Publications by authors named "Christopher Brown"

769 Publications

Small circular interfering RNAs (sciRNAs) as a potent therapeutic platform for gene-silencing.

Nucleic Acids Res 2021 Sep 11. Epub 2021 Sep 11.

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

In order to achieve efficient therapeutic post-transcriptional gene-silencing mediated by the RNA interference (RNAi) pathway, small interfering RNAs (siRNAs) must be chemically modified. Several supra-RNA structures, with the potential to stabilize siRNAs metabolically have been evaluated for their ability to induce gene silencing, but all have limitations or have not been explored in therapeutically relevant contexts. Covalently closed circular RNA transcripts are prevalent in eukaryotes and have potential as biomarkers and disease targets, and circular RNA mimics are being explored for use as therapies. Here we report the synthesis and evaluation of small circular interfering RNAs (sciRNAs). To synthesize sciRNAs, a sense strand functionalized with the trivalent N-acetylgalactosamine (GalNAc) ligand and cyclized using 'click' chemistry was annealed to an antisense strand. This strategy was used for synthesis of small circles, but could also be used for synthesis of larger circular RNA mimics. We evaluated various sciRNA designs in vitro and in vivo. We observed improved metabolic stability of the sense strand upon circularization and off-target effects were eliminated. The 5'-(E)-vinylphosphonate modification of the antisense strand resulted in GalNAc-sciRNAs that are potent in vivo at therapeutically relevant doses. Physicochemical studies and NMR-based structural analysis, together with molecular modeling studies, shed light on the interactions of this novel class of siRNAs, which have a partial duplex character, with the RNAi machinery.
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http://dx.doi.org/10.1093/nar/gkab724DOI Listing
September 2021

Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates.

Sci Rep 2021 Sep 9;11(1):17977. Epub 2021 Sep 9.

CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, CA, 90045, USA.

Huntington's disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer's disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer's disease patients.
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http://dx.doi.org/10.1038/s41598-021-97334-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429736PMC
September 2021

Extended Noninvasive Glucose Monitoring in the Interstitial Fluid Using an Epidermal Biosensing Patch.

Anal Chem 2021 Sep 3;93(37):12767-12775. Epub 2021 Sep 3.

Department of Nanoengineering, University of California, San Diego, La Jolla, San Diego, California 92093, United States.

An effective, noninvasive glucose monitoring technology could be a pivotal factor for addressing the major unmet needs for managing diabetes mellitus (DM). Here, we describe a skin-worn, disposable, wireless electrochemical biosensor for extended noninvasive monitoring of glucose in the interstitial fluid (ISF). The wearable platform integrates three components: a screen-printed iontophoretic electrode system for ISF extraction by reverse iontophoresis (RI), a printed three-electrode amperometric glucose biosensor, and an electronic interface for control and wireless communication. Prolonged on-body glucose monitoring of up to 8 h, including clinical trials conducted in individuals with and without DM, demonstrated good correlation between glucose blood and ISF concentrations and the ability to monitor dynamically changing glucose levels upon food consumption, with no evidence of skin irritation or discomfort. Such successful extended operation addresses the challenges reported for the GlucoWatch platform by using a lower RI current density at shorter extraction times, along with a lower measurement frequency. Such a noninvasive skin-worn platform could address long-standing challenges with existing glucose monitoring platforms.
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http://dx.doi.org/10.1021/acs.analchem.1c02887DOI Listing
September 2021

Morning and evening salivary cortisol levels in patients with chronic widespread pain and those at high risk.

Eur J Pain 2021 Aug 26. Epub 2021 Aug 26.

Division of Neuroscience and Experimental Psychology, Human Pain Research Group, University of Manchester, Manchester, UK.

Background: Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation has been implicated in chronic widespread pain (CWP); the hallmark of fibromyalgia (FM). This is the first study to compare HPA axis changes in individuals with CWP and those at high risk of symptom development.

Methods: We sought to determine differences in morning and evening salivary cortisol levels in FM (n = 19), those at-risk (n = 20) and pain-free controls (n = 17). Risk factors included non-CWP pain, somatic symptoms, illness behaviour and sleep disturbance. We conducted the study in the absence of centrally acting medication, to address limitations of previous research.

Results: Repeated measures ANOVA revealed significant main effects of group (p = 0.003), and time of day (p = 0.002), with no significant interaction. Cortisol levels were higher in FM (p = 0.027) and at-risk (p = 0.003) groups, compared to controls, but there was no significant difference between FM and at-risk groups. The main effect of group remained significant with sleep problems (p = 0.021) and life events (p = 0.007), but was not significant with anxiety (p = 0.076) or depression (p = 0.098) scores as covariates. With sleep problems as a covariate, cortisol levels remained significantly higher only in the at-risk group (p = 0.017).

Conclusions: This study indicates elevated salivary cortisol in FM and those at high risk, and identifies anxiety, depression and sleep problems as potential contributing factors. The results shed light on the dynamic relationship between stress, mood and sleep disorders and the brain's resilience to pain.

Significance: This study examines neurobiological changes in chronic widespread pain and high risk individuals. One strength of the study is the absence of centrally acting medication. We found high salivary cortisol common to Fibromyalgia and those at risk and identified contributing factors. Our results offer insight into the early mechanistic changes underlying Fibromyalgia development and open up possibilities for early diagnosis and prevention.
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http://dx.doi.org/10.1002/ejp.1854DOI Listing
August 2021

Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments.

Nat Genet 2021 Sep 12;53(9):1322-1333. Epub 2021 Aug 12.

Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.

The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease.
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http://dx.doi.org/10.1038/s41588-021-00909-9DOI Listing
September 2021

Adverse effects of COVID-19-related lockdown on pain, physical activity and psychological well-being in people with chronic pain.

Br J Pain 2021 Aug 21;15(3):357-368. Epub 2020 Nov 21.

Department of Psychology, Institute of Population Health Sciences, University of Liverpool, Liverpool, UK.

Countries across the world imposed lockdown restrictions during the COVID-19 pandemic. It has been proposed that lockdown conditions, including social and physical distancing measures, may disproportionately impact those living with chronic pain and require rapid adaptation to treatment and care strategies. Using an online methodology, we investigated how lockdown restrictions in the United Kingdom impacted individuals with chronic pain (N = 431) relative to a healthy control group (N = 88). Data were collected during the most stringent period of lockdown in the United Kingdom (mid-April to early-May 2020). In accordance with the fear-avoidance model, we hypothesised lockdown-related increases in pain and psychological distress, which would be mediated by levels of pain catastrophising. Responses indicated that people with chronic pain perceived increased pain severity, compared to their estimation of typical pain levels prior to lockdown (p < .001). They were also more adversely affected by lockdown conditions compared to pain-free individuals, demonstrating greater self-perceived increases in anxiety and depressed mood, increased loneliness and reduced levels of physical exercise (p ⩽ .001). Hierarchical regression analysis revealed that pain catastrophising was an important factor relating to the extent of self-perceived increases in pain severity during lockdown (β = .27, p < .001) and also mediated the relationship between decreased mood and pain. Perceived decreases in levels of physical exercise also related to perceptions of increased pain (β = .15, p < .001). Interestingly, levels of pain intensity (measured at two time points at pre and during lockdown) in a subgroup (N = 85) did not demonstrate a significant change. However, individuals in this subgroup still reported self-perceived pain increases during lockdown, which were also predicted by baseline levels of pain catastrophising. Overall, the findings indicate that people with chronic pain suffer adverse effects of lockdown including self-perceived increases in their pain. Remote pain management provision to target reduction of pain catastrophising and increase health behaviours including physical activity could be beneficial for this vulnerable population.
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http://dx.doi.org/10.1177/2049463720973703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339954PMC
August 2021

[C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins.

J Med Chem 2021 Aug 5;64(16):12003-12021. Epub 2021 Aug 5.

IRBM, IRBM Science Park S.p.A., Via Pontina Km 30,600, Pomezia, Rome 00071, Italy.

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-]pyrimidine series that show selective binding to mHTT aggregates over Aβ- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [C]- was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00667DOI Listing
August 2021

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Nat Commun 2021 07 23;12(1):4487. Epub 2021 Jul 23.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95 percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
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http://dx.doi.org/10.1038/s41467-021-24334-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302763PMC
July 2021

Chirality matters: stereo-defined phosphorothioate linkages at the termini of small interfering RNAs improve pharmacology in vivo.

Nucleic Acids Res 2021 Jul 15. Epub 2021 Jul 15.

Alnylam Pharmaceuticals, 675 W. Kendall St, Cambridge, MA 02142, USA.

A critical challenge for the successful development of RNA interference-based therapeutics therapeutics has been the enhancement of their in vivo metabolic stability. In therapeutically relevant, fully chemically modified small interfering RNAs (siRNAs), modification of the two terminal phosphodiester linkages in each strand of the siRNA duplex with phosphorothioate (PS) is generally sufficient to protect against exonuclease degradation in vivo. Since PS linkages are chiral, we systematically studied the properties of siRNAs containing single chiral PS linkages at each strand terminus. We report an efficient and simple method to introduce chiral PS linkages and demonstrate that Rp diastereomers at the 5' end and Sp diastereomers at the 3' end of the antisense siRNA strand improved pharmacokinetic and pharmacodynamic properties in a mouse model. In silico modeling studies provide mechanistic insights into how the Rp isomer at the 5' end and Sp isomer at the 3' end of the antisense siRNA enhance Argonaute 2 (Ago2) loading and metabolic stability of siRNAs in a concerted manner.
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http://dx.doi.org/10.1093/nar/gkab544DOI Listing
July 2021

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis.

Nat Med 2021 Sep 12;27(9):1544-1552. Epub 2021 Jul 12.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Washington, Seattle, WA, USA.

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children's evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.
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http://dx.doi.org/10.1038/s41591-021-01404-8DOI Listing
September 2021

Attentional modulation of neural dynamics in tactile perception of complex regional pain syndrome patients.

Eur J Neurosci 2021 08 22;54(4):5601-5619. Epub 2021 Jul 22.

Consciousness and Cognition Lab, Department of Psychology, University of Cambridge, Cambridge, UK.

Body perceptual disturbances are an increasingly acknowledged set of symptoms and possible clinical markers of complex regional pain syndrome (CRPS), but the neurophysiological and neurocognitive changes that underlie them are still far from being clear. We adopted a multivariate and neurodynamical approach to the analysis of EEG modulations evoked by touch to highlight differences between patients and healthy controls, between affected and unaffected side of the body, and between "passive" (i.e., no task demands and equiprobable digit stimulation) and "active" tactile processing (i.e., where a digit discrimination task was administered and spatial probability manipulated). When correct identifications are considered, an early reduction in cortical decodability (28-56 ms) distinguishes CRPS patients from healthy volunteers. However, when error trials are included in the classifier's training, there is an unexpected increased decodability in the CRPS group compared with healthy volunteers (280-320 ms). These group differences in neural processing seemed to be driven by the affected rather than the unaffected side. We corroborated these findings with several exploratory analyses of neural representation dynamics and behavioural modelling, highlighting the need for single participant analyses. Although several limitations impacted the robustness and generalizability of these comparisons, the proposed analytical approach yielded promising insights (as well as possible biomarkers based on neural dynamics) into the relatively unexplored alterations of tactile decision-making and attentional control mechanisms in chronic CRPS.
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http://dx.doi.org/10.1111/ejn.15387DOI Listing
August 2021

Five-Year Survival of Transcatheter Aortic Valve Implantation in High-Risk Patients.

Heart Lung Circ 2021 Jun 30. Epub 2021 Jun 30.

Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. Electronic address:

Background: Although transcatheter aortic valve implantation (TAVI) has become the standard treatment for severe aortic stenosis in high-risk patients in Australia, there is still limited data on long term survival.

Methods: All patients undergoing TAVI at a single tertiary institution between September 2009 and December 2015 were included. The primary outcome was survival, by linkage of patients with the National Death Index of the Australian Institute of Health and Welfare. Post-procedure data and echocardiographic measurements were retrospectively analysed for all patients.

Results: A total of 186 patients were included. It was a high-risk patient population (mean EuroSCORE 31.5±20.5, mean age 83.0±8.2 years). Valve prostheses used were Edwards SAPIEN (ES) (Edwards, Irvine, CA, USA) in 16.1%, Edwards SAPIEN XT (ESXT) in 74.2%, and Medtronic CoreValve (MCV) (Medtronic, Minneapolis, MN, USA) in 9.7%. Median survival time for the entire cohort was 68.2 months (95% Confidence Interval [CI]; Lower Limit [LL] 58.0 months, Upper Limit [UL] not defined). The 2- and 5-year estimates of survival were 85% (LL 80%, UL 90%) and 56% (LL 48%, UL 66%), respectively. There was no statistically significant difference in median survival between the ES and ESXT valves, or implantation approach. Survival was greater in patients with creatinine <200 μmol/L compared to >200 μmol/L (68.8 months [LL 61.4, UL n/a] vs 48.0 months [LL 25.5, UL n/a]). Over the study period, there was a statistically significant trend in increasing mean transvalvular gradient (ES: 1.66 mmHg/yr, p=0.0058; ESXT: 2.50 mmHg/yr, p≤0.001) and maximum velocity (ESXT: 0.16 m/s/yr, p=0.004) and decreasing valve area (ESXT: -0.07 cm/yr, p<0.001). There was substantial attrition of patient echocardiographic follow-up (number of echocardiograms followed up at 5 years=6, number at risk=41).

Conclusions: This study has demonstrated acceptable survival in a high-risk cohort of patients undergoing TAVI, with comparable results to larger international experiences. There was a trend for worsening haemodynamics that needs to be monitored. Future studies need to examine patient quality of life and the performance of newer generation prostheses.
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http://dx.doi.org/10.1016/j.hlc.2021.05.093DOI Listing
June 2021

Automatic detection of fish and tracking of movement for ecology.

Ecol Evol 2021 Jun 18;11(12):8254-8263. Epub 2021 May 18.

Coastal and Marine Research Centre Australian Rivers Institute School of Environment and Science Griffith University Gold Coast QLD Australia.

Animal movement studies are conducted to monitor ecosystem health, understand ecological dynamics, and address management and conservation questions. In marine environments, traditional sampling and monitoring methods to measure animal movement are invasive, labor intensive, costly, and limited in the number of individuals that can be feasibly tracked. Automated detection and tracking of small-scale movements of many animals through cameras are possible but are largely untested in field conditions, hampering applications to ecological questions.Here, we aimed to test the ability of an automated object detection and object tracking pipeline to track small-scale movement of many individuals in videos. We applied the pipeline to track fish movement in the field and characterize movement behavior. We automated the detection of a common fisheries species (yellowfin bream, along a known movement passageway from underwater videos. We then tracked fish movement with three types of tracking algorithms (MOSSE, Seq-NMS, and SiamMask) and evaluated their accuracy at characterizing movement.We successfully detected yellowfin bream in a multispecies assemblage (F1 score =91%). At least 120 of the 169 individual bream present in videos were correctly identified and tracked. The accuracies among the three tracking architectures varied, with MOSSE and SiamMask achieving an accuracy of 78% and Seq-NMS 84%.By employing this integrated object detection and tracking pipeline, we demonstrated a noninvasive and reliable approach to studying fish behavior by tracking their movement under field conditions. These cost-effective technologies provide a means for future studies to scale-up the analysis of movement across many visual monitoring systems.
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http://dx.doi.org/10.1002/ece3.7656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216886PMC
June 2021

-Heterocyclic carbene-carbodiimide (NHC-CDI) betaine adducts: synthesis, characterization, properties, and applications.

Chem Sci 2021 Jan 19;12(8):2699-2715. Epub 2021 Jan 19.

Department of Chemistry, Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge Massachusetts 02139 USA

-Heterocyclic carbenes (NHCs) are an important class of reactive organic molecules used as ligands, organocatalysts, and σ-donors in a variety of electroneutral ylide or betaine adducts with main-group compounds. An emerging class of betaine adducts made from the reaction of NHCs with carbodiimides (CDIs) form zwitterionic amidinate-like structures with tunable properties based on the highly modular NHC and CDI scaffolds. The adduct stability is controlled by the substituents on the CDI nitrogens, while the NHC substituents greatly affect the configuration of the adduct in the solid state. This is intended as a primer to these adducts, touching on their history, synthesis, characterization, and general properties. Despite the infancy of the field, NHC-CDI adducts have been applied as amidinate-type ligands for transition metals and nanoparticles, as junctions in zwitterionic polymers, and to stabilize distonic radical cations. These applications and potential future directions are discussed.
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http://dx.doi.org/10.1039/d0sc06465cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179359PMC
January 2021

Controlling ultralong room temperature phosphorescence in organic compounds with sulfur oxidation state.

Chem Sci 2020 Nov 2;12(1):188-195. Epub 2020 Nov 2.

Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada

Sulfur oxidation state is used to tune organic room temperature phosphorescence (RTP) of symmetric sulfur-bridged carbazole dimers. The sulfide-bridged compound exhibits a factor of 3 enhancement of the phosphorescence efficiency, compared to the sulfoxide and sulfone-bridged analogs, despite sulfone bridges being commonly used in RTP materials. In order to investigate the origin of this enhancement, temperature dependent spectroscopy measurements and theoretical calculations are used. The RTP lifetimes are similar due to similar crystal packing modes. Computational studies reveal that the lone pairs on the sulfur atom have a profound impact on enhancing intersystem crossing rate through orbital mixing and screening, which we hypothesize is the dominant factor responsible for increasing the phosphorescence efficiency. The ability to tune the electronic state without altering crystal packing modes allows the isolation of these effects. This work provides a new perspective on the design principles of organic phosphorescent materials, going beyond the rules established for conjugated ketone/sulfone-based organic molecules.
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http://dx.doi.org/10.1039/d0sc04715eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178747PMC
November 2020

The Nonclinical Disposition and PK/PD Properties of GalNAc-conjugated siRNA Are Highly Predictable and Build Confidence in Translation to Man.

Drug Metab Dispos 2021 Jun 21. Epub 2021 Jun 21.

Alnylam Pharmaceuticals Inc., United States.

Conjugation of oligonucleotide therapeutics, including small interfering ribonucleic acids (siRNAs) or antisense oligonucleotides (ASOs) to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI® (givosiran) for the treatment of acute hepatic porphyria, OXLUMO (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio® (inclisiran) for the treatment of hypercholesterolemia, the technology has been well-validated clinically. While much knowledge has been gained over decades of development there is a paucity of published literature on the DMPK properties of GalNAc-siRNA. With this in mind the goals of this mini-review are to provide an aggregate analysis of these nonclinical ADME data to build confidence on the translation of these properties to human. Upon subcutaneous administration, GalNAc-conjugated siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic (PK) properties that reflect rapid elimination through ASGPR-mediated uptake from circulation into hepatocytes. These studies confirm that liver PK, including half-life and, most importantly, siRNA levels in RNA-induced silencing complex (RISC) in hepatocytes are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the absorption, distribution, metabolism and excretion (ADME) properties of GalNAc-conjugated siRNAs. These studies demonstrate that the PK/PD and ADME properties of GalNAc-conjugated siRNAs are highly conserved across species, largely predictable, and can be accurately scaled to human, allowing us to identify efficacious and safe clinical dosing regimens in the absence of human liver PK profiles. Several nonclinical ADME studies have been conducted in order to provide a comprehensive overview of the disposition and elimination of GalNAc-conjugated siRNAs and the PK/PD translation between species. These studies demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species building confidence in the ability to extrapolate to human.
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http://dx.doi.org/10.1124/dmd.121.000428DOI Listing
June 2021

Thermal Analysis of a Mixture of Ribosomal Proteins by vT-ESI-MS: Toward a Parallel Approach for Characterizing the .

Anal Chem 2021 06 8;93(24):8484-8492. Epub 2021 Jun 8.

Department of Chemistry, Indiana University, Bloomington, Indiana 47401, United States.

The thermal stabilities of endogenous, intact proteins and protein assemblies in complex mixtures were characterized in parallel by means of variable-temperature electrospray ionization coupled to mass spectrometry (vT-ESI-MS). The method is demonstrated by directly measuring the melting transitions of seven proteins from a mixture of proteins derived from ribosomes. A proof-of-concept measurement of a fraction of an lysate is provided to extend this approach to characterize the thermal stability of a proteome. As the solution temperature is increased, proteins and protein complexes undergo structural and organizational transitions; for each species, the folded ↔ unfolded and assembled ↔ disassembled populations are monitored based on changes in vT-ESI-MS charge state distributions and masses. The robustness of the approach illustrates a step toward the proteome-wide characterization of thermal stabilities and structural transitions-the
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http://dx.doi.org/10.1021/acs.analchem.1c00772DOI Listing
June 2021

Depressive Symptoms and Social Context Modulate Oxytocin's Effect on Negative Memory Recall.

Soc Cogn Affect Neurosci 2021 Jun 8. Epub 2021 Jun 8.

Department of Psychology, Concordia University, Montreal, Quebec, Canada.

Oxytocin promotes social affiliation across various species, in part by altering social cognition to facilitate approach behaviour. However, the effects of intranasal oxytocin on human social cognition are mixed, perhaps because its effects are context-dependent and subject to inter-individual differences. Few studies have included explicit manipulations of social context to test this supposition. We examined oxytocin's effects on autobiographical memory recall in two contexts, with and without social contact, and evaluated whether these effects were moderated by depressive symptoms. Two non-clinical samples (Study 1 N = 48; Study 2 N = 63) completed randomised, placebo-controlled, within-subject experiments. We assessed autobiographical memory recall across two sessions (intranasal oxytocin or placebo) and two contexts (memories elicited by an experimenter or by computer). Overall, intranasal oxytocin increased ratings of vividness of recalled memories during the social context only. Individuals with elevated depressive symptoms also recalled memories that were more negative following oxytocin relative to placebo only in the non-social context across the two studies. Findings highlight the negative consequences of increasing oxytocin bioavailability in vulnerable persons in the absence of social contact. Contextual factors such as social isolation among depressed populations may complicate the clinical use of oxytocin.
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http://dx.doi.org/10.1093/scan/nsab072DOI Listing
June 2021

Inhibition of cortical somatosensory processing during and after low frequency peripheral nerve stimulation in humans.

Clin Neurophysiol 2021 07 16;132(7):1481-1495. Epub 2021 Apr 16.

Department of Psychological Sciences, University of Liverpool, Liverpool, UK; Institute for Risk and Uncertainty, University of Liverpool, Liverpool, UK.

Objective: Transcutaneous low-frequency stimulation (LFS) elicits long-term depression-like effects on human pain perception. However, the neural mechanisms underlying LFS are poorly understood. We investigated cortical activation changes occurring during LFS and if changes were associated with reduced nociceptive processing and increased amplitude of spontaneous cortical oscillations post-treatment.

Methods: LFS was applied to the radial nerve of 25 healthy volunteers over two sessions using active (1 Hz) or sham (0.02 Hz) frequencies. Changes in resting electroencephalography (EEG) and laser-evoked potentials (LEPs) were investigated before and after LFS. Somatosensory-evoked potentials were recorded during LFS and source analysis was carried out.

Results: Ipsilateral midcingulate and operculo-insular cortex source activity declined linearly during LFS. Active LFS was associated with attenuated long-latency LEP amplitude in ipsilateral frontocentral electrodes and increased resting alpha (8-12 Hz) and beta (16-24 Hz) band power in electrodes overlying operculo-insular, sensorimotor and frontal cortical regions. Reduced ipsilateral operculo-insular cortex source activity during LFS correlated with a smaller post-treatment alpha-band power increase.

Conclusions: LFS attenuated somatosensory processing both during and after stimulation.

Significance: Results further our understanding of the attenuation of somatosensory processing both during and after LFS.
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http://dx.doi.org/10.1016/j.clinph.2021.03.024DOI Listing
July 2021

Transcriptome-wide association analysis identifies DACH1 as a kidney disease risk gene that contributes to fibrosis.

J Clin Invest 2021 05;131(10)

Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Genome-wide association studies (GWAS) for kidney function identified hundreds of risk regions; however, the causal variants, target genes, cell types, and disease mechanisms remain poorly understood. Here, we performed transcriptome-wide association studies (TWAS), summary Mendelian randomization, and MetaXcan to identify genes whose expression mediates the genotype effect on the phenotype. Our analyses identified Dachshund homolog 1 (DACH1), a cell-fate determination factor. GWAS risk variant was associated with lower DACH1 expression in human kidney tubules. Human and mouse kidney single-cell open chromatin data (snATAC-Seq) prioritized estimated glomerular filtration rate (eGFR) GWAS variants located on an intronic regulatory region in distal convoluted tubule cells. CRISPR-Cas9-mediated gene editing confirmed the role of risk variants in regulating DACH1 expression. Mice with tubule-specific Dach1 deletion developed more severe renal fibrosis both in folic acid and diabetic kidney injury models. Mice with tubule-specific Dach1 overexpression were protected from folic acid nephropathy. Single-cell RNA sequencing, chromatin immunoprecipitation, and functional analysis indicated that DACH1 controls the expression of cell cycle and myeloid chemotactic factors, contributing to macrophage infiltration and fibrosis development. In summary, integration of GWAS, TWAS, single-cell epigenome, expression analyses, gene editing, and functional validation in different mouse kidney disease models identified DACH1 as a kidney disease risk gene.
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http://dx.doi.org/10.1172/JCI141801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121513PMC
May 2021

Long-term declines and recovery of meadow area across the world's seagrass bioregions.

Glob Chang Biol 2021 Sep 20;27(17):4096-4109. Epub 2021 Jun 20.

Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada.

As human impacts increase in coastal regions, there is concern that critical habitats that provide the foundation of entire ecosystems are in decline. Seagrass meadows face growing threats such as poor water quality and coastal development. To determine the status of seagrass meadows over time, we reconstructed time series of meadow area from 175 studies that surveyed 547 sites around the world. We found an overall trajectory of decline in all seven bioregions with a global net loss of 5602 km (19.1% of surveyed meadow area) occurring since 1880. Declines have typically been non-linear, with rapid and historical losses observed in several bioregions. The greatest net losses of area occurred in four bioregions (Tropical Atlantic, Temperate North Atlantic East, Temperate Southern Oceans and Tropical Indo-Pacific), with declining trends being the slowest and most consistent in the latter two bioregions. In some bioregions, trends have recently stabilised or reversed. Losses, however, still outweigh gains. Despite consistent global declines, meadows show high variability in trajectories, within and across bioregions, highlighting the importance of local context. Studies identified 12 different drivers of meadow area change, with coastal development and water quality as the most commonly cited. Overall, however, attributions were primarily descriptive and only 10% of studies used inferential attributions. Although ours is the most comprehensive dataset to date, it still represents only one-tenth of known global seagrass extent, with conspicuous historical and geographic biases in sampling. It therefore remains unclear whether the bioregional patterns of change documented here reflect changes in the world's unmonitored seagrass meadows. The variability in seagrass meadow trajectories, and the attribution of change to numerous drivers, suggest we urgently need to improve understanding of the causes of seagrass meadow loss if we are to improve local-scale management.
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http://dx.doi.org/10.1111/gcb.15684DOI Listing
September 2021

Early Fusion Rates After Direct Lateral Lumbar Interbody Fusion With Bone-Morphogenetic Protein.

Int J Spine Surg 2021 Jun 7;15(3):423-428. Epub 2021 May 7.

Department of Orthopaedic Surgery, Duke University Medical Center; Durham, North Carolina.

Background: Direct lateral (transpsoas) lumbar interbody fusion (LLIF) reportedly achieves union by 1 year postoperatively, but how soon fusion occurs after these minimally invasive procedures is unclear. This study investigated LLIF fusion progression at 6 months and 1 year in a large-scale cohort using bone morphogenetic protein (BMP) graft and examined risk factors associated with failed fusion.

Methods: Patients undergoing primary LLIF with a single surgical team from 2015 through 2016 with polyetheretherketone (PEEK) iimplants and BMP graft were identified. Retrospective chart review included demographics and medical history, construct length and location, and concurrent L5-S1 fusion. Inclusion criteria included minimum 1-year follow-up and postoperative lumbar computed tomography at 6 months and 1 year, which was independently assessed for bony union at each level.

Results: 166 patients underwent LLIF at a total of 312 levels. Seventy-nine patients (48%) underwent 1-level fusion; 45 (27%), 2 levels; and 42 (25%), 3 or more levels. At 6 months, 160 (51%) levels showed fusion. At 1 year, 70% of the remainder were fused, and total fusion rate was 85%. Fusion rates from L1 through L4 were similar (84%-87%). Nonunion was not significantly associated with construct length ( .19), concurrent anterior L5-S1 interbody fusion ( .50), age ( .70), BMI ( .15), or comorbidities such as diabetes ( .86) or thyroid disease ( .46).

Conclusions: This large retrospective cohort study corroborates prior 1-year LLIF fusion rate reports (85%) independent of construct length or location or medical comorbidities. Significantly, half showed fusion by 6 months, earlier than previously described and validating the efficacy of LLIF.

Level Of Evidence: 5.

Clinical Relevance: This study presents a large cohort of patients to support effective lumbar fusion after LLIF with BMP-2.
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http://dx.doi.org/10.14444/8063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176839PMC
June 2021

Whole lung tissue is the preferred sampling method for amplicon-based characterization of murine lung microbiota.

Microbiome 2021 05 5;9(1):99. Epub 2021 May 5.

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

Background: Low-biomass microbiome studies (such as those of the lungs, placenta, and skin) are vulnerable to contamination and sequencing stochasticity, which obscure legitimate microbial signal. While human lung microbiome studies have rigorously identified sampling strategies that reliably capture microbial signal from these low-biomass microbial communities, the optimal sampling strategy for characterizing murine lung microbiota has not been empirically determined. Performing accurate, reliable characterization of murine lung microbiota and distinguishing true microbial signal from noise in these samples will be critical for further mechanistic microbiome studies in mice.

Results: Using an analytic approach grounded in microbial ecology, we compared bacterial DNA from the lungs of healthy adult mice collected via two common sampling approaches: homogenized whole lung tissue and bronchoalveolar lavage (BAL) fluid. We quantified bacterial DNA using droplet digital PCR, characterized bacterial communities using 16S rRNA gene sequencing, and systematically assessed the quantity and identity of bacterial DNA in both specimen types. We compared bacteria detected in lung specimens to each other and to potential source communities: negative (background) control specimens and paired oral samples. By all measures, whole lung tissue in mice contained greater bacterial signal and less evidence of contamination than did BAL fluid. Relative to BAL fluid, whole lung tissue exhibited a greater quantity of bacterial DNA, distinct community composition, decreased sample-to-sample variation, and greater biological plausibility when compared to potential source communities. In contrast, bacteria detected in BAL fluid were minimally different from those of procedural, reagent, and sequencing controls.

Conclusions: An ecology-based analytical approach discriminates signal from noise in this low-biomass microbiome study and identifies whole lung tissue as the preferred specimen type for murine lung microbiome studies. Sequencing, analysis, and reporting of potential source communities, including negative control specimens and contiguous biological sites, are crucial for biological interpretation of low-biomass microbiome studies, independent of specimen type. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01055-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101028PMC
May 2021

A BMP/Activin A Chimera Induces Posterolateral Spine Fusion in Nonhuman Primates at Lower Concentrations Than BMP-2.

J Bone Joint Surg Am 2021 Aug;103(16):e64

Orthopedic Research and Pharmaceutical Development Consultant, Hudson, Massachusetts.

Background: Supraphysiologic bone morphogenetic protein (BMP)-2 concentrations are required to induce spinal fusion. In this study, a BMP-2/BMP-6/activin A chimera (BV-265), optimized for BMP receptor binding, delivered in a recombinant human collagen:CDHA [calcium-deficient hydroxyapatite] porous composite matrix (CM) or bovine collagen:CDHA granule porous composite matrix (PCM), engineered for optimal BV-265 retention and guided tissue repair, was compared with BMP-2 delivered in a bovine absorbable collagen sponge (ACS) wrapped around a MASTERGRAFT Matrix (MM) ceramic-collagen rod (ACS:MM) in a nonhuman primate noninstrumented posterolateral fusion (PLF) model.

Methods: In vivo retention of 125I-labeled-BV-265/CM or PCM was compared with 125I-labeled-BMP-2/ACS or BMP-2/buffer in a rat muscle pouch model using scintigraphy. Noninstrumented PLF was performed by implanting CM, BV-265/CM, BV-265/PCM, or BMP-2/ACS:MM across L3-L4 and L5-L6 or L3-L4-L5 decorticated transverse processes in 26 monkeys. Computed tomography (CT) images were acquired at 0, 4, 8, 12, and 24 weeks after surgery, where applicable. Manual palpation, μCT (microcomputed tomography) or nCT (nanocomputed tomography), and histological analysis were performed following euthanasia.

Results: Retention of 125I-labeled-BV-265/CM was greater than BV-265/PCM, followed by BMP-2/ACS and BMP-2/buffer. The CM, 0.43 mg/cm3 BMP-2/ACS:MM, and 0.05 mg/cm3 BV-265/CM failed to generate PLFs. The 0.15-mg/cm3 BV-265/CM or 0.075-mg/cm3 BV-265/PCM combinations were partially effective. The 0.25-mg/cm3 BV-265/CM and 0.15 and 0.3-mg/cm3 BV-265/PCM combinations generated successful 2-level PLFs at 12 and 24 weeks.

Conclusions: BV-265/CM or PCM can induce fusion in a challenging nonhuman primate noninstrumented PLF model at substantially lower concentrations than BMP-2/ACS:MM.

Clinical Relevance: BV-265/CM and PCM represent potential alternatives to induce PLF in humans at substantially lower concentrations than BMP-2/ACS:MM.
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http://dx.doi.org/10.2106/JBJS.20.02036DOI Listing
August 2021

Functional Characterization of Organoids Derived From Irreversibly Damaged Liver of Patients With NASH.

Hepatology 2021 Apr 26. Epub 2021 Apr 26.

Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background And Aims: NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology.

Approach And Results: We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response.

Conclusion: Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.
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http://dx.doi.org/10.1002/hep.31857DOI Listing
April 2021

Antiviral peptides from aquatic organisms: Functionality and potential inhibitory effect on SARS-CoV-2.

Aquaculture 2021 Aug 15;541:736783. Epub 2021 Apr 15.

Department of Aquaculture, Sylhet Agricultural University, Sylhet 3100, Bangladesh.

Several antiviral peptides (AVPs) from aquatic organisms have been effective in interfering with the actions of infectious viruses, such as Human Immunodeficiency Virus-1 and Herpes Simplex Virus-1 and 2. AVPs are able to block viral attachment or entry into host cells, inhibit internal fusion or replication events by suppressing viral gene transcription, and prevent viral infections by modulating host immunity. Therefore, as promising therapeutics, the potential of aquatic AVPs for use against the COVID-19 pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is considered. At present no therapeutic drugs are yet available. A total of 32 AVPs derived from fish and shellfish species are discussed in this review paper with notes on their properties and mechanisms of action in the inhibition of viral diseases both in humans and animals, emphasizing on SARS-CoV-2. The molecular structure of novel SARS-CoV-2 with its entry mechanisms, clinical signs and symptoms are also discussed. In spite of only a few study of these AVPs against SARS-CoV-2, aquatic AVPs properties and infection pathways (entry, replication and particle release) into coronaviruses are linked in this paper to postulate an analysis of their potential but unconfirmed actions to impair SARS-CoV-2 infection in humans.
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http://dx.doi.org/10.1016/j.aquaculture.2021.736783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049179PMC
August 2021

Variability in reporting of key outcome predictors in acute myocardial infarction cardiogenic shock trials.

Catheter Cardiovasc Interv 2021 Apr 19. Epub 2021 Apr 19.

The Carl and Edyth Lindner Center for Research and Education, The Christ Hospital, Cincinnati, Ohio, USA.

Background: Among acute myocardial infarction patients with cardiogenic shock (AMICS), a number of key variables predict mortality, including cardiac arrest (CA) and shock classification as proposed by Society for Cardiovascular Angiography and Intervention (SCAI). Given this prognostic importance, we examined the frequency of reporting of high risk variables in published randomized controlled trials (RCTs) of AMICS patients.

Methods: We identified 15 RCTs enrolling 2,500 AMICS patients and then reviewed rates of CA, baseline neurologic status, right heart catheterization data, lactate levels, inotrope and vasopressor requirement, hypothermia, mechanical ventilation, left ventricular ejection fraction (LVEF), mechanical circulatory support, and specific cause of death based on the primary manuscript and Data in S1.

Results: A total of 2,500 AMICS patients have been enrolled in 15 clinical trials over 21 years with only four trials enrolling >80 patients. The reporting frequency and range for key prognostic factors was: neurologic status (0% reported), hypothermia (28% reported, prevalence 33-75%), specific cause of death (33% reported), cardiac index and wedge pressure (47% reported, range 1.6-2.3 L min m and 15-24 mmHg), lactate (60% reported, range 4-7.7 mmol/L), LVEF (73% reported, range 25-45%), CA (80% reported, prevalence 0-92%), MCS (80% reported, prevalence 13-100%), and mechanical ventilation (93% reported, prevalence 35-100%). This variability was reflected in the 30-day mortality which ranged from 20-73%.

Conclusions: In a comprehensive review of seminal RCTs in AMICS, important predictors of outcome were frequently not reported. Future efforts to standardize CS trial data collection and reporting may allow for better assessment of novel therapies for AMICS.
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http://dx.doi.org/10.1002/ccd.29710DOI Listing
April 2021

Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease.

Cell 2021 May 16;184(10):2633-2648.e19. Epub 2021 Apr 16.

Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.
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http://dx.doi.org/10.1016/j.cell.2021.03.050DOI Listing
May 2021
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