detection subject to a constraint on the worst-case probability of false alarm, an efficient robust kernel test is proposed and is shown to be asymptotically optimal. Numerical results are provided to demonstrate the performance of the proposed robust tests.
Providing personalized behavioral information as feedback to drivers can lead to safer practices. However, feedback efficacy is likely moderated by the driver's level of motivation towards behavioral change. Gamification of feedback, which is the incorporation of game design elements intended to motivate drivers toward safe behaviors, could potentially reduce unsafe behaviors in the long term. This article assesses a gamified driver feedback design in mitigating driver distraction and enhancing driving performance among younger drivers. A driving simulator study was conducted with 42 drivers, 21–30 years old, comparing: 1) no feedback; 2) real-time feedback; 3) real-time feedback + postdrive feedback; and 4) real-time feedback + postdrive feedback + game design elements to examine their impact on distraction engagement (manual-visual interactions with an in-vehicle display) and driving performance. Groups that received postdrive feedback, both with and without gamification elements, showed reduced distraction engagement and enhanced driving performance compared to no feedback. Between the two types of postdrive feedback, the nongamified feedback provided more benefits in reducing the 95th percentile glance duration to the in-vehicle display, and the one with gamification provided more benefits in reducing the rate of manual interactions with the in-vehicle display. Meanwhile, no benefits were observed with the real-time feedback only condition over no feedback. Despite minor differences in efficacy, both postdrive and gamification feedback appear to be effective countermeasures for distracted driving in the short term. Future research should investigate other game designs for driver feedback and assess the impact of feedback gamification over longer-term exposure.
  • Ruodan Liu
    Ruodan Liu
  • Naoki Masuda
    Naoki Masuda
Hypergraphs have been a useful tool for analyzing population dynamics such as opinion formation and the public goods game occurring in overlapping groups of individuals. In the present study, we propose and analyze evolutionary dynamics on hypergraphs, in which each node takes one of the two types of different but constant fitness values. For the corresponding dynamics on conventional networks, under the birth-death process and uniform initial conditions, most networks are known to be amplifiers of natural selection; amplifiers by definition enhance the difference in the strength of the two competing types in terms of the probability that the mutant type fixates in the population. In contrast, we provide strong computational evidence that a majority of hypergraphs are suppressors of selection under the same conditions by combining theoretical and numerical analyses. We also show that this suppressing effect is not explained by one-mode projection, which is a standard method for expressing hypergraph data as a conventional network. Our results suggest that the modeling framework for structured populations in addition to the specific network structure is an important determinant of evolutionary dynamics, paving a way to studying fixation dynamics on higher-order networks including hypergraphs.
Purpose of Review Use of renin–angiotensin–aldosterone system (RAAS) inhibiting medications is critical in the prevention of cardiovascular disease and kidney function decline in patients with chronic kidney disease (CKD); however, these agents can lead to hyperkalemia, an electrolyte disorder associated with risk of arrythmia, conduction disorders, and increased overall mortality. Discontinuation, or reduction of dose, of RAAS inhibitor therapy in hyperkalemic patients with CKD can lead to loss of kidney and cardiovascular protection afforded by these medications. Given the high prevalence of hyperkalemia among patients with CKD utilizing RAAS inhibitors, clear management principles are critical to minimize risk and maximize benefit when facing this clinical dilemma. Recent Findings Strategies to mitigate hyperkalemia that do not interfere with optimal RAAS inhibitor therapy should be prioritized when managing potassium elevation in patients with CKD. These strategies include discontinuing non-RAAS inhibitor medications known to cause hyperkalemia, correction of metabolic acidosis, and maximization of medication therapies that lower serum potassium, including diuretics and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Initiation of potassium exchange resins should also be considered to allow for sustained RAAS inhibitor utilization. An approach which employs multiple strategies concurrently is important to mitigate hyperkalemia and maintain long-term use of RAAS-inhibitors. Summary Persistence of RAAS inhibitor use in patients with CKD is important to slow kidney function decline, delay onset of dialysis or the need for kidney transplant, and prevent adverse cardiovascular outcomes. When hyperkalemia develops among patients with CKD utilizing a RAAS inhibitor, a deliberate effort to reduce serum potassium levels using an approach that allows for continuation of maximally dosed RAAS inhibitor therapy is important. Patient education and engagement in the potassium management process is important for sustained success.
  • Florian Wittlinger
    Florian Wittlinger
  • Surbhi P Chitnis
    Surbhi P Chitnis
  • Calvin D Pham
    Calvin D Pham
  • [...]
  • David E Heppner
    David E Heppner
Targeted small-molecule therapies in mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) have undergone several generations of development in response to acquired drug resistance. With the emergence of the highly prevalent T790M and C797S drug-resistant mutations, a diverse arsenal of ATP-competitive molecules has led to the front-line drug AZD9291 (osimertinib) and several in clinical development. Several allosteric inhibitors bind a site adjacent to the ATP-binding site and exhibit synergy when dosed in combination with certain ATP-competitive inhibitors. Structure-guided design of molecules that anchor to both sites simultaneously, namely ATP-allosteric bivalent inhibitors, have been reported as proof-of-concept EGFR mutant-selective compounds, however their properties are underexplored and currently exhibit modest activity in human cancer cell lines. To better understand the structural and functional properties of such molecules, we have carried out structure-activity relationships (SAR) defining the groups of the allosteric pocket that are responsible for enabling mutant selectivity and potency of this series. We find that the back pocket phenol ring enables stronger binding while the methylisoindolinone is responsible for enabling selectivity for the oncogenic mutations. An optimized allosteric site-binding group and a C797-targeting ATP-site scaffold exhibit inhibitory effects in a variety of EGFR mutant cell lines, which is improved over earlier examples. Additionally, a closely related reversible-binding analogue exhibits mutant-selective activity and ~1 nM biochemical potency against L858R/T790M/C797S and promising antiproliferative effects in human cancer cells indicating that ATP-allosteric bivalent kinase inhibitors may serve as tool compounds in understanding overcoming these important resistance mechanisms. These results highlight the utility of bivalent ATP-allosteric compounds in understanding the impact certain functional groups have in the potency and mutant-selectivity enabled by allosteric pocket binding. The results of this study incentivize further investigations of compounds that bind within an exit vector made accessible in the inactive αC-helix “out” conformation as a novel approach for kinase inhibitors.
Objective Telomere length (TL) is a posited pathway through which chronic stress results in biological dysregulation and subsequent adverse health outcomes. Food insecurity is associated with shorter TL. Social support, which is defined by the size and function of an individual’s social network, is associated with better health outcomes. The present study assesses whether social support modifies the relationship between food security and TL. Design Cross-sectional study design. Linear regression was used to assess the association between social support and TL, stratified by social support level. A multiplicative interacted model was used to formally test modification. Setting Data come from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2001-2002 waves. Participants Adults aged 60 years and older who have measurements for TL. Results Our sample comprised 2,674 participants, and 63.5% of the total sample had low social support, with 13.3% being food insecure. In fully adjusted models, food insecurity was negatively though modestly associated (P=0.13) with TL. Associations between food insecurity and TL were significantly modified by social support (interaction P=0.026), whereby food insecurity had a stronger effect among individuals with high social support (coefficient = -0.099 (95% CI: -0.161, -0.038)) compared to low social support (coefficient = -0.001, (95% CI: -0.033, 0.032)). Conclusion Food insecurity is modestly associated with shorter TL. Contrary to our hypothesis, food insecurity had more deleterious effects on TL among participants with high social support than low social support. Results may indicate that the food insecure population is a higher needs population, and increased social support reflects these needs rather than providing protective effects.
Background and Purpose This study was dedicated to investigating the agreement of the calculated results of two CT perfusion (CTP) postprocessing software packages, including parameter maps and ischemic volume, focusing on the infarct core volume (ICV) and penumbra volume (PV). Methods A retrospective collection of 235 patients with acute ischemic stroke who underwent CTP examination were enrolled. All images had been analyzed with two software pipelines, RAPID CTP and AccuCTP, and the comparative analysis was based on ICV and PV results calculated by both software packages. The agreement of parameter maps was evaluated by root mean square error and Bland‐Altman analysis. The ICV and PV agreement was evaluated by intraclass correlation coefficient (ICC) and Bland‐Altman analysis. The accuracy of ICV and PV based on multiple thresholds was also analyzed. Results The ICV and PV of AccuCTP and RAPID CTP show excellent agreement. The relative differences of the parameter maps were all within 10% and the Bland‐Altman analysis also showed a strong agreement. From ordinary least squares fitting results, both ICV and PV had a remarkably high goodness of fit (ICV, R ² = 0.975 [ p <.001]; PV, R ² = 0.964 [ p <.001]). For the ICC analysis, both had high ICC scores (ICV ICC 0.984, 95% CI [confidence interval] 0.973‐0.989; PV ICC 0.955, 95% CI 0.947‐0.964). Furthermore, multi‐threshold analysis on the basis of ICV and PV also achieved reliable analytical accuracy. Conclusions The image analysis results of AccuCTP are in excellent agreement with RAPID CTP and can be used as an alternative analysis tool to RAPID CTP software in stroke clinical practice.
There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNβ)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNβ formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNβ-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. Pregnant women with multiple sclerosis exposed to IM IFNβ-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8–12 weeks. Data were collected on IM IFNβ-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. Three-hundred and two patients with a median (range) age of 31.0 (16–48) years and a median (range) gestational age at the time of enrollment of 10.1 (4–39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNβ-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks’ gestation (rate 10.5%; 95% confidence interval 7.2–15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8–10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNβ-1a exposure. This large US registry study suggests IM IFNβ-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNβ-1a use during pregnancy. NCT00168714, 15 September, 2005.
  • Layla M. Ortiz
    Layla M. Ortiz
  • Natasha O’Malley
    Natasha O’Malley
  • Kenneth Blum
    Kenneth Blum
  • [...]
  • Panayotis K. Thanos
    Panayotis K. Thanos
Methylphenidate and mixed amphetamine salts (MAS) are psychostimulant medications widely prescribed for various psychiatric disorders. Although these medications are known to adversely impact bone mineral content and density, as well as biomechanical integrity during skeletal development in rats, their effect on bone density in children remains largely unknown. The primary aim of this work was to investigate the effects of methylphenidate and MAS on bone density following distal radius fractures in pediatric populations, and secondarily assess any impact on healing. The retrospective case-control study was designed to assess fracture healing in patients treated with stimulant drugs and matched controls. For the primary outcome, X-rays ( n = 188) were evaluated using an optical density image analysis technique to compare bone density throughout the bone healing process. Results showed that methylphenidate and MAS significantly reduced bone healing by approximately 20% following distal radius fractures in these children. The data also suggested that duration of psychostimulant use played a role in bone healing; the longer the treatment (1–5 years), the lower the bone density was observed (by approximately 52%) as compared to controls (no medication). However, subjects taking these drugs for longer than 5 years did not show a significant difference. Our results suggested that children taking psychostimulants for up to 5 years had slower bone healing following distal radius fractures. Orthopedic surgeons planning elective surgeries should be cognizant of this as a potential issue in recovery after any elective bone procedures and preoperatively optimize bone health as well as counsel patients and their families.
While the accessibility of enhancers is dynamically regulated during development, promoters tend to be constitutively accessible and poised for activation by paused Pol II. By studying Lola-I, a Drosophila zinc finger transcription factor, we show here that the promoter state can also be subject to developmental regulation independently of gene activation. Lola-I is ubiquitously expressed at the end of embryogenesis and causes its target promoters to become accessible and acquire paused Pol II throughout the embryo. This promoter transition is required but not sufficient for tissue-specific target gene activation. Lola-I mediates this function by depleting promoter nucleosomes, similar to the action of pioneer factors at enhancers. These results uncover a level of regulation for promoters that is normally found at enhancers and reveal a mechanism for the de novo establishment of paused Pol II at promoters.
Importance Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower–hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher–hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO 2 ) in either group (0.2% vs −0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and Relevance In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO 2 . Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. Trial Registration Identifier: NCT01702805
Signaling modules, such as mitogen-activated protein kinase (MAPK) pathways, are evolutionarily conserved drivers of cell differentiation and stress responses. In many fungal species including pathogens, MAPK pathways control filamentous growth, where cells differentiate into an elongated cell type. The convenient model budding yeast Saccharomyces cerevisiae undergoes filamentous growth by the filamentous growth (fMAPK) pathway; however, the inducers of the pathway remain unclear, perhaps because pathway activity has been mainly studied in laboratory conditions. To address this knowledge gap, an ecological framework was used, which uncovered new fMAPK pathway inducers, including pectin, a material found in plants, and the metabolic byproduct ethanol. We also show that induction by a known inducer of the pathway, the non-preferred carbon source galactose, required galactose metabolism and induced the pathway differently than glucose limitation or other non-preferred carbon sources. By exploring fMAPK pathway function in fruit, we found that induction of the pathway led to visible digestion of fruit rind through a known target, PGU1 , which encodes a pectolytic enzyme. Combinations of inducers (galactose and ethanol) stimulated the pathway to near-maximal levels, which showed dispensability of several fMAPK pathway components (e.g., mucin sensor, p21-activated kinase), but not others (e.g., adaptor, MAPKKK) and required the Ras2-protein kinase A pathway. This included a difference between the transcription factor binding partners for the pathway, as Tec1p, but not Ste12p, was partly dispensable for fMAPK pathway activity. Thus, by exploring ecologically relevant stimuli, new modes of MAPK pathway signaling were uncovered, perhaps revealing how a pathway can respond differently to specific environments. IMPORTANCE Filamentous growth is a cell differentiation response and important aspect of fungal biology. In plant and animal fungal pathogens, filamentous growth contributes to virulence. One signaling pathway that regulates filamentous growth is an evolutionarily conserved MAPK pathway. The yeast Saccharomyces cerevisiae is a convenient model to study MAPK-dependent regulation of filamentous growth, although the inducers of the pathway are not clear. Here, we exposed yeast cells to ecologically relevant compounds (e.g., plant compounds), which identified new inducers of the MAPK pathway. In combination, the inducers activated the pathway to near-maximal levels but did not cause detrimental phenotypes associated with previously identified hyperactive alleles. This context allowed us to identify conditional bypass for multiple pathway components. Thus, near-maximal induction of a MAPK pathway by ecologically relevant inducers provides a powerful tool to assess cellular signaling during a fungal differentiation response.
In the century after emancipation, the long shadow of slavery left African Americans well short of the freedom promised to them. While sharecropping and debt peonage entrapped Black people in the South, European colonialism had bred a new slavery that menaced the liberty of even more Africans. A core group of Black freedom movement leaders, including Ida B. Wells and W. E. B. Du Bois, followed their nineteenth-century predecessors in insisting that the continuation of racial slavery anywhere put Black freedom on the line everywhere. They even predicted the consequences that ignited the recent nationwide Black Lives Matter movement—the rise of a prison industrial complex and the consequent erosion of African Americans' faith in the criminal justice system. The Freedom Movement's Lost Legacy: Black Abolitionism since Emancipation is the first historical account of the Black freedom movement's response to modern slavery in the twentieth century. Keith P. Griffler details how the mainstream international antislavery movement became complicit in the enslavement of Black and brown people across the world through its sponsorship of racist international antislavery law that gave the "new slavery" explicit legal sanction. Black freedom movement activists, thinkers, and organizers did more than call out this breathtaking betrayal of abolitionist principles: they dedicated themselves to the eradication of slavery in whatever forms it assumed on the global stage and developed an expansive vision of human freedom. This timely and important work reminds us that the resurgence of today's Black freedom movements is a manifestation and continuation of the traditions and efforts of these early Black leaders and abolitionists—an important chapter in the history of antislavery and the ongoing Black freedom struggle.
The use of orally‐administered therapeutic proteins for treatment of inflammatory bowel disease (IBD) has been limited due to the harsh gastrointestinal environment and low bioavailability that affects delivery to diseased sites. Here, a nested delivery system, termed Gal‐IL10‐EVs (C/A) that protects interleukin 10 (IL‐10) from degradation in the stomach and enables targeted delivery of IL‐10 to inflammatory macrophages infiltrating the colonic lamina propria, is reported. Extracellular vesicles (EVs) carrying IL‐10 are designed to be secreted from genetically engineered mammalian cells by a plasmid system, and EVs are subsequently modified with galactose, endowing the targeted IL‐10 delivery to inflammatory macrophages. Chitosan/alginate (C/A) hydrogel coating on Gal‐IL10‐EVs enables protection from harsh conditions in the gastrointestinal tract and favorable delivery to the colonic lumen, where the C/A hydrogel coating is removed at the diseased sites. Gal‐IL10‐EVs control the production of reactive oxygen species (ROS) and inhibit the expression of proinflammatory cytokines. In a murine model of colitis, Gal‐IL10‐EVs (C/A) alleviate IBD symptoms including inflammatory responses and disrupt colonic barriers. Taken together, Gal‐IL10‐EVs (C/A) features biocompatibility, pH‐responsive drug release, and macrophage‐targeting as a therapeutic platform for oral delivery of bioactive proteins for treating intestinal diseases.
Food insecurity, defined as unpredictable access to food that may not meet a person’s nutritional needs, is paradoxically associated with higher BMI (kg/m2) and obesity. Research has shown delay discounting, a behavioral economic measure of the preference for immediate rather than delayed rewards, is related to higher BMI, and moderates the relationship between income and food insecurity. Based on this research, we used regression models to test whether delay discounting, consideration of future consequences, and perceived stress were atemporal mediators of the food insecurity-BMI relation in 313 mothers, controlling for demographic variables. A secondary aim was to replicate the finding that delay discounting moderates the relationship between low income and high food insecurity. Results showed that low income was associated with higher food insecurity, and higher food insecurity was associated with higher BMI. Delay discounting was the only variable that was indirectly related to both paths of the food-insecurity-BMI relation. Delay discounting accounted for 22.2% of the variance in the low-income-food insecurity-obesity relation, and the total model accounted for 38.0% of the variance. The relation between low income and food insecurity was moderated by delay discounting. These data suggest that delay discounting is a potential mediator of the relationship between food insecurity and high BMI, which suggests reducing discounting in the future could be a novel target to reduce food insecurity and help people with food insecurity to reduce their excess body weight. Trial Registration. This trial is registered with NCT02873715.
Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.
Conjugated polymers with chiral side chains are of interest in areas including chiral photonics, optoelectronics, and chemical and biological sensing. However, the low dissymmetry factors of most neat polymer thin films have limited their practical application. Here, we demonstrate a robust method to increase the absorption dissymmetry factor in a poly‐fluorene‐thiophene ( PF8TS series) system by varying molecular weight and introducing an achiral plasticizer, polyethylene monoalcohol (PEM‐OH). Extending chain length within the optimal range and adding this long‐chain alcohol significantly enhanced the chiroptical properties of spin‐coated and annealed thin films. Mueller matrix ellipsometric analysis showed good agreement with the steady‐state transmission measurements confirming a strong chiral response (circular dichroism and circular birefringence), ruling out linear dichroism, birefringence, and specific reflection effects. Solid‐state NMR studies of annealed hybrid chiral polymer systems showed enhancement of signals associated with aromatic π‐stacked backbone and the ordered side‐chain conformations. Further studies using Raman spectrometry, X‐ray diffraction, differential scanning calorimetry, atomic force microscopy, and polarized optical microscopy indicate that PEM‐OH facilitates mesoscopic crystal domain ordering upon annealing. This provides new insights into routes for tuning optical activity in conjugated polymers. This article is protected by copyright. All rights reserved
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12,922 members
Mahdi M Moosa
  • Department of Physics
Sara Metcalf
  • Department of Geography
Matthew Knepley
  • Department of Computer Science and Engineering
Senthilvelan Manohar
  • Center for Hearing and Deafness
14260, Buffalo, NY, United States
Head of institution
Satish Tripathi