bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 induces a hyperactive phenotype in circulating platelets
Authors: Comer Shane P. , Cullivan Sarah , Szklanna Paulina B. , Weiss Luisa , Cullen Steven , Kelliher Sarah , Smolenski Albert , Moran Niamh , Murphy Claire , Altaie Haidar , Curran John , O’Reilly Katherine , Cotter Aoife G. , Marsh Brian , Gaine Sean , Mallon Patrick , McCullagh Brian , Ní Áinle Fionnuala , Kevane Barry , Maguire Patricia B.
Published: July 2020

Background

Coronavirus disease 2019 (COVID-19), caused by novel coronavirus SARS-CoV-2, has to date affected over 13.3 million globally. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated.

Objectives

Here, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and non-severe COVID-19.

Methods

An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with non-severe disease (not requiring intensive care), general medical in-patients without COVID-19 and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis.

Results

We show that routine clinical blood parameters including increased MPV and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit admission. Strikingly, agonist-induced ADP release was dramatically higher in COVID-19 patients compared with non-COVID-19 hospitalized patients and circulating levels of PF4, sP-selectin and TPO were also significantly elevated in COVID-19.

Conclusion

Distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and non-severe COVID-19. Moreover, we have determined that COVID-19 patients possess hyperactive circulating platelets. These data suggest that abnormal platelet reactivity may contribute to hypercoagulability in COVID-19. Further investigation of platelet function in COVID-19 may provide additional insights into the aetiology of thrombotic risk in this disease and may contribute to the optimisation of thrombosis prevention and treatment strategies.

Essentials

Routine platelet-related clinical blood parameters (MPV, PNR) are associated with disease severity in COVID-19.

Agonist-induced ADP release is dramatically higher in COVID-19 patients compared with non-COVID-19 hospitalized patients.

Circulating levels of PF4, sP-selectin levels and TPO are significantly elevated in COVID-19.

Identification of a hyperactive platelet phenotype may warrant re-evaluation of current thrombotic prevention strategies in COVID-19 treatment.
Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2
Authors: Kim Jeonghwan , Mukherjee Anindit , Nelson Dylan , Jozic Antony , Sahay Gaurav
Published: July 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters through the airways and infects the lungs, causing lethal pulmonary damage in vulnerable patients. This virus contains spike proteins on its envelope that binds to human angiotensin-converting enzyme 2 (hACE2) expressed on the surface of airway cells, enabling entry of the virus for causing infection1,2. In severe cases, the virus enters the circulatory system, contributing to multiorgan failure. Soluble form of hACE2 binds to SARS-CoV-2 spike protein and prevents viral entry into target cells3. Moreover, soluble recombinant ACE2 ameliorates lung injury4but its short half-life limits its therapeutic utility5. Here, we engineered synthetic mRNA to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. Novel lipid nanoparticles (LNPs) were used to package mRNA and transfect mammalian cells for enhanced production of secreted proteins. Intravenously administered LNP led to hepatic delivery of the mRNA. This elicited secretion of hsACE2 into the blood circulation within 2 h, and levels of circulating hsACE2 peaked at 6 h and gradually decreased over several days. Since the primary site of entry and pathogenesis for SARS-CoV-2 is the lungs, we instilled LNPs into the lungs and were able to detect hsACE2 in the bronchoalveolar lavage fluid within 24 h and lasted for 48 h. Through co-immunoprecipitation, we found that mRNA-generated hsACE2 was able to bind with the receptor binding domain of the SARS-CoV-2 spike protein. Furthermore, hsACE2 was able to strongly inhibit (over 90%) SARS-CoV-2 pseudovirus infection. Our proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed for pulmonary and extrapulmonary neutralization of SARS-CoV-2 and open new treatment opportunities for COVID-19.
Benchmarking challenging small variants with linked and long reads
Authors: Wagner Justin , Olson Nathan D , Harris Lindsay , McDaniel Jennifer , Khan Ziad , Farek Jesse , Mahmoud Medhat , Stankovic Ana , Kovacevic Vladimir , Yoo Byunggil , Miller Neil , Rosenfeld Jeffrey A. , Ni Bohan , Zarate Samantha , Kirsche Melanie , Aganezov Sergey , Schatz Michael , Narzisi Giuseppe , Byrska-Bishop Marta , Clarke Wayne , Evani Uday S. , Markello Charles , Shafin Kishwar , Zhou Xin , Sidow Arend , Bansal Vikas , Ebert Peter , Marschall Tobias , Lansdorp Peter , Hanlon Vincent , Mattsson Carl-Adam , Barrio Alvaro Martinez , Fiddes Ian T , Xiao Chunlin , Fungtammasan Arkarachai , Chin Chen-Shan , Wenger Aaron M , Rowell William J , Sedlazeck Fritz J , Carroll Andrew , Salit Marc , Zook Justin M
Published: July 2020

Genome in a Bottle (GIAB) benchmarks have been widely used to help validate clinical sequencing pipelines and develop new variant calling and sequencing methods. Here, we use accurate linked reads and long reads to expand the prior benchmarks in 7 samples to include difficult-to-map regions and segmental duplications that are not readily accessible to short reads. Our new benchmark adds more than 300,000 SNVs, 50,000 indels, and 16 % new exonic variants, many in challenging, clinically relevant genes not previously covered (e.g.,PMS2). For HG002, we include 92% of the autosomal GRCh38 assembly, while excluding problematic regions for benchmarking small variants (e.g., copy number variants and reference errors) that should not have been in the previous version, which included 85% of GRCh38. By including difficult-to-map regions, this benchmark identifies eight times more false negatives in a short read variant call set relative to our previous benchmark.We have demonstrated the utility of this benchmark to reliably identify false positives and false negatives across technologies in more challenging regions, which enables continued technology and bioinformatics development.
NT3/TrkC pathway modulates the expression of UCP-1 and adipocyte size in human and murine adipose tissue
Authors: Bové María , Monto Fermi , Guillem-Llobat Paloma , Ivorra M Dolores , Noguera M Antonia , Zambrano Andrea , Sirerol-Piquer Ma Salome , Requena Ana Cristina , García-Alonso Mauricio , Tejerina Teresa , Real José T. , Fariñas Isabel , D’Ocon Pilar
Published: July 2020

NT3, through activation of its tropomyosin-related kinase receptor C (TrkC), modulates neuronal survival and neural stem cell differentiation. It is widely distributed in peripheral tissues (specially vessels and pancreas) and this ubiquitous pattern suggests a role for NT3, outside the nervous system and related to metabolic functions. The presence of the NT3/TrkC pathway in the adipose tissue (AT) has never been investigated. Present work studies in human and murine adipose tissue (AT) the presence of elements of the NT3/TrkC pathway and its role on lipolysis and adipocyte differentiation. qRT-PCR and immunoblot indicate that NT3 was present in human retroperitoneal AT and decreases with age. NT3 was also present in rat isolated adipocytes and retroperitoneal, interscapular, perivascular and perirenal AT. Histological analysis evidences that NT3 was mainly present in vessels irrigating AT close associated to sympathetic fibers. Similar mRNA levels of TrkC and β-adrenoceptors were found in all ATs assayed and in isolated adipocytes. NT3, through TrkC activation, exert a mild effect in lipolysis. Addition of NT3 during the differentiation process of human pre-adipocytes resulted in smaller adipocytes and increased uncoupling protein-1 (UCP-1) without changes in β-adrenoceptors. Similarly, transgenic mice with reduced expression of NT3 (Ntf3 knock-in lacZ reporter mice) or lacking endothelial NT3 expression (Ntf3flox1/flox2;Tie2-Cre+/0) displayed enlarged white and brown adipocytes and lower UCP-1 expression.

Conclusions

NT3, mainly released by blood vessels, activates TrkC and regulates adipocyte differentiation and browning. Disruption of NT3/TrkC signaling conducts to hypertrophied white and brown adipocytes with reduced expression of the thermogenesis marker UCP-1
AD-linked R47H-TREM2mutation induces disease-enhancing proinflammatory microglial states in mice and humans
Authors: Sayed Faten A. , Kodama Lay , Udeochu Joe C. , Fan Li , Carling Gillian K. , Le David , Li Qingyun , Zhou Lu , Mathys Hansruedi , Wang Minghui , Niu Xiang , Mazutis Linas , Jiang Xueqiao , Wang Xueting , Wong Man Ying , Gao Fuying , Telpoukhovskaia Maria , Tracy Tara E. , Frost Georgia , Zhou Yungui , Li Yaqiao , Brendel Matthew , Qiu Yue , Cheng Zuolin , Yu Guoqiang , Hardy John , Coppola Giovanni , Gong Shiaoching , Wang Fei , DeTure Michael A. , Zhang Bin , Xie Lei , Dickson Dennis W. , Luo Wenjie , Gan Li
Published: July 2020

The hemizygous R47H variant ofTREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2with matched sex, pathology andAPOEstatus, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of humanTREM2(hTREM2)with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.
Improving gene-network inference with graph-wavelets and making insights about ageing associated regulatory changes in lungs
Authors: Mishra Shreya , Srivastava Divyanshu , Kumar Vibhor
Published: July 2020

Using gene-regulatory-networks based approach for single-cell expression profiles can reveal un-precedented details about the effects of external and internal factors. However, noise and batch effect in sparse single-cell expression profiles can hamper correct estimation of dependencies among genes and regulatory changes. Here we devise a conceptually different method using graph-wavelet filters for improving gene-network (GWNet) based analysis of the transcriptome. Our approach improved the performance of several gene-network inference methods. Most Importantly, GWNet improved consistency in the prediction of generegulatory-network using single-cell transcriptome even in presence of batch effect. Consistency of predicted gene-network enabled reliable estimates of changes in the influence of genes not highlighted by differential-expression analysis. Applying GWNet on the single-cell transcriptome profile of lung cells, revealed biologically-relevant changes in the influence of pathways and master-regulators due to ageing. Surprisingly, the regulatory influence of ageing on pneumocytes type II cells showed noticeable similarity with patterns due to effect of novel coronavirus infection in Human Lung.
Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis Differentially Influence Pain Processing and Modulation in Male and Female Mice
Authors: Yu Waylin , Stanhope Christina M. , Rivera Sanchez Natalia del R. , Moseley Garrett A. , Kash Thomas L.
Published: July 2020

The bed nucleus of the stria terminalis (BNST) plays an emerging yet understudied role in pain. Corticotropin-releasing factor (CRF) is an important source of pain modulation in the BNST, with local pharmacological inhibition of CRF receptors conditionally impacting the sensory and affective-motivational components of pain. Knowledge on how pain dynamically engages CRF neurons in the BNST and is influenced by intra-BNST production of CRF, however, remains unknown. In the present study, we utilizedin vivocalcium imaging to show robust and synchronized recruitment of BNSTCRF+neurons during acute exposure to noxious heat. Distinct patterns of recruitment were observed by sex, as the magnitude and timing of heat responsive activity in BNSTCRF+neurons differed for male and female mice. We then established the necessity of CRF for intact pain behaviors by genetically deletingCrfin the BNST, which reduced thermal and mechanical nociceptive sensitivity for both sexes, and increased paw attending in female mice, suggesting a divergent role for CRF with respect to active coping responses to pain. Together, these findings demonstrate that CRF in the BNST contributes to multiple facets of the pain experience and may play a key role in the sex-specific expression of pain-related behaviors.
Foraging gene and xenobiotic stresses relationships inDrosophila melanogaster
Authors: Marcel Amichot , Sophie Tarès
Published: July 2020

In several insect species, the foraging behaviour has been demonstrated to be controlled by theforaginggene (for) which encodes for a cGMP-dependent protein kinase (PKG). In wild Drosophila populations, rover and sitter individuals coexist and are characterized by high and low PKG activity levels respectively. Because of their increased foraging behaviour, we postulated that rover flies are more exposed to environmental stresses than sitter flies. Thus, we tested whether rover and sitter flies differ in their fitness by using insecticides as chemical stressors. We showed that their responses are different depending on the insecticide used and are linked to variations of cytochrome P450s activities. Furthermore, the expression of the insecticide metabolizing cytochrome P450Cyp6a2was shown to be under the control of theforgene. We evidence here a new physiological function for theforgene in Drosophila and we demonstrate its involvement in the adaptation to chemicals in the environment.
Analysis and modeling of cancer drug responses using cell cycle phase-specific rate effects
Authors: Gross Sean M. , Mohammadi Farnaz , Sanchez-Aguila Crystal , Zhan Paulina J. , Liby Tiera A. , Dane Mark A. , Meyer Aaron S. , Heiser Laura M.
Published: July 2020

Identifying effective therapeutic strategies that can prevent tumor cell proliferation is a major challenge to improving outcomes for patients with breast cancer. Here we sought to deepen our understanding of how clinically relevant anti-cancer agents modulate cell cycle progression. We genetically engineered breast cancer cell lines to express a cell cycle reporter and then tracked drug-induced changes in cell number and cell cycle phase, which revealed drug-specific cell cycle effects that varied across time. This suggested that a computational model that could account for cell cycle phase durations would provide a framework to explore drug-induced changes in cell cycle changes. Toward that goal, we developed a linear chain trick (LCT) computational model, in which the cell cycle was partitioned into subphases that faithfully captured drug-induced dynamic responses. The model inferred drug effects and localized them to specific cell cycle phases, which we confirmed experimentally. We then used our LCT model to predict the effect of unseen drug combinations that target cells in different cell cycle phases. Experimental testing confirmed several model predictions and identified combination treatment strategies that may improve therapeutic response in breast cancer patients. Overall, this integrated experimental and modeling approach opens new avenues for assessing drug responses, predicting effective drug combinations, and identifying optimal drug sequencing strategies.
Brain geometry matters in Alzheimer’s disease progression: a simulation study
Authors: Hoore Masoud , Kelling Jeffrey , Sayadmanesh Mahsa , Mitra Tanmay , Schips Marta , Meyer-Hermann Michael
Published: July 2020

The Amyloid cascade hypothesis (ACH) for Alzheimer’s disease (AD) is modeled over the whole brain tissue with a set of partial differential equations. Our results show that the amyloid plaque formation is critically dependent on the secretion rate of amyloid β (Aβ), which is proportional to the product of neural density and neural activity. Neural atrophy is similarly related to the secretion rate of Aβ. Due to a heterogeneous distribution of neural density and brain activity throughout the brain, amyloid plaque formation and neural death occurs heterogeneously in the brain. The geometry of the brain and microglia migration in the parenchyma bring more complexity into the system and result in a diverse amyloidosis and dementia pattern of different brain regions. Although the pattern of amyloidosis in the brain cortex from in-silico results is similar to experimental autopsy findings, they mismatch at the central regions of the brain, suggesting that ACH is not able to explain the whole course of AD without considering other factors, such as tau-protein aggregation or neuroinflammation.
Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging
Authors: Rosselot Carolina , Alvarsson Alexandra , Wang Peng , Li Yansui , Beliard Kara , Lu Geming , Li Rosemary , Liu Hongtao , Gillespie Virginia , Tzavaras Nikolaos , Kumar Kunal , DeVita Robert J. , Stewart Andrew F. , Stanley Sarah A. , Garcia-Ocaña Adolfo
Published: July 2020

463 million people globally suffer from diabetes. The majority are deficient in insulin-producing pancreatic beta cells, although beta cells remain in most people with diabetes. Unfortunately, although many diabetes drugs exist, none is able to increase adult human beta cell numbers. Recently, small molecules that inhibit the kinase, DYRK1A, have been suggested to induce human beta cell replicationin vitroandin vivoas assessed using proliferation markers, and this is enhanced by drugs that stimulate the GLP1 receptor (GLP1R) on beta cells. DYRK1A inhibitors also enhance human beta cell differentiation and function. However, it is unknown whether any drug can actually increase human beta cell massin vivo, reflecting: 1) the intrinsic resistance of human beta cells to regeneration; and, 2) the current technical inability to accurately assess human beta cell massin vivo. Here, we demonstrate for the first time that combining a DYRK1A inhibitor with a GLP1R agonist increases actual human beta cell numbers and overall massin vivoby 400-700% in diabetic and non-diabetic mice over three months. We further describe a novel application of tissue-clearing and 3D imaging for quantification of human beta cell mass. These findings should be transformative for diabetes treatment.
Interneuron Specific Gamma Synchronization Indexes Cue Uncertainty and Prediction Errors in Lateral Prefrontal and Anterior Cingulate Cortex
Authors: Boroujeni Kianoush Banaie , Tiesinga Paul , Womelsdorf Thilo
Published: July 2020

Inhibitory interneurons are believed to realize critical gating functions in cortical circuits, but it has been difficult to ascertain the content of gated information for well characterized interneurons in primate cortex. Here, we address this question by characterizing putative interneurons in primate prefrontal and anterior cingulate cortex while monkeys engaged in attention demanding reversal learning. We find that subclasses of narrow spiking neurons have a relative suppressive effect on the local circuit indicating they are inhibitory interneurons. One of these interneuron subclasses showed prominent firing rate modulations and (35-45 Hz) gamma synchronous spiking during periods of uncertainty in both, lateral prefrontal cortex (LPFC) and in anterior cingulate cortex (ACC). In LPFC this interneuron subclass activated when the uncertainty of attention cues was resolved during flexible learning, whereas in ACC it fired and gamma-synchronized when outcomes were uncertain and prediction errors were high during learning. Computational modeling of this interneuron-specific gamma band activity in simple circuit motifs suggests it could reflect a soft winner-take-all gating of information having high degree of uncertainty. Together, these findings elucidate an electrophysiologically-characterized interneuron subclass in the primate, that forms gamma synchronous networks in two different areas when resolving uncertainty during adaptive goal-directed behavior.
Programmed cell senescence in the mouse developing spinal cord and notochord
Authors: Domínguez-Bautista Jorge Antolio , Acevo-Rodríguez Pilar Sarah , Castro-Obregón Susana
Published: July 2020

Programmed cell senescence is a cellular process that seems to contribute to morphogenesis during embryo development, in addition to cell proliferation, migration, differentiation and programmed cell death, and has been observed in evolutionary distant organisms like mammals, amphibians and fish. Programmed cell senescence is a phenotype similar to stress-induced cellular senescence, characterized by the expression of cell cycle inhibitors such as CDKN1A/p21, increased activity of a lysosomal enzyme with beta-galactosidase activity (coined senescence-associated beta-galactosidase) and, most importantly, secretion of growth factors, interleukins, chemokines, metalloproteases, etc., collectively known as a senescent-associated secretory phenotype that instructs surrounding tissue. How wide is the distribution of programmed cell senescence during mouse development and its specific mechanisms to shape the embryo are still poorly understood. Here, we investigated whether markers of programmed cell senescence are found in the developing mouse spinal cord and notochord. We found discrete areas and developmental windows with high senescence-associated beta galactosidase in both spinal cord and notochord; expression of CDKN1A/p21 was documented in epithelial cells of the spinal cord and the notochord. Treatment of mice embryos developed ex-utero in the presence of the senolytic ABT-263 resulted in decrease senescence-associated beta-galactosidase activity and number of motoneurons. Our data suggest that several cell types undergo programmed cell senescence in developing spinal cord and notochord contributing to morphogenesis.

Contribution to the Field Statement

Cellular senescence is a state in which cells no longer divide but have the remarkable ability to secrete signaling molecules that alter the tissue where they reside. In adults, this state is typically induced by stress situations that cause DNA damage so cells with altered genome do not multiply. Senescent cells also form when a tissue is injured; they help to regenerate damaged tissue and contribute to wound healing. Phagocytic cells eliminate them when their function is done, having a transient existence. During vertebrate development some cells acquire a very similar phenotype, coined programmed cell senescence, and interestingly they have been found in regions that organize the pattern of development of some organs. How wide is the distribution of programmed cell senescence during development and how they help to shape the embryo are still poorly understood. We discovered in mice embryos different types of cells with senescent features located in particular regions of the developing nervous system: where motoneurons form and in a region that secrete molecules that instruct the embryo where different types of neurons will be created. We propose that programed cell senescence contributes to the morphogenesis of the nervous system.
CoVaccine HT™ adjuvant potentiates robust immune responses to recombinant SARS-CoV-2 Spike S1 immunisation
Authors: Haun Brien K. , Lai Chih-Yun , Williams Caitlin A. , Wong Teri Ann , Lieberman Michael M. , Pessaint Laurent , Andersen-Elyard Hanne , Lehrer Axel T.
Published: July 2020

The current COVID-19 pandemic has claimed hundreds of thousands of lives and its causative agent, SARS-CoV-2, has infected millions, globally. The highly contagious nature of this respiratory virus has spurred massive global efforts to develop vaccines at record speeds. In addition to enhanced immunogen delivery, adjuvants may greatly impact protective efficacy of a SARS-CoV-2 vaccine. To investigate adjuvant suitability, we formulated protein subunit vaccines consisting of the recombinant S1 domain of SARS-CoV-2 Spike protein alone or in combination with either CoVaccine HT™ or Alhydrogel. CoVaccine HT™ induced high titres of antigen-binding IgG after a single dose, facilitated affinity maturation and class switching to a greater extent than Alhydrogel and elicited potent cell-mediated immunity as well as virus neutralising antibody titres. Data presented here suggests that adjuvantation with CoVaccine HT™ can rapidly induce a comprehensive and protective immune response to SARS-CoV-2.
Rpb4 and Puf3 imprint and post-transcriptionally control the stability of a common set of mRNAs in yeast
Authors: Garrido-Godino A.I. , Gupta I. , Gutiérrez-Santiago F. , Martínez-Padilla A.B. , Alekseenko A. , Steinmetz L.M. , Pérez-Ortín J.E. , Pelechano V. , Navarro F.
Published: July 2020

Gene expression involving RNA polymerase II is regulated by the concerted interplay between mRNA synthesis and degradation, crosstalk in which mRNA decay machinery and transcription machinery respectively impact transcription and mRNA stability. Rpb4, and likely dimer Rpb4/7, seem the central components of the RNA pol II governing these processes. In this work we unravel the molecular mechanisms participated by Rpb4 that mediate the posttranscriptional events regulating mRNA imprinting and stability. By RIP-Seq, we analyzed genome-wide the association of Rpb4 with mRNAs and demonstrated that it targeted a large population of more than 1400 transcripts. A group of these mRNAs was also the target of the RNA binding protein, Puf3. We demonstrated that Rpb4 and Puf3 physically, genetically, and functionally interact and also affect mRNA stability, and likely the imprinting, of a common group of mRNAs. Furthermore, the Rpb4 and Puf3 association with mRNAs depends on one another. We also demonstrated, for the first time, that Puf3 associates with chromatin in an Rpb4-dependent manner. Our data also suggest that Rpb4 could be a key element of the RNA pol II that coordinates mRNA synthesis, imprinting and stability in cooperation with RBPs.
North American deer mice are susceptible to SARS-CoV-2
Authors: Griffin Bryan D. , Chan Mable , Tailor Nikesh , Mendoza Emelissa J. , Leung Anders , Warner Bryce M. , Duggan Ana T. , Moffat Estella , He Shihua , Garnett Lauren , Tran Kaylie N. , Banadyga Logan , Albietz Alixandra , Tierney Kevin , Audet Jonathan , Bello Alexander , Vendramelli Robert , Boese Amrit S. , Fernando Lisa , Lindsay L. Robbin , Jardine Claire M. , Wood Heidi , Poliquin Guillaume , Strong James E. , Drebot Michael , Safronetz David , Embury-Hyatt Carissa , Kobasa Darwyn
Published: July 2020

The zoonotic spillover of the pandemic SARS-coronavirus 2 (SARS-CoV-2) from an animal reservoir, currently presumed to be the Chinese horseshoe bat, into a naïve human population has rapidly resulted in a significant global public health emergency. Worldwide circulation of SARS-CoV-2 in humans raises the theoretical risk of reverse zoonosis events with wildlife, reintroductions of SARS-CoV-2 into permissive non-domesticated animals, potentially seeding new host reservoir species and geographic regions in which bat SARS-like coronaviruses have not historically been endemic. Here we report that North American deer mice (Peromyscus maniculatus) and some closely related members of theCricetidaefamily of rodents possess key amino acid residues within the angiotensin-converting enzyme 2 (ACE2) receptor known to confer SARS-CoV-2 spike protein binding.Peromyscusrodent species are widely distributed across North America and are the primary host reservoirs of several emerging pathogens that repeatedly spill over into humans includingBorrelia burgdorferi, the causative agent of Lyme disease, deer tick virus, and Sin Nombre orthohantavirus, the causative agent of hantavirus pulmonary syndrome (HPS). We demonstrate that adult deer mice are susceptible to SARS-CoV-2 infection following intranasal exposure to a human isolate, resulting in viral replication in the upper and lower respiratory tract with little or no signs of disease. Further, shed infectious virus is detectable in nasal washes, oropharyngeal and rectal swabs, and viral RNA is detectable in feces and occasionally urine. We further show that deer mice are capable of transmitting SARS-CoV-2 to naïve deer mice through direct contact. The extent to which these observations may translate to wild deer mouse populations remains unclear, and the risk of reverse zoonosis and/or the potential for the establishment ofPeromyscusrodents as a North American reservoir for SARS-CoV-2 is unknown. Nevertheless, efforts to monitor wild, peri-domesticPeromyscusrodent populations are likely warranted as the SARS-CoV-2 pandemic progresses.
TSG Targeting KDM5A affects osteogenic differentiation of bone mesenchymal stem cells induced by bone morphogenetic protein 2
Authors: Wei Min , Jiang Yi , Huang Yuanqing
Published: July 2020

To investigate the effect of 2, 3, 5, 4’-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSC) and its molecular mechanism. The effects of TSG on alkaline phosphatase positive cloning and mineralized nodule formation were also detected. Total mRNA and protein were extracted and effects of TSG on the expression levels of osteopontin (OPN), osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), Osterix and Col1a1 were detected by real-time fluorescence quantitative PCR. Western Blotting was used to detect the inhibitory effect of TSG on KDM5A. BMSCs were transfected with Small interfering RNA (siRNA) targeting KDM5A (si-KMD5A) and pcDNA3.1 KMD5A. TSG significantly increased the activity of ALP and the number of alkaline phosphatase clones and calcified nodule formation. The OPN, OCN, Runx2 and Osterix expression levels were significantly increased among the osteoblasts after TSG treatment. The mechanism study showed that the effect of TSG is realized by inhibiting KDM5A. KDM5A signaling may be involved in the regulation of osteogenic differentiation of rBMSC. TSG can promote osteogenic differentiation and maturation of rBMSC at 0.1-50 μmol / L. The mechanism of action was realized by inhibiting the expression of KDM5A.
Survey on Sharīʿah non-compliant events in Islamic banks in the practice of tawarruq financing in Malaysia
Authors: Ali Mohammad Mahbubi , Hassan Rusni
Published: July 2020

Purpose

Tawarruq (Islamic commodity financing) has evolved as the most ubiquitous concept in Malaysia’s Islamic banking industry. Nevertheless, the extensive use of tawarruq has invoked a number of Sharīʿah (Islamic law) concerns in its practice. This study aims to investigate the Sharīʿah non-compliant (SNC) phenomena in the practice of tawarruq financing in Malaysia.

Design/methodology/approach

This study adopts qualitative research methodology, combining both descriptive and content analysis. A self-administered questionnaire was distributed to 16 Malaysian Islamic commercial banks to unveil the Sharīʿah non-compliance issues in the application of tawarruq in Islamic banks (IBs) in Malaysia.

Findings

The study found that some practices of tawarruq in Malaysia might not comply with the Sharīʿah, mainly due to the improper sequencing of contracts. The study also discovered that IBs adopt different approaches in dealing with SNC events and the income derived therefrom. Finally, the study noted the influence of board of director/management on certain Sharīʿah decisions particularly on the treatment of non-ḥalāl (impermissible) income.

Practical implications

The findings of the study serve as a reference to industry players and regulators in formulating a Sharīʿah non-compliance risk management framework for tawarruq practices.

Originality/value

The survey on SNC issues in tawarruq practice constitutes the first of its kind in the existing literature.
Promoting family inclusive practice in home treatment teams
Authors: Griffiths Maria , Allen Jo , Patel Krisna , Bell Victoria
Published: July 2020

Purpose

Families play an instrumental role in helping relatives experiencing mental health issues to stay well. In the context of wider initiatives promoting family and carer needs, this study aims to evaluate the feasibility, acceptability and potential benefits of bespoke training to develop clinicians’ skills in working with families in crisis.

Design/methodology/approach

The study was an uncontrolled evaluation of a one-day workshop for home treatment team staff using pre- and post-questionnaires.

Findings

In total, 83 staff members participated. Overall, there was a strong agreement for the involvement of families, which increased marginally after training. There were significant changes in views about talking to family members without service user consent (p = 0.001) and keeping them informed of their relative’s well-being (p = 0.02). Qualitative feedback indicated that participants enjoyed the interactive elements, particularly role-playing. Training provided an opportunity to practice skills, share knowledge and facilitate the integration of family work into their professional role.

Research limitations/implications

Confident support for families contributes to effective mediation of crisis and continuation of care; factors important in reducing admission rates and protecting interpersonal relationships. Overall, the consistency of responses obtained from participants suggests that this workshop offers a helpful introduction to a family approach at times of a mental health crisis.

Originality/value

This pilot evaluation suggests this new one-day workshop, is a feasible and acceptable training program, which is beneficial in developing clinicians’ skills in working with families in a crisis.
Detection of fraud in high‐quality rice by near‐infrared spectroscopy
Authors: Liu Yachao , Li Yongyu , Peng Yankun , Yang Yanming , Wang Qi
Published: July 2020

A key feature of food fraud is the use of a lower value ingredient to imitate an authentic product. This study was based on near‐infrared spectroscopy (NIRS) analysis technology, partial least squares discriminant analysis (PLS‐DA), and a support vector machine (SVM) to detect whether high‐quality rice was mixed with other varieties of rice. As an aid to qualitative discrimination, PLS was used to establish the quantitative analysis model to assist in the recognition of the degree of fraud. Due to the direct correlation between the results of NIRS analysis and the homogeneity of the samples, four groups of samples with different physical forms (full granules, 40 mesh, 70 mesh, and 100 mesh) were prepared, each group consisted of 20 pure samples and 140 mixed samples, and the mixing ratio was between 5% and 50%, with an interval of 5%. Regarding qualitative analysis, the performance of the model has no obvious relationship with the physical state of the sample, the qualitative model of PLS‐DA and SVM can detect the fraudulent rice with a 5% detection limit, respectively. Regarding quantitative analysis, the performance of the prediction model was closely related to the particle size of the samples: 100 mesh > 70 mesh > 40 mesh > full grains. The determination coefficient and root mean square errors of the optimal prediction result were 0.96 and 2.93, respectively. These results demonstrate that NIRS analysis technology is a reliable and fast tool to determine whether high‐quality rice contains other varieties of rice.

Practical Application

The work of this article is based on the current background of increasingly serious rice fraud, using near‐infrared spectroscopy to quickly identify fraudulent rice, to a certain extent, and effectively alleviate the rice fraud. This technology can serve for the supervision of food regulatory agencies on rice fraud, and can also be used in food factories to ensure the authenticity of raw materials of rice.
Osteomorphological features of the hind limb bones of Saiga antelope (Saiga tatarica)
Authors: Jing Libaihe , He Peng , Ding Dongfang , Qu Can , Shao Baoping , Ma Jizhong , Wang Jianlin
Published: July 2020

The intralimb indices and calcaneal linear metrics are known as the reliable predictors of locomotor adaptation in artiodactyls. The osteological features of hindlimb in adult Saiga (Saiga tatarica) were described, and its correlation with cursoriality and habitat adaptation was discussed. Gross anatomy data showed Saiga owned the deep acetabulum as a broad lunate surface, the large acetabular anteversion, the well‐developed ischiatic tuberosity and the prominent gluteal lines. It also presented the robust rough line and the strong gluteal

tuberosity. A proximodistally elongated eminence located on the cranially distal tibia, which had not been found in goat. The tibial extensor groove was deep. The calcaneal tuberosity was robust. Digital anatomy data showed Saiga owned the higher metatarsal‐femur ratio than forest musk deer and sheep. Comparing with wild bovids and sheep, Saiga presented a transitional variation in calcaneal form. The mean greatest length of the calcaneus (GLC) and the height of the sustentacular facet (HSF) in Saiga were shorter than that in sheep and longer than that in wild bovids respectively (F = 587.492; F = 10.264, p < .05). The wild bovids had longer cubonavicular facets than the other two groups (F = 18.587, p < .05). The great metatarsal–femur ratio of Saiga implied a superior cursorial ability and high conservation confronting the different habitats. The calcaneal linear metrics might shed light on lifestyle‐related functional adaptation over decades of short‐term evolution in the semi‐free range environment.
Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles
Authors: Thorén Linda , Lindh Jonatan D. , Ackehed Gerd , Kringen Marianne Kristiansen , Hall Per , Bergh Jonas , Molden Espen , Margolin Sara , Eliasson Erik
Published: July 2020

Aims

Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6‐dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects.

Methods

In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006–2014, with on‐going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real‐time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography–tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records.

Results

In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6–5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced‐function alleles, 2 null‐alleles, or a null/reduced‐function combination. CYP2D6*41 was the most common reduced‐function allele (82%) and 17 of 21 CYP2D6*41‐carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null‐alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate‐to‐severe side effects were reported in a concentration‐dependent manner.

Conclusion

Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null‐alleles, but also in carriers of 2 reduced‐function alleles. This finding may be highly relevant for future, genotype‐based dose considerations.
Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia
Authors: Corbingi Andrea , Innocenti Idanna , Tomasso Annamaria , Pasquale Raffaella , Visentin Andrea , Varettoni Marzia , Flospergher Elena , Autore Francesco , Morelli Francesca , Trentin Livio , Reda Gianluigi , Efremov Dimitar G. , Laurenti Luca
Published: July 2020

The relationship between chronic lymphocytic leukaemia (CLL) and qualitative/quantitative gammaglobulin abnormalities is well established. Nevertheless, in order to better understand this kind of connection, we examined 1505 patients with CLL and divided them into four subgroups on the basis of immunoglobulin (Ig) aberrations at diagnosis. A total of 73 (4·8%), 149 (10%), 200 (13·2%) and 1083 (72%) patients were identified with IgM monoclonal gammopathy (IgM/CLL), IgG monoclonal gammopathy (IgG/CLL), hypogammaglobulinaemia (hypo‐γ) and normal Ig levels (γ‐normal) respectively. IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12. Patients with any type of Ig abnormality had shorter treatment‐free survival (TFS) but no significant impact affecting overall survival (OS) compared to those with normal Ig levels.
Sequence stratigraphy of a Middle to Upper Ordovician foreland succession (Ottawa Embayment, central Canada): Evidence for tectonic control on sequence architecture along southern Laurentia
Authors: Oruche Nkechi E. , Dix George R.
Published: July 2020

The Middle to Upper Ordovician foreland succession of the Ottawa Embayment in central Canada is divided into nine transgressive‐regressive sequences that defines net deepening of a platform succession over ~15 m.y. from peritidal to outer ramp settings, then a return to peritidal conditions over ~3 m.y. related to basin filling by orogen‐derived siliciclastics. With a backdrop of net eustatic rise through the Middle to Late Ordovician, there are several different expressions of structural influence on sequence development in the embayment. During the Middle Ordovician (Darriwilian), foreland‐basin initiation was marked by regional onlap with abundant synsedimentary deformation across a faulted trailing‐margin platform interior; subsequent craton‐interior uplift resulted in voluminous influx of siliciclastics contemporary with local structurally influenced local channelization; then, a formation of a platform‐interior shale basin defines continued intrabasin tectonism. During the Late Ordovician (Sandbian, early Katian), structural influence was superimposed on sea‐level rise as indicated by renewed local development of a platform‐interior shale basin; differential subsidence and thickness variation of platform carbonate successions; abrupt deepening across shallow‐water shoal facies; and, micrograben development coincident with foreland‐platform drowning. These stratigraphic patterns are far‐field expressions of distal orogen development amplified in the platform interior through basement reactivation along an inherited buried Precambrian fault system. Comparison of Upper Ordovician (Sandbian‐lower Katian) sequence stratigraphy in the Ottawa Embayment with eustatic frameworks defined for the Appalachian Basin reveals greater regional variation associated with Sandbian sequences compared to regional commonality in base level through the early Katian.
Gender Discrimination, Perceived School Unfairness, Depressive Symptoms, and Sleep Duration Among Middle School Girls
Authors: N. Bell Ariana , Juvonen Jaana
Published: July 2020

The current study examines how gender discrimination by adults in school is linked with depressive symptoms and sleep duration over time in middle school. The main goal is to test one psychological mechanism that can account for such associations: perceived school unfairness. Relying on a racially‐ethnically diverse sample of girls (N = 2,718, Mage = 13.01, SDage = 0.39) from 26 middle schools, multilevel mediation analyses revealed that girls who experienced school‐based gender discrimination by an adult in seventh grade reported higher levels of perceived school unfairness in eighth grade. Moreover, perceived unfairness, in turn, was associated with more depressive symptoms and shorter sleep durations by eighth grade. Implications of changes in adolescent girls’ sleep and mood related to their experiences of gender discrimination are discussed.
Interactive Subsurface Scattering for Materials With High Scattering Distances
Authors: Maisch Sebastian , Ropinski Timo
Published: July 2020

Existing algorithms for rendering subsurface scattering in real time cannot deal well with scattering over longer distances. Kernels for image space algorithms become very large in these circumstances and separation does not work anymore, while geometry‐based algorithms cannot preserve details very well. We present a novel approach that deals with all these downsides. While for lower scattering distances, the advantages of geometry‐based methods are small, this is not the case anymore for high scattering distances (as we will show). Our proposed method takes advantage of the highly detailed results of image space algorithms and combines it with a geometry‐based method to add the essential scattering from sources not included in image space. Our algorithm does not require pre‐computation based on the scene's geometry, it can be applied to static and animated objects directly. Our method is able to provide results that come close to ray‐traced images which we will show in direct comparisons with images generated by PBRT. We will compare our results to state of the art techniques that are applicable in these scenarios and will show that we provide superior image quality while maintaining interactive rendering times.