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Abstract Background The dissolution of dental calculus, safely and at home, is among the more challenging issues facing the over-the-counter healthcare industry. Pontis Biologics, Inc. has developed novel model of calculus development and structure and has formulated a dentifrice (Tartarase™) using digestive enzymes as active ingredients that is shown to dissolve dental calculus in this Proof of Principle clinical trial. Methods This investigation was designed to evaluate the safety and efficacy of a novel enzyme formulation to remove existing calculus deposits in 4 weeks, measured using the Volpe-Manhold Index (V-MI) on lingual surfaces of 6 lower anterior teeth. The test formulation was compared to Crest Cavity Protection, as a control dentifrice. A total of 40 randomized test subjects began the study with 20 assigned to the control dentifrice and 20 assigned to the Tartarase groups (ten each, one brushing with Tartarase twice daily and one brushed with Tartarase and wore a dental tray filled with Tartarase for 30 min then brushed again with Tartarase, once daily). Results The Crest group experienced a 12% increase in calculus, in contrast to the results of both Tartarase groups that experienced a 40% reduction in calculus in 4 weeks of unsupervised at home use of the Tartarase toothpaste formulation. Conclusions This proof of principle study demonstrates that a dentifrice, formulated along the lines of the Tartarase material, is capable of combating calculus accumulation using the same oral hygiene habits that are common worldwide. Trial registration This trial was registered retrospectively at clinicaltrials.gov and has the Unique Identification Number: NCT06139835, 14/11/2023.

Abstract Fast neutron beams (E $$_n > $$ n > 1 MeV) are of relevance for many scientific and industrial applications. This paper explores fast neutron production using a TANDEM accelerator at the Legnaro National Laboratories, via an energetic ion beam (90 MeV $$^{14}N$$ 14 N ) onto a lithium target. The high energy models for nuclear collision of FLUKA foresee large neutron yields for reactions of this kind. The experiment aimed at validating the expected neutron yields from FLUKA simulations, using two separate and independent set-ups: one based on the multi-foil activation technique, and the other on the time of flight technique, by using liquid scintillator detectors. The results of the experiment show clear agreement of the measured spectra with the FLUKA simulations, both in the shape and the magnitude of the neutron flux at the measured positions. The neutron spectrum is centered around the 8 MeV range with mild tails, and a maximum neutron energy spanning up to 50 MeV. These advantageous results provide a starting point in the development of fast neutron beams based on high energy ion beams from medium-sized accelerator facilities.

Abstract The ability to conduct cost‐effective wildlife monitoring at scale is rapidly increasing due to the availability of inexpensive autonomous recording units (ARUs) and automated species recognition, presenting a variety of advantages over human‐based surveys. However, estimating abundance with such data collection techniques remains challenging because most abundance models require data that are difficult for low‐cost monoaural ARUs to gather (e.g., counts of individuals, distance to individuals), especially when using the output of automated species recognition. Statistical models that do not require counting or measuring distances to target individuals in combination with low‐cost ARUs provide a promising way of obtaining abundance estimates for large‐scale wildlife monitoring projects but remain untested. We present a case study using avian field data collected in the forests of Pennsylvania during the spring of 2020 and 2021 using both traditional point counts and passive acoustic monitoring at the same locations. We tested the ability of the Royle–Nichols and time‐to‐detection models to estimate the abundance of two species from detection histories generated by applying a machine‐learning classifier to ARU‐gathered data. We compared abundance estimates from these models with estimates from the same models fit using point‐count data and to two additional models appropriate for point counts, the N‐mixture model and distance models. We found that the Royle–Nichols and time‐to‐detection models can be used with ARU data to produce abundance estimates similar to those generated by a point‐count‐based study but with greater precision. ARU‐based models produced confidence or credible intervals that were on average 31.9% (±11.9 SE) smaller than their point‐count counterpart. Our findings were consistent across two species with differing relative abundance and habitat use patterns. The higher precision of models fit using ARU data is likely due to higher cumulative detection probability, which itself may be the result of greater survey effort using ARUs and machine‐learning classifiers to sample significantly more time for focal species at any given point. Our results provide preliminary support for the use of ARUs in abundance‐based study applications, and thus may afford researchers a better understanding of habitat quality and population trends, while allowing them to make more informed conservation recommendations and actions.

Abstract We describe in this work an evaluation of bundles of hollow mesoporous silicon nanotubes to facilitate transfection of HeLa cells using small interfering RNA designed to knock down expression of Enhanced Green Fluorescent Protein (eGFP). These experiments entail direct visualization of the nanotube bundles associated with the cells using both scanning electron microscopy (SEM) and confocal fluorescence imaging. These nanotube bundles are generated by surface modification of nanotube arrays with aminopropyl‐triethoxysilane (APTES), followed by their ultrasonication in water, to create the amine‐terminated structures capable of electrostatic conjugation of siRNA at an efficiency of 23%–50% (depending on initial siRNA concentration). Delivery and transfection to HeLa cells are verified by quantification of fluorescence imaging; an average percent knockdown of ∼50% eGFP is achieved. As nanoscale drug delivery vehicles are expected to be resorbed in clinical use, we also assess SiNT bundle degradation during the above in vitro timescale using scanning and transmission electron (TEM) microscopies. We conclude with a brief discussion of challenges and opportunities in future experiments involving this platform.

Abstract This work reports the pore‐filling of porous silicon (PSi) and the loading of silicon nanotubes (SiNTs) with Pt‐Fe nanoparticles (NPs) and the corresponding different magnetic behavior of the two composite systems. The fabrication of magnetic hard/soft nanostructures is in demand for the purpose of achieving both a high energy product as well as the replacement of rare earth permanent magnets. Pt‐Fe templated by PSi shows a higher coercivity and remanence than SiNTs/Pt‐Fe and thus a higher hard magnetic performance, the difference between coercivities being about 57%. Considering that the Pt‐Fe deposits employ different molar ratios of Pt to Fe the coercivities vary in a range of 5% in the case of both template types. Comparing Pt‐Fe loaded samples with Co‐loaded samples in all cases, an increase of the coercivity and the remanence is observed for Pt‐Fe, whereas in the case of PSi as template material the increase is significantly stronger (about twice as much) than in the case of SiNTs samples. Furthermore, the samples are investigated at high temperatures up to 950 K to determine the Curie temperature of the systems.

Abstract Golden‐winged Warblers (Vermivora chrysoptera) have become rare across much of their historic breeding range and response to conservation efforts is variable. Evidence from several recent studies suggests that breeding output is a primary driver explaining responses to conservation and it is hypothesized that differences in food availability may be driving breeding output disparity between two subpopulations of the warbler's Appalachian breeding range. Herein, we studied two subpopulations: central Pennsylvania (“central subpopulation”), where breeding productivity is relatively low, and eastern Pennsylvania (“eastern subpopulation”), where breeding productivity is relatively high. To test the food‐availability hypothesis in this system, we measured density of caterpillars, plasma lipid metabolites (triglycerides [TRIG; fat deposition] and glycerol [GLYC; fat breakdown]), body mass of adults males, and acquired body mass data for fledglings at 38 sites managed for nesting habitat. Consistent with our prediction, leaf‐roller caterpillar density, the group upon which Golden‐winged Warblers specialize, was 45× lower in the central subpopulation than the eastern subpopulation. TRIG concentrations were highest within the eastern subpopulation during breeding grounds arrival. The change in TRIG concentrations from the breeding‐grounds‐arrival stage to the nestling‐rearing stage was subpopulation dependent: TRIG decreased in the eastern subpopulation and was constant in the central subpopulation, resulting in similar concentrations during the nestling‐rearing stage. Furthermore, GLYC concentrations were higher in the eastern subpopulation, which suggests greater energy demands in this region. Despite this, adult male warblers in the eastern subpopulation maintained a higher average body mass. Finally, fledgling body mass was 16% greater in the eastern subpopulation than the central subpopulation before and after fledging. Collectively, our results suggest that poor breeding success of Golden‐winged Warblers in the central subpopulation could be driven by lower availability of primary prey during the breeding season (leaf‐roller caterpillars), and this, in turn, limits their response to conservation efforts.

Effective planning for natural resource management and wildlife conservation requires detailed information on vegetation structure at landscape scales and how structure is influenced by land-use practices. In many forested landscapes, the largest impacts of land use on forest structure are driven by forest management activities, which can include invasive species control, prescribed fire, partial harvests (e.g. shelterwood harvests) or overstory removals and clearcuts. Active timber management is often used to achieve forest conservation objectives, but to be used effectively, managers require knowledge of harvest frequency and extent in adjacent forests and at landscape scales. In this paper, we develop a timber harvest mapping workflow using machine learning (XGBoost algorithm) and single campaign airborne light detection and ranging (LiDAR) surveys for the state of Pennsylvania, USA. We show that harvest type (shelterwood and overstory removals) can be mapped at high accuracy (overall accuracy = 94.9%), including broad age classes defined by the number of years since harvest. Errors of omission (false negatives) were lowest for recent (30 m from an edge). The expectation that these harvest treatments would be rarer in private forests was not supported by the model results, which is likely due to the model’s inability to distinguish between alternative natural processes (weather damage, wildfire, pathogens, etc.) and forest treatment types (high-grading and firewood collection) that result in similar forest structures to the trained classes in the XGBoost model. This study provides a framework and validation for combining approachable machine-learning techniques with large-campaign LiDAR to accurately predict forest structure with application to a host of forestry, natural resource, and conservation-related problems. Future efforts that refine the model’s ability to better distinguish between more complex harvest classes and natural processes would be valuable.

Abstract Identifying factors that drive variation in vital rates among populations is a prerequisite to understanding a species' population biology and, ultimately, to developing effective conservation strategies. This is especially true for imperiled species like the golden‐winged warbler (Vermivora chrysoptera) that exhibit strong spatial heterogeneity in demography and responds variably to conservation interventions. Habitat management actions recommended for breeding grounds conservation include timber harvest, shrub shearing, and prescribed fire that maintain or create early successional woody communities. Herein, we assessed variation in the survival of nests [n = 145] and fledglings [n = 134] at 17 regenerating timber harvest sites within two isolated populations in Pennsylvania that differed in productivity and response to habitat management. Although the overall survival of nests and fledglings was higher in the eastern population than the central population, this was only true when the nest phases and fledgling phases were considered wholly. Indeed, survival rates of nestlings and recently fledged young (1–5 days post‐fledging) were lower in the central population, whereas eggs and older fledglings (6–30 days post‐fledging) survived at comparable rates in both populations. Fledglings in the central population were smaller (10% lower weight) and begged twice as much as those in the eastern population, suggesting food limitation may contribute to lower survival rates. Fledgling survival in the central population, but not the eastern, also was a function of habitat features (understory vegetation density [positive] and distance to mature forest [negative]) and individual factors (begging effort [negative]). Our findings illustrate how identifying how survival varies across specific life stages can elucidate potential underlying demographic drivers, such as food resources in this case. In this way, our work underscores the importance of studying and decomposing stage‐specific demography in species of conservation concern.

IntroductionThere is overwhelming evidence of declines in native bee populations and therefore a need for increased monitoring to track these declines and assist in conservation and restoration efforts. Bees can be sampled non-lethally through visual surveys (e.g., distance transects) or lethally through active (e.g., hand netting) or passive (e.g., traps that lure insects from afar) methods. These lethal methods suffer from imperfect detection that is difficult to account for and can confound inferences about habitat characteristics. Additionally, evidence suggests that lethal sampling methods can even invert habitat quality patterns such that high-quality sites yield fewer individuals and low-quality sites yield more individuals.MethodsTo study potential biases associated with imperfect detection, we used hierarchical density estimation with visual surveys to estimate density of bees within 40 young forest patches across Pennsylvania, USA. We surveyed bee communities non-lethally using visual surveys and lethally using blue-vane traps and bee bowls every two weeks between May and September 2019. We collected data on blooming flowers, vegetation structure, and weather during times of survey.ResultsWe found that bee densities estimated from distance transects had a positive relationship with floral resource availability. In contrast, abundance measured via bee bowls and blue-vane traps had no relationship, or sometimes even negative trends with habitat quality, including floral resource availability. Raw bee counts within 2-m of the transect always correlated with modeled densities, showing that some methods do not share the biases of attractive traps.DiscussionOur study demonstrates that failing to account for imperfect detection can impact the interpretation of pollinator surveys and adds to a growing body of literature that acknowledges the value of distance sampling for insects like bees to better understand species’ habitat needs and to monitor populations for conservation.

Abstract We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation (DRT). The trial met its primary endpoint of major pathological response, which was significantly higher following DRT with no new safety signals. Here, we report on the prespecified secondary endpoint of disease-free survival (DFS) regardless of treatment assignment and the prespecified exploratory analysis of DFS in each arm of the trial. DFS at 2 and 3 years across patients in both arms of the trial were 73% (95% CI: 62.1–84.5) and 65% (95% CI: 52.5–76.9) respectively. For the exploratory endpoint of DFS in each arm of the trial, three-year DFS was 63% (95% CI: 46.0–80.4) in the durvalumab monotherapy arm compared to 67% (95% CI: 49.6–83.4) in the dual therapy arm. In addition, we report post hoc exploratory analysis of progression-free survival as well as molecular correlates of response and recurrence through high-plex immunophenotyping of sequentially collected peripheral blood and gene expression profiles from resected tumors in both treatment arms. Together, our results contribute to the evolving landscape of neoadjuvant treatment regimens for NSCLC and identify easily measurable potential biomarkers of response and recurrence.

Advanced breast cancer remains a significant oncological challenge, requiring new approaches to improve clinical outcomes. This study investigated an innovative theranostic agent using the MCM-41-NH2-DTPA-Gd3⁺-MIH nanomaterial, which combined MRI imaging for detection and a novel chemotherapy agent (MIH 2.4Bl) for treatment. The nanomaterial was based on the mesoporous silica type, MCM-41, and was optimized for drug delivery via functionalization with amine groups and conjugation with DTPA and complexation with Gd3+. MRI sensitivity was enhanced by using gadolinium-based contrast agents, which are crucial in identifying early neoplastic lesions. MIH 2.4Bl, with its unique mesoionic structure, allows effective interactions with biomolecules that facilitate its intracellular antitumoral activity. Physicochemical characterization confirmed the nanomaterial synthesis and effective drug incorporation, with 15% of MIH 2.4Bl being adsorbed. Drug release assays indicated that approximately 50% was released within 8 h. MRI phantom studies demonstrated the superior imaging capability of the nanomaterial, with a relaxivity significantly higher than that of the commercial agent Magnevist. In vitro cellular cytotoxicity assays, the effectiveness of the nanomaterial in killing MDA-MB-231 breast cancer cells was demonstrated at an EC50 concentration of 12.6 mg/mL compared to an EC50 concentration of 68.9 mg/mL in normal human mammary epithelial cells (HMECs). In vivo, MRI evaluation in a 4T1 syngeneic mouse model confirmed its efficacy as a contrast agent. This study highlighted the theranostic capabilities of MCM-41-NH2-DTPA-Gd3⁺-MIH and its potential to enhance breast cancer management.

Body composition (BC), a measure of body fat mass (FM), lean body mass (LBM), and bone mineral content (BMC), can be used as a predictor of cardiorespiratory fitness (CRF). Prior studies have established a relationship between BC and VO2max in healthy individuals over 35 years of age. However, this relationship is poorly understood in chronic disease populations. The focus of the study was to assess the relationship between BC, cardiorespiratory fitness, and chronic kidney disease (CKD). A cross-sectional analysis was conducted among 24 (9 males and 15 females) individuals diagnosed with mid-spectrum CKD (stages G2–G3b) who completed a health screening, dual-energy X-ray absorptiometry (DEXA) scan, and underwent a VO2max exercise test. Normality tests, descriptive statistics, Pearson’s correlations, t-tests, and ANOVAs were conducted in SAS v.9.4. The average percent body fat (%BF) was 36.28 ± 8.47%, LBM was 109.4 ± 29.1 lb, BMC was 2308.7 ± 735.1 g, and VO2max was 20.13 ± 5.04 mL/kg/min−1. BC was able to predict CRF via VO2max (R2 = 0.721, p < 0.001) and CKD stage (R2 = 0.390, p < 0.017). Positive correlations were observed in LBM (r = 0.750, p < 0.0018) and BMC (r = 0.647, p < 0.001), and negative correlations were observed with FM (r = −0.384, p < 0.032) and %BF (r = −0.802, p < 0.0001). BC was able to predict both CRF and CKD stages, with significant associations observed between BC, VO2max, and CKD stage. The progression of the CKD stage was associated with lower LBM, BMC, and VO2max values, indicating a graded effect of BC on CRF and CKD stage.

Abstract Background Corneal transplants are the most common type of transplant and increasing in frequency. Donor cornea tissues are a rare source of herpes simplex virus (HSV) transmission and not routinely tested for presence of HSV. Donor graft-to-recipient transmission typically causes graft failure and anterior uveitis, and extra-ocular HSV disease has not been previously reported. We present a case of HSV transmission from donor cornea tissue that nearly cost the corneal transplant recipient his life. Case report An elderly immunocompetent man developed an acute illness 10 days after having donor corneal tissue implanted in a Descemet membrane endothelial keratoplasty (DMEK). He was found to have HSV necrotizing hepatitis per liver biopsy, trilineage cytopenia, rhabdomyolysis, acute kidney failure, altered mental status, early-stage hemophagocytic lymphohistiocytosis (HLH), and donor corneal tissue implant infection resulting in graft failure and anterior uveitis. HSV DNA was detected in cerebral spinal fluid, peripheral blood, explanted donor corneal tissue, and anterior chamber fluid (220 million HSV DNA copies per mL). HSV-1 seroconversion denoted a primary HSV infection, and the patient had no other risk factor for HSV acquisition. Early recognition of HSV dissemination prompting treatment with intravenous acyclovir, as well as a short course of HLH-directed therapy, resolved the systemic illness. Vision was restored to near normal by replacement of the infected corneal graft with new donor DMEK tissue in conjunction with intravitreal foscarnet treatment. Conclusion Awareness of the potential risk of donor cornea tissue transmitting HSV and leading to life-threatening HSV disease is paramount to early diagnosis and treatment. The role of donor cornea tissue in HSV transmission and disease merits additional attention and investigation.

Tooth color is a major driver of facial esthetics. While permanent changes in tooth shade can be achieved by bleaching and restorations, there is a need for cosmetic products that can cause reversible color changes. This randomized controlled clinical study assessed the effectiveness and safety of a novel color-correcting product (Hismile™ V34 Color Corrector Serum™) versus a placebo (vehicle control lacking the color-change dyes). A single-center, randomized, controlled, examiner-blind, two-group, parallel design, single-use study design was followed. The test products were applied on a cotton bud for 30 s, and then, rinsed off. Tooth shade for maxillary central incisors was measured at baseline, immediately, and at 30 and 60 min, using the Vita Bleachedguide 3D-Master® Shade Guide and the EasyShade Advanced 4.0 spectrophotometer (for determining values of L*a*b*). The subjects (N = 60) had a baseline shade of 1M2 (rank 9) or darker. A single application of the test product resulted in an immediate and significant (p < 0.001) three shade improvement (26.2%) according to the shade guide, and the same significant benefits extended to 30 and 60 min. The placebo product did not alter tooth shade (p = 0.326). These changes were accompanied by significant improvements in the L value (whiteness) up to 30 min, and a reduction in b* (yellowness) for up to 60 min. Two-thirds of subjects using the test product stated in a survey that their teeth appeared both whiter and brighter. No safety issues arose from the use of the test product or vehicle control. These results indicate that using a color corrector can achieve worthwhile changes to tooth shade for up to 60 min.

The Blue-winged Warbler ( Vermivora cyanoptera ) is a relatively understudied shrubland-associated species that has experienced sustained population declines in portions of its breeding range. Detailed evaluations of Blue-winged Warbler breeding season habitat requirements are needed to inform ongoing and future conservation efforts and, ultimately, stem population declines. Here, we use radio telemetry, field-measured vegetation data, and Light Detection and Ranging (LiDAR) to assess Blue-winged Warbler breeding season space use and habitat selection in southwest Pennsylvania. During the 2019 and 2020 breeding seasons, we tracked 27 male Blue-winged Warblers and mapped their core home ranges (50% kernel density estimate) and total home ranges (95% kernel density estimate). The scale of Blue-winged Warbler space use was similar to that of other Vermivora with a mean total home range size of 12.9 ha and a mean core home range (i.e., high use area of the home range) size of 2.9 ha. Blue-winged Warbler core home ranges had more shrub cover and herbaceous cover but less overhead cover and leaf litter than peripheral (area of total home range outside of core area) home ranges. Core areas were also dominated by shrubland and forest-shrubland ecotone, while peripheral home ranges contained greater forest cover. Finally, LiDAR data suggested that core home ranges contained more structural heterogeneity (rugosity metrics) and more short-stature vegetation (% returns between 1 and 5 m) than peripheral home ranges. These results suggest that although Blue-winged Warblers require shrubland communities in the core of their breeding season home ranges, the availability of adjacent forest cover that forms structurally complex ecotones is also essential. Therefore, conservation practices that aim to create or maintain habitat for this declining bird should promote structurally complex shrubland adjacent to forest-shrubland ecotones.

Habitat restoration and creation within human-altered landscapes can buffer the impacts of climate change on wildlife. The Forestry Reclamation Approach (FRA) is a coal surface mine reclamation practice that enhances reforestation through soil decompaction and the planting of native trees. Recently, wetland creation has been coupled with FRA to increase habitat available for wildlife, including amphibians. Our objective was to evaluate the response of pond-breeding amphibians to the FRA by comparing species occupancy, richness, and abundance across two FRA age-classes (2–5-year and 8–11-year reclaimed forests), traditionally reclaimed sites that were left to naturally regenerate after mining, and in mature, unmined forests in the Monongahela National Forest (West Virginia, USA). We found that species richness and occupancy estimates did not differ across treatment types. Spotted Salamanders (Ambystoma maculatum) and Eastern Newts (Notophthalmus viridescens) had the greatest estimated abundances in wetlands in the older FRA treatment. Additionally, larger wetlands had greater abundances of Eastern Newts, Wood Frogs (Lithobates sylvaticus), and Green Frogs (L. clamitans) compared to smaller wetlands. Our results suggest that wetland creation and reforestation increases the number of breeding sites and promotes microhabitat and microclimate conditions that likely maximize the resilience of pond-breeding amphibians to anticipated climate changes in the study area.

Silicon nanotubes (Si NTs) have a unique structure among the silicon nanostructure family, which is useful for diverse applications ranging from therapeutics to lithium storage/recycling. Their well-defined structure and high surface area make them ideal for sensing applications. In this work, we demonstrate the formation of Au nanoparticles (NPs) functionalized with 4-Mercaptophenylboronic acid (MPBA) on porous Si NTs (pSi NTs) fabricated using ZnO nanowires as a template. The system was characterized, and the proposed structure was confirmed using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). Varying glucose concentrations in phosphate-buffered saline (PBS) (0.5–80 mM) were introduced to the Si NT nanocomposite system. The glucose is detectable at low concentrations utilizing surface-enhanced Raman spectroscopy (SERS), which shows a concentration-dependent peak shift in the benzene ring breathing mode (~1071 cm−1) of MPBA. Complementing these measurements are simulations of the Raman hot spots associated with plasmonic enhancement of the Au NPs using COMSOL. This biocompatible system is envisioned to have applications in nanomedicine and microfluidic devices for real-time, non-invasive glucose sensing.

Blood flow restriction (BFR) may become ineffective or potentially dangerous without sufficient standardization. The purpose of this investigation was therefore to (1) assess the viability of multiple sizes of a novel BFR cuff to determine arterial occlusion pressure (AOP) and (2) compare resting arterial, venous and calf muscle pump (cMP)-mediated blood flow between the aforementioned conditions and a commonly employed wide-rigid, tourniquet-style cuff. In randomized, counter-balanced, and crossover fashion, 20 apparently healthy males (18–40 years) donned a widely employed wide-rigid (WR) cuff, along with the largest (NE) and manufacturer-recommended sizes (NER) of a novel narrow-elastic cuff. Participants subsequently assessed AOP, as well as (at 80%AOP) arterial, venous, and venous cMP flow relative to baseline values via ultrasound. All analyses were performed at a significance level of p < 0.05. Analyses revealed a significant condition effect for AOP (p < 0.001; ηp2 = 0.907) whereby WR was significantly lower than both NE and NER; in addition, the latter two did not differ. Compared with baseline, there were no statistically significant differences between cuffs for either arterial or cMP-mediated blood flow. Unsurprisingly, no participants demonstrated venous blood flow at 80% AOP. These findings support the viability of a novel narrow-elastic BFR product, evidenced by consistent AOP acquisition and equivocal blood flow parameters.

Abstract Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact of TTBK1 inhibition in diseases like Alzheimer’s disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 knockout in iPSCs, confirming a role for TTBK2 in ciliogenesis.

Background Resistance exercise training (RET) is a common and well-established method to induce hypertrophy and improvement in strength. Interestingly, fish oil supplementation (FOS) may augment RET-induced adaptations. However, few studies have been conducted on young, healthy adults. Methods A randomized, placebo-controlled design was used to determine the effect of FOS, a concentrated source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), compared to placebo (PL) on RET-induced adaptations following a 10-week RET program (3 days·week−1). Body composition was measured by dual-energy x-ray absorptiometry (LBM, fat mass [FM], percent body fat [%BF]) and strength was measured by 1-repetition maximum barbell back squat (1RMSQT) and bench press (1RMBP) at PRE (week 0) and POST (10 weeks). Supplement compliance was assessed via self-report and bottle collection every two weeks and via fatty acid dried blood spot collection at PRE and POST. An a priori α-level of 0.05 was used to determine statistical significance and Cohen’s d was used to quantify effect sizes (ES). Results Twenty-one of 28 male and female participants (FOS, n = 10 [4 withdrawals]; PL, n = 11 [3 withdrawals]) completed the 10-week progressive RET program and PRE/POST measurements. After 10-weeks, blood EPA+DHA substantially increased in the FOS group (+109.7%, p

BackgroundBelantamab mafodotin (belamaf) has demonstrated clinically meaningful antimyeloma activity in patients with heavily pretreated multiple myeloma. However, it is highly active against dividing cells, contributing to off-target adverse events, particularly ocular toxicity. Changes in best corrected visual acuity (BCVA) and corneal examination findings are routinely monitored to determine Keratopathy Visual Acuity (KVA) grade to inform belamaf dose modification.ObjectiveWe aimed to develop a semiautomated mobile app to facilitate the grading of ocular events in clinical trials involving belamaf.MethodsThe paper process was semiautomated by creating a library of finite-state automaton (FSA) models to represent all permutations of KVA grade changes from baseline BCVA readings. The transition states in the FSA models operated independently of eye measurement units (e.g., Snellen, logMAR, decimal) and provided a uniform approach to determining KVA grade changes. Together with the FSA, the complex decision tree for determining the grade change based on corneal examination findings was converted into logical statements for accurate and efficient overall KVA grade computation. First, a web-based user interface, conforming to clinical practice settings, was developed to simplify the input of key KVA grading criteria. Subsequently, a mobile app was developed that included additional guided steps to assist in clinical decision-making.ResultsThe app underwent a robust Good Clinical Practice validation process. Outcomes were reviewed by key stakeholders, our belamaf medical lead, and the systems integration team. The time to compute a patient's overall KVA grade using the Belamaf Eye Exam (BEE) app was reduced from a 20- to 30-min process to

A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (4c and 4g) or donating (4f) substituents on the benzyl ring as well as introduction of non-aromatic groups such as the cyclohexylmethyl (4t) were shown to maintain CSNK2A activity. The CSNK2A activity was also retained with N-methylation of SGC-CK2-2, but α-methyl substitution of the benzyl substituent led to a 10-fold reduction in potency. CSNK2A inhibition potency was restored with indene-based compound 4af, with activity residing in the S-enantiomer (4ag). Analogs with the highest CSNK2A potency showed good activity for inhibition of Mouse Hepatitis Virus (MHV) replication. Conformational analysis indicated that analogs with the best CSNK2A inhibition (4t, 4ac, and 4af) exhibited smaller differences between their ground state conformation and their predicted binding pose. Analogs with reduced activity (4ad, 4ae, and 4ai) required more substantial conformational changes from their ground state within the CSNK2A protein pocket.

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood–brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.

This position stand aims to provide an evidence-based summary of the energy and nutritional demands of tactical athletes to promote optimal health and performance while keeping in mind the unique challenges faced due to work schedules, job demands, and austere environments. After a critical analysis of the literature, the following nutritional guidelines represent the position of the International Society of Sports Nutrition (ISSN). General Recommendations Nutritional considerations should include the provision and timing of adequate calories, macronutrients, and fluid to meet daily needs as well as strategic nutritional supplementation to improve physical, cognitive, and occupational performance outcomes; reduce risk of injury, obesity, and cardiometabolic disease; reduce the potential for a fatal mistake; and promote occupational readiness. Military Recommendations Energy demands should be met by utilizing the Military Dietary Reference Intakes (MDRIs) established and codified in Army Regulation 40-25. Although research is somewhat limited, military personnel may also benefit from caffeine, creatine monohydrate, essential amino acids, protein, omega-3-fatty acids, beta-alanine, and L-tyrosine supplementation, especially during high-stress conditions. First Responder Recommendations Specific energy needs are unknown and may vary depending on occupation-specific tasks. It is likely the general caloric intake and macronutrient guidelines for recreational athletes or the Acceptable Macronutrient Distribution Ranges for the general healthy adult population may benefit first responders. Strategies such as implementing wellness policies, setting up supportive food environments, encouraging healthier food systems, and using community resources to offer evidence-based nutrition classes are inexpensive and potentially meaningful ways to improve physical activity and diet habits. The following provides a more detailed overview of the literature and recommendations for these populations.

Background The Army Combat Fitness Test (ACFT), an updated and newly developed metric to assess combat readiness, may require specialized exercise and nutritional interventions. The purpose of this cross-sectional study was to investigate the relationship between body composition, erythrocyte long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA), serum vitamin D (VITD) and ACFT performance. Methods Sixty cadets (43 males, 17 females; 20.9 ± 3.8 years; 173.6 ± 10.2 cm; 75.6 ± 13.7 kg) completed the 6-event ACFT (3-repetition maximum trap-bar deadlift [3DL], standing power toss [SPT], hand-release pushups [HRPU], sprint-drag-carry shuttle run [SDC], leg tuck [LTK], or plank [PLK], and 2-mile run [2MR]), body composition analysis via dual-energy x-ray absorptiometry (percent body fat [%BF], lean body mass [LBM], fat-free mass index [FFMI (LBM+bone mineral content)]), and an omega-3 questionnaire. A sub-sample (n = 50) completed blood draws for fatty acid (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and VITD analysis. Significance was set at p

Metaproteomics is a powerful tool for the characterization of metabolism, physiology, and functional interactions in microbial communities, including plant-associated microbiota. However, the metaproteomic methods that have been used to study plant-associated microbiota are very laborious and require large amounts of plant tissue, hindering wider application of these methods. We optimized and evaluated different protein extraction methods for metaproteomics of plant-associated microbiota in two different plant species (Arabidopsis and maize). Our main goal was to identify a method that would work with low amounts of input material (40 to 70 mg) and that would maximize the number of identified microbial proteins. We tested eight protocols, each comprising a different combination of physical lysis method, extraction buffer, and cell-enrichment method on roots from plants grown with synthetic microbial communities. We assessed the performance of the extraction protocols by liquid chromatography-tandem mass spectrometry–based metaproteomics and found that the optimal extraction method differed between the two species. For Arabidopsis roots, protein extraction by beating whole roots with small beads provided the greatest number of identified microbial proteins and improved the identification of proteins from gram-positive bacteria. For maize, vortexing root pieces in the presence of large glass beads yielded the greatest number of microbial proteins identified. Based on these data, we recommend the use of these two methods for metaproteomics with Arabidopsis and maize. Furthermore, detailed descriptions of the eight tested protocols will enable future optimization of protein extraction for metaproteomics in other dicot and monocot plants. [Graphic: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Xenia effects describe the genetic contribution of pollen to seed phenotypes. Here the authors show that paternal imprinting of Ded1 contributes to the xenia effect in maize by setting the pace of endosperm development.

KH-type splicing regulatory protein (KHSRP) regulates levels of several neuronal mRNAs linked to nervous system development and function.

Abstract Developing effective monitoring techniques for sensitive wildlife populations is essential for improving conservation outcomes. The American woodcock (Scolopax minor; hereafter woodcock) is an upland migratory game bird traditionally surveyed by documenting displaying males in spring. Surveys of displaying males are limiting in a variety of important ways such as brief detection window and male‐centric observations. Thermal technology may overcome limitations of traditional monitoring techniques by increasing detections of non‐singing woodcock, however, the efficacy of thermal imaging for detecting woodcock remains unknown. To quantify woodcock detection probability using thermal imaging, we deployed and searched for heat‐emitting woodcock mounts along transects within early‐successional habitats in central Pennsylvania during 2020. We deployed 110 woodcock mounts and successfully detected 63 (57.2%). Detection rate declined as a function of increasing vegetation density and distance from transect. Although detection probability of woodcock was imperfect, thermal cameras may provide a solution for researchers aiming to assess presence or density of woodcock when coupled with analytical methods that account for imperfect detection.

Natural glues offer great potential as bio-inspired solutions to problems associated with the performance of synthetic adhesives. Spider viscous glues are elastic pressure sensitive adhesives (PSAs) that physically adhere to surfaces on contact across a range of environmental conditions. Extracting useful components from these secretions remains a challenge that can be met by the comparative analyses of functional analogues. Here we used 1H NMR spectroscopy and mass spectrometry to ascertain the organic salt compositions of the PSAs of four different species of Australian spiders belonging to two lineages that independently acquired aqueous gluey secretions: the St Andrew’s cross (Argiope keyserlingi), the redback (Latrodectus hasselti), the false widow (Steatoda grossa), and the daddy long-legs spider (Pholcus phalangiodes). The PSAs from each of these spiders contained similar organic salts, albeit in variable concentrations. The adhesives of the false widow and daddy long-legs spider had mixtures of only a few components, of which betaine predominated, while the PSAs of the other spiders predominantly contained small organic acids such as GABA/GABA-amide, isethionate, and choline salts. Our results suggest that the PSA composition of spiders is likely to be influenced more by environmental factors than evolutionary history and are guided by common principles. Our findings could be valuable for facilitating the design of more sustainable synthetic glues.

The clinical usefulness MRI biomarkers for aging and dementia studies relies on precise brain morphological measurements; however, scanner and/or protocol variations may introduce noise or bias. One approach to address this is post-acquisition scan harmonization. In this work, we evaluate deep learning (neural style transfer, CycleGAN and CGAN), histogram matching, and statistical (ComBat and LongComBat) methods. Participants who had been scanned on both GE and Siemens scanners (cross-sectional participants, known as Crossover (n = 113), and longitudinally scanned participants on both scanners (n = 454)) were used. The goal was to match GE MPRAGE (T1-weighted) scans to Siemens improved resolution MPRAGE scans. Harmonization was performed on raw native and preprocessed (resampled, affine transformed to template space) scans. Cortical thicknesses were measured using FreeSurfer (v.7.1.1). Distributions were checked using Kolmogorov-Smirnov tests. Intra-class correlation (ICC) was used to assess the degree of agreement in the Crossover datasets and annualized percent change in cortical thickness was calculated to evaluate the Longitudinal datasets. Prior to harmonization, the least agreement was found at the frontal pole (ICC = 0.72) for the raw native scans, and at caudal anterior cingulate (0.76) and frontal pole (0.54) for the preprocessed scans. Harmonization with NST, CycleGAN, and HM improved the ICCs of the preprocessed scans at the caudal anterior cingulate (>0.81) and frontal poles (>0.67). In the Longitudinal raw native scans, over- and under-estimations of cortical thickness were observed due to the changing of the scanners. ComBat matched the cortical thickness distributions throughout but was not able to increase the ICCs or remove the effects of scanner changeover in the Longitudinal datasets. CycleGAN and NST performed slightly better to address the cortical thickness variations between scanner change. However, none of the methods succeeded in harmonizing the Longitudinal dataset. CGAN was the worst performer for both datasets. In conclusion, the performance of the methods was overall similar and region dependent. Future research is needed to improve the existing approaches since none of them outperformed each other in terms of harmonizing the datasets at all ROIs. The findings of this study establish framework for future research into the scan harmonization problem.

Dentifrice performance in the removal of dental plaque is influenced by the interactions of dentifrice components with tooth surfaces. This randomized controlled clinical study assessed the effectiveness and safety of a novel fluoride dentifrice formulation that included a micro-fibrillated cellulose network with entangled microcrystalline cellulose and silica particles (ProtegeraTM), and compared this to a positive control fluoride dentifrice (Crest Cavity Protection™). Whole mouth dental plaque levels in 82 healthy adults were measured after the first supervised use, and following a week of twice daily use at home. Overall, the test dentifrice was at least three times and up to four times more effective in whole-mouth plaque reductions, with a 38.6% reduction on first use, a 30.9% reduction at day 7, and a 41.6% reduction from day 1 to day 7, compared to reductions of 12.0%, 9.6% and 11.6%, respectively for the positive control, and up to seven times more effective in lingual plaque reductions, than the reference dentifrice (p < 0.001), with a 27.7% reduction on first use, a 22.3% reduction at day 7, and a 31.0% reduction from day 1 to day 7, compared to reductions of 4.4%, 2.2%, and 4.5%, respectively, for the positive control. No safety issues arose from the use of the test dentifrice. These results indicate that including micro-fibrillated cellulose enhances plaque removal effectiveness, without causing adverse changes to oral soft tissues.

Fatty fish, which include mackerel, herring, salmon and sardines, and certain species of algae (e.g., Schizochytrium sp., Crytthecodiniumcohnii and Phaeodactylumtricornutum) are the only naturally rich sources of the omega-3 polyunsaturated fatty acids (n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are the most biologically active members of the n-3 PUFA family. Limited dietary sources and fluctuating content of EPA and DHA in fish raise concerns about the status of EPA and DHA among athletes, as confirmed in a number of studies. The beneficial effects of EPA and DHA include controlling inflammation, supporting nervous system function, maintaining muscle mass after injury and improving training adaptation. Due to their inadequate intake and beneficial health-promoting effects, athletes might wish to consider using supplements that provide EPA and DHA. Here, we provide an overview of the effects of EPA and DHA that are relevant to athletes and discuss the pros and cons of supplements as a source of EPA and DHA for athletes.

Here the authors digested chromatin with DNA fragmentation factor (DFF) prior to chromatin immunoprecipitation (DFF-ChIP) to depict transcription complex interactions with neighboring nucleosomes in cells. Applying this method to human cytomegalovirus (HMCV)-infected cells, they find that the viral genome is underchromatinized, leading to fewer transcription complex interactions with nucleosomes.

Abstract Ruffed grouse (Bonasa umbellus) populations are declining throughout their range, which has prompted efforts to understand drivers of the decline. Ruffed grouse monitoring efforts often rely on acoustic drumming surveys, in which a surveyor listens for the distinctive drumming sound that male ruffed grouse produce during the breeding season. Field‐based drumming surveys can fail to detect ruffed grouse when the birds drum infrequently or irregularly, making this species an excellent candidate for remote acoustic sensing with automated recording units (ARUs). An accurate automated recognition method for ruffed grouse drumming could enable effective and efficient use of ARU data for monitoring efforts; however, no such tool is currently available. Here we develop an automated method for detecting ruffed grouse drumming in audio recordings. Our detector uses a signal processing pipeline designed to recognize the accelerating pattern of drumming. We show that the automated recognition method accurately and efficiently detects drumming events in a set of labeled ARU field recordings. In a case study with 56 locations in Central Pennsylvania, we compared detections of ruffed grouse from 4 survey methods: field‐based acoustic drumming surveys, surveys conducted by humans listening to ARU recordings, and automated recognition for both a 1‐day and a 28‐day period. Field‐based surveys detected drumming at 9 of 56 locations (16%), while surveys conducted by humans listening to ARU recordings detected drumming at 8 locations (14%). Using automated recognition, the 1‐day recording period produced detections at 17 locations (30%) and the 28‐day recording period produced detections at 34 locations (61%). Our case study supports the idea that automated recognition can unlock the value of ARU datasets by temporally expanding the survey period. We provide an open‐source Python implementation of the recognition method to support further use in ruffed grouse monitoring efforts.

Abstract Best management practices are often written by researchers to guide land managers and landowners in the creation of habitat for wildlife species of interest. These documents are based on research evaluating the habitat needs of a species, but they also describe tools and strategies managers can implement to create or restore desired conditions. Shrub and sapling shearing is a management practice often used to improve habitat for early‐successional species, yet little monitoring or research has focused on wildlife response to shearing. The goal of this research was to formally evaluate the effect of shrub and sapling shearing as a best management strategy for Golden‐winged Warbler (Vermivora chrysoptera) conservation at a regional scale. Specifically, we surveyed for male Golden‐winged Warblers during the breeding season in sheared sites and untreated reference sites across portions of the western Great Lakes to assess the effects of (1) management status (i.e., sheared aspen or alder vs. untreated sites) and (2) patch‐level vegetation characteristics on male abundance. We found that male Golden‐winged Warbler abundance was twice as high in sheared sites than in mature reference sites and peaked when sapling cover was ~40%. Male abundance was also negatively associated with percent cover of forbs and nonvegetated ground. These findings highlight the importance of patch‐level heterogeneity when implementing shearing treatments for Golden‐winged Warblers and demonstrate the potential need for pretreatment site assessments to help focus conservation efforts for this species. Ultimately, our results support the use of a site‐specific, nuanced approach to shearing implementation to maximize cost efficiency and desired species outcomes.

In recent years there has been growing interest in the use of machine learning across the pharmacovigilance lifecycle to enhance safety monitoring of drugs and vaccines. Here we describe the scope of industry-based research into the use of machine learning for safety purposes. We conducted an examination of the findings from a previously published systematic review; 393 papers sourced from a literature search from 2000–2021 were analyzed and attributed to either industry, academia, or regulatory authorities. Overall, 33 papers verified to be industry contributions were then assigned to one of six categories representing the most frequent PV functions (data ingestion, disease-specific studies, literature review, real world data, signal detection, and social media). RWD and social media comprised 63% (21/33) of the papers, signal detection and data ingestion comprised 18% (6/33) of the papers, while disease-specific studies and literature reviews represented 12% (4/33) and 6% (2/33) of the papers, respectively. Herein we describe the trends and opportunities observed in industry application of machine learning in pharmacovigilance, along with discussing the potential barriers. We conclude that although progress to date has been uneven, industry is very interested in applying machine learning to the pharmacovigilance lifecycle, which it is hoped may ultimately enhance patient safety.

ABSTRACT Human cytomegalovirus (HCMV) is an opportunistic pathogen that infects most of the population. The complex 236 kbp genome encodes more than 170 open reading frames, whose expression is temporally regulated by both viral transcriptional regulators and cellular factors that control chromatin and transcription. Here, we have used state of the art genomic technologies to investigate the viral transcriptome in conjunction with 2 key transcriptional regulators: Pol II and H3K27Ac. Although it is well known that the major immediate early (IE) proteins activate early gene expression through both direct and indirect interactions, and that histone modifications play an important role in regulating viral gene expression, the role of the IE proteins in modulating viral chromatin is not fully understood. To address this question, we have used a virus engineered for conditional expression of the IE proteins combined with RNA and Chromatin immunoprecipitation (ChIP) analyses to assess the role of these proteins in modulating both viral chromatin and gene expression. Our results show that (i) there is an enhancer-like element in OriLyt that is extraordinarily enriched in H3K27Ac; (ii) in addition to activation of viral gene expression, the IE proteins play a critical role in recruitment of Pol II and H3K27Ac to this element. IMPORTANCE HCMV is an important human pathogen associated with complications in transplant patients and birth defects. The complex program of viral gene expression is regulated by both viral proteins and host factors. Here, we have investigated the role of the immediate early proteins in regulating the viral epigenome. Our results show that the viral immediate early proteins bring about an enormous enrichment of H3K27Ac marks at the OriLyt RNA4.9 promoter, concomitant with an increase in RNA4.9 expression. This epigenetic characteristic adds importantly to the view that OriLyt has structural and functional characteristics of a strong enhancer that, we now discover, is regulated by IE proteins.

Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood–nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1-/- mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand–receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/.

The key thermodynamic characteristics of the pseudogap state in cuprate superconductors are reviewed. These include YBa2Cu3O7−δ, Y0.8Ca0.2Ba2Cu3O7−δ, YBa2Cu4O8, Bi2Sr2CaCu2O8+δ, La2−xSrxCuO4, and Tl2Ba2CuO4. The electronic specific heat was extracted using a differential technique, and the evolution of the specific-heat coefficient γ and electronic entropy S as a function of temperature, doping, and magnetic field reveals a canonical behavior summarized by the following. The normal-state gap which opens in the pseudogap domain apparently remains open to the highest temperatures investigated. The gap decreases in magnitude with increasing doping and closes abruptly at a critical doping of p ≈ 0.19 holes/Cu, independent of temperature. In this picture, the pseudogap is separated from the pseudogap-free region of the phase diagram by a vertical line similar to the vertical line separating the incoherent and coherent antinodal quasiparticle states found in ARPES. The important role of fluctuations is evident by a diverging enhancement of γ(T) on either side of Tc, and this enables extraction of the mean-field transition temperature Tcmf>Tc, defining a crescent of parapairing above Tc(p) which extends across the entire superconducting phase diagram and which is quite distinct from pseudogap phenomenology. The data are consistent with d-wave pairing and the BCS ratios are extracted, revealing canonical near-weak-coupling behavior across the over-doped region with a sudden suppression occurring at p ≈ 0.19 when the pseudogap sets in.

Abstract Background Home blood pressure measurements have equal or even greater predictive value than clinic blood pressure measurements regarding cardiovascular outcomes. With advances in home blood pressure monitors, we face an imminent flood of home measurements, but current electronic health record systems lack the functionality to allow us to use this data to its fullest. We designed a data visualization display for blood pressure measurements to be used for shared decision making around hypertension. Methods We used an iterative, rapid-prototyping, user-centred design approach to determine the most appropriate designs for this data display. We relied on visual cognition and human factors principles when designing our display. Feedback was provided by expert members of our multidisciplinary research team and through a series of end-user focus groups, comprised of either hypertensive patients or their healthcare providers required from eight academic, community-based practices in the Midwest of the United States. Results A total of 40 participants were recruited to participate in patient (N = 16) and provider (N = 24) focus groups. We describe the conceptualization and development of data display for shared decision making around hypertension. We designed and received feedback from both patients and healthcare providers on a number of design elements that were reported to be helpful in understanding blood pressure measurements. Conclusions We developed a data display for substantial amounts of blood pressure measurements that is both simple to understand for patients, but powerful enough to inform clinical decision making. The display used a line graph format for ease of understanding, a LOWESS function for smoothing data to reduce the weight users placed on outlier measurements, colored goal range bands to allow users to quickly determine if measurements were in range, a medication timeline to help link recorded blood pressure measurements with the medications a patient was taking. A data display such as this, specifically designed to encourage shared decision making between hypertensive patients and their healthcare providers, could help us overcome the clinical inertia that often results in a lack of treatment intensification, leading to better care for the 35 million Americans with uncontrolled hypertension.

Abstract Background As exome sequencing (ES) integrates into clinical practice, we should make every effort to utilize all information generated. Copy-number variation can lead to Mendelian disorders, but small copy-number variants (CNVs) often get overlooked or obscured by under-powered data collection. Many groups have developed methodology for detecting CNVs from ES, but existing methods often perform poorly for small CNVs and rely on large numbers of samples not always available to clinical laboratories. Furthermore, methods often rely on Bayesian approaches requiring user-defined priors in the setting of insufficient prior knowledge. This report first demonstrates the benefit of multiplexed exome capture (pooling samples prior to capture), then presents a novel detection algorithm, mcCNV (“multiplexed capture CNV”), built around multiplexed capture. Results We demonstrate: (1) multiplexed capture reduces inter-sample variance; (2) our mcCNV method, a novel depth-based algorithm for detecting CNVs from multiplexed capture ES data, improves the detection of small CNVs. We contrast our novel approach, agnostic to prior information, with the the commonly-used ExomeDepth. In a simulation study mcCNV demonstrated a favorable false discovery rate (FDR). When compared to calls made from matched genome sequencing, we find the mcCNV algorithm performs comparably to ExomeDepth. Conclusion Implementing multiplexed capture increases power to detect single-exon CNVs. The novel mcCNV algorithm may provide a more favorable FDR than ExomeDepth. The greatest benefits of our approach derive from (1) not requiring a database of reference samples and (2) not requiring prior information about the prevalance or size of variants.

Reconstituted high-density lipoprotein nanoparticles (rHDL NPs) have been utilized as delivery vehicles to a variety of targets, including cancer cells. However, the modification of rHDL NPs for the targeting of the pro-tumoral tumor-associated macrophages (TAMs) remains largely unexplored. The presence of mannose on nanoparticles can facilitate the targeting of TAMs which highly express the mannose receptor at their surface. Here, we optimized and characterized mannose-coated rHDL NPs loaded with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an immunomodulatory drug. Lipids, recombinant apolipoprotein A-I, DMXAA, and different amounts of DSPE-PEG-mannose (DPM) were combined to assemble rHDL-DPM-DMXAA NPs. The introduction of DPM in the nanoparticle assembly altered the particle size, zeta potential, elution pattern, and DMXAA entrapment efficiency of the rHDL NPs. Collectively, the changes in physicochemical characteristics of rHDL NPs upon the addition of the mannose moiety DPM indicated that the rHDL-DPM-DMXAA NPs were successfully assembled. The rHDL-DPM-DMXAA NPs induced an immunostimulatory phenotype in macrophages pre-exposed to cancer cell-conditioned media. Furthermore, rHDL-DPM NPs delivered their payload more readily to macrophages than cancer cells. Considering the effects of the rHDL-DPM-DMXAA NPs on macrophages, the rHDL-DPM NPs have the potential to serve as a drug delivery platform for the selective targeting of TAMs.

ABSTRACT Human cytomegalovirus (HCMV) immediate-early 2 (IE2) protein is a multifunctional transcription factor that is essential for lytic HCMV infection. IE2 functions as an activator of viral early genes, negatively regulates its own promoter, and is required for viral replication. The mechanisms by which IE2 executes these distinct functions are incompletely understood. Using PRO-Seq, which profiles nascent transcripts, and a recently developed DFF-chromatin immunoprecipitation (DFF-ChIP; employs chromatin digestion by the endonuclease DNA fragmentation factor prior to IP) approach that resolves occupancy and local chromatin environment, we show that IE2 controls viral gene transcription in three distinct capacities during late HCMV infection and reveal mechanisms that involve direct binding of IE2 to viral DNA. IE2 represses a subset of viral promoters by binding within their core promoter regions and blocking the assembly of preinitiation complexes (PICs). Remarkably, IE2 forms a repressive complex at the major immediate-early promoter region involving direct association of IE2 with nucleosomes and TBP. IE2 stimulates transcription by binding nearby, but not within, core promoter regions. In addition, IE2 functions as a direct roadblock to transcription elongation. At one locus, this function of IE2 appears to be important for the synthesis of a spliced viral RNA. Consistent with the minimal observed effects of IE2 depletion on host gene transcription, IE2 does not functionally engage the host genome. Our results reveal mechanisms of transcriptional control by IE2, uncover a previously unknown function of IE2 as a Pol II elongation modulator, and demonstrate that DFF-ChIP is a useful tool for probing transcription factor occupancy and interactions between transcription factors and nucleosomes at high resolution. IMPORTANCE HCMV infects more than half of the world population and persists lifelong in its hosts. Although generally asymptomatic, HCMV infection can lead to life-threating disease in immunosuppressed individuals. Moreover, HCMV is the leading infectious cause of birth defects in the United States. As there are no vaccines effective against HCMV and antiviral drugs exhibit toxicity and are undermined by resistant HCMV variants, other vulnerabilities in HCMV must be explored. Here, we characterize the mechanism by which IE2 controls transcription during late HCMV infection. We demonstrate that IE2 engages numerous consensus sites across the HCMV genome and functions as an activator, repressor, or elongation modulator depending on the context of IE2 binding sites in relation to Pol II initiation and elongation complexes. Our findings have important implications for the ongoing exploration of IE2 as an antiviral drug target.

Increasingly, patient-generated safety insights are shared online, via general social media platforms or dedicated healthcare fora which give patients the opportunity to discuss their disease and treatment options. We evaluated three areas of potential interest for the use of social media in pharmacovigilance. To evaluate how social media may complement existing safety signal detection capabilities, we identified two use cases (drug/adverse event [AE] pairs) and then evaluated the frequency of AE discussions across a range of social media channels. Changes in frequency over time were noted in social media, then compared to frequency changes in Food and Drug Administration Adverse Event Reporting System (FAERS) data over the same time period using a traditional disproportionality method. Although both data sources showed increasing frequencies of AE discussions over time, the increase in frequency was greater in the FAERS data as compared to social media. To demonstrate the robustness of medical/AE insights of linked posts we manually reviewed 2,817 threads containing 21,313 individual posts from 3,601 unique authors. Posts from the same authors were linked together. We used a quality scoring algorithm to determine the groups of linked posts with the highest quality and manually evaluated the top 16 groups of posts. Most linked posts (12/16; 75%) contained all seven relevant medical insights assessed compared to only one (of 1,672) individual post. To test the capability of actively engage patients via social media to obtain follow-up AE information we identified and sent consents for follow-up to 39 individuals (through a third party). We sent target follow-up questions (identified by pharmacovigilance experts as critical for causality assessment) to those who consented. The number of people consenting to follow-up was low (20%), but receipt of follow-up was high (75%). We observed completeness of responses (37 out of 37 questions answered) and short average time required to receive the follow-up (1.8 days). Our findings indicate a limited use of social media data for safety signal detection. However, our research highlights two areas of potential value to pharmacovigilance: obtaining more complete medical/AE insights via longitudinal post linking and actively obtaining rapid follow-up information on AEs.

BackgroundEnrollment in pregnancy registries is challenging despite substantial awareness-raising activities, generally resulting in low recruitment owing to limited safety data. Understanding patient and physician awareness of and attitudes toward pregnancy registries is needed to facilitate enrollment. Crowdsourcing, in which services, ideas, or content are obtained by soliciting contributions from a large group of people using web-based platforms, has shown promise for improving patient engagement and obtaining patient insights. ObjectiveThis study aimed to use web-based crowdsourcing platforms to evaluate Belimumab Pregnancy Registry (BPR) awareness among patients and physicians and to identify potential barriers to pregnancy registry enrollment with the BPR as a case study. MethodsWe conducted 2 surveys using separate web-based crowdsourcing platforms: Amazon Mechanical Turk (a 14-question patient survey) and Sermo RealTime (a 11-question rheumatologist survey). Eligible patients were women, aged 18-55 years; diagnosed with systemic lupus erythematosus (SLE); and pregnant, recently pregnant (within 2 years), or planning pregnancy. Eligible rheumatologists had prescribed belimumab and treated pregnant women. Responses were descriptively analyzed. ResultsOf 151 patient respondents over a 3-month period (n=88, 58.3% aged 26-35 years; n=149, 98.7% with mild or moderate SLE; and n=148, 98% from the United States), 51% (77/151) were currently or recently pregnant. Overall, 169 rheumatologists completed the survey within 48 hours, and 59.2% (100/169) were based in the United States. Belimumab exposure was reported by 41.7% (63/151) patients, whereas 51.7% (75/145) rheumatologists had prescribed belimumab to 10 patients who were pregnant or trying to conceive. Of the patients exposed to belimumab, 51% (32/63) were BPR-aware, and 45.5% (77/169) of the rheumatologists were BPR-aware. Overall, 60% (38/63) of patients reported belimumab discontinuation because of pregnancy or planned pregnancy. Among the 77 BPR-aware rheumatologists, 70 (91%) referred patients to the registry. Concerns among rheumatologists who did not prescribe belimumab during pregnancy included unknown pregnancy safety profile (119/169, 70.4%), and 61.5% (104/169) reported their patients’ concerns about the unknown pregnancy safety profile. Belimumab exposure during or recently after pregnancy or while trying to conceive was reported in patients with mild (6/64, 9%), moderate (22/85, 26%), or severe (1/2, 50%) SLE. Rheumatologists more commonly recommended belimumab for moderate (84/169, 49.7%) and severe (123/169, 72.8%) SLE than for mild SLE (36/169, 21.3%) for patients trying to conceive recently or currently pregnant. Overall, 81.6% (138/169) of the rheumatologists suggested a belimumab washout period before pregnancy of 0-30 days (44/138, 31.9%), 30-60 days (64/138, 46.4%), or >60 days (30/138, 21.7%). ConclusionsIn this case, crowdsourcing efficiently obtained patient and rheumatologist input, with some patients with SLE continuing to use belimumab during or while planning a pregnancy. There was moderate awareness of the BPR among patients and physicians.