• A Continuum Deformation Approach for Growth Analysis of COVID-19 in the United States

      Hemmati, S.; Rastgoftar, H.; Aerospace and Mechanical Engineering Department, University of Arizona (Nature Research, 2021)
      The COVID-19 global pandemic has significantly impacted every aspect of life all over the world. The United States is reported to have suffered more than 20% of the global casualties from this pandemic. It is imperative to investigate the growth dynamics of the disease in the US based on varying geographical and governmental factors that best manifest itself in each State of the Country. This paper utilizes a hybrid machine learning and continuum deformation-based approach for analyzing the stability and growth rate of the pandemic. To this end, principal stress values of the pandemic continuum body are obtained using Mohr’s Circle method and overlapping, moving windows of data are analysed successively. This helps in finding the correlations between the growth rate and Governments’ action/Public’s reaction. Government actions include “state of emergency”, “shelter at place”, and “phase declarations”. We also consider the vaccination rate milestones, which shows us the coordinated Governments’ action/Public’s reaction. Finally, a number of recommendations are made to the Governments and people for better management of future pandemics. © 2021, The Author(s).
    • A re-appraisal of the ENSO response to volcanism with paleoclimate data assimilation

      Zhu, F.; Emile-Geay, J.; Anchukaitis, K.J.; Hakim, G.J.; Wittenberg, A.T.; Morales, M.S.; Toohey, M.; King, J.; Laboratory of Tree-Ring Research, University of Arizona; School of Geography, Development, and Environment, University of Arizona; et al. (Nature Research, 2022)
      The potential for explosive volcanism to affect the El Niño-Southern Oscillation (ENSO) has been debated since the 1980s. Several observational studies, based largely on tree-ring proxies, have since found support for a positive ENSO phase in the year following large eruptions. In contrast, recent coral data from the heart of the tropical Pacific suggest no uniform ENSO response to explosive volcanism over the last millennium. Here we leverage paleoclimate data assimilation to integrate both tree-ring and coral proxies into a reconstruction of ENSO state, and re-appraise this relationship. We find only a weak statistical association between volcanism and ENSO, and identify the selection of volcanic events as a key variable to the conclusion. We discuss the difficulties of conclusively establishing a volcanic influence on ENSO by empirical means, given the myriad factors affecting the response, including the spatiotemporal details of the forcing and ENSO phase preconditioning. © 2022, The Author(s).
    • Accelerated biological aging in COVID-19 patients

      Cao, X.; Li, W.; Wang, T.; Ran, D.; Davalos, V.; Planas-Serra, L.; Pujol, A.; Esteller, M.; Wang, X.; Yu, H.; et al. (Nature Research, 2022)
      Chronological age is a risk factor for SARS-CoV-2 infection and severe COVID-19. Previous findings indicate that epigenetic age could be altered in viral infection. However, the epigenetic aging in COVID-19 has not been well studied. In this study, DNA methylation of the blood samples from 232 healthy individuals and 413 COVID-19 patients is profiled using EPIC methylation array. Epigenetic ages of each individual are determined by applying epigenetic clocks and telomere length estimator to the methylation profile of the individual. Epigenetic age acceleration is calculated and compared between groups. We observe strong correlations between the epigenetic clocks and individual’s chronological age (r > 0.8, p < 0.0001). We also find the increasing acceleration of epigenetic aging and telomere attrition in the sequential blood samples from healthy individuals and infected patients developing non-severe and severe COVID-19. In addition, the longitudinal DNA methylation profiling analysis find that the accumulation of epigenetic aging from COVID-19 syndrome could be partly reversed at late clinic phases in some patients. In conclusion, accelerated epigenetic aging is associated with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, the accumulation of epigenetic aging from COVID-19 may contribute to the post-COVID-19 syndrome among survivors. © 2022, The Author(s).
    • All-sky dynamical response of the Galactic halo to the Large Magellanic Cloud

      Conroy, Charlie; Naidu, Rohan P; Garavito-Camargo, Nicolás; Besla, Gurtina; Zaritsky, Dennis; Bonaca, Ana; Johnson, Benjamin D; Steward Observatory, University of Arizona (Nature Research, 2021-04-21)
      Gravitational interactions between the Large Magellanic Cloud (LMC) and the stellar and dark matter halo of the Milky Way are expected to give rise to disequilibrium phenomena in the outer Milky Way1-7. A local wake is predicted to trail the orbit of the LMC, and a large-scale overdensity is predicted to exist across a large area of the northern Galactic hemisphere. Here we report the detection of both the local wake and northern overdensity (hereafter the 'collective response') in a map of the Galaxy based on 1,301 stars at Galactocentric distances between 60 and 100 kiloparsecs. The location of the wake is in good agreement with an N-body simulation that includes the dynamical effect of the LMC on the Milky Way halo. The density contrast of the wake and collective response are stronger in the data than in the simulation. The detection of a strong local wake is independent evidence that the Magellanic clouds are on their first orbit around the Milky Way. The wake traces the path of the LMC, which will provide insight into the orbit of the LMC, which in turn is a sensitive probe of the mass of the LMC and the Milky Way. These data demonstrate that the outer halo is not in dynamical equilibrium, as is often assumed. The morphology and strength of the wake could be used to test the nature of dark matter and gravity.
    • Alpine permafrost could account for a quarter of thawed carbon based on Plio-Pleistocene paleoclimate analogue

      Cheng, F.; Garzione, C.; Li, X.; Salzmann, U.; Schwarz, F.; Haywood, A.M.; Tindall, J.; Nie, J.; Li, L.; Wang, L.; et al. (Nature Research, 2022)
      Estimates of the permafrost-climate feedback vary in magnitude and sign, partly because permafrost carbon stability in warmer-than-present conditions is not well constrained. Here we use a Plio-Pleistocene lacustrine reconstruction of mean annual air temperature (MAAT) from the Tibetan Plateau, the largest alpine permafrost region on the Earth, to constrain past and future changes in permafrost carbon storage. Clumped isotope-temperatures (Δ47-T) indicate warmer MAAT (~1.2 °C) prior to 2.7 Ma, and support a permafrost-free environment on the northern Tibetan Plateau in a warmer-than-present climate. Δ47-T indicate ~8.1 °C cooling from 2.7 Ma, coincident with Northern Hemisphere glacial intensification. Combined with climate models and global permafrost distribution, these results indicate, under conditions similar to mid-Pliocene Warm period (3.3–3.0 Ma), ~60% of alpine permafrost containing ~85 petagrams of carbon may be vulnerable to thawing compared to ~20% of circumarctic permafrost. This estimate highlights ~25% of permafrost carbon and the permafrost-climate feedback could originate in alpine areas. © 2022, The Author(s).
    • Ambulatory electrocardiography, heart rate variability, and pharmacologic stress testing in cats with subclinical hypertrophic cardiomyopathy

      Walker, A.L.; Ueda, Y.; Crofton, A.E.; Harris, S.P.; Stern, J.A.; Department of Cellular and Molecular Medicine, University of Arizona (Nature Research, 2022)
      The utility of ambulatory electrocardiography (AECG) to evaluate cats with subclinical hypertrophic cardiomyopathy (HCM) for arrhythmias and heart rate variability (HRV) is not well defined but may provide information regarding risk stratification. This prospective study used AECG to evaluate ectopy and HRV in subclinical HCM cats compared to healthy controls and is the first to implement a pharmacologic cardiac stress test. Twenty-three purpose-bred, Maine coon cross cats (16 HCM, 7 control) underwent 48-h of continuous AECG. Terbutaline (0.2-0.3 mg/kg) was administered orally at 24 and 36 h. Heart rate, ectopy frequency and complexity and HRV parameters, including standard deviation of normal R-R intervals (SDNN), were compared pre-terbutaline and post-terbutaline and across phenotype, genotype and sex. Genotype for an HCM-causative mutation was significantly associated with the frequency of supraventricular (P = 0.033) and ventricular (P = 0.026) ectopy across all cats. Seven HCM cats and zero healthy cats had a sinus arrhythmia. Mean heart rate was significantly higher post-terbutaline (p < 0.0001). HCM cats had significantly greater HRV compared to controls (SDNN: p = 0.0006). Male cats had significantly higher HRV (SDNN: p = 0.0001) and lower mean heart rates (p = 0.0001). HRV decreased post-terbutaline (SDNN: p = 0.0008) and changes in HRV observed between sexes were attenuated by terbutaline. © 2022. The Author(s).
    • An alternative domain-swapped structure of the Pyrococcus horikoshii PolII mini-intein

      Williams, J.E.; Jaramillo, M.V.; Li, Z.; Zhao, J.; Wang, C.; Li, H.; Mills, K.V.; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona (Nature Research, 2021)
      Protein splicing is a post-translational process by which an intein catalyzes its own excision from flanking polypeptides, or exteins, concomitant with extein ligation. Many inteins have nested homing endonuclease domains that facilitate their propagation into intein-less alleles, whereas other inteins lack the homing endonuclease (HEN) and are called mini-inteins. The mini-intein that interrupts the DNA PolII of Pyrococcus horikoshii has a linker region in place of the HEN domain that is shorter than the linker in a closely related intein from Pyrococcus abyssi. The P. horikoshii PolII intein requires a higher temperature for catalytic activity and is more stable to digestion by the thermostable protease thermolysin, suggesting that it is more rigid than the P. abyssi intein. We solved a crystal structure of the intein precursor that revealed a domain-swapped dimer. Inteins found as domain swapped dimers have been shown to promote intein-mediated protein alternative splicing, but the solved P. horikoshii PolII intein structure has an active site unlikely to be catalytically competent. © 2021, The Author(s).
    • An insight into thermal properties of BC3-graphene hetero-nanosheets: a molecular dynamics study

      Dehaghani, M.Z.; Molaei, F.; Yousefi, F.; Sajadi, S.M.; Esmaeili, A.; Mohaddespour, A.; Farzadian, O.; Habibzadeh, S.; Mashhadzadeh, A.H.; Spitas, C.; et al. (Nature Research, 2021)
      Simulation of thermal properties of graphene hetero-nanosheets is a key step in understanding their performance in nano-electronics where thermal loads and shocks are highly likely. Herein we combine graphene and boron-carbide nanosheets (BC3N) heterogeneous structures to obtain BC3N-graphene hetero-nanosheet (BC3GrHs) as a model semiconductor with tunable properties. Poor thermal properties of such heterostructures would curb their long-term practice. BC3GrHs may be imperfect with grain boundaries comprising non-hexagonal rings, heptagons, and pentagons as topological defects. Therefore, a realistic picture of the thermal properties of BC3GrHs necessitates consideration of grain boundaries of heptagon-pentagon defect pairs. Herein thermal properties of BC3GrHs with various defects were evaluated applying molecular dynamic (MD) simulation. First, temperature profiles along BC3GrHs interface with symmetric and asymmetric pentagon-heptagon pairs at 300 K, ΔT = 40 K, and zero strain were compared. Next, the effect of temperature, strain, and temperature gradient (ΔT) on Kaptiza resistance (interfacial thermal resistance at the grain boundary) was visualized. It was found that Kapitza resistance increases upon an increase of defect density in the grain boundary. Besides, among symmetric grain boundaries, 5–7–6–6 and 5–7–5–7 defect pairs showed the lowest (2 × 10–10 m2 K W−1) and highest (4.9 × 10–10 m2 K W−1) values of Kapitza resistance, respectively. Regarding parameters affecting Kapitza resistance, increased temperature and strain caused the rise and drop in Kaptiza thermal resistance, respectively. However, lengthier nanosheets had lower Kapitza thermal resistance. Moreover, changes in temperature gradient had a negligible effect on the Kapitza resistance. © 2021, The Author(s).
    • Analysis of the Coptis chinensis genome reveals the diversification of protoberberine-type alkaloids

      Liu, Y.; Wang, B.; Shu, S.; Li, Z.; Song, C.; Liu, D.; Niu, Y.; Liu, J.; Zhang, J.; Liu, H.; et al. (Nature Research, 2021)
      Chinese goldthread (Coptis chinensis Franch.), a member of the Ranunculales, represents an important early-diverging eudicot lineage with diverse medicinal applications. Here, we present a high-quality chromosome-scale genome assembly and annotation of C. chinensis. Phylogenetic and comparative genomic analyses reveal the phylogenetic placement of this species and identify a single round of ancient whole-genome duplication (WGD) shared by the Ranunculaceae. We characterize genes involved in the biosynthesis of protoberberine-type alkaloids in C. chinensis. In particular, local genomic tandem duplications contribute to member amplification of a Ranunculales clade-specific gene family of the cytochrome P450 (CYP) 719. The functional versatility of a key CYP719 gene that encodes the (S)-canadine synthase enzyme involved in the berberine biosynthesis pathway may play critical roles in the diversification of other berberine-related alkaloids in C. chinensis. Our study provides insights into the genomic landscape of early-diverging eudicots and provides a valuable model genome for genetic and applied studies of Ranunculales. © 2021, The Author(s).
    • Approximate Bayesian Computation of radiocarbon and paleoenvironmental record shows population resilience on Rapa Nui (Easter Island)

      DiNapoli, R.J.; Crema, E.R.; Lipo, C.P.; Rieth, T.M.; Hunt, T.L.; The Honors College and School of Anthropology, University of Arizona, Tucson, AZ, United States (Nature Research, 2021)
      Examining how past human populations responded to environmental and climatic changes is a central focus of the historical sciences. The use of summed probability distributions (SPD) of radiocarbon dates as a proxy for estimating relative population sizes provides a widely applicable method in this research area. Paleodemographic reconstructions and modeling with SPDs, however, are stymied by a lack of accepted methods for model fitting, tools for assessing the demographic impact of environmental or climatic variables, and a means for formal multi-model comparison. These deficiencies severely limit our ability to reliably resolve crucial questions of past human-environment interactions. We propose a solution using Approximate Bayesian Computation (ABC) to fit complex demographic models to observed SPDs. Using a case study from Rapa Nui (Easter Island), a location that has long been the focus of debate regarding the impact of environmental and climatic changes on its human population, we find that past populations were resilient to environmental and climatic challenges. Our findings support a growing body of evidence showing stable and sustainable communities on the island. The ABC framework offers a novel approach for exploring regions and time periods where questions of climate-induced demographic and cultural change remain unresolved. © 2021, The Author(s).
    • Archival influenza virus genomes from Europe reveal genomic variability during the 1918 pandemic

      Patrono, L.V.; Vrancken, B.; Budt, M.; Düx, A.; Lequime, S.; Boral, S.; Gilbert, M.T.P.; Gogarten, J.F.; Hoffmann, L.; Horst, D.; et al. (Nature Research, 2022)
      The 1918 influenza pandemic was the deadliest respiratory pandemic of the 20th century and determined the genomic make-up of subsequent human influenza A viruses (IAV). Here, we analyze both the first 1918 IAV genomes from Europe and the first from samples prior to the autumn peak. 1918 IAV genomic diversity is consistent with a combination of local transmission and long-distance dispersal events. Comparison of genomes before and during the pandemic peak shows variation at two sites in the nucleoprotein gene associated with resistance to host antiviral response, pointing at a possible adaptation of 1918 IAV to humans. Finally, local molecular clock modeling suggests a pure pandemic descent of seasonal H1N1 IAV as an alternative to the hypothesis of origination through an intrasubtype reassortment. © 2022, The Author(s).
    • Augmenting ideational fluency in a creativity task across multiple transcranial direct current stimulation montages

      Chrysikou, E.G.; Morrow, H.M.; Flohrschutz, A.; Denney, L.; University of Arizona (Nature Research, 2021)
      Neuroimaging and transcranial direct current stimulation (tDCS) research has revealed that generating novel ideas is associated with both reductions and increases in prefrontal cortex (PFC) activity, and engagement of posterior occipital cortex, among other regions. However, there is substantial variability in the robustness of these tDCS‐induced effects due to heterogeneous sample sizes, different creativity measures, and methodological diversity in the application of tDCS across laboratories. To address these shortcomings, we used twelve different montages within a standardized tDCS protocol to investigate how altering activity in frontotemporal and occipital cortex impacts creative thinking. Across four experiments, 246 participants generated either the common or an uncommon use for 60 object pictures while undergoing tDCS. Participants also completed a control short-term memory task. We applied active tDCS for 20 min at 1.5 mA through two 5 cm × 5 cm electrodes over left or right ventrolateral prefrontal (areas F7, F8) or occipital (areas O1, O2) cortex, concurrent bilateral stimulation of these regions across polarities, or sham stimulation. Cathodal stimulation of the left, but not right, ventrolateral PFC improved fluency in creative idea generation, but had no effects on originality, as approximated by measures of semantic distance. No effects were obtained for the control tasks. Concurrent bilateral stimulation of the ventrolateral PFC regardless of polarity direction, and excitatory stimulation of occipital cortex did not alter task performance. Highlighting the importance of cross-experimental methodological consistency, these results extend our past findings and contribute to our understanding of the role of left PFC in creative thinking. © 2021, The Author(s).
    • Automated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma

      Moore, Michael R.; Friesner, Isabel D.; Rizk, Emanuelle M.; Fullerton, Benjamin T.; Mondal, Manas; Trager, Megan H.; Mendelson, Karen; Chikeka, Ijeuru; Kurc, Tahsin; Gupta, Rajarsi; et al. (Nature Research, 2021-02-02)
      Accurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan–Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51–11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms. © 2021, The Author(s).
    • Bacterial vaginosis and health-associated bacteria modulate the immunometabolic landscape in 3D model of human cervix

      Łaniewski, P.; Herbst-Kralovetz, M.M.; Department of Basic Medical Sciences, College of Medicine – Phoenix, University of Arizona; Department of Obstetrics and Gynecology, College of Medicine – Phoenix, University of Arizona (Nature Research, 2021)
      Bacterial vaginosis (BV) is an enigmatic polymicrobial condition characterized by a depletion of health-associated Lactobacillus and an overgrowth of anaerobes. Importantly, BV is linked to adverse gynecologic and obstetric outcomes: an increased risk of sexually transmitted infections, preterm birth, and cancer. We hypothesized that members of the cervicovaginal microbiota distinctly contribute to immunometabolic changes in the human cervix, leading to these sequelae. Our 3D epithelial cell model that recapitulates the human cervical epithelium was infected with clinical isolates of cervicovaginal bacteria, alone or as a polymicrobial community. We used Lactobacillus crispatus as a representative health-associated commensal and four common BV-associated species: Gardnerella vaginalis, Prevotella bivia, Atopobium vaginae, and Sneathia amnii. The immunometabolic profiles of these microenvironments were analyzed using multiplex immunoassays and untargeted global metabolomics. A. vaginae and S. amnii exhibited the highest proinflammatory potential through induction of cytokines, iNOS, and oxidative stress-associated compounds. G. vaginalis, P. bivia, and S. amnii distinctly altered physicochemical barrier-related proteins and metabolites (mucins, sialic acid, polyamines), whereas L. crispatus produced an antimicrobial compound, phenyllactic acid. Alterations to the immunometabolic landscape correlate with symptoms and hallmarks of BV and connected BV with adverse women’s health outcomes. Overall, this study demonstrated that 3D cervical epithelial cell colonized with cervicovaginal microbiota faithfully reproduce the immunometabolic microenvironment previously observed in clinical studies and can successfully be used as a robust tool to evaluate host responses to commensal and pathogenic bacteria in the female reproductive tract. © 2021, The Author(s).
    • Belief propagation with quantum messages for quantum-enhanced classical communications

      Rengaswamy, N.; Seshadreesan, K.P.; Guha, S.; Pfister, H.D.; Department of Electrical and Computer Engineering, The University of Arizona; College of Optical Sciences, The University of Arizona (Nature Research, 2021)
      For space-based laser communications, when the mean photon number per received optical pulse is much smaller than one, there is a large gap between communications capacity achievable with a receiver that performs individual pulse-by-pulse detection, and the quantum-optimal “joint-detection receiver” that acts collectively on long codeword-blocks of modulated pulses; an effect often termed “superadditive capacity”. In this paper, we consider the simplest scenario where a large superadditive capacity is known: a pure-loss channel with a coherent-state binary phase-shift keyed (BPSK) modulation. The two BPSK states can be mapped conceptually to two non-orthogonal states of a qubit, described by an inner product that is a function of the mean photon number per pulse. Using this map, we derive an explicit construction of the quantum circuit of a joint-detection receiver based on a recent idea of “belief-propagation with quantum messages” (BPQM). We quantify its performance improvement over the Dolinar receiver that performs optimal pulse-by-pulse detection, which represents the best “classical” approach. We analyze the scheme rigorously and show that it achieves the quantum limit of minimum average error probability in discriminating 8 (BPSK) codewords of a length-5 binary linear code with a tree factor graph. Our result suggests that a BPQM receiver might attain the Holevo capacity of this BPSK-modulated pure-loss channel. Moreover, our receiver circuit provides an alternative proposal for a quantum supremacy experiment, targeted at a specific application that can potentially be implemented on a small, special-purpose, photonic quantum computer capable of performing cat-basis universal qubit logic. © 2021, The Author(s).
    • Bidirectional interconversion of microwave and light with thin-film lithium niobate

      Xu, Y.; Sayem, A.A.; Fan, L.; Zou, C.-L.; Wang, S.; Cheng, R.; Fu, W.; Yang, L.; Xu, M.; Tang, H.X.; et al. (Nature Research, 2021)
      Superconducting cavity electro-optics presents a promising route to coherently convert microwave and optical photons and distribute quantum entanglement between superconducting circuits over long-distance. Strong Pockels nonlinearity and high-performance optical cavity are the prerequisites for high conversion efficiency. Thin-film lithium niobate (TFLN) offers these desired characteristics. Despite significant recent progresses, only unidirectional conversion with efficiencies on the order of 10−5 has been realized. In this article, we demonstrate the bidirectional electro-optic conversion in TFLN-superconductor hybrid system, with conversion efficiency improved by more than three orders of magnitude. Our air-clad device architecture boosts the sustainable intracavity pump power at cryogenic temperatures by suppressing the prominent photorefractive effect that limits cryogenic performance of TFLN, and reaches an efficiency of 1.02% (internal efficiency of 15.2%). This work firmly establishes the TFLN-superconductor hybrid EO system as a highly competitive transduction platform for future quantum network applications. © 2021, The Author(s).
    • Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

      UK National PAH Cohort Study Consortium; Department of Cellular and Molecular Medicine, University of Arizona (Nature Research, 2021)
      Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH. © 2021, The Author(s).
    • Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity

      LaVigne, J.E.; Hecksel, R.; Keresztes, A.; Streicher, J.M.; Department of Pharmacology, College of Medicine, University of Arizona (Nature Research, 2021)
      Limited evidence has suggested that terpenes found in Cannabis sativa are analgesic, and could produce an “entourage effect” whereby they modulate cannabinoids to result in improved outcomes. However this hypothesis is controversial, with limited evidence. We thus investigated Cannabis sativa terpenes alone and with the cannabinoid agonist WIN55,212 using in vitro and in vivo approaches. We found that the terpenes α-humulene, geraniol, linalool, and β-pinene produced cannabinoid tetrad behaviors in mice, suggesting cannabimimetic activity. Some behaviors could be blocked by cannabinoid or adenosine receptor antagonists, suggesting a mixed mechanism of action. These behavioral effects were selectively additive with WIN55,212, suggesting terpenes can boost cannabinoid activity. In vitro experiments showed that all terpenes activated the CB1R, while some activated other targets. Our findings suggest that these Cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids. © 2021, The Author(s).
    • Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells

      Al-Rashed, F.; Ahmad, Z.; Snider, A.J.; Thomas, R.; Kochumon, S.; Melhem, M.; Sindhu, S.; Obeid, L.M.; Al-Mulla, F.; Hannun, Y.A.; et al. (Nature Research, 2021)
      Ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain not fully understood. Here, we investigated the role of CERK in TNF-α-induced inflammatory responses in monocytes. Our results show that disruption of CERK activity in monocytes, either by chemical inhibitor NVP-231 or by small interfering RNA (siRNA), results in the defective expression of inflammatory markers including CD11c, CD11b and HLA-DR in response to TNF-α. Our data show that TNF-α upregulates ceramide phosphorylation. Inhibition of CERK in monocytes significantly reduced the secretion of IL-1β and MCP-1. Similar results were observed in CERK-downregulated cells. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was reduced by inhibition of CERK. Additionally, NF-κB/AP-1 activity was suppressed by the inhibition of CERK. Clinically, obese individuals had higher levels of CERK expression in PBMCs compared to lean individuals, which correlated with their TNF-α levels. Taken together, these results suggest that CERK plays a key role in regulating inflammatory responses in human monocytes during TNF-α stimulation. CERK may be a relevant target for developing novel therapies for chronic inflammatory diseases. © 2021, The Author(s).
    • Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

      NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; University of Arizona (Nature Research, 2021)
      Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids. © 2021, The Author(s).