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Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy flux and immature autophagosomes. MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16 INK4A and CDKN1A/p21 CIP1 . Furthermore, induction of autophagy in aVICs by ATG (autophagy related) gene overexpression restored autophagy flux, with a concomitant reduction in CDKN1A and CDKN2A expression and senescence-associated secretory phenotype (SASP). Conversely, autophagy deficiency induced CDKN1A and CDKN2A accumulation and SASP, whereas ATG re-expression alleviated senescent phenotypic transformation. Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment. SQSTM1/p62 was identified as the autophagy receptor to selectively sequester CDKN1A and CDKN2A cargoes for autophagic degradation. Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders. Abbreviations : ACTA2/α-SMA: actin alpha 2, smooth muscle; AKT: AKT serine/threonine kinase; aVICs: activated valve interstitial cells; ATG: autophagy related; baf-A1: bafilomycin A 1 ; BrdU, bromodeoxyuridine; BSA: bovine serum albumin; CDKIs, cyclin-dependent kinase inhibitors; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; co-IP: co-immunoprecipitation; DMSO: dimethylsulfoxide; ECM, extracellular matrix; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; eGFP: green fluorescent protein; ELISA: enzyme-linked immunosorbent assay; HEK-293T, human embryonic kidney 293T; HRP: horseradish peroxidase; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: MAP1LC3/LC3-interacting region; MFS: Marfan syndrome; MKI67/Ki-67: marker of proliferation Ki-67; MMVD: myxomatous mitral valve degeneration; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; OE: overexpression; PBST, phosphate-buffered saline with 0.1% Tween-20; PCNA: proliferating cell nuclear antigen; PIK3CA/PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PLA: proximity ligation assays; PSMA1: proteasome 20S subunit alpha 1; PSMB5: proteasome 20S subunit beta 5; qVICs: quiescent valve interstitial cells; qRT-PCR: quantitative real-time PCR; SA-GLB1/β-gal: SA-senescence-associated GLB1/β-galactosidase; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; RPS6KB1/p70 S6K: ribosomal protein S6 kinase B1; SMAD: SMAD family member; SQSTM1/p62: sequestosome 1; STEM: scanning transmission electron microscopy; TGFB: transforming growth factor beta; TGFBR: transforming growth factor beta receptor; TP53/p53: tumor protein p53; UPS: ubiquitin-proteasome system; WT, wild-type.

The efficacy of aerial application and chemigation of insecticides is not well explored for western bean cutworm, Striacosta albicosta (Smith), management in corn. In the short term, inadequate application of insecticides can lead to control failures when insect pests are not effectively targeted. In the longer term, exposure to sublethal insecticide concentrations can contribute to the evolution of insecticide resistance. The goal of this study was to compare aerial application and chemigation under simulated conditions to determine the most effective insecticide application method for managing S. albicosta. Three larval stages were exposed to the highest and lowest label rates of commercial formulations of bifenthrin (36.8 and 112.1 g a.i. ha-1) and chlorantraniliprole (52.7 and 75.1 g a.i. ha-1). Experiments were conducted in spray chambers, utilizing a carrier volume of 18.7 L ha-1 for aerial application and 1.57 cm ha-1 for chemigation. Mortality was recorded at 16, 24, and 41 h after infestation. The simulated aerial application was more effective than simulated chemigation in controlling S. albicosta, resulting in 100% mortality 24 h after infestation. Within the chemigation applications, chlorantraniliprole treatments were effective at both rates for all instars, while the high rate of bifenthrin exhibited greater efficacy than the lower rate. In conclusion, it was evidenced that the same insecticide active ingredients do not yield equivalent efficacy when applied via aerial application compared to chemigation. The present study highlights the importance of selecting appropriate insecticide application methods in controlling S. albicosta larvae., (© The Author(s) 2025. Published by Oxford University Press on behalf of Entomological Society of America.)

Cutting-edge photonic devices frequently rely on microparticle components to focus and manipulate light. Conventional methods used to produce these microparticle components frequently offer limited control of their structural properties or require low-throughput nanofabrication of more complex structures. Here, we employ a synthetic biology approach to produce environmentally friendly, living microlenses with tunable structural properties. We engineered Escherichia coli bacteria to display the silica biomineralization enzyme silicatein from aquatic sea sponges. Our silicatein-expressing bacteria can self-assemble a shell of polysilicate "bioglass" around themselves. Remarkably, the polysilicate-encapsulated bacteria can focus light into intense nanojets that are nearly an order of magnitude brighter than unmodified bacteria. Polysilicate-encapsulated bacteria are metabolically active for up to 4 mo, potentially allowing them to sense and respond to stimuli over time. Our data demonstrate that synthetic biology offers a pathway for producing inexpensive and durable photonic components that exhibit unique optical properties., Competing Interests: Competing interests statement:L.M.S. and A.S.M. Modified bacteria and methods of use for bioglass microlenses. Provisional US patent application No. 63/338,490, filed May 5, 2022. International Patent Cooperation Treaty patent application filed May 5, 2023.

The establishment of industrial hemp (Cannabis sativa L.) fields near row crops has raised concerns about the potential adverse effects of herbicide drift on hemp production. This study examined hemp susceptibility to drift of herbicides registered for use in corn and/or soybeans. Herbicide solutions (2,4-D, dicamba, glufosinate, glyphosate, imazethapyr, lactofen, mesotrione) were applied separately in the wind tunnel (3.6 m s -1 airspeed), simulating drift scenarios, with conventional TP95015EVS (TP) and air inclusion AI95015EVS (AI) flat fan nozzles calibrated to deliver 140 L ha -1 carrier volume at 230 kPa. Mylar cards and hemp plants (20-25 cm tall) were placed downwind up to 12 m. Spray deposition from mylar cards was quantified using fluorometry and hemp biomass was collected 21 post application. Results indicated the nozzle design influenced downwind deposition; 5% of spray deposits from the TP nozzle reached 5.9 m downwind versus 2.0 m for the AI nozzle. Glyphosate, glufosinate, and mesotrione caused the highest biomass reductions, with 50% reductions observed at 19.3 (inferred), 8.7, and 9.3 m downwind for TP nozzle, and 4.1, 4.0, and 2.9 m for AI nozzle. These findings suggest herbicide applications at airspeeds of 3.6 m s -1 or greater present a risk to nearby hemp fields., Competing Interests: Declarations Competing interests The authors declare no competing interests. Data availability The datasets generated and/or analyzed during the current study are available from the corresponding author on a reasonable request., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Hearing loss has not been thoroughly investigated as a comorbidity in larger cohorts with neurofibromatosis type 1 (NF1)., Methods: Available audiometric data were reviewed from patients with NF1 seen at a tertiary pediatric hospital to assess prevalence and risk factors for hearing loss., Results: Of 1172 patients with NF1 seen between 2010 and 2022, 90 had available audiometric data and 48 of 90 patients (53%) had one or more audiogram revealing hearing loss. Those not referred to audiology were presumed to have normal hearing, resulting in a conservative hearing loss estimate of 4% for children and young adults with NF1. Of 90 patients with audiograms, 29 (32%) had conductive loss (CHL), 15 (17%) had sensorineural loss (SNHL), and 3 (3%) had mixed hearing loss. Hearing loss type was undetermined for one patient. For children with CHL, six had permanent CHL secondary to plexiform neurofibroma, 19 CHL were transient due to active middle ear dysfunction, and four CHL cases were indeterminate in etiology. For three children with SNHL or mixed hearing loss, etiology included history of ototoxic chemotherapy and/or family history of SNHL. In the 16 patients with SNHL or mixed hearing loss with more than one audiogram over time, progressive hearing decline was noted in eight of 16, and 26 of 178 hearing thresholds (15%) progressed., Conclusions: Our findings suggest that audiometric evaluations should be considered for at least a subset of children with NF1, given the higher-than-expected rate of hearing loss in patients with NF1 compared with the general population., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: In this study, we reviewed proximal humeral fractures surgically treated with open reduction and internal fixation (ORIF) to test the null hypothesis that there is no association between fracture characteristics and surgeon characteristics in outcomes after surgical management of displaced proximal humeral fractures with ORIF., Methods: A retrospective review of surgically treated proximal humeral fractures was done at a tertiary-level hospital. The data were organized into two categories: fracture characteristics and surgeon characteristics., Results: There were 314 proximal humeral fractures treated with ORIF. In total, there were 112 failures (36%). Bivariate Pearson correlations demonstrated that the number of proximal humerus fixation surgeries performed by an individual surgeon was associated with adequate calcar reduction (r = 0.995, P < 0.001) and greater tuberosity reduction (r = 0.994, P < 0.001). Years of experience was positively associated with adequate calcar reduction (r = 0.594, P = 0.012) and greater tuberosity reduction (r = 0.589, P = 0.013). Regression analysis of two surgeons versus the rest of the cohort demonstrated significantly lower failure rates (P = 0.001)., Discussion: Complex proximal humeral fractures (3-part and 4-part) have better calcar reduction and tuberosity reduction when treated by surgeons with greater volume of proximal humeral fracture surgery. Among surgeons with high volume, there may be individuals who have the unique ability to provide markedly better results., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Photonic devices are cutting-edge optical materials that produce narrow, intense beams of light, but their synthesis typically requires toxic, complex methodology. Here we employ a synthetic biology approach to produce environmentally-friendly, living microlenses with tunable structural properties. We engineered Escherichia coli bacteria to display the silica biomineralization enzyme silicatein from aquatic sea sponges. Our silicatein-expressing bacteria can self-assemble a shell of polysilicate "bioglass" around themselves. Remarkably, the polysilicate-encapsulated bacteria can focus light into intense nanojets that are nearly an order of magnitude brighter than unmodified bacteria. Polysilicate-encapsulated bacteria are metabolically active for up to four months, potentially allowing them to sense and respond to stimuli over time. Our data demonstrate that engineered bacterial particles have the potential to revolutionize the development of multiple optical and photonic technologies., Competing Interests: Competing interests Statement: The authors declare no competing interests.

Objectives: Evaluate the rate of preserved vestibular function in pediatric cochlear implant surgery., Study Design: Retrospective case review., Methods: Pre- and post-operative vestibular tests were compared in children who underwent cochlear implantation at a tertiary level pediatric hospital over a 4-year period., Results: Data from 59 implanted ears in 44 children was included. Median age was 2.8 years at initial testing (range 7 months - 21 years) with 1:1 male/female ratio. Implant surgeries were 26 unilateral, 13 bilateral simultaneous, and 5 bilateral sequential. The majority were implanted with slim, non-styletted electrodes (86.4%) via a round window approach (91.5%). Normal pre-operative results were preserved post-operatively on rotary chair testing in 75% (21/28) of patients, cervical vestibular evoked myogenic potential testing in (75%) 30/40 of ears tested, ocular vestibular evoked myogenic potential testing in 85.7% (6/7) of ears tested, video head impulse testing in 100% (9/9) of ears tested, and computerized dynamic posturography in 100% (5/5) of patients tested. Overall, 62.5% of patients had no new deficits on any vestibular test performed post-operatively., Conclusions: Preservation rates of vestibular function following cochlear implant surgery were higher in this cohort than what has been reported in many earlier studies. Contemporary, less traumatic electrodes and insertion techniques may be a significant factor. The risk of causing a new, severe bilateral vestibular loss with long-term functional impacts appears to be low. Further study is warranted on the impacts of different cochlear implant electrode designs and insertion approaches on post-operative vestibular preservation., Level of Evidence: 4, Case Series Laryngoscope, 134:1913-1918, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Mutations at a highly conserved homologous residue in three closely related muscle myosins cause three distinct diseases involving muscle defects: R671C in β-cardiac myosin causes hypertrophic cardiomyopathy, R672C and R672H in embryonic skeletal myosin cause Freeman-Sheldon syndrome, and R674Q in perinatal skeletal myosin causes trismus-pseudocamptodactyly syndrome. It is not known whether their effects at the molecular level are similar to one another or correlate with disease phenotype and severity. To this end, we investigated the effects of the homologous mutations on key factors of molecular power production using recombinantly expressed human β, embryonic, and perinatal myosin subfragment-1. We found large effects in the developmental myosins but minimal effects in β myosin, and magnitude of changes correlated partially with clinical severity. The mutations in the developmental myosins dramatically decreased the step size and load-sensitive actin-detachment rate of single molecules measured by optical tweezers, in addition to decreasing overall enzymatic (ATPase) cycle rate. In contrast, the only measured effect of R671C in β myosin was a larger step size. Our measurements of step size and bound times predicted velocities consistent with those measured in an in vitro motility assay. Finally, molecular dynamics simulations predicted that the arginine to cysteine mutation in embryonic, but not β, myosin may reduce pre-powerstroke lever arm priming and ADP pocket opening, providing a possible structural mechanism consistent with the experimental observations. This paper presents direct comparisons of homologous mutations in several different myosin isoforms, whose divergent functional effects are a testament to myosin's highly allosteric nature., Competing Interests: Competing interests statement:J.A.S. is cofounder and on the Scientific Advisory Board of Cytokinetics, Inc., a company developing small molecule therapeutics for treatment of HCM. J.A.S. is cofounder and CEO, and K.M.R. is cofounder and Research and Clinical Advisor, of Kainomyx, Inc., a company developing small molecule therapeutics targeting myosins in parasites. G.R.B. is cofounder and equity holder in Decrypt Biomedicine.

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer's disease. The role of amyloid beta 42 (Aβ 42 ) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ 42 , which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ 42 . Increasing circulating Aβ 42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aβ 40 isoform does not have these same effects on the heart. Administration of an Aβ-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aβ 42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ 42 inhibits mitochondrial complex I. These data reveal a role for systemic Aβ 42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer's disease could be effective in combating obesity-induced heart failure., (© 2024. The Author(s).)

Triclosan is a widely used antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive lifetime exposures to triclosan, yet data on the chronic dermal toxicity/carcinogenicity of triclosan are still lacking. We evaluated the toxicity/carcinogenicity of triclosan administered dermally to B6C3F1 mice for 104 weeks. Groups of 48 male and 48 female B6C3F1 mice received dermal applications of 0, 1.25, 2.7, 5.8, or 12.5 mg triclosan/kg body weight (bw)/day in 95% ethanol, 7 days/week for 104 weeks. Vehicle control animals received 95% ethanol only; untreated, naïve control mice did not receive any treatment. There were no significant differences in survival among the groups. The highest dose of triclosan significantly decreased the body weight of mice in both sexes, but the decrease was ≤ 9%. Minimal-to-mild epidermal hyperplasia, suppurative inflammation (males only), and ulceration (males only) were observed at the application site in the treated groups, with the highest incidence occurring in the 12.5 mg triclosan/kg bw/day group. No tumors were identified at the application site. Female mice had a positive trend in the incidence of pancreatic islet adenoma. In male mice, there were positive trends in the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined), with the increase of carcinoma being significant in the 5.8 and 12.5 mg/kg/day groups and the increase in hepatocellular adenoma or carcinoma (combined) being significant in the 2.7, 5.8, and 12.5 mg/kg/day groups., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in natural killer (NK) cells, lymphocytes that recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK-cell and B-cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date., Objectives: The investigators aimed to identify the genetic cause of NK-cell immunodeficiency in 2 families and herein describe the functional consequences of 2 novel loss-of-function variants in PLCG2., Methods: The investigators employed whole-exome sequencing in conjunction with mass cytometry, microscopy, functional assays, and a mouse model of PLCG2 haploinsufficiency to investigate 2 families with NK-cell immunodeficiency., Results: The investigators identified novel heterozygous variants in PLCG2 in 2 families with severe and/or recurrent herpesvirus infections. In vitro studies demonstrated that these variants were loss of function due to haploinsufficiency with impaired NK-cell calcium flux and cytotoxicity. In contrast to previous PLCG2 variants, B-cell function remained intact. Plcg2 +/- mice also displayed impaired NK-cell function with preserved B-cell function, phenocopying human disease., Conclusions: PLCG2 haploinsufficiency represents a distinct syndrome from previous variants characterized by NK-cell immunodeficiency with herpesvirus susceptibility, expanding the spectrum of PLCG2-related disease., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite considerable interest in robotic surgery, successful incorporation of robotics into transplant programs has been challenging. Lack of a dedicated OR team with expertise in both robotics and transplant is felt to be a major barrier. This paper assesses the impact of a dedicated robotic transplant team (DART) on program growth and fellowship training at one of the largest robotic transplant programs in North America., Methods: This is a single center, retrospective review of all robotic operations performed on the transplant surgery service from October 2017 to October 2022. DART was incorporated in February 2020 and included transplant first assists (RFAs), scrub technologists and circulating nurses who received robotic training. Robotic experience before and after DART was compared to assess its impact on program growth and training., Results: Four hundred and two robotic cases were performed by five transplant surgeons: 63 pre-DART and 339 post-DART. 40% of cases were transplant-related and 59.5%, HPB. There was a significant increase in case volume (2.5-10.6 cases/month, p < .0001) and complexity (36.5% vs. 70.3% high complexity cases, p < .0001) post-DART. RFA case coverage increased from 17% to 95%, and participation of transplant fellows as primary surgeons increased from 17% to 95% post-DART period (both p < .05). Conversion rates (9.5% vs. 4.1%) and room turn-around-times (TAT) (58.4 vs. 40.3 min) were lower post-DART (p < .05). There were no emergent conversions, conversions in transplant patients, or robot-related complications in either group., Conclusion: OR teams with expertise in robotics and transplant surgery can accelerate growth of robotic transplant programs while maintaining patient safety., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Oligodendrocyte progenitor cells (OPCs) receive synaptic innervation from glutamatergic and GABAergic axons and can be dynamically regulated by neural activity, resulting in activity-dependent changes in patterns of axon myelination. However, it remains unclear to what extent other types of neurons may innervate OPCs. Here, we provide evidence implicating midbrain dopamine neurons in the innervation of oligodendrocyte lineage cells in the anterior corpus callosum and nearby white matter tracts of male and female adult mice. Dopaminergic axon terminals were identified in the corpus callosum of DAT-Cre mice after injection of an eYFP reporter virus into the midbrain. Furthermore, fast-scan cyclic voltammetry revealed monoaminergic transients in the anterior corpus callosum, consistent with the anatomical findings. Using RNAscope, we further demonstrate that ~ 40% of Olig2 + /Pdfgra + cells and ~ 20% of Olig2 + /Pdgfra- cells in the anterior corpus callosum express Drd1 and Drd2 transcripts. These results suggest that oligodendrocyte lineage cells may respond to dopamine released from midbrain dopamine axons, which could affect myelination. Together, this work broadens our understanding of neuron-glia interactions with important implications for myelin plasticity by identifying midbrain dopamine axons as a potential regulator of corpus callosal oligodendrocyte lineage cells., (© 2023. The Author(s).)

Background: TGFβ signaling appears to contribute to the pathogenesis of myxomatous mitral valve disease (MMVD) in both dogs and humans. However, little is known about the extent of the downstream signaling changes that will then affect cell phenotype and function in both species., Objective: Identify changes in downstream signals in the TGFβ pathway in canine MMVD and examine the effects of antagonism of one significant signal (SMAD2 was selected)., Materials and Methods: Canine cultures of normal quiescent valve interstitial cells (qVICs) and disease-derived activated myofibroblasts (aVICs) ( n = 6) were examined for TGFβ signaling protein expression using a commercial antibody array. Significant changes were confirmed, and additional proteins of interest downstream in the TGFβ signaling pathway and markers of cell phenotype were examined (PRAS40, S6K, elF4E IRS-1, αSMA, and VIM), using protein immunoblotting. RT-PCR examined expression of gene markers of VIC activation ( ACTA2, TAGLN , and MYH10 ; encoding the proteins αSMA, SM22, and Smemb, respectively). Attenuation of pSMAD2 in aVICs was examined using a combination of RNA interference technology (siRNA) and the SMAD7 (antagonizes SMAD2) agonist asiaticoside., Results: The antibody array identified significant changes ( P < 0.05) in 19 proteins, of which six were phosphorylated (p). There was increased expression of pSMAD2 and pRAC1 and decreased expression of pmTOR, pERK1/2, and pAKT1. Expression of pPRAS40 and pIRS-1 was increased, as was the mTOR downstream transcription factor pS6K, with increased expression of peIF4E in aVICs, indicating negative feedback control of the PI3K/AKT/mTOR pathway. SMAD2 antagonism by siRNA and the SMAD7 agonist asiaticoside decreased detection of pSMAD by at least 50%, significantly decreased expression of the aVIC gene markers ACTA2, TAGLN , and MYH10 , and pαSMA, pAKT2, and pERK1, but had no effect on pS6K, pERK2, or pVIM expression in aVICs. SMAD2 antagonism transitioned diseased aVICs to normal qVICs, while maintaining a mesenchymal phenotype (VIM+) while concurrently affecting non-canonical TGFβ signaling., Conclusion: MMVD is associated with changes in both the canonical and non-canonical TGFβ signaling pathway. Antagonism of SMAD2 transitions diseased-activated myofibroblasts back to a normal phenotype, providing data that will inform studies on developing novel therapeutics to treat MMVD in dogs and humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 McNair, Markby, Tang, MacRae and Corcoran.)

The family of ∼60 clustered protocadherins (Pcdhs) are cell adhesion molecules encoded by a genomic locus that regulates expression of distinct combinations of isoforms in individual neurons resulting in what is thought to be a neural surface "barcode" which mediates same-cell interactions of dendrites, as well as interactions with other cells in the environment. Pcdh mediated same-cell dendrite interactions were shown to result in avoidance while interactions between different cells through Pcdhs, such as between neurons and astrocytes, appear to be stable. The cell biological mechanism of the consequences of Pcdh based adhesion is not well understood although various signaling pathways have been recently uncovered. A still unidentified cytoplasmic regulatory mechanism might contribute to a "switch" between avoidance and adhesion. We have proposed that endocytosis and intracellular trafficking could be part of such a switch. Here we use "stub" constructs consisting of the proximal cytoplasmic domain (lacking the constant carboxy-terminal domain spliced to all Pcdh-γs) of one Pcdh, Pcdh-γA3, to study trafficking. We found that the stub construct traffics primarily to Rab7 positive endosomes very similarly to the full length molecule and deletion of a substantial portion of the carboxy-terminus of the stub eliminates this trafficking. The intact stub was found to be ubiquitinated while the deletion was not and this ubiquitination was found to be at non-lysine sites. Further deletion mapping of the residues required for ubiquitination identified potential serine phosphorylation sites, conserved among Pcdh-γAs, that can reduce ubiquitination when pseudophosphorylated and increase surface expression. These results suggest Pcdh-γA ubiquitination can influence surface expression which may modulate adhesive activity during neural development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2023 Ptashnik, LaMassa, Mambetalieva, Schnall, Bucaro and Phillips.)

This publisher's note contains a correction to Appl. Opt.62, 3485 (2023)APOPAI0003-693510.1364/AO.487089.

Background: Ultrasound is a powerful tool for diagnostic purposes and provides insight into both normal and pathologic tissue structure. Spatial frequency analysis (SFA) methods characterize musculoskeletal tissue organization from ultrasound images. Both sonographers in clinical imaging and researchers may alter a minimized range of ultrasound settings to optimize image quality, and it is important to know how these small adjustments of these settings affect SFA parameters. The purpose of this study was to investigate the effects of making small adjustments in a typical default ultrasound machine setting on extracted spatial frequency parameters (peak spatial frequency radius (PSFR), Mmax, Mmax%, and Sum) in the biceps femoris muscle., Methods: Longitudinal B-mode images were collected from the biceps femoris muscle in 36 participants. The window depth, foci locations, and gain were systematically adjusted consistent with clinical imaging procedures for a total of 27 images per participant. Images were analyzed by identifying a region of interest (ROI) in the middle portion of the muscle belly in a template image and using a normalized two-dimensional cross-correlation technique between the template image and subsequent images. The ROI was analyzed in the frequency domain using conventional SFA methods. Separate linear mixed effects models were run for each extracted parameter., Results: PSFR was affected by modifications in focus location only (p < 0.001) with differences noted between all locations. Mmax% was influenced by the interaction of gain and focus location (p < 0.001) but was also independently affected by increasing window depth (p < 0.001). Both Mmax and Sum parameters were sensitive to small changes in machine settings with the interaction of focus location and window depth (p < 0.001 for both parameters) as well as window depth and gain (p < 0.001 for both) influencing the extracted values., Conclusions: Frequently adjusted imaging settings influence some SFA statistics. PSFR and Mmax% appear to be most robust to small changes in image settings, making them best suited for comparison across individuals and between studies, which is appealing for the clinical utility of the SFA method., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mutations at a highly conserved homologous residue in three closely related muscle myosins cause three distinct diseases involving muscle defects: R671C in β -cardiac myosin causes hypertrophic cardiomyopathy, R672C and R672H in embryonic skeletal myosin cause Freeman Sheldon syndrome, and R674Q in perinatal skeletal myosin causes trismus-pseudocamptodactyly syndrome. It is not known if their effects at the molecular level are similar to one another or correlate with disease phenotype and severity. To this end, we investigated the effects of the homologous mutations on key factors of molecular power production using recombinantly expressed human β , embryonic, and perinatal myosin subfragment-1. We found large effects in the developmental myosins, with the most dramatic in perinatal, but minimal effects in β myosin, and magnitude of changes correlated partially with clinical severity. The mutations in the developmental myosins dramatically decreased the step size and load-sensitive actin-detachment rate of single molecules measured by optical tweezers, in addition to decreasing ATPase cycle rate. In contrast, the only measured effect of R671C in β myosin was a larger step size. Our measurements of step size and bound times predicted velocities consistent with those measured in an in vitro motility assay. Finally, molecular dynamics simulations predicted that the arginine to cysteine mutation in embryonic, but not β , myosin may reduce pre-powerstroke lever arm priming and ADP pocket opening, providing a possible structural mechanism consistent with the experimental observations. This paper presents the first direct comparisons of homologous mutations in several different myosin isoforms, whose divergent functional effects are yet another testament to myosin's highly allosteric nature., Competing Interests: Competing interest statement J.A.S. is cofounder and on the Scientific Advisory Board of Cytokinetics, Inc., a company developing small molecule therapeutics for treatment of hypertrophic cardiomyopathy. J.A.S. is cofounder and CEO, and K.M.R. is cofounder and Research and Clinical Advisor, of Kainomyx, Inc., a company developing small molecule therapeutics targeting myosins in parasites. G.R.B. is cofounder and equity holder in Decrypt Biomedicine.

Refugia can facilitate the persistence of species under long-term environmental change, but it is not clear if Pleistocene refugia will remain functional as anthropogenic climate change progresses. Dieback in populations restricted to refugia therefore raises concerns about their long-term persistence. Using repeat field surveys, we investigate dieback in an isolated population of Eucalyptus macrorhyncha during two droughts and discuss prospects for its continued persistence in a Pleistocene refugium. We first confirm that the Clare Valley in South Australia has constituted a long-term refugium for the species, with the population being genetically highly distinct from other conspecific populations. However, the population lost >40 % of individuals and biomass through the droughts, with mortality being just below 20 % after the Millennium Drought (2000-2009) and almost 25 % after the Big Dry (2017-2019). The best predictors of mortality differed after each drought. While north-facing aspect of a sampling location was significant positive predictor after both droughts, biomass density and slope were significant negative predictors only after the Millennium Drought, and distance to the north-west corner of the population, which intercepts hot, dry winds, was a significant positive predictor after the Big Dry only. This suggests that more marginal sites with low biomass and sites located on flat plateaus were more vulnerable initially, but that heat-stress was an important driver of dieback during the Big Dry. Therefore, the causative drivers of dieback may change during population decline. Regeneration occurred predominantly on southern and eastern aspects, which would receive the least solar radiation. While this refugial population is experiencing severe decline, some gullies with lower solar radiation appear to support relatively healthy, regenerating stands of red stringybark, providing hope for persistence in small pockets. Monitoring and managing these pockets during future droughts will be essential to ensure the persistence of this isolated and genetically unique population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Udo Sarnow reports financial support was provided by Royal Society of South Australia Incorporated., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Emergency Department Observation Unit (EDOU) patients with chest pain have a high prevalence of smoking, a key cardiovascular disease risk factor. While in the EDOU, there is an opportunity to initiate smoking cessation therapy (SCT), but this is not standard practice. This study aims to describe the missed opportunity for EDOU-initiated SCT by determining the proportion of smokers who receive SCT in the EDOU and within 1-year of EDOU discharge and to evaluate if SCT rates vary by race or sex., Methods: We performed an observational cohort study of patients ≥18 years old being evaluated for chest pain in a tertiary care center EDOU from 3/1/2019-2/28/2020. Demographics, smoking history, and SCT were determined by electronic health record review. Emergency, family medicine, internal medicine, and cardiology records were reviewed to determine if SCT occurred within 1-year of their initial visit. SCT was defined as behavioral interventions or pharmacotherapy. Rates of SCT in the EDOU, 1-year follow-up period, and the EDOU through 1-year of follow-up were calculated. SCT rates from the EDOU through 1-year were compared between white vs. non-white and male vs. female patients using a multivariable logistic regression model including age, sex, and race., Results: Among 649 EDOU patients, 24.0% (156/649) were smokers. These patients were 51.3% (80/156) female and 46.8% (73/156) white, with a mean age of 54.4 ± 10.5 years. From the EDOU encounter through 1-year of follow-up, only 33.3% (52/156) received SCT. In the EDOU, 16.0% (25/156) received SCT. During the 1-year follow-up period, 22.4% (35/156) had outpatient SCT. After adjusting for potential confounders, SCT rates from the EDOU through 1-year were similar among whites vs. non-whites (aOR 1.19, 95% CI 0.61-2.32) and males vs. females (aOR 0.79, 95% CI 0.40-1.56)., Conclusions: SCT was rarely initiated in the EDOU among chest pain patients who smoke and most patients who did not receive SCT in the EDOU never received SCT at 1-year of follow-up. Rates of SCT were similarly low among race and sex subgroups. These data suggest an opportunity exists to improve health by initiating SCT in the EDOU., Competing Interests: Conflicts of interest Dr. Ashburn receives funding from NHLBI (T32HL076132). Dr. Snavely receives funding from Abbott and HRSA (1H2ARH399760100). Dr. Rikhi receives funding from NHLBI (T32HL076132). Dr. Stopyra receives research funding from NCATS/NIH (KL2TR001421), HRSA (H2ARH39976-01-00), Roche Diagnostics, Abbott Laboratories, Pathfast, Genetesis, Cytovale, Forest Devices, Vifor Pharma, and Chiesi Farmaceutici. Dr. Mahler receives funding/support from Roche Diagnostics, Abbott Laboratories, Ortho Clinical Diagnostics, Siemens, Grifols, Pathfast, Quidel, Genetesis, Cytovale, and HRSA (1H2ARH399760100). He is a consultant for Roche, Quidel, Abbott, Genetesis, Inflammatix, Radiometer, and Amgen and is the Chief Medical Officer for Impathiq Inc. The other authors report no conflicts., (Copyright © 2023 Elsevier Inc. All rights reserved.)

PI3K/AKT/mTOR signalling contributes to several cardiovascular disorders. The aim of this study was to examine the PI3K/AKT/mTOR pathway in myxomatous mitral valve disease (MMVD). Double-immunofluorescence examined expression of PI3K and TGF-β1 in canine valves. Valve interstitial cells (VICs) from healthy or MMVD dogs were isolated and characterized. Healthy quiescent VICs (qVICs) were treated with TGF-β1 and SC-79 to induce activated myofibroblast phenotypes (aVICs). Diseased valve-derived aVICs were treated with PI3K antagonists and expression of RPS6KB1 (encoding p70 S6K) was modulated using siRNA and gene overexpression. SA-β-gal and TUNEL staining were used to identify cell senescence and apoptosis, and qPCR and ELISA to examine for senescence-associated secretory phenotype. Protein immunoblotting was used to examine expression of phosphorylated and total proteins. TGF-β1 and PI3K are highly expressed in mitral valve tissues. Activation of PI3K/AKT/mTOR and increased expression of TGF-β are found in aVICs. TGF-β transitions qVICs to aVICs by upregulation of PI3K/AKT/mTOR. Antagonism of PI3K/AKT/mTOR reverses aVIC myofibroblast transition by inhibiting senescence and promoting autophagy. Upregulation of mTOR/S6K induces transformation of senescent aVICs, with reduced capacity for apoptosis and autophagy. Selective knockdown of p70 S6K reverses cell transition by attenuating cell senescence, inhibiting apoptosis and improving autophagy. TGF-β-induced PI3K/AKT/mTOR signalling contributes to MMVD pathogenesis and plays crucial roles in the regulation of myofibroblast differentiation, apoptosis, autophagy and senescence in MMVD., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Gradient-index Alvarez lenses (GALs), a new, to the best of our knowledge, type of freeform optical component, are surveyed in this work for their unique properties in generating variable optical power. GALs display similar behavior to conventional surface Alvarez lenses (SALs) by means of a freeform refractive index distribution that has only recently been achievable in fabrication. A first-order framework is described for GALs including analytical expressions for their refractive index distribution and power variation. A useful feature of Alvarez lenses for introducing bias power is also detailed and is helpful for both GALs and SALs. The performance of GALs is studied, and the value of three-dimensional higher-order refractive index terms is demonstrated in an optimized design. Last, a fabricated GAL is demonstrated along with power measurements agreeing closely with the developed first-order theory.

Freeform gradient index (F-GRIN) lenses have been recently shown to enable compact optical design. However, aberration theory is only fully developed for rotationally symmetric distributions with a well-defined optical axis. The F-GRIN has no well-defined optical axis, and rays are continuously perturbed along their trajectory. Optical performance can be understood without abstracting optical function to numerical evaluation. The present work derives freeform power and astigmatism along an axis through a zone of an F-GRIN lens with freeform surfaces. Zonal power and astigmatism can be assessed without tracing any rays, capturing mixed contributions of the F-GRIN and freeform surface. Theory is compared with a commercial design software numerical raytrace evaluation. The comparison shows that the raytrace-free (RTF) calculation represents all raytrace contributions within a margin of error. In one example, it is demonstrated that linear terms of index and surface alone in an F-GRIN corrector can correct the astigmatism of a tilted spherical mirror. Accounting for the induced effects of the spherical mirror, RTF calculation provides the amount of astigmatism correction of the optimized F-GRIN corrector.

Potential for off-target movements follows every herbicide application. Because the launch of acetolactate synthase (ALS)- and 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide-tolerant crops will increase the treated area, there is a need to assess the possible negative consequences of any particle drift from those herbicides. Drift happens with every pesticide application, requiring mitigation. Various factors influence drift. Some, such as nozzle type, working pressure, and boom height, can be managed. Others, such as wind, are not easy to manage. In our study, an herbicide tank mixture of mesotrione with rimsulfuron plus thifensulfuron-methyl was sprayed in a low-speed wind tunnel to simulate drift. The airspeed was set at 4.4 m s -1 , representing the labeled upper limit for applications. The herbicide solution was sprayed through XR110015 and TTI110015 nozzles. Eight crops were exposed to herbicide drift treatments and biomass data were collected. Droplet size spectra and tracer depositions were evaluated. Tracer deposition was on average threefold higher in all downwind distances (0.5, 1, 2, 3, 4, 6, 9, and 12 m) from the XR nozzle in comparison to the TTI nozzle. As a consequence, greater biomass reduction was recorded for applications with the XR compared to the TTI nozzle from 1 to 12 m downwind. At 12-m distance, biomass was decreased by 7-78% using XR nozzle while 1-27% using the TTI nozzle. Because drift can injure crops, it is very important to mitigate drift from application of formulations containing mesotrione and rimsulfuron plus thifensulfuron-methyl in combination. This can be done by selecting the appropriate nozzle and ensuring optimal distances between crops., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Here we provide the 'Global Spectrum of Plant Form and Function Dataset', containing species mean values for six vascular plant traits. Together, these traits -plant height, stem specific density, leaf area, leaf mass per area, leaf nitrogen content per dry mass, and diaspore (seed or spore) mass - define the primary axes of variation in plant form and function. The dataset is based on ca. 1 million trait records received via the TRY database (representing ca. 2,500 original publications) and additional unpublished data. It provides 92,159 species mean values for the six traits, covering 46,047 species. The data are complemented by higher-level taxonomic classification and six categorical traits (woodiness, growth form, succulence, adaptation to terrestrial or aquatic habitats, nutrition type and leaf type). Data quality management is based on a probabilistic approach combined with comprehensive validation against expert knowledge and external information. Intense data acquisition and thorough quality control produced the largest and, to our knowledge, most accurate compilation of empirically observed vascular plant species mean traits to date., (© 2022. The Author(s).)

With the advent of 3D printing optical elements, new techniques for manufacturing gradient-index (GRIN) optics have been realized that blend multiple materials in the deposition process. A method to achieve spectral splitting using multi-material GRIN optics is presented. The GRIN is additionally used to generate optical power, allowing for planar entrance and exit surfaces. It is shown that this simultaneous focusing and spectral splitting is not feasible with a two-material GRIN. A comparative design study is then conducted using three and four-material GRIN. A four-material design with optimized materials is also presented to showcase the potential for this new design form.

Recent advancements in additive manufacturing have enabled new methods of fabricating gradient-index (GRIN) optics by blending multiple materials in the deposition process. A design study highlighting the advantages of multi-material GRIN optics is presented. It is shown that additional materials in the GRIN allow for higher orders of color correction. A new multi-material refractive index representation, which constrains the GRIN to real materials, is also presented.

Numerous studies have analysed the relationship between C4 plant cover and climate. However, few have examined how different C4 taxa vary in their response to climate, or how environmental factors alter C4:C3 abundance. Here we investigate (a) how proportional C4 plant cover and richness (relative to C3) responds to changes in climate and local environmental factors, and (b) if this response is consistent among families. Proportional cover and richness of C4 species were determined at 541 one-hectare plots across Australia for 14 families. C4 cover and richness of the most common and abundant families were regressed against climate and local parameters. C4 richness and cover in the monocot families Poaceae and Cyperaceae increased with latitude and were strongly positively correlated with January temperatures, however C4 Cyperaceae occupied a more restricted temperature range. Seasonal rainfall, soil pH, soil texture, and tree cover modified proportional C4 cover in both families. Eudicot families displayed considerable variation in C4 distribution patterns. Proportional C4 Euphorbiaceae richness and cover were negatively correlated with increased moisture availability (i.e. high rainfall and low aridity), indicating they were more common in dry environments. Proportional C4 Chenopodiaceae richness and cover were weakly correlated with climate and local environmental factors, including soil texture. However, the explanatory power of C4 Chenopodiaceae models were poor, suggesting none of the factors considered in this study strongly influenced Chenopodiaceae distribution. Proportional C4 richness and cover in Aizoaceae, Amaranthaceae, and Portulacaceae increased with latitude, suggesting C4 cover and richness in these families increased with temperature and summer rainfall, but sample size was insufficient for regression analysis. Results demonstrate the unique relationships between different C4 taxa and climate, and the significant modifying effects of environmental factors on C4 distribution. Our work also revealed C4 families will not exhibit similar responses to local perturbations or climate., Competing Interests: The authors have declared that no competing interests exist.

We present experimental results on optical trapping of Yb-doped β-NaYF subwavelength-thickness high-aspect-ratio hexagonal prisms with a micron-scale radius. The prisms are trapped in vacuum using an optical standing wave, with the normal vector to their face oriented along the beam propagation direction, yielding much higher trapping frequencies than those typically achieved with microspheres of similar mass. This platelike geometry simultaneously enables trapping with low photon-recoil-heating, high mass, and high trap frequency, potentially leading to advances in high frequency gravitational wave searches in the Levitated Sensor Detector, currently under construction. The material used here has previously been shown to exhibit internal cooling via laser refrigeration when optically trapped and illuminated with light of suitable wavelength. Employing such laser refrigeration methods in the context of our work may enable higher trapping intensity and thus higher trap frequencies for gravitational wave searches approaching the several hundred kilohertz range.

Background: Field experiments were conducted across multiple sites in 2012 and 2013 to describe sensitivity of soybean to 2,4-D (six doses) and dicamba (seven doses) at V3 and R1 growth stages. Further experiments were conducted under greenhouse conditions in 2017 and 2018 to compare soybean response to several dicamba herbicides across a broader range of doses than those tested in the field., Results: Soybean yield loss was 6.1-fold greater from 2,4-D exposure at V3 compared to R1 and 1.4 times greater from dicamba exposure at R1 than at V3. In V3 exposures, soybean was 15.4 times more sensitive to dicamba than 2,4-D and 134.4-fold more sensitive to dicamba when exposed at R1. Plant injury and height correlations to grain yield resulted in coefficients ranging from 0.65 to 0.91. In greenhouse experiments, five dicamba products were tested at up to 19 doses and as low as 0.002 g ae ha -1 (3.6 × 10 -6 % of maximum single use-rate); however, no differences were observed among formulations used in dicamba-resistant crops versus traditional formulations. A no observable effects dose was not identified due to responses observed even at the lowest doses tested, although hormesis effects were observed in plant height., Conclusion: These data suggest that the sensitivity of soybean to dicamba is much greater than what has previously been reported. However, as has been indicated by previous work, that injury does not always result in yield loss. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Purpose: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects women of African ancestry (WAA) and is often associated with poor survival. Although there is a high prevalence of TNBC across West Africa and in women of the African diaspora, there has been no comprehensive genomics study to investigate the mutational profile of ancestrally related women across the Caribbean and West Africa., Methods: This multisite cross-sectional study used 31 formalin-fixed paraffin-embedded (FFPE) samples from Barbadian and Nigerian TNBC participants. High-resolution whole exome sequencing (WES) was performed on the Barbadian and Nigerian TNBC samples to identify their mutational profiles and comparisons were made to African American, European American and Asian American sequencing data obtained from The Cancer Genome Atlas (TCGA). Whole exome sequencing was conducted on tumors with an average of 382 × coverage and 4335 × coverage for pooled germline non-tumor samples., Results: Variants detected at high frequency in our WAA cohorts were found in the following genes NBPF12, PLIN4, TP53 and BRCA1. In the TCGA TNBC cases, these genes had a lower mutation rate, except for TP53 (32% in our cohort; 63% in TCGA-African American; 67% in TCGA-European American; 63% in TCGA-Asian). For all altered genes, there were no differences in frequency of mutations between WAA TNBC groups including the TCGA-African American cohort. For copy number variants, high frequency alterations were observed in PIK3CA, TP53, FGFR2 and HIF1AN genes., Conclusion: This study provides novel insights into the underlying genomic alterations in WAA TNBC samples and shines light on the importance of inclusion of under-represented populations in cancer genomics and biomarker studies., (© 2022. The Author(s).)

Objective: The aggressive triple-negative breast cancer (TNBC) subtype disproportionately affects women of African ancestry across the diaspora, but its frequency across Africa has not been widely studied. This study seeks to estimate the frequency of TNBC among African populations., Design: Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework., Data Sources: PubMed, EMBASE, African Journals Online and Web of Science were searched on 25 April 2021., Eligibility Criteria for Selecting Studies: We included studies that use breast cancer tissue samples from indigenous African women with sample size of eligible participants ≥40 and full receptor status for all three receptors (oestrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2)) reported., Data Extraction and Synthesis: Two independent reviewers extracted data and assessed risk of bias using the modified assessment tool by Hoy et al. (2012) for prevalence studies. A random-effects meta-analysis was performed, and data were pooled using the inverse-variance method and logit transformation. Pooled frequencies were reported with 95% CIs calculated with the Clopper-Pearson method and heterogeneity quantified with I 2 statistic. GRADE assessed the certainty of the evidence., Results: 1808 potentially eligible studies were identified of which 67 were included in the systematic review and 60 were included in the meta- analysis. Pooled TNBC frequency across African countries represented was estimated to be 27.0%; 95% CI: 24.0% to 30.2%, I 2 =94%. Pooled TNBC frequency was highest across West Africa, 45.7% (n=15, 95% CI: 38.8% to 52.8%, I 2 =91%) and lowest in Central Africa, 14.9% (n=1, 95% CI: 8.9 % to 24.1%). Estimates for TNBC were higher for studies that used Allred guidelines for ER/PR status compared with American Society of Clinical Oncology(ASCO)/College of American Pathologists(CAP) guidelines, and for studies that used older versions of ASCO/CAP guidelines for assessing HER2 status. Certainty of evidence was assessed to be very low using GRADE approach., Conclusion: TNBC frequency was variable with the highest frequency reported in West Africa. Greater emphasis should be placed on establishing protocols for assessing receptor status due to the variability among studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Polyethylene glycol (PEG) is present in a variety of products. Little is known regarding the accumulation of high-molecular-weight PEGs or the long-term effects resulting from PEG accumulation in certain tissues, especially the choroid plexus. We evaluated the toxicity of high-molecular-weight PEGs administered to Sprague Dawley rats. Groups of 12 rats per sex were administered subcutaneous injections of 20, 40, or 60 kDa PEG or intravenous injections of 60 kDa PEG at 100 mg PEG/kg body weight/injection once a week for 24 weeks. A significant decrease in triglycerides occurred in the 60 kDa PEG groups. PEG treatment led to a molecular-weight-related increase in PEG in plasma and a low level of PEG in cerebrospinal fluid. PEG was excreted in urine and feces, with a molecular-weight-related decrease in the urinary excretion. A higher prevalence of anti-PEG IgM was observed in PEG groups; anti-PEG IgG was not detected. PEG treatment produced a molecular-weight-related increase in vacuolation in the spleen, lymph nodes, lungs, and ovaries/testes, without an inflammatory response. Mast cell infiltration at the application site was noted in all PEG-treated groups. These data indicate that subcutaneous and intravenous exposure to high-molecular-weight PEGs produces anti-PEG IgM antibody responses and tissue vacuolation without inflammation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Predictions of the Earth system, such as weather forecasts and climate projections, require models informed by observations at many levels. Some methods for integrating models and observations are very systematic and comprehensive (e.g., data assimilation), and some are single purpose and customized (e.g., for model validation). We review current methods and best practices for integrating models and observations. We highlight how future developments can enable advanced heterogeneous observation networks and models to improve predictions of the Earth system (including atmosphere, land surface, oceans, cryosphere, and chemistry) across scales from weather to climate. As the community pushes to develop the next generation of models and data systems, there is a need to take a more holistic, integrated, and coordinated approach to models, observations, and their uncertainties to maximize the benefit for Earth system prediction and impacts on society.

Coddington's equations and their generalized forms are useful for lens design and analysis of optical performance. Generalized Coddington's equations (GCE) exist in literature for analysis of decentered systems and freeform surfaces, but not for gradient index (GRIN) lenses. In this work, GCE are presented for the analysis of freeform GRIN lenses with freeform surfaces. Examples are shown where the presented theory converges on Coddington's equations and known paraxial GRIN behavior. The method also correctly shows known afocal behavior proximate to azimuthally directed rays in a cylindrical GRIN. The latter case is one of analytically validated local freeform behavior.

Background: There is renewed interest amongst crop protection professionals and regulators in the adoption of spray hoods to further reduce pesticide off-target movement during applications. Although the benefits of sprayer hoods have been reported since the early 1950s, adoption has been relatively low among farmers and applicators. The objective of this study was to evaluate the effectiveness of spray hoods in reducing pesticide drift of spray solutions from nozzles typically used for herbicide applications in row crops with tolerance to dicamba or 2,4-D., Results: Hooded applications substantially reduced spray drift potential across all treatment scenarios compared to conventional applications. Hooded applications using the AIXR nozzle without drift-reducing adjuvant (DRA) had a similar area under the drift curve (31.5) compared to conventional applications (open sprayer) using the TTI nozzle with DRA (27.7), despite the major droplet size differences between these treatments (D V50  = 447.5 and 985 μm, respectively)., Conclusion: These results indicate that the adoption of spray hoods combined with proper nozzle selection, and the use of DRAs can substantially reduce spray drift potential during pesticide applications. The use of this technology can be complementary to other drift-reducing technologies. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Background: Early-postemergence herbicide applications in the USA often include residual herbicides such as S-metolachlor to suppress late late-emerging Amaranthus spp. Although this practice benefits weed control, herbicide tankmixes can influence spray droplet size and drift potential during applications. The addition of S-metolachlor products to dicamba spray solutions generally decreases spray droplet size and increases spray drift potential. Advances in formulation technology fostered the development of products with reduced spray drift potential, especially for herbicide premixes containing multiple active ingredients. The objective of this study was to compare the drift potential of a novel dicamba plus S-metolachlor premix formulation (capsule suspension) against a tankmix containing dicamba (soluble liquid) and S-metolachlor (emulsifiable concentrate) using different venturi nozzles., Results: The MUG nozzle had greater D V0.5 (1128.6 μm) compared to the ULDM (930.3 μm), TDXL-D (872.9 μm), and TTI nozzles (854.8 μm). The premix formulation had greater D V0.5 (971.0 μm) compared to the tankmix (922.3 μm). Nozzle influenced spray drift deposition (P < 0.0001) and soybean biomass reduction (P = 0.0465). Herbicide formulation influenced spray drift deposition (P < 0.0001), and biomass reduction of soybean (P < 0.0001) and cotton (P = 0.0479). The novel capsule suspension formulation (premix) of dicamba plus S-metolachlor had reduced area under the drift curve (AUDC) (577.6) compared to the tankmix (913.7). Applications using the MUG nozzle reduced AUDC (459.9) compared to the other venturi nozzles (ranging from 677.4 to 1141.7)., Conclusion: Study results evidence that advances in pesticide formulation can improve pesticide drift mitigation. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Laws of reflection and refraction between homogeneous media and gradient index (GRIN) ray behavior are both derived from Fermat's principle. Design methods for GRIN can be difficult to analytically develop. This Letter proposes a foundation for complete replacement of refracting and total internally reflecting optical interfaces in existing designs with GRIN distribution. The proposed method can aid in incorporating GRIN into existing optical designs. Refraction in GRIN is specified to match the ray striking and leaving the optical interface in both position and angle. This result is shown for a collection of similar GRIN functions. One GRIN function is analyzed over a full space of attainable ray bend angles. A local arbitrarily oriented planar interface is replaced with GRIN distribution, and ray behavior is maintained.

We conducted a quasi-experimental field study of an organization-wide suggestion program and a follow-up laboratory experiment to examine the effects of choice of rewards on employee creativity. As hypothesized, the results of both studies showed that choice had positive, significant effects on the number of creative ideas employees generated and the creativity level of those ideas. Results of the quasi-experiment also showed that creative self-efficacy (CSE) mediated the effects of reward choice. Two general categories of rewards were examined in our studies-those that directly benefited the idea generator (Self) and those that directly benefited charities (Other). We explored the effects of these reward categories on employee creativity and whether employee creative personality interacted with the reward categories to affect employee creativity. Results showed that the reward categories did not have a significant impact on employee creativity. However, both studies demonstrated that in the Other reward condition, employees with a creative personality produced ideas higher in creativity than those with a less creative personality. The quasi-experiment also showed that CSE mediated the effects of the Reward × Creative Personality interaction. We discussed the implications of these results for the future research and practice. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Orthopedic sports surgery of the knee and shoulder is generally considered to be safe and effective. Vascular complications can occur during or after arthroscopy of either joint. A thorough understanding of anatomy, particularly when placing portals in non-routine locations, is extremely important. Prompt recognition of any vascular complication is of significant importance. This review will discuss the potential vascular complications for both knee and shoulder sports surgery, review the relevant anatomy, and discuss the treatment and expected outcome of each., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Raytrace evaluation capable of evaluating progressive addition lens (PAL) designs with freeform surface and gradient index (GRIN) contributions is presented. The method is validated on an analytically generated PAL start design and on optimized surface designs. Surface raytrace evaluations are compared with the surface-geometric evaluation commonly presented for freeform surface PAL designs. The evaluation is also tested on analytically generated freeform GRIN PAL designs with spherical and plano surfaces. The raytrace method agrees with the analytic performance and surface-geometric performance near the center of the lens and deviates at the edge of the lens, due to ray obliquity with the surfaces and aggregate contributions of surfaces and/or GRIN. These deviations are expected, as the raytrace model accounts for more physical contributions to optical performance, including pupil diameter and eye position. This raytrace method enables the evaluation of lens performance contributions other than from polished surfaces on homogeneous materials, enabling further exploration of GRIN in PAL designs.

The annular folded lens (AFL) is a design form offering large aperture, high-resolution imaging in a very axially compact package. The folded optic can be made monolithic for easier fabrication and alignment, yet the introduction of refractive surfaces with a dispersive optical material gives way to chromatic aberrations. AFL designs using homogeneous media are generally limited to the monochromatic regime, with polychromatic performance greatly reduced. By introducing freeform gradient-index (F-GRIN) media, monolithic AFL designs can achieve higher monochromatic performance as well as provide color correction for diffraction-limited polychromatic imaging. Monochromatic and polychromatic design methodologies are surveyed where the F-GRIN is constrained to remain feasible for fabrication.

Background: Hamstring strain injury (HSI) diagnosis is often corroborated using ultrasound. Spatial frequency analysis (SFA) is a quantitative ultrasound method that has proven useful in characterizing altered tissue organization. The purpose of this study was to determine changes in muscular tissue organization using SFA following HSI., Methods: Ultrasound B-mode images were captured at time of injury (TOI) and return to sport (RTS) in collegiate athletes who sustained an HSI. Spatial frequency parameters extracted from two-dimensional Fourier Transforms in user-defined regions of interest (ROI) were analyzed. Separate ROIs encompassed injured and adjacent tissue within the same image of the injured limb and mirrored locations in the contralateral limb at TOI. The ROIs for RTS images were drawn to correspond to the injury-matched location determined from TOI imaging. Peak spatial frequency radius (PSFR) and the fascicular banded pattern relative to image background (Mmax%) were compared between injured and adjacent portions within the same image with separate paired t-tests. Within-image differences of SFA parameters in the injured limb were calculated and compared between TOI and RTS with Wilcoxon rank sum tests., Results: Within the injured limb at TOI, PSFR differences in injured and healthy regions did not strictly meet statistical significance (p = 0.06), while Mmax% was different between regions (p < 0.001). No differences were observed between regions in the contralateral limb at TOI (PSFR, p = 0.16; Mmax%, p = 0.30). Significant within-image differences in PSFR (p = 0.03) and Mmax% (p = 0.04) at RTS were detected relative to TOI., Conclusions: These findings are a first step in determining the usefulness of SFA in muscle injury characterization and provide quantitative assessment of both fascicular disruption and edema presence in acute HSI., (© 2021. The Author(s).)

Dicamba is an important herbicide for controlling post-emergent resistant weeds in soybean farming. Recently, the scientific community and general public have further examined off-target transport mechanisms (e.g., spray drift, volatilization, and tank contamination) and the visual responses of soybeans to ultralow dicamba concentrations. This paper synthesizes key chemical concepts and environmental processes associated with dicamba formulations, transport mechanisms, drift measurements, and plant responses. This paper proposes additional areas of research and actions to increase our understanding and communicate the science findings, which should provide farmers with more robust tools and practices for sustainable dicamba use.

Aim: To determine the reasons for hospitalizations in the CANagliflozin cardioVascular Assessment Study (CANVAS) programme and the effects of the sodium-glucose co-transporter-2 inhibitor canagliflozin on hospitalization., Materials and Methods: A secondary analysis was performed on the CANVAS programme that included 10 142 participants with type 2 diabetes randomized to canagliflozin or placebo. The primary outcome was the rate of total (first plus all recurrent) all-cause hospitalizations (ACH). Secondary outcomes were total hospitalizations categorized by the Medical Dictionary for Regulatory Activities hierarchy at the system organ class level, reported by investigators at each centre. Outcomes were assessed using negative binomial models., Results: Of the 7115 hospitalizations reported, the most common reasons were cardiac disorders (23.7%), infections and infestations (15.0%), and nervous system disorders (9.0%). The rate of total ACH was lower in the canagliflozin group (n = 5795) compared with the placebo group (n = 4347): 197.9 versus 215.8 participants per 1000 patient-years, respectively (rate ratio [RR] 0.92; 95% confidence interval [CI] 0.86, 0.98). Canagliflozin reduced the rate of total hospitalizations because of cardiac disorders (RR 0.81; 95% CI 0.75, 0.88). There was no significant difference between the canagliflozin and placebo groups in the rates of total hospitalizations because of infections and infestations (RR 0.96; 95% CI 0.86, 1.02) or nervous system disorders (RR 0.96; 95% CI 0.88, 1.05)., Conclusions: In the CANVAS programme, the most common reasons for hospitalization were cardiac disorders, infections and infestations, and nervous system disorders. Canagliflozin, compared with placebo, reduced the rate of total ACH., (© 2021 John Wiley & Sons Ltd.)