cssi/SciSciGPT-SciSciNet huggingface dataset:
Increasing the Endoplasmic Reticulum Pool of the F508del Allele of the Cystic Fibrosis Transmembrane Conductance Regulator Leads to Greater Folding Correction by Small Molecule Therapeutics

Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present. In human primary airway cells, the paucity of Band B F508del is even more pronounced, although F508del and WT mRNA concentrations are comparable. Therefore, to augment levels of "repairable" F508del CFTR and identify small molecules that then correct this pool, we developed compound library screening protocols based on automated protein detection. First, cell-based imaging measurements were used to semi-quantitatively estimate distribution of F508del CFTR by high content analysis of two-dimensional images. We evaluated ~2,000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository in a pilot screen and identified agents that increase the F508del protein pool. Second, we analyzed ~10,000 compounds representing diverse chemical scaffolds for effects on total CFTR expression using a multi-plate fluorescence protocol and describe compounds that promote F508del maturation. Together, our findings demonstrate proof of principle that agents identified in this fashion can augment the level of endoplasmic reticulum (ER) resident "Band B" F508del CFTR suitable for pharmacologic correction. As further evidence in support of this strategy, PYR-41-a compound that inhibits the E1 ubiquitin activating enzyme-was shown to synergistically enhance F508del rescue by C18, a small molecule corrector. Our combined results indicate that increasing the levels of ER-localized CFTR available for repair provides a novel route to correct F508del CFTR.
Chromatin Remodeling in Heart Failure

Chromatin provides a dynamic DNA scaffold that reacts to physiological and pathological signals to control the accessibility of DNA sequence and the genomic responses to environmental stimuli. Chromatin can be regulated by nucleosome remodeling, histone modification, and DNA methylation. Histone and DNA modifications occur by covalent alterations of the side chains of histone or bases of DNA, catalyzed by specific histone- and DNA-modifying enzymes, whereas nucleosome or chromatin-remodeling controls noncovalent changes of nucleosomes, including their position and histone composition, effected by adenosine triphosphate (ATP)-dependent chromatin-remodeling complexes. Within the nucleosome, the chromatin remodelers can replace canonical histones with variant forms of histones, which are involved in cardiac stress response. In addition, chromatin remodelers can interact with histone- and DNA-modifying enzymes to control chromatin structure and reprogram gene expression in pathologically stressed hearts. More recently, a chromatin-remodeling factor was found to interact with a cardiac-specific long noncoding RNA to control gene expression and maintain cardiac homeostasis. These functional aspects of chromatin remodelers are critical for the pathogenesis of cardiomyopathy and heart failure. This chapter is focused on the recent progress in understanding the roles of chromatin-remodeling factors in heart failure, new chromatin-based mechanisms, and potential therapeutic strategies for heart failure.
Response to John Cairns: The Contribution of Transiently Hypermutable Cells to Mutation in Stationary Phase

IN his letter, John Cairns reiterates the model described in his Appendix ([Cairns 1999][1]) to Rosche and Foster ([1999][2]) and seems to be concerned that we have not adopted it as an explanation for our observations ([Bull et al. 2000][3]). His model is that most Lac+ adaptive mutants arise in
5d Metal(IV) Imide Complexes. The Impact (or Lack Thereof) of d-Orbital Occupation on Methane Activation and Functionalization

This research evaluates 5d metal imide complexes, (OH)2M═NMe (M = W, Re, or Os), and their reactions with methane to form dimethylamine. Each is calculated to follow a consistent reaction pathway regardless of the metal’s d-orbital occupation, whereby the methane C–H bond undergoes oxidative addition (OA) to the metal and then the methyl migrates from the metal to the nitrogen to form an amide. Finally, hydrogen migrates to the nitrogen before dissociating to form amine products. While homolytic M–imide, M–amide M–H, and M–CH3 bond dissociation free energies (BDFEs) were analyzed, the BDFEs of neither hexavalent nor tetravalent metal moieties reflect the oxidative addition kinetics. Instead, a strain theory approach, supported by electron density analysis for the OA transition state, is found to be explanatory. Notably, the rate-determining step, the hydrogen migration transition state, has a consistent jump in free energy versus the preceding intermediate, (OH)2MIV(H)—N(CH3)Me, for all metals evaluated. ...
Normal Pulmonary Artery Pressure in Sickle Cell Patient with Severe Iron Deficiency Anemia.

One-third of adults with sickle cell disease (SCD) have echocardiographic (ECHO) evidence of pulmonary hypertension (PHTN), a complication associated with early mortality. Because the pulmonary artery pressures in most SCD patients with PHTN are only mildly elevated, the question arises whether such increases are primarily a reflection of the high cardiac output state that accompanies the anemia. Recently we treated a 45 year-old woman with homozygous sickle-cell disease and profound iron deficiency due to heavy menstrual flow. Two ECHOs were done while she was severely iron deficient (Hb 5 g/dl, MCV 57 fl, reticulocytes 72,407/mm 3 , serum bilirubin 0.5 mg/dl, iron 29 mcg/dl, transferrin 376 mg/dl, and ferritin 3.6 ng/ml). Her pulmonary artery systolic pressure (PAs) was calculated from the tricuspid regurgitant jet velocity (TRV) using the Bernoullie equation: 4(TRV 3 ) + central venous pressure (assumed at 10 mm Hg). The PAs was normal, 24 mm Hg, even though the patient also had M-mode evidence of left ventricular diastolic dysfunction and a small pericardial effusion. Treatment with intravenous iron and red cell transfusion partially improved her iron deficiency and anemia (Hb 7 g/dl, MCV 67 fl, serum bilirubin 0.7 mg/dl, iron 54 mcg/dl, transferrin 322 mg/dl, and ferritin 33.9 ng/ml) but also increased her hemolytic rate: though LDH data are unavailable, the reticulocyte count rose to 117,900/mm 3 . Repeat ECHO exams at this time showed that her pulmonary artery systolic pressures increased to 35–36 mm Hg. These values are at or near the lower range of pulmonary artery systolic pressures (36–70 mm Hg) measured in SCD patients in whom PHTN was diagnosed at cardiac catheterization. The figure compares hematologic values, and pulmonary artery systolic pressure in our iron deficient SS patient at baseline and during treatment. This experience, though anecdotal, suggests that the PHTN in SCD is unrelated to the anemia per se and, by implication, also unrelated to the high cardiac output. The patient’s mild pulmonary systolic hypertension actually developed with improvement of her anemia. Our hypothesis is that when the patient’s iron deficiency was most severe, the low MCHC decreased Hb S polymerization and decreased hemolysis, as in other iron deficient SCD patients. Her relatively low hemolytic rate may have prevented the mild PHTN, which developed once treatment improved her iron deficiency but increased hemolysis. Our hypothesis is consistent also with an emerging new paradigm in sickle cell disease pathophysiology: a strong link between hemolysis-related nitric oxide system (NO) dysfunction and risks for pulmonary hypertension, leg ulcers, priapism, and death. In this context it is interesting that iron deficiency anemia up-regulates vascular nitric oxide synthase in animals. In humans iron deficiency increases NO production even in the absence of anemia. Hence, this patient’s iron depletion may have contributed to the maintenance of her low pulmonary pressures also by a direct NO-mediated vascular effect.
3-2-06. Somatosensory Evoked Potentials (SEPs) in Vitamin B12 deficiency

Abstract Vitamin B12 deficiency mainly affects the dorsal column. In this study, we investigated which part of the sensory pathway is affected in vitamin B12 deficiency using NCS and SEPs. We retrospectively reviewed EMG database of Teikyo University and Mitsui Memorial Hospital from 2008 to 2016, and enrolled patients who presented with sensory symptoms and/or gait disturbance, and whose serum B12 level was below 170 ng/ml. Enrolled were 17 patients. Spinal MRI demonstrated abnormalities in 4/17. NCS was abnormal in 3/15 patients for the sural nerve and in 5/12 patients for the median nerve. When NCS and peripheral segments of the SEPs were combined, conduction delay was detected in 12/15 patients for the lower limb and 8/13 patients for the upper limb. Delay of the central conduction was rarer, 3/15 patients in tibial SEPs. N9o to P13/14o segment in median SEPs was abnormal in 4/8 patients, although this is a mixture of the peripheral and central conductions. Vitamin B12 deficiency patients showed abnormalities of the peripheral nerve conduction more frequently than those of the central conduction. SEPs are useful in localizing the lesion along the sensory pathway, not only for CCT but for peripheral conduction.
Biomechanical Head-to-Head Comparison of 2 Sutures and the Giftbox Versus Bunnell Techniques for Midsubstance Achilles Tendon Ruptures.

Background:Acute midsubstance Achilles tendon ruptures are a common orthopaedic problem for which the optimal repair technique and suture type remain controversial. Head-to-head comparisons of curr...
Three-Coordinate Copper(II) Aryls: Key Intermediates in C–O Bond Formation

Copper(II) aryl species are proposed key intermediates in Cu-catalyzed cross-coupling reactions. Novel three-coordinate copper(II) aryls [CuII]-C6F5 supported by ancillary β-diketiminate ligands form in reactions between copper(II) alkoxides [CuII]-OtBu and B(C6F5)3. Crystallographic, spectroscopic, and DFT studies reveal geometric and electronic structures of these Cu(II) organometallic complexes. Reaction of [CuII]-C6F5 with the free radical NO(g) results in C-N bond formation to give [Cu](η2-ONC6F5). Remarkably, addition of the phenolate anion PhO- to [CuII]-C6F5 directly affords diaryl ether PhO-C6F5 with concomitant generation of the copper(I) species [CuI](solvent) and {[CuI]-C6F5}-. Experimental and computational analysis supports redox disproportionation between [CuII]-C6F5 and {[CuII](C6F5)(OPh)}- to give {[CuI]-C6F5}- and [CuIII](C6F5)(OPh) unstable toward reductive elimination to [CuI](solvent) and PhO-C6F5.
Africa: Clues About the Tendencies of the Global South

The “global political economy” and “development” are in flux in the second half of the second decade of the twenty-first century, challenging both analysis and policy. Yet, Africa has continued to grow along with Asia, indicative of burgeoning South-South ties, or a South-East axis. What is “emerging” is debatable: companies? economies? middle classes? powers? states? technologies? even universities? However, NTS threats are also proliferating, now including the “water-energy-food” “nexus”. Regional and transnational perspectives need to be continually refined to ensure that “global IR” is informed by the heterogeneous Global South.
Masculinity and Science in Britain, 1830–1918

Heather Ellis makes an effort in this interesting study to treat an aspect of masculinity that she believes has been under-represented in most previous work on science and masculinity. She cites a ...
Evidence of Alternative Modes of B Cell Activation Involving Acquired Fab Regions of N-Glycosylation in Antibody-Secreting Cells Infiltrating the Labial Salivary Glands of Patients With Sjögren's Syndrome.

Objective To better understand the role of B cells, the potential mechanisms responsible for their aberrant activation, and the production of autoantibodies in the pathogenesis of Sjogren's syndrome (SS), this study explored patterns of selection pressure and sites of N-glycosylation acquired by somatic mutation (acN-glyc) in the IgG variable (V) regions of antibody-secreting cells (ASCs) isolated from the minor salivary glands of patients with SS and non-SS control patients with sicca symptoms. Methods A novel method to produce and characterize recombinant monoclonal antibodies (mAb) from single cell-sorted ASC infiltrates was applied to concurrently probe expressed genes (all heavy- and light-chain isotypes as well as any other gene of interest not related to immunoglobulin) in the labial salivary glands of patients with SS and non-SS controls. V regions were amplified by reverse transcription-polymerase chain reaction, sequenced, and analyzed for the incidence of N-glycosylation and selection pressure. For specificity testing, the amplified regions were expressed as either the native mAb or mutant mAb lacking the acN-glyc motif. Protein modeling was used to demonstrate how even an acN-glyc site outside of the complementarity-determining region could participate in, or inhibit, antigen binding. Results V-region sequence analyses revealed clonal expansions and evidence of secondary light-chain editing and allelic inclusion, of which neither of the latter two have previously been reported in patients with SS. Increased frequencies of acN-glyc were found in the sequences from patients with SS, and these acN-glyc regions were associated with an increased number of replacement mutations and lowered selection pressure. A clonal set of polyreactive mAb with differential framework region 1 acN-glyc motifs was also identified, and removal of the acN-glyc could nearly abolish binding to autoantigens. Conclusion These findings support the notion of an alternative mechanism for the selection and proliferation of some autoreactive B cells, involving V-region N-glycosylation, in patients with SS.
Digital Humanities Within a Global Context: Creating Borderlands of Localized Expression

As scholars have begun the digitization of the world’s cultural materials, the understanding of what is to be digitized and how that digitization occurs remains narrowly imagined, with a distinct bias toward North American and European notions of culture, value and ownership. Humanists are well aware that cultural knowledge, aesthetic value and copyright/ownership are not monolithic, yet digital humanities work often expects the replication of narrow ideas of such. Drawing on the growing body of scholarship that situates the digital humanities in a broad global context, this paper points to areas of tension within the field and posits ways that digital humanities practitioners might resist such moves to homogenize the field. Working within the framework of border studies, the paper considers how working across national barriers might further digital humanities work. Finally, ideas of ownership and/or copyright are unique to country of origin and, as such, deserve careful attention. While open access is appealing in many digital humanities projects, it is not always appropriate, as work with indigenous cultural artifacts has revealed.
Seizing Teachable Moments to Develop Integrative Middle Level Curriculum

None of us was quite sure what was happening on the infamous morning of September 11, 2001. Throughout the day, as news spread through the school grapevine about the attacks on the World Trade Center and the Pentagon, my students were asking questions and drawing conclusions about the tragic story that was unfolding before us. When they came to school on September 12, they brought even more questions, and so did I. Who were the people responsible for these acts of terror? Why would they do such a thing? How should we, as individuals and as a nation, respond to these attacks? Despite the flood of information that immediately inundated the media, few things were certain. One thing, however, was crystal clear to me—I had to change my world geography curriculum. September 11, 2001, was a critical teachable moment that provided me and my team with an avenue to middle level curriculum that was relevant, challenging, integrative, and exploratory (see Virtue, 2002). As Erb (2005) suggested in his November Middle School Journal column, Hurricane Katrina has opened a similar window of opportunity for middle
Using the Habit App for Weight Loss Problem Solving: Development and Feasibility Study.

Background: Reviews of weight loss mobile apps have revealed they include very few evidence-based features, relying mostly on self-monitoring. Unfortunately, adherence to self-monitoring is often low, especially among patients with motivational challenges. One behavioral strategy that is leveraged in virtually every visit of behavioral weight loss interventions and is specifically used to deal with adherence and motivational issues is problem solving. Problem solving has been successfully implemented in depression mobile apps, but not yet in weight loss apps. Objective: This study describes the development and feasibility testing of the Habit app, which was designed to automate problem-solving therapy for weight loss. Methods: Two iterative single-arm pilot studies were conducted to evaluate the feasibility and acceptability of the Habit app. In each pilot study, adults who were overweight or obese were enrolled in an 8-week intervention that included the Habit app plus support via a private Facebook group. Feasibility outcomes included retention, app usage, usability, and acceptability. Changes in problem-solving skills and weight over 8 weeks are described, as well as app usage and weight change at 16 weeks. Results: Results from both pilots show acceptable use of the Habit app over 8 weeks with on average two to three uses per week, the recommended rate of use. Acceptability ratings were mixed such that 54% (13/24) and 73% (11/15) of participants found the diet solutions helpful and 71% (17/24) and 80% (12/15) found setting reminders for habits helpful in pilots 1 and 2, respectively. In both pilots, participants lost significant weight (P=.005 and P=.03, respectively). In neither pilot was an effect on problem-solving skills observed (P=.62 and P=.27, respectively). Conclusions: Problem-solving therapy for weight loss is feasible to implement in a mobile app environment; however, automated delivery may not impact problem-solving skills as has been observed previously via human delivery. Trial Registration: ClinicalTrials.gov NCT02192905; https://clinicaltrials.gov/ct2/show/NCT02192905 (Archived by WebCite at http://www.webcitation.org/6zPQmvOF2)
Modeling People Wearing Body Armor and Protective Equipment: Applications to Vehicle Design

Vehicle interiors are complex human-machine interfaces, posing substantial design challenges, particularly when the vehicle is also a workplace. These challenges are compounded by the wide variability in human size, shape, and preference. For law-enforcement officers, firefighters, soldiers, and other workers, specialized clothing or body borne gear can affect their accommodation, comfort, safety, and ability to perform. Digital human modeling has the potential to provide designers with accurate tools to represent human variability, but current software generally lacks the ability to represent accurate seated body shapes for occupants with body borne protective equipment. This paper presents an overview of research to develop body shape modeling tools for vehicles that incorporate body armor representations. Laser scan data drawn from a large-scale study of men in seated postures was used to develop a predictive model that generates body shape as a function of standard anthropometric dimensions and seat and workspace variables. The model is postured using a data-based approach that incorporates the effects of body armor and gear on posture. Importantly, the space claim for the body armor and body borne gear is validated by reference to laser scan data.
Numerical and Experimental Determination of Nonlinear Normal Modes of a Circular Perforated Plate

It is commonly known that nonlinearities in structures can lead to large amplitude responses that are not predicted by traditional theories. Thus a linear design could lead to premature failure if the structure actually behaves nonlinearly, or, conversely, nonlinearities could potentially be exploited to reduce stresses relative to the best possible design with a purely linear structure. When examining structures that operate in environments where a nonlinear response is possible, one can gain insight into the free and forced responses of a nonlinear system by determining the structure’s nonlinear normal modes (NNMs). NNMs extend knowledge gained from established linear normal modes (LNMs) into the nonlinear response range by quantifying how the unforced vibration frequency depends on the input energy. Recent works have shown that periodic excitations can be used to isolate a single NNM, providing a means for measuring NNMs in the laboratory. An extension of the modal indicator function can be used to ensure that the measured response is on the desired NNM. The experimentally measured NNMs can then be compared to numerically calculated NNMs for model validation. In this investigation, a circular perforated plate containing a distributed geometric nonlinearity is considered. This plate has demonstrated nonlinear responses when the displacements become comparable to the plate thickness. However, the system is challenging to model because the nonlinear response is potentially sensitive to small geometric features, residual stresses within the structure, and the boundary conditions.
Refining the nuclear localization signal within the Egr transcriptional coregulator NAB2.

NAB1 and 2 are coregulators for early growth response (Egr) transcription factors. The NAB1 nuclear localization signal (NLS) was previously described as a bipartite NLS of sequence R(X2 )K(X11 )KRXK. The sequence is conserved in NAB2 as K(X2 )R(X11 )KKXK; however, whether it functions as the NAB2 NLS has not been tested. We show that the KKXK motif in NAB2 is necessary and sufficient to mediate nuclear localization. Mutation of the KKXK motif to AAXA causes cytoplasmic localization of NAB2, while Lys/Arg-to-Ala mutations of the upstream K(X2 )R motif have no effect. Fusion of the KKXK motif to cytoplasmic protein eIF2Be causes nuclear localization. Altogether, this study refines our knowledge of the NAB2 NLS, demonstrating that KKXK343-346 is necessary and sufficient for nuclear localization.
Psychological Well-Being and Parent-Child Relationship Quality in Relation to Child Autism: An Actor-Partner Modeling Approach.

Parents of children with autism spectrum disorder (ASD) often report poor psychological well-being, including a high level of parenting stress and depressive symptoms. Little is known about the extent to which poor parent psychological well-being alters the emotional quality of the parent-child relationship in a context of child ASD. This study examined the association between actor (one's own) and partner (one's partner's) level of parenting stress and depressive symptoms and the emotional quality of the parent-child relationship using a Five Minute Speech Sample (FMSS) in 150 families of children with ASD, aged 5-12 years (85.7% male). Mothers and fathers were aged 38.69 (SD = 5.62) and 40.76 (SD = 6.19), respectively; 76% of mothers and 68% of fathers had a college degree. Structural equation modeling, using Analysis of Moment Structures software, was used to test Actor-Partner Interdependence Models. Results indicated that mother's level of parenting stress and depressive symptoms were associated with her own FMSS Warmth and Criticism toward the child with ASD 12 months later in negative and positive directions. Mother's level of parenting stress was also negatively associated with father's FMSS Warmth toward the child with ASD 12 months later. Finally, father's level of parenting stress was positively associated with his FMSS Criticism toward the child with ASD. Overall, findings indicate that the mother-child and father-child relationship are both impacted by parent psychological well-being in families of children with ASD; however, actor effects are stronger for mothers and partner effects were only found for fathers. Implications for interventions are discussed.
Asian Zika virus isolate significantly changes the transcriptional profile and alternative RNA splicing events in a neuroblastoma cell line

Abstract Alternative splicing of pre-mRNAs expands a single genetic blueprint to encode multiple functionally diverse protein isoforms. Viruses have previously been shown to interact with, depend on, and alter host splicing machinery. The consequences however incited by viral infection on the global alternative slicing (AS) landscape are under appreciated. Here we investigated the transcriptional and alternative splicing profile of neuronal cells infected with a contemporary Puerto Rican Zika virus (ZIKVPR) isolate, the prototypical Ugandan ZIKV (ZIKVMR) isolate and dengue virus 2 (DENV2). Our analyses revealed that ZIKVPR induced significantly more differential changes in expressed genes compared to ZIKVMR or DENV2, despite all three viruses showing equivalent infectivity and viral RNA levels. Consistent with the transcriptional profile, ZIKVPR induced a higher number of alternative splicing events compared to ZIKVMR or DENV2, and gene ontology analyses highlighted alternative splicing changes in genes associated with mRNA splicing. All three viruses modulated alternative splicing with ZIKVPR having the largest impact on splicing. ZIKV alteration of the transcriptomic landscape during infection caused changes in cellular RNA homeostasis, which might dysregulate neurodevelopment and function leading to neuropathologies such as microcephaly and Guillain-Barre syndrome associated with the ZIKV infection.
α-Gal and other recent findings that have informed our understanding of anaphylaxis.

Abstract Objective To summarize the current understanding of anaphylaxis, with an emphasis on major findings that have been reported within the last 10 years. Data Sources Queries relating to anaphylaxis, immunoglobulin E (IgE), and mast cells were conducted with PubMed and Google Scholar, searching for primary articles and review papers. Study Selections We focused on articles written in English and which were reported in major allergy and immunology journals. Results Anaphylaxis represents an extreme manifestation of a form of allergic immunity that appears to have evolved to protect against “toxic” threats that present at skin and mucosal barriers. The factors that have contributed to a rise in anaphylaxis are increasingly appreciated to relate to changes in hygiene and microbial ecology that have occurred with industrialization. Induction of allergen-specific IgG4 is often part of the allergic response and is associated with protection against anaphylaxis. The recognition of the α-Gal syndrome suggests that carbohydrates can be epitopes that are relevant to anaphylaxis and that IgE-mediated reactions do not always occur “immediately.” Conclusion Our understanding of anaphylaxis has advanced significantly over the past 10 years. It is anticipated that ongoing research will build on this foundation to further advance our knowledge of anaphylaxis and also translate into clinically meaningful therapies.
Exploiting tumor position differences between deep inspiration and expiration in lung stereotactic body radiation therapy planning

Abstract Purpose: We demonstrate proof of principle that normal tissue doses can be greatly reduced in lung stereotactic body radiation therapy (SBRT) for mobile tumors, if the delivered dose is split between opposite respiratory states. Methods: Patients that underwent 5 fraction lung SBRT at our institution and had deep inspiration breath hold (DIBH) and free breathing 4D computed tomography scans were included. Volumetric modulated arc therapy plans were generated on both respiratory phases and a third composite plan was generated delivering half the dose using the DIBH plan and the other half using the expiratory phase plan for each fraction. Computed tomography scans for the composite plan were fused based on ribs adjacent to the tumor to evaluate the dose volume histogram of critical structures. Results: Four patients with 4 total tumors had requisite planning scans available. Tumor size was between 0.7 to 2.9 cm and tumor movement 1.4 to 2.9 cm. Median reduction in the chest wall (CW) V30Gy for the composite plan was 74.6% (range 33.7 to 100%), 76.9% (range 32.9 to 100%), and 89.3% (range 69.5 to 100%) compared to the DIBH, expiration phase, and free breathing plans, respectively. Median reduction in CW maximum dose for the composite plan was 23.3% (range 0.27% to 46.4%), 23.5% (range 3.2 to 48.2%), and 23.4% (range 0.27% to 48.4%) compared to the DIBH, expiration phase, and free breathing plans, respectively. Greater reduction in CW maximum dose was observed when patients had no overlap in planning target volumes between DIBH and expiration phases (median reduction 43.9% for no overlap vs 2.7% with overlap). Between all plans, lung V20Gy absolute differences were within 1.3%. For 2 of 4 patients, the composite plan met constraints for 3 fraction SBRT, while standard plans did not. Conclusions: We conclude that composite DIBH-expiration SBRT planning has the potential to improve organ at risk sparing.
Development and optimization of orthotopic liver metastasis xenograft mouse models in uveal melanoma

Patients with metastatic uveal melanoma (MUM) in the liver usually die within 1 year. The development of new treatments for MUM has been limited by the lack of diverse MUM cell lines and appropriate animal models. We previously reported that orthotopic xenograft mouse models established by direct injection of MUM cells into the liver were useful for the analysis associated with tumor microenvironment in the liver. However, considering that patients with UM metastasize to the liver hematogenously, direct liver injection model might not be suitable for investigation on various mechanisms of liver metastasis. Here, we aim to establish new orthotopic xenograft models via hematogenous dissemination of tumor cells to the liver, and to compare their characteristics with the hepatic injection model. We also determine if hepatic tumors could be effectively monitored with non-invasive live imaging. tdtTomate-labeled, patient-derived MUM cells were injected into the liver, spleen or tail vein of immunodeficient NSG mice. Tumor growth was serially assessed with In Vivo Imaging System (IVIS) images once every week. Established hepatic tumors were evaluated with CT scan and then analyzed histologically. We found that splenic injection could consistently establish hepatic tumors. Non-invasive imaging showed that the splenic injection model had more consistent and stronger fluorescent intensity compared to the hepatic injection model. There were no significant differences in tumor growth between splenic injection with splenectomy and without splenectomy. The splenic injection established hepatic tumors diffusely throughout the liver, while the hepatic injection of tumor cells established a single localized tumor. Long-term monitoring of tumor development showed that tumor growth, tumor distribution in the liver, and overall survival depended on the number of tumor cells injected to the spleen. We established a new orthotopic hepatic metastatic xenograft mouse model by splenic injection of MUM cells. The growth of orthotopic hepatic tumors could be monitored with non-invasive IVIS imaging. Moreover, we evaluated the therapeutic effect of a MEK inhibitor by using this model. Our findings suggest that our new orthotopic liver metastatic mouse model may be useful for preclinical drug screening experiments and for the analysis of liver metastasis mechanisms.
Leaf gas exchange recovery of soybean from water-deficit stress

As the risk of drought attributable to climate change increases, the development of high-yielding, drought-adapted cultivars will be critical for minimizing yield losses in crops like soybean (Glyc...
Building Knowledge:The Research Mission in American Universities, 1890–2018

In American universities, research has been one mission among several. This was the case at the beginning of the twentieth century when American universities were provincial outposts in the world of science; and it was true at the end of the century, when they were global leaders – the model for world-class universities. This chapter examines the role of the research mission in the evolution of American universities and relates this mission to the extent to which institutions engaged a learned faculty and advanced students and provided them with the resources to pursue knowledge. The dialectic between the university development of a research capacity and the resources competitively available in the research economy is traced. Due to the expense of pursuing a research mission, the largest and/or wealthiest institutions were the original American research universities. After the Second World War, the increasing volume of federal research support allowed more institutions to develop a research mission. The specialized requirements of research tasks and the needs of research patrons caused much university research to be located in semi-autonomous centers and institutes. The achievements of American academic science have been possible, in large measure, due to the abundance of the research economy, the economic relevance of academic research, and the organizational flexibility of universities in accommodating a research mission.
Quit ratios for cigarette smoking among individuals with opioid misuse and opioid use disorder in the United States

Abstract Background The prevalence of cigarette smoking is more than two times higher among individuals with versus without opioid misuse and/or opioid use disorders (OUD). Overall, smoking cessation has increased over time although it is unknown whether it has similarly increased for those with opioid misuse or OUD. The current study examined cigarette quit ratios from 2002 to 2018 among US individuals with and without opioid misuse or OUD. Methods Data came from the National Survey on Drug Use and Health, a yearly cross-sectional survey of US civilians 12 years or older. Annual quit ratios (i.e., proportion of former smokers among lifetime-smokers) were estimated from 2002 to 2018. Logistic regression tested time trends in quit ratios by opioid misuse/OUD. Results Past-month smoking prevalence was much higher for persons with versus without opioid misuse (64.6 % versus 25.7 %) and OUD (73.3 % versus 26.0 %). In 2018, quit ratios for individuals with opioid misuse (18.0 %) or OUD (10.0 %) were less than half of those without opioid misuse (48.3 %) or OUD (48.1 %). After adjusting for background characteristics, the quit ratio did not change over time among individuals with opioid misuse or OUD in contrast to an increase in quit ratios for those without opioid misuse or OUD. For those without opioid misuse or OUD, males had higher quit ratios than females. Conclusions Cigarette quit ratios remain dramatically lower among those with opioid misuse or OUD. Public health and clinical attention are needed to increase cessation and reduce smoking consequences for individuals with opioid misuse and OUD.
Unpacking complex phenomena through qualitative inquiry: The case of teacher identity research

Despite the key contributions of qualitative inquiry in developing deeper understandings of people’s lived experiences within varied contexts, the field of educational psychology has not been fully...
A Creative Path Towards Becoming Female Engineer Enabling the Next Opportunities in Computing

This chapter shows my creative journey to becoming a female engineer working on the cutting edge of computation and neuromorphic techniques. This chapter shows my real-life journey from early childhood, early education, through my professional career as a faculty member at Georgia Tech. Through this timeframe, I have had the fortune to work on neurally inspired topics, programmable and configurable analog areas, and helping to develop the future of computation. Through this timeframe I have walked through many non-technical paths resulting in experiences that are part of my larger story.
Probabilistic composite design

Probabilistic composite design is described in terms of a computational simulation. This simulation tracks probabilistically the composite design evolution from constituent materials, fabrication process, through composite mechanics and structural components. Comparisons with experimental data are provided to illustrate selection of probabilistic design allowables, test methods/specimen guidelines, and identification of in situ versus pristine strength, For example, results show that: in situ fiber tensile strength is 90% of its pristine strength; flat-wise long-tapered specimens are most suitable for setting ply tensile strength allowables: a composite radome can be designed with a reliability of 0.999999; and laminate fatigue exhibits wide-spread scatter at 90% cyclic-stress to static-strength ratios.
Social Support and Coping Strategies in Patients with Traumatic Brachial Plexus Injury

Emotional and social characteristics may influence rehabilitation and recovery after traumatic brachial plexus injury. We sought to investigate if traumatic brachial plexus injury patients have different levels of social support and employ distinct coping strategies from uninjured control subjects. In addition, we studied which coping strategies are more commonly used among traumatic brachial plexus injury patients. Questionnaires for social support (Interpersonal Support Evaluation List and Social Support Questionnaire) and coping strategies (Brief-Coping Orientation to Problems Experienced) were administered to traumatic brachial plexus injury patients and an age- and sex-matched volunteer cohort (without brachial plexus injury). There were no differences in interpersonal support (mean [SD] = 26.0 [8.6], 26.5 [6.8]), number of persons available for emotional support, and satisfaction with support between traumatic brachial plexus injury patients (n = 36) and volunteers (n = 43). The following coping strategies were more common among traumatic brachial plexus injury patients: active coping, self-distraction, denial, behavioral disengagement, venting, planning, self-blame, and acceptance. Patients with traumatic brachial plexus injury have similar levels of social support as healthy volunteers but are more likely to use an array of coping strategies. Surgeons and other clinicians should be aware of coping strategies favored by patients, particularly the potential for behaviors detrimental to recovery such as behavioral disengagement, self-blame, and denial. This work will inform future investigations into the influence of social support and coping strategies on clinical outcomes after traumatic brachial plexus injury.
Ventilated Patients With COVID-19 Show Airflow Obstruction.

Objective:Many patients with coronavirus disease 2019 (COVID-19) need mechanical ventilation secondary to acute respiratory distress syndrome. Information on the respiratory system mechanical chara...
Career Ladders for Medical Assistants in Primary Care Clinics.

This study examines the use of career ladders for medical assistants (MAs) in primary care practices as a mechanism for increasing wages and career opportunity for MAs. A growing body of research on primary care suggests that successful expansion of support staff roles such as MAs may have positive organizational and quality of care outcomes, but little is known about worker outcomes. Evaluate the effectiveness of career ladders in improving wages and career opportunity among MAs. We use a mixed-methods design to evaluate the impact of career ladders on MA job quality. We draw on interview data collected from 115 key informants at four large health systems (ranging from 24 to 29 clinics each), and we analyze wage and employment data for MAs from primary care clinics in the four health systems in the sample. We describe the MA career ladder context and infrastructure within primary care clinics and evaluate the rewards to MAs for participation in the career ladder programs. The expanded roles within career ladders for MAs focused on the following four clinical and educational areas: panel management and care coordination, EHR documentation support, supporting delivery of person-centered care, and supervision and training. The three primary components of the career ladder infrastructure were training and education for MAs and providers, credentialing and certification for MAs, and differentiated job levels for MAs. The use of career ladders in the four large health systems in our case study sample resulted in yearly income increases ranging from $3000 to $10,000 annually. Investing in career ladders in primary care clinics can improve MA job quality while also potentially addressing issues of equity, efficiency, and quality in the health care sector.
Circumferential fusion with open versus percutaneous posterior fusion for lumbar isthmic spondylolisthesis

Abstract Study design Retrospective cohort study. Objective To investigate the clinical and radiographic differences between patients who underwent anterior lumber interbody fusion (ALIF) with either open or percutaneous posterior fusion for lumbar isthmic spondylolisthesis. Summary of background data Circumferential fusion for isthmic spondylolisthesis is commonly performed with superior clinical outcomes, fusion rates, and restoration of sagittal balance when compared to posterior fusion alone. The outcomes comparing traditional open versus percutaneous posterior fusion in this setting have not been fully evaluated. Methods A retrospective review of patients who underwent ALIF with either traditional open or percutaneous posterior fusion for isthmic spondylolisthesis between 2014 and 2019 was conducted. Patient demographics, surgical characteristics, and radiographic and clinical outcomes were compared between groups. Results A total of 79 patients were included in the final analysis, with 49 in the Open group and 30 in the Percutaneous group. No differences were found with regard to demographic factors between groups including sex, body mass index (BMI), diabetic status, and smoking status. The percutaneous group had less estimated blood loss (EBL, 69.2 mL) and shorter length of stay (3.06 days) compared to the open group (446 mL, p = 0.017; 3.98 days, p = 0.003). Both groups demonstrated significant improvement in all clinical outcome measures after surgery (PCS-12, MCS-12, ODI, VAS Back, and VAS Leg scores). The percutaneous group achieved greater ∆VAS Back (Open = 3.55, Perc = 5.17; p = 0.045) and also had a significantly greater improvements in recovery ratio for VAS Back (Open: 0.43, Perc: 0.73; p = 0.037) and ODI (Open: 0.40, Perc = 0.67; p = 0.031). Regression analysis demonstrated percutaneous surgery to be significant predictor of superior improvement in VAS Back scores (β = 1.957, p = 0.027). Conclusion ALIF with percutaneous posterior fusion affords greater improvement in back pain and disability when compared to ALIF with open posterior fusion for isthmic spondylolisthesis. Level of evidence III.
SToRytelling to Improve Disease outcomes in Gout (STRIDE-GO): a multicenter, randomized controlled trial in African American veterans with gout.

Background Urate-lowering therapy (ULT) adherence is low in gout, and few, if any, effective, low-cost, interventions are available. Our objective was to assess if a culturally appropriate gout-storytelling intervention is superior to an attention control for improving gout outcomes in African-Americans (AAs). Methods In a 1-year, multicenter, randomized controlled trial, AA veterans with gout were randomized to gout-storytelling intervention vs. a stress reduction video (attention control group; 1:1 ratio). The primary outcome was ULT adherence measured with MEMSCap™, an electronic monitoring system that objectively measured ULT medication adherence. Results The 306 male AA veterans with gout who met the eligibility criteria were randomized to the gout-storytelling intervention (n = 152) or stress reduction video (n = 154); 261/306 (85%) completed the 1-year study. The mean age was 64 years, body mass index was 33 kg/m2, and gout disease duration was 3 years. ULT adherence was similar in the intervention vs. control groups: 3 months, 73% versus 70%; 6 months, 69% versus 69%; 9 months, 66% versus 67%; and 12 months, 61% versus 64% (p > 0.05 each). Secondary outcomes (gout flares, serum urate and gout-specific health-related quality of life [HRQOL]) in the intervention versus control groups were similar at all time points except intervention group outcomes were better for the following: (1) number of gout flares at 9 months were fewer, 0.7 versus 1.3 in the previous month (p = 0.03); (2) lower/better scores on two gout specific HRQOL subscales: gout medication side effects at 3 months, 32.8 vs. 39.6 (p = 0.02); and unmet gout treatment need at 3 months, 30.9 vs. 38.2 (p = 0.003), and 6 months, 29.5 vs. 34.5 (p = 0.03), respectively. Conclusions A culturally appropriate gout-storytelling intervention was not superior to attention control for improving gout outcomes in AAs with gout. Trial registration Registered at ClinicalTrials.gov NCT02741700.
Intracellular Calcium Stores and Ischemic Neuronal Death

Disruption of cellular regulation of calcium has long been implicated in the mechanism of neruonal death following cerebral ischemia and reperfusion9,17. While much research has been directed at the potential role of calcium influx in ischemia, less attention has been paid to other mechanisms of calcium regulation that may be altered. We are investigating the possibility that altered storage and release of Ca2+ from the endoplasmic reticulum (ER) contributes to ischemic neuronal death.
Endotoxin and cytokine detection systems as biomarkers for sepsis-induced renal injury.

Background: A reliable biomarker as an indicator of the presence of severe sepsis is an unmet medical need. Methods: Review of recent literature on this topic focusing upon endotoxin and cytokine as
Effective Lagrangian of unitary Fermi gas from e expansion

Using $\ensuremath{\epsilon}$ expansion technique proposed by Nishida and Son [Phys. Rev. Lett. 97, 050403 (2006)] we derive an effective Lagrangian (Ginzburg-Landau-type functional) of the degenerate unitary Fermi gas to the next-to-leading order in $\ensuremath{\epsilon}$. It is demonstrated that for many realistic situations it is sufficient to retain leading order terms in the derivative expansion. The functional is used to study vortex structure in the symmetric gas, and interface between normal and superfluid phases in the polarized gas. Typical vortex size, ${r}_{0}{k}_{F}=0.92$, where ${k}_{F}$ is Fermi momentum, agrees well with results of previous work [A. Bulgac and Y. Yu, Phys. Rev. Lett. 91, 190404 (2003)]. Surface free energy is about 3 times larger than the value previously quoted in the literature.