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Cannabinoid hemp is a dioecious crop where pistillate plants are selectively grown to maximize cannabinoid yields. Errant pollination can reduce pistillate flower yields, cannabinoid concentrations, and lead to unmarketable flowers due to the presence of undesirable seeds. We compared pollen sensitivity and agronomic performance of diploid (2n = 2x = 20 chromosomes) and triploid (2n = 3x = 30 chromosomes) cannabinoid hemp in open-field conditions. The high-CBD variety Lifter and high-CBG variety White CBG were evaluated in both their diploid and triploid counterparts in fields with and without pollen. Trials were conducted during the 2021 and 2022 field seasons in Kentucky, New York, and North Carolina (n = 6 site years). Triploids produced taller and wider plants than diploids; however, this did not result in yield differences in the pollen-free environment. In the presence of pollen, triploid Lifter and White CBG produced 87% and 77% fewer seeds than their diploid counterparts, respectively. Increased seed production in diploids also resulted in a significant reduction of seed-free biomass and cannabinoid concentrations compared to triploids. In the absence of pollen, we did not find any appreciable differences in seed-free biomass or cannabinoid concentrations between triploids and diploids. Though not completely pollen-insensitive, triploidy is an effective means to reduce seed production and improve yields and quality in cannabinoid hemp in the presence of pollen. [ABSTRACT FROM AUTHOR]

Abstract Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.

Abstract Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.

INTRODUCTION 1870 I. DAMAGES VERSUS INJUNCTIONS: THE PRESENT DICHOTOMY 1873 II. DAMAGES AND INJUNCTIONS FROM THE FOUNDING ONWARD 1879 III. THE WEAK CASE(S) FOR INJUNCTIONS OVER DAMAGES 1882 A. Abbasi [...]

Accurate motor control is mediated by internal models of how neural activity generates movement. We examined neural correlates of an adapting internal model of visuomotor gain in motor cortex while two macaques performed a reaching task in which the gain scaling between the hand and a presented cursor was varied. Previous studies of cortical changes during visuomotor adaptation focused on preparatory and perimovement epochs and analyzed trial-averaged neural data. Here, we recorded simultaneous neural population activity using multielectrode arrays and focused our analysis on neural differences in the period before the target appeared. We found that we could estimate the monkey's internal model of the gain using the neural population state during this pretarget epoch. This neural correlate depended on the gain experienced during recent trials and it predicted the speed of the subsequent reach. To explore the utility of this internal model estimate for brain-machine interfaces, we performed an offline analysis showing that it can be used to compensate for upcoming reach extent errors. Together, these results demonstrate that pretarget neural activity in motor cortex reflects the monkey's internal model of visuomotor gain on single trials and can potentially be used to improve neural prostheses.SIGNIFICANCE STATEMENT When generating movement commands, the brain is believed to use internal models of the relationship between neural activity and the body's movement. Visuomotor adaptation tasks have revealed neural correlates of these computations in multiple brain areas during movement preparation and execution. Here, we describe motor cortical changes in a visuomotor gain change task even before a specific movement is cued. We were able to estimate the gain internal model from these pretarget neural correlates and relate it to single-trial behavior. This is an important step toward understanding the sensorimotor system's algorithms for updating its internal models after specific movements and errors. Furthermore, the ability to estimate the internal model before movement could improve motor neural prostheses being developed for people with paralysis.

RationaleUnderstanding the reliability and repeatability of clinical measurements used in the diagnosis, treatment and monitoring of disease progression is of critical importance across all disciplines of clinical practice and in clinical trials to assess therapeutic efficacy and safety.ObjectivesOur goal is to understand normal variability for assessing true changes in health status and to more accurately utilize this data to differentiate disease characteristics and outcomes.MethodsOur study is the first study designed entirely to establish the repeatability of a large number of instruments utilized for the clinical assessment of COPD in the same subjects over the same period. We utilized SPIROMICS participants (n = 98) that returned to their clinical center within 6 weeks of their baseline visit to repeat complete baseline assessments. Demographics, spirometry, questionnaires, complete blood cell counts (CBC), medical history, and emphysema status by computerized tomography (CT) imaging were obtained.ResultsPulmonary function tests (PFTs) were highly repeatable (ICC's >0.9) but the 6 minute walk (6MW) was less so (ICC = 0.79). Among questionnaires, the Saint George's Respiratory Questionnaire (SGRQ) was most repeatable. Self-reported clinical features, such as exacerbation history, and features of chronic bronchitis, often produced kappa values

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.

RationaleChronic bronchitis is, by definition, a chronic condition, but the development and remission of this condition in cigarette smokers with or without chronic obstructive pulmonary disease (COPD) are poorly understood. Also, it is unclear how the persistence or new development of chronic bronchitis affects symptoms and outcomes.ObjectivesTo ascertain the relationship between smoking status and the presence or absence of chronic bronchitis and the subsequent effects on symptoms and outcomes.MethodsWe analyzed 1,775 current or ex-smokers with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 0-IV COPD in phase 2 of the Genetic Epidemiology of COPD (COPDGene) Study, which included subjects after 5 years of follow-up from phase 1. We asked subjects at enrollment and at 5 years of follow-up about symptoms consistent with chronic bronchitis. We divided subjects into four groups: persistent chronic bronchitis- (negative at phase 1/negative at phase 2), resolved chronic bronchitis (positive/negative), new chronic bronchitis (negative/positive), and persistent chronic bronchitis+ (positive/positive). We analyzed respiratory symptoms, health-related quality of life, lung function, exacerbation frequency, and 6-minute walk distance.Measurements and main resultsCompared with the persistent chronic bronchitis- group, members of the persistent chronic bronchitis+ group were more likely to have continued smoking (53.4%). Subjects with new chronic bronchitis were more likely to have resumed (6.6%) or continued smoking (45.6%), whereas subjects with resolved chronic bronchitis were more likely to have quit smoking (23.5%). Compared with the persistent chronic bronchitis- group, the other groups had a shorter 6-minute walk distance, worse lung function, greater exacerbation frequency, and worse respiratory symptoms. Modified Medical Research Council dyspnea and St. George's Respiratory Questionnaire scores worsened between phase 1 and phase 2 in subjects with new chronic bronchitis but improved in the resolved chronic bronchitis group. On multinomial logistic regression, quitting smoking conferred an odds ratio (OR) of 4.289 (95% confidence interval [CI], 2.689-6.842) for resolved chronic bronchitis, whereas resuming smoking had an OR of 4.585 (95% CI, 2.008-10.471) for new chronic bronchitis. Persistent smoking had an OR of 2.621 (95% CI, 1.677-4.096) and 5.767 (95% CI, 3.702-8.983) for subjects with new chronic bronchitis and subjects with persistent chronic bronchitis, respectively.ConclusionsPersistent and newly developed chronic bronchitis are associated with continued or resumed smoking, greater respiratory symptoms, worse health-related quality of life, worse lung function, and greater exacerbation frequency. These findings stress the importance of repeatedly assessing chronic cough and sputum production in smokers to identify those at risk for poor outcomes.

BackgroundSecond-hand smoke (SHS) exposure has been linked to the development of and morbidity from lung disease. We sought to advance understanding of the impact of SHS on health-related outcomes in individuals with COPD.MethodsAmong the participants with COPD in SPIROMICS, recent SHS exposure was quantified as (1) hours of reported exposure in the past week or (2) reported living with a smoker. We performed adjusted regression for SHS with outcomes, testing for interactions with gender, race, smoking and obesity.ResultsOf the 1580 participants with COPD, 20% reported living with a smoker and 27% reported exposure in the past week. Living with a smoker was associated with worse St George's Respiratory Questionnaire score (SGRQ, β 3.10; 95% CI 0.99 to 5.21), COPD Assessment Test score (β 1.43; 95% CI 0.52 to 2.35) and increased risk for severe exacerbations (OR 1.51, 95% CI 1.04 to 2.17). SHS exposure in the past week was associated with worse SGRQ (β 2.52; 95% CI 0.47 to 4.58), nocturnal symptoms (OR 1.58; 95% CI 1.19 to 2.10), wheezing (OR 1.34; 95% CI 1.02 to 1.77), chronic productive cough (OR 1.77; 95% CI 1.33 to 2.35) and difficulty with cough and sputum (Ease of Cough and Sputum scale, β 0.84; 95% CI 0.42 to 1.25). SHS was associated with increased airway wall thickness on CT but not emphysema. Active smokers, obese individuals and individuals with less severe airflow obstruction also had higher susceptibility to SHS for some outcomes.ConclusionIndividuals with COPD, including active smokers, have significant SHS exposure, associated with worse outcomes and airway wall thickness. Active smokers and obese individuals may have worse outcomes associated with SHS.Trial registration numberNCT01969344 (clinicaltrials.gov).

Recently, over 40 states in the United States adopted the Common Core State Standards for Mathematics (CCSSM) which include standards for content and eight standards for mathematical practices. The purpose of this study was to better understand the nature of young children's mathematical practices through an exploratory examination of the practices of a group of second-grade students engaged in several mathematical tasks focused on rational number concepts. Twenty-five second-grade students completed three fraction tasks in structured clinical interviews. The interviews and student work were analyzed using an interpretational analysis to examine the data for constructs, themes, and patterns that were useful in explaining children's mathematical practices. The results reveal that children used a variety of mathematical practices during the interviews to respond to the mathematical problems presented. Children's mathematical practices were both a product that they used to solve the mathematical situations, and a process that was developing during the interactions of the interview. The findings lead to new insights about how mathematical practices develop and what promotes their development.

Mutation rate estimates for vegetatively reproducing organisms are rare, despite their frequent occurrence across the tree of life. Here we report mutation rate estimates in two vegetatively reproducing duckweed species, Lemna minor and Spirodela polyrhiza. We use a modified approach to estimating mutation rates by taking into account the reduction in mutation detection power that occurs when new individuals are produced from multiple cell lineages. We estimate an extremely low per generation mutation rate in both species of duckweed and note that allelic coverage at de novo mutation sites is very skewed. We also find no substantial difference in mutation rate between mutation accumulation lines propagated under benign conditions and those grown under salt stress. Finally, we discuss the implications of interpreting mutation rate estimates in vegetatively propagating organisms.

Abstract Objective To quantify peripheral nerve lesions in symptomatic and asymptomatic hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PNP) by analyzing the magnetization transfer ratio (MTR) of the sciatic nerve, and to test its potential as a novel biomarker for macromolecular changes. Methods Twenty‐five patients with symptomatic ATTRv‐PNP, 30 asymptomatic carriers of the mutant transthyretin gene (mutTTR), and 20 age‐/sex‐matched healthy controls prospectively underwent magnetization transfer contrast imaging at 3 Tesla. Two axial three‐dimensional gradient echo sequences with and without an off‐resonance saturation rapid frequency pulse were conducted at the right distal thigh. Sciatic nerve regions of interest were manually drawn on 10 consecutive axial slices in the images without off‐resonance saturation, and then transferred to the corresponding slices that were generated by the sequence with the off‐resonance saturation pulse. Subsequently, the MTR and cross‐sectional area (CSA) of the sciatic nerve were evaluated. Detailed neurologic and electrophysiologic examinations were conducted in all ATTRv‐PNP patients and mutTTR‐carriers. Results Sciatic nerve MTR and CSA reliably differentiated between ATTRv‐PNP, mutTTR‐carriers, and controls. MTR was lower in ATTRv‐PNP (26.4 ± 0.7; P

Abstract Introduction Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers. Methods We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) ( 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB. Results The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR

Production of friction particulate ceramic matrix composites (PCMCs) by powder metallurgy method was carried out using iron 105 μm millscale, 50 μm silica sand, 80 μm magnesia and 53 μm bentonite clay as input materials. Different formulation of the blend of these materials were prepared and the composites were produced. Microstructural, frictional, thermal and wear characterisation were determined using standardised methods. The ceramic composites exhibited very good properties in terms of thermal stability (heat resistance), coefficient of friction (COF) and resistance to wear. The specific values of these properties exhibited by sample D having 12 wt. % iron millscale addition in terms of high resistance to thermal decomposition in the temperature region (0 – 1600 0 C) indicating thermal stability, appreciable high COF (0.59) and very low wear rate of 1.9093 x 10-6 g/m are desirable. The uniform dispersion of the particles as observed in the microstructure and strong bonding/adhesion contributed to the enhancement of the properties. These results are indication that the composite is very suitable for application in areas where high resistance to thermal stress and abrasive wear are required such as the brake assembly of automobiles, specifically the brake pads.

Heart and kidney failure often co-exist and confer high morbidity and mortality. The complex bi-directional nature of heart and kidney dysfunction is referred to as cardiorenal syndrome, and can be induced by acute or chronic dysfunction of either organ or secondary to systemic diseases. The five clinical subtypes of cardiorenal syndrome are categorized by the perceived primary precipitant of organ injury but lack precision. Traditional biomarkers such as serum creatinine are also limited in their ability to provide an early and accurate diagnosis of cardiorenal syndrome. Novel biomarkers have the potential to assist in the diagnosis of cardiorenal syndrome and guide treatment by evaluating the relative roles of implicated pathophysiological pathways such as hemodynamic dysfunction, neurohormonal activation, endothelial dysfunction, inflammation and oxidative stress, and fibrosis. In this review, we assess the utility of biomarkers that correlate with kidney and cardiac (dys)function, inflammation/oxidative stress, fibrosis, and cell cycle arrest, as well as emerging novel biomarkers (thrombospondin-1/CD47, glycocalyx and interleukin-1β) that may provide prediction and prognostication of cardiorenal syndrome, and guide potential development of targeted therapeutics.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and P2 separately. The best number of LCA classes was determined through both statistical fit and interpretation of the patterns. Results: We found four classes of medication patterns at both phases. LCA showed that both phases shared similar characteristics in their medication patterns: LC0: low medication; LC1: hypertension (HTN) or cardiovascular disease (CVD)+high cholesterol (Hychol) medication predominant; LC2: HTN/CVD+type 2 diabetes (T2D) +Hychol medication predominant; LC3: Hychol medication predominant. Conclusions: We found similar multimorbidity medication patterns among smokers at P1 and P2 in the COPDGene cohort, which provides an understanding of how multimorbidity medication clustered and how different chronic diseases combine in smokers.

The free calcium (Ca2+) levels in pancreatic beta cell organelles have been the subject of many recent investigations. Under pathophysiological conditions, disturbances in these pools have been linked to altered intracellular communication and cellular dysfunction. To facilitate studies of subcellular Ca2+ signaling in beta cells and, particularly, signaling between the endoplasmic reticulum (ER) and mitochondria, we designed a novel dual Ca2+ sensor which we termed DS-1. DS-1 encodes two stoichiometrically fluorescent proteins within a single plasmid, G-CEPIA-er, targeted to the ER and R-CEPIA3-mt, targeted to mitochondria. Our goal was to simultaneously measure the ER and mitochondrial Ca2+ in cells in real time. The Kds of G-CEPIA-er and R-CEPIA3-mt for Ca2+ are 672 and 3.7 μM, respectively. Confocal imaging of insulin-secreting INS-1 832/13 expressing DS-1 confirmed that the green and red fluorophores correctly colocalized with organelle-specific fluorescent markers as predicted. Further, we tested whether DS-1 exhibited the functional properties expected by challenging an INS-1 cell to glucose concentrations or drugs having well-documented effects on the ER and mitochondrial Ca2+ handling. The data obtained were consistent with those seen using other single organelle targeted probes. These results taken together suggest that DS-1 is a promising new approach for investigating Ca2+ signaling within multiple organelles of the cell.