bluuebunny/crossref_metadata_2025 huggingface dataset:
Surface-associated antigen induces B-cell permeabilization and lysosome exocytosis facilitating antigen uptake and presentation to T-cells
Authors: Maeda Fernando Y. , van Haaren Jurriaan J. H. , Langley David B. , Christ Daniel , Andrews Norma W. , Song Wenxia
Published: July 2020

B-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown. Here we show that BCR-mediated recognition of antigen tethered to beads, to planar lipid-bilayers or expressed on cell surfaces causes localized plasma membrane (PM) permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers PM repair responses involving lysosomal exocytosis, and B-cells permeabilized by surface-associated antigen internalize more antigen than cells that remain intact. Higher affinity antigens cause more B-cell permeabilization and lysosomal exocytosis and are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, providing the extracellular hydrolases that facilitate antigen internalization and presentation.
Mtg16-dependent repression of E protein activity is required for early lymphopoiesis
Authors: Acharya Pankaj , Sampathi Shilpa , Flaherty David K. , Matlock Brittany K. , Williams Christopher S. , Hiebert Scott W. , Stengel Kristy R.
Published: July 2020

The ETO/MTG family of transcriptional co-repressors play a key role in adult stem cell functions in various tissues. These factors are commonly found in complex with E proteins such as E2A, HEB, and Lyl1 as well as PRDM14 and BTB/POZ domain factors. Structural studies identified a region in the first domain of MTGs that is conserved in theDrosophilahomologue Nervy (Nervy Homology Domain-1, or NHR1) that is essential for ETO/MTG8 to inhibit E protein-dependent transcription. The Cancer Genome Atlas (TCGA) identified cancer associated single nucleotide variants (SNVs) near the MTG16:E protein contact site. We tested these SNVs using sensitive yeast two-hybrid association assays, which suggested that only P209T significantly affected E protein binding. We then used CRISPR-Cas9 and homology directed DNA repair to insert P209T and a known inactivating mutation, F210A, into NHR1 ofMtg16in the germ line of mice. These mice developed normally, but in competitive bone marrow transplantation assays, the F210A-containing stem cells failed to contribute to lymphopoiesis, while P209T mutant cells were reduced in mature T cell populations. High content fluorescent activated analytical flow cytometry assays identified a defect in the multi-potent progenitor to common lymphoid progenitor transition during lymphopoiesis. These data indicate that the cancer associated changes are likely benign polymorphisms, and the MTG:E protein association is required for lymphopoiesis, but less important for myelopoiesis and stem cell functions.
Prokaryotic rRNA-mRNA interactions are involved in all translation steps and shape bacterial transcripts
Authors: Elitzur Shir Bahiri , Cohen-Kupiec Rachel , Yacobi Dana , Fine Larissa , Apt Boaz , Diament Alon , Tuller Tamir
Published: July 2020

The well-established Shine-Dalgarno model suggests that translation initiation in bacteria is regulated via base-pairing between ribosomal RNA (rRNA) and mRNA. However, little is currently known about the contribution of such interactions to the rest of the translation process and to the way bacterial transcript evolve. We used novel computational analyses and modelling of 823 bacterial genomes coupled with experiments to demonstrate that rRNA-mRNA interactions are diverse and regulate not only initiation, but all translation steps from pre-initiation to termination across the many bacterial phyla that have the Shine-Dalgarno sequence. As these interactions dictate translation efficiency, they serve as a driving evolutionary force for shaping transcripts in bacteria. We observed selection for strong rRNA-mRNA interactions in regions where such interactions are likely to enhance initiation, regulate early elongation and ensure the fidelity of translation termination. We discovered selection against strong interactions and for intermediate interactions in coding regions and present evidence that these interactions maximize elongation efficiency while also enhancing initiation by ‘guiding’ free ribosomal units to the start codon.

Importance

Previous research has reported the significant influence of rRNA-mRNA interactions mainly in the initiation phase of translation. The results reported in this paper suggest that, in addition to the rRNA-mRNA interactions near the start codon that trigger initiation in bacteria, rRNA-mRNA interactions affect all sub-stages of the translation process (pre-initiation, initiation, elongation, termination). In addition, these interactions affect the way evolutionary forces shape the bacterial transcripts while considering trade-offs between the effects of different interactions across different transcript regions on translation efficacy and efficiency. Due to the centrality of the translation process, these findings are relevant to all biomedical disciplines.
Screening of Botanical Drugs Against Lassa Virus Entry
Authors: Liu Yang , Guo Jiao , Cao Junyuan , Zhang Guangshun , Jia Xiaoying , Wang Peilin , Xiao Gengfu , Wang Wei
Published: July 2020

Lassa virus (LASV) belongs to the Old WorldMammarenavirusgenus (familyArenaviridae) and is classified as a category A biological threat agent. At present, there are no approved drugs or vaccines specific for LASV. In this study, high-throughput screening of a botanical drug library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein (GPC). Two hit compounds, bergamottin and casticin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that casticin inhibited LASV entry by blocking low pH-induced membrane fusion. Adaptive mutant analyses demonstrated that the F446L mutation, located in the transmembrane domain of GP2, conferred resistance to casticin. Furthermore, casticin extended its antiviral spectrum to the New World (NW) pathogenic mammarenaviruses, and mutation of the conserved F446 conferred NW resistance to casticin. Unlike casticin, bergamottin has little effect on LASV GPC-mediated membrane fusion, while it inhibited LASV entry by blocking endocytic trafficking. Our study shows that both bergamottin and casticin are candidates for LASV therapy, indicating that the conserved F446 plays important roles in drug resistance in mammarenaviruses.

IMPORTANCE

Currently, there is no approved therapy to treat Lassa fever (LASF); we aimed to find candidates for LASF therapy. Herein, we screened a botanical drug library and identified two compounds, bergamottin and casticin, that inhibited LASV entry via different mechanisms.
β-Coronaviruses use lysosomal organelles for cellular egress
Authors: Ghosh S , Dellibovi-Ragheb TA , Pak E , Qiu Q , Fisher M , Takvorian PM , Bleck C , Hsu V , Fehr AR , Perlman S , Achar SR , Straus MR , Whittaker GR , de Haan CAM , Altan-Bonnet G , Altan-Bonnet N
Published: July 2020

β-Coronaviruses are a family of positive-strand enveloped RNA viruses that include the severe acute respiratory syndrome-CoV2 (SARS-CoV2). While much is known regarding their cellular entry and replication pathways, their mode of egress remains uncertain; however, this is assumed to be via the biosynthetic secretory pathway by analogy to other enveloped viruses. Using imaging methodologies in combination with virus-specific reporters, we demonstrate that β-Coronaviruses utilize lysosomal trafficking for egress from cells. This pathway is regulated by the Arf-like small GTPase Arl8b; thus, virus egress is insensitive to inhibitors of the biosynthetic secretory pathway. Coronavirus infection results in lysosome deacidification, inactivation of lysosomal degradation and disruption of antigen presentation pathways. This coronavirus-induced exploitation of lysosomes provides insights into the cellular and immunological abnormalities observed in patients and suggests new therapeutic modalities.
High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2
Authors: Vanhove Bernard , Duvaux Odile , Rousse Juliette , Royer Pierre-Joseph , Evanno Gwénaëlle , Ciron Carine , Lheriteau Elsa , Vacher Laurent , Gervois Nadine , Oger Romain , Jacques Yannick , Conchon Sophie , Salama Apolline , Duchi Roberto , Lagutina Irina , Perota Andrea , Delahaut Philippe , Ledure Matthieu , Paulus Melody , So Ray T. , Mok Chris Ka-Pun , Bruzzone Roberto , Bouillet Marc , Brouard Sophie , Cozzi Emanuele , Galli Cesare , Blanchard Dominique , Bach Jean-Marie , Soulillou Jean-Paul
Published: July 2020

Perfusion of convalescent plasma (CP) has demonstrated a potential to improve the pneumonia induced by SARS-CoV-2, but procurement and standardization of CP are barriers to its wide usage. Many monoclonal antibodies (mAbs) have been developed but appear insufficient to neutralize SARS-CoV-2 unless two or three of them are being combined. Therefore, heterologous polyclonal antibodies of animal origin, that have been used for decades to fight against infectious agents might represent a highly efficient alternative to the use of CP or mAbs in COVID-19 by targeting multiple antigen epitopes. However, conventional heterologous polyclonal antibodies trigger human natural xenogeneic antibody responses particularly directed against animal-type carbohydrate epitopes, mainly the N-glycolyl form of the neuraminic acid (Neu5Gc) and the Gal α1,3-galactose (αGal), ultimately forming immune complexes and potentially leading to serum sickness or allergy. To circumvent these drawbacks, we engineered animals lacking the genes coding for the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) and α1,3-galactosyl-transferase (GGTA1) enzymes to produce glyco-humanized polyclonal antibodies (GH-pAb) lacking Neu5Gc and α-Gal epitopes. We found that pig IgG Fc domains fail to interact with human Fc receptors and thereby should confer the safety advantage to avoiding macrophage dependent exacerbated inflammatory responses, a drawback possibly associated with antibody responses against SARS-CoV-2 or to avoiding a possible antibody-dependent enhancement (ADE). Therefore, we immunized CMAH/GGTA1 double knockout (DKO) pigs with the SARS-CoV-2 spike receptor-binding domain (RBD) to elicit neutralizing antibodies. Animals rapidly developed a hyperimmune response with anti-SARS-CoV-2 end-titers binding dilutions over one to a million and end-titers neutralizing dilutions of 1:10,000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV-19, neutralized Spike/angiotensin converting enzyme-2 (ACE-2) interaction at a concentration < 1μg/mL and inhibited infection of human cells by SARS-CoV-2 in cytopathic assays. These data and the accumulating safety advantages of using glyco-humanized swine antibodies in humans warranted clinical assessment of XAV-19 to fight against COVID-19.
AKT-likekinase promotes cell survival during nutritional stress in trypanosomatids
Authors: Mejía Andrés Felipe Díez , Pedroza María Magdalena , Orrego Lina M. , Muñoz Sergio Andrés Pulido , Echeverry María Clara , Rojas Mauricio , Soares Maurilio José , Pérez-Victoria José María , Muskus Carlos Enrique , Robledo Sara María , Marín-Villa Marcel , Varela-Miranda Rubén E.
Published: July 2020

Tritryps are protozoan parasites that belong to the Trypanosomatidae family, which encompasses the etiologic agents of leishmaniasis, African and American trypanosomiasis. These parasites undergo different stress conditions across their life cycle, such as nutritional stress, which needs to be deadened in order to guarantee the survival of the parasite inside its vector and mammal hosts. Here we show that the lack of the serine threonine kinase PKB / AKT-likefunction, either by allosteric inhibition of its Plekstrin domain (PH) inT. cruzi, the reduction of the gene transcripts inT. bruceiby RNAi assays, or by AKT-like gene knockout inL. major, reduce the tolerance to nutritional stress of parasites that triggers apoptosis-like events, including DNA fragmentation, mitochondrial damage and loss of plasma membrane integrity. Additionally, we observed that double knockout of Akt-likeinL. majorimpairs its infective capacity. This work confirms some of the previously described functions regarding parasite survival for AKT-like kinases in theLeishmaniagenus. The present work also provides strong evidence of the probable function of Akt-likeinT. cruzi andT. bruceisurvival and infectivity.

Author summary

Endemic countries for neglected tropical diseases are called to play a paramount role in the discovery of new drug candidates through the application of new drug development strategies. Rational drug design method have proven to be compatible with the development of new drug for orphan and neglected diseases since it substantially reduces the costs of discovery and development, a desirable condition for public funded initiatives. Previously we have identified a new parasite protein kinase (AKT-like) as promising new target candidate by means of computational tools and probed its biological role in trypanosomatids. Here we show that inhibition of the AKT-likekinase in trypanosomatids by different approaches (chemical inhibition, interference RNA and gene knockout) decreases the fitness and survival of the parasitesin vitro, interfering with the capacity of the parasites to react and survive stress conditions similar to those experienced by the cell in the natural life cycle. Additionally our results strongly supports the potential of a new family of compounds previously described by bioinformatics means as potential trypanocidal agents. Altogether we show that the specific inhibition of the AKT-like is a promising strategy for the further development of anti-trypanosome drugs.
VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells
Authors: Temerozo Jairo R. , Sacramento Carolina Q. , Fintelman-Rodrigues Natalia , Pão Camila R. R. , de Freitas Caroline S. , Dias Suelen Silva Gomes , Ferreira André C. , Mattos Mayara , Soares Vinicius Cardoso , Teixeira Lívia , Azevedo-Quintanilha Isaclaudia G. , Hottz Eugenio D. , Kurtz Pedro , Bozza Fernando A. , Bozza Patrícia T. , Souza Thiago Moreno L. , Bou-Habib Dumith Chequer
Published: July 2020

Infection by SARS-CoV-2 may elicit uncontrolled and damaging inflammatory responses. Thus, it is critical to identify compounds able to inhibit virus replication and thwart the inflammatory reaction. Here, we show that the plasma levels of the immunoregulatory neuropeptide VIP are elevated in patients with severe COVID-19, correlating with reduced inflammatory mediators and with survival on those patients. In vitro, VIP and PACAP, highly similar neuropeptides, decreased the SARS-CoV-2 genome replication in human monocytes and viral production in lung epithelial cells, also reducing cell death. Both neuropeptides inhibited the production of proinflammatory mediators in lung epithelial cells and in monocytes. VIP and PACAP prevented in monocytes the SARS-CoV-2-induced activation of NF-kB and SREBP1 and SREBP2, transcriptions factors involved in proinflammatory reactions and lipid metabolism, respectively. They also promoted CREB activation, a transcription factor with antiapoptotic activity and negative regulator of NF-kB. Specific inhibition of NF-kB and SREBP1/2 reproduced the anti-inflammatory, antiviral and cell death protection effects of VIP and PACAP. Our results support further clinical investigations of these neuropeptides against COVID-19.
The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer
Authors: Morgan Ethan L. , Patterson Molly R. , Barba-Moreno Diego , Wilson Adam , Macdonald Andrew
Published: July 2020

Ubiquitination is a critical regulator of cellular homeostasis. Aberrations in the addition or removal of ubiquitin can result in the development of cancer and key components of the ubiquitination machinery serve as oncogenes or tumour suppressors. An emerging target in the development of cancer therapeutics are the deubiquitinase (DUB) enzymes that remove ubiquitin from protein substrates. Whether this class of enzyme plays a role in cervical cancer has not been fully explored. By interrogating the cervical cancer data from the TCGA consortium, we noted that the DUB USP13 is amplified in approximately 15% of cervical cancer cases. We confirmed that USP13 expression was increased in cervical cancer cell lines, cytology samples from patients with cervical disease and in cervical cancer tissue. Depletion of USP13 inhibited cervical cancer cell proliferation. Mechanistically, USP13 bound to, deubiquitinated and stabilised Mcl-1, a pivotal member of the anti-apoptotic Bcl-2 family and the reduced Mcl-1 expression contributed to the observed proliferative defect. Importantly, the expression of USP13 and Mcl-1 proteins correlated in cervical cancer tissue. Finally, we demonstrated that depletion of USP13 expression or inhibition of USP13 enzymatic activity increased the sensitivity of cervical cancer cells to the BH3 mimetic inhibitor ABT-263. Together, our data demonstrates that USP13 is a potential oncogene in cervical cancer that functions to stabilise the pro-survival protein Mcl-1, offering a potential therapeutic target for these cancers.
Estimating maximal microbial growth rates from cultures, metagenomes, and single cells via codon usage patterns
Authors: Weissman Jake L. , Hou Shengwei , Fuhrman Jed A.
Published: July 2020

Maximal growth rate is a basic parameter of microbial lifestyle that varies over several orders of magnitude, with doubling times ranging from a matter of minutes to multiple days. Growth rates are typically measured using laboratory culture experiments. Yet, we lack sufficient understanding of the physiology of most microbes to design appropriate culture conditions for them, severely limiting our ability to assess the global diversity of microbial growth rates. Genomic estimators of maximal growth rate provide a practical solution to survey the distribution of microbial growth potential, regardless of cultivation status. We developed an improved maximal growth rate estimator, and implement this estimator in an easy-to-use R package (gRodon), which outperforms the state-of-the-art growth estimator in multiple settings, including in a community context where we implement a novel species abundance correction for metagenomes. Additionally, we estimate maximal growth rates from over 200,000 genomes, metagenome-assembled genomes, and single-cell amplified genomes to survey growth potential across the range of prokaryotic diversity. We provide these compiled maximal growth rates in a publicly-available database (EGGO), which we use to illustrate how culture collections show a strong bias towards organisms capable of rapid growth. We demonstrate how this database can be used to propagate maximal growth rate predictions to organisms for which we lack genomic information, on the basis of 16S rRNA sequence alone. Finally, we observe a bias in growth predictions for extremely slow-growing organisms, ultimately leading us to suggest a novel evolutionary definition of oligotrophy based on the selective regime an organism occupies.

Significance

Despite the wide perception that microbes have rapid growth rates, many environments like seawater and soil are often dominated by microorganisms that can only grow very slowly. Our knowledge about growth is necessarily biased towards easily culturable organisms, which turn out to be those that tend to grow fast, because microbial growth rates have traditionally been measured using lab growth experiments. But how are potential growth rates distributed in nature? We developed a tool to predict maximum growth rate from an organism’s genome sequence (gRodon). We predicted the growth rates of over 200,000 organisms and compiled these predictions in a publicly-available database (EGGO), which illustrates how current collections of cultured microbes are strongly biased towards fast-growing organisms.
Insights into the value of seasonal climate forecasts to agriculture
Authors: Darbyshire Rebecca , Crean Jason , Cashen Michael , Anwar Muhuddin Rajin , Broadfoot Kim M , Simpson Marja , Cobon David H , Pudmenzky Christa , Kouadio Louis , Kodur Shreevatsa
Published: July 2020

Seasonal climate forecasts (forecasts) aim to reduce climate‐related productivity risk by helping farmers make decisions that minimise losses in poor years and maximise profits in good years. Most Australian forecast valuations have focused on fertiliser decisions to wheat operations, and few assessments have evaluated the benefit of incremental improvements of forecast skill. These gaps have limited our understanding of forecast value to the broader agriculture sector and the benefit of investments to improve forecast skill. To address these gaps, we consistently assessed forecast value for seven Australian case studies (southern grains, northern grains, southern beef, northern beef, lamb, cotton, and sugar). We implemented a three‐stage methodology which consisted of engagement with industry practitioners; modelling production under different climatic and environmental conditions; and economic modelling to evaluate forecast value for eleven levels of forecast skill. Our results show that forecast value was often low and highly variable. Value was found to vary based on forecast attributes (forecast skill, resolution and state), industry application and prevailing conditions (environmental and market). This is the first Australian valuation study where the same methodological approach was applied across multiple industries, incremental improvements in skill were valued, and prevailing conditions were explicitly evaluated for impact on value.
‘Walking in two worlds’: A qualitative review of income management in Cape York
Authors: Scott John , Staines Zoe , Higginson Angela , Lauchs Mark , Ryan Vanessa , Zhen Liuissa
Published: July 2020

The Cape York Welfare Reform (CYWR) initiative aims to reduce ‘passive dependence’ on welfare and restore ‘positive social norms’ to revitalise cultural and social networks and support economic engagement in Indigenous communities in the Cape York Region of Australia. Critics of the initiative and, in particular, its income management (IM) policies have associated it with a broader neoliberal reform agenda that delineates social ‘problems’ from their historical and structural context. This paper discusses key qualitative findings from a strategic review of CYWR, paying particular attention to the ways in which Cape York IM (CYIM) straddles both Indigenous and settler social norms, while perpetuating neoliberal conceptualisations of welfare ‘dependency’. We situate these findings within the existing literature on Australia's other IM models and also consider them in relation to subsequent government responses to the review and associated policies. We argue that CYIM represents a unique initiative, the subtle nuances of which have been largely ignored or misunderstood by critics. Further, we conclude that any extension or revision of this initiative should be considered with respect to deep and wide‐ranging consultation of the Indigenous communities subject to CYWR. However, such consultation has not been the standard practice in Australian contexts.
Royal commissions and policy influence
Authors: Mintrom Michael , O'Neill Deirdre , O'Connor Ruby
Published: July 2020

Royal commissions are established at the Commonwealth and state levels in Australia to investigate matters of significant public concern. These distinctive entities are highly respected both by government and the community. They are typically expected to produce reports that will have significant impact. Although a large number are created primarily to determine why specific events happened and where accountabilities lie, many are expected to generate findings and recommendations that will lead to policy change. We review common strategies that actors in and around government deploy with the purpose of shaping public policy. This leads to an exploration of the influence strategies deployed by three Australian royal commissions that achieved high levels of policy impact. Lessons are drawn for how future royal commissions might create policy legacies that deliver high public value.
Liver damage at admission is an independent prognostic factor for COVID‐19
Authors: Chen Liu Ying , Chu Hui Kuan , Bai Tao , Tu Sheng Jin , Wei Yuan , Li Zhong Lin , Hu Li Lin , Zhu Rui , Zhang Lei , Han Chao Qun , Xiao Li , He Qi , Song Jun , Liu Wei Hua , Zhu Qing Jing , Chen Hua , Yang Ling , Hou Xiao Hua
Published: July 2020

Objective

Abnormal liver function is a common form of extra‐pulmonary organ damage in patients with coronavirus disease 2019 (COVID‐19). Patients with severe COVID‐19 have a higher probability and progression of liver injury than those without severe disease. We aimed to evaluate the prognosis of liver injury in patients with COVID‐19.

Methods

We retrospectively included 502 patients with laboratory‐confirmed SARS‐CoV‐2 infection. Clinical features and survival of patients with and without liver injury were compared. Cox proportional hazards models were used to determine the variables that might have an effect on survival.

Results

Among the 502 patients enrolled, 301 patients had abnormal liver function with increased neutrophil count, C‐reactive protein, creatinine, troponin I (TnI), D‐dimer, lactose dehydrogenase and creatine kinase. Patients with abnormal liver functions had a higher mortality rate (28.9% vs 9.0%, P < 0.001), a higher ratio of male sex (65.1% vs 40.8%, P < 0.001) and a higher chance of developing systemic inflammatory response syndrome (53.5% vs 41.3%, P = 0.007). Among patients with abnormal liver functions, patients with grade 2 liver damage (with both abnormal alanine aminotransferase or aspartate aminotransferase levels and abnormal alkaline phosphatase or gamma‐glutamyl transpeptidase levels) had a higher ratio of male patients, elevated neutrophil count, procalcitonin, D‐dimer levels and mortality rate. Multivariate Cox regression analyses suggested that the grade of liver damage (hazard ratio: 1.377, 95% confidence interval: 1.000‐1.896, P = 0.049) was an independent predictor of death.

Conclusions

Patients with COVID‐19 and abnormal liver functions have a higher mortality than those with normal liver functions. Liver damage is an independent prognostic factor of COVID‐19.
A Proposal for a New Universal Development Commitment
Authors: Sumner Andy , Gulrajani Nilima , Wickstead Myles , Glennie Jonathan
Published: July 2020

Most developed countries have accepted, in principle at least, the 50‐year‐old commitment of contributing 0.7 per cent of gross national income to supporting the development of developing countries. But what if all countries made a universal development commitment, meaning a scaled contribution? We propose a new universal and scaled financial commitment to development, informed by but not necessarily identical to official development assistance. This paper: (1) sets out how a new era is emerging of higher global ambitions – for example, to end poverty; (2) proposes a new way to raise and govern international public funds; and (3) discusses the possible size and use of contributions, and the evolution in global governance and democracy that a new deal would entail. We conclude with a set of questions that the proposal raises.
Association Between Methamphetamine Use and Psychiatric Hospitalization, Chemical Restraint, and Emergency Department Length of Stay
Authors: Murphy Charles E. , Wang Ralph C. , Coralic Zlatan , Lai Andrew R. , Raven Maria
Published: July 2020

Objectives

Methamphetamine intoxication is an increasing cause of emergency department (ED) visits in the United States, particularly in the west. In San Francisco, California, 47% of patients visiting psychiatric emergency services are intoxicated with methamphetamine. Such patients often visit the ED due to acute psychiatric symptoms, yet ED‐based research investigating the outcomes and resource utilization of these visits is limited.

Methods

We examined a retrospective cohort of ED patients requiring ED‐based psychiatric consultation from June 2017 to July 2018. We evaluated the association between methamphetamine visits and need for chemical restraint, psychiatric hospitalization, and length of stay (LOS).

Results

We identified 2,087 ED visits with psychiatric consults. Based on urine toxicology results and discharge diagnosis, 403 visits involved methamphetamine with or without other drugs, 480 involved other drugs without methamphetamine, and 1,204 had no evidence of drug use. Methamphetamine visits were associated with increased odds of chemical restraint compared to visits without drug use (adjusted odds ratio [AOR] = 3.2, 95% CI = 2.1 to 5.2, p < 0.001), but not other drug visits (AOR = 1.2, 95% CI = 0.8 to 1.9, p = 0.4). Methamphetamine visits had lower odds of psychiatric hospitalization than other drug visits (AOR = 0.62, 95% CI = 0.41 to 0.95, p = 0.03) and longer adjusted LOS than visits without drug use (+4.3 hours, 95% CI = 4.1 to 8.3 hours, p < 0.001) but not other drug visits (+1.5 hours, 95% CI = −0.6 to 3.7 hours, p = 0.2).

Conclusions

Methamphetamine ED visits were associated with increased odds of needing chemical restraint and of an increased ED LOS but not with psychiatric inpatient admission. These results indicate an opportunity to improve the efficiency of ED care for these patients.
The temporal association between incident late‐life depression and incident dementia
Authors: Heser K. , Fink A. , Reinke C. , Wagner M. , Doblhammer G.
Published: July 2020

Objective

There is an established association between depression and subsequent dementia. The present study examined temporal associations between incident late‐life depression and subsequent dementia, also considering age and sex.

Methods

We used longitudinal health claims data from the largest German health insurance provider (‘Allgemeine Ortskrankenkasse’) considering up to 9 follow‐up years in piecewise exponential models. ICD‐10 codes were used to define incident depression and dementia in individuals ≥65 years (n = 97 110).

Results

Incident depression was associated with a higher risk of subsequent dementia (incidence rate ratios (IRR) adjusted for age and sex: IRR = 1.58, 95% CI = 1.51–1.64). The strongest association was found for the shortest interval of 1 quarter (IRR = 2.04, 95% CI = 1.88–2.21), with significant associations up to an interval of roughly 3 years. The association was more pronounced and lasted for more quarters in the younger portion of this study group (ages from 65–74: IRR = 2.00, 95% CI = 1.83–2.18; 75–84: IRR = 1.64, 95% CI = 1.55–1.73; ≥85: IRR = 1.19, 95% CI = 1.08–1.31). It was stronger among men than women (men: IRR = 1.98, 95% CI = 1.84–2.14; women: IRR = 1.44, 95% CI = 1.37–1.51) with no sex‐specific temporal association.

Conclusion

This large claims data study confirmed that incident late‐life depression is associated with a higher risk of dementia within the 3 years following diagnosis. Hence, incident late‐life depression should prompt further cognitive examinations and referrals to specialists. This might apply especially to younger seniors and men.
Morphology of the tongue and laryngeal entrance in the Common pheasant (Phasianus colchicus); a light and scanning electron microscopic study
Authors: Mohammad Payam Elyasi Seyed , Goodarzi Nader
Published: July 2020

The present work was carried out to describe morphological features of the tongue and laryngeal entrance of the Common pheasantPhasianus colchicus, using light and scanning electron microscopy. The lingual apex was taper‐shaped with a shallow median sulcus. A V‐shaped papillary crest with 15–20 caudally directed conical papillae was located between the radix and corpus linguae. The second row of papillae consisting of three caudolaterally directed conical papillae was arranged caudal to the main papillary crest. The mons laryngealis was equipped caudally with a double‐layer of large conical papillae as pharyngeal crest, and few small conical papillae were seen around the glottis. Scanning electron microscope (SEM) observation showed that the apex linguae and corpus were covered with compact filiform papillae, while the radix linguae were free of papillae. Numerous openings of salivary gland can be seen on the radix linguae and mons laryngealis at higher magnification. On histological sections, all parts of the tongue and mons laryngealis were covered with a keratinised stratified squamous epithelium. The keratinised layer became thinner rostro‐caudally. The simple alveolar salivary glands were distributed in the submucosa from the apex linguae to the radix linguae as well as the mons laryngealis. PAS staining revealed mucin‐secreting activity of this glands. According to the findings, although the tongue and laryngeal entrance of the Common pheasant is characteristics of a galliform bird, it has some features similar to passeriformes and falconiformes.
Circulating microRNA‐15b‐5p as a biomarker for asthma‐COPD overlap
Authors: Hirai Keita , Shirai Toshihiro , Shimoshikiryo Takayuki , Ueda Megumi , Gon Yasuhiro , Maruoka Shuichiro , Itoh Kunihiko
Published: July 2020

Background

It remains unclear how to characterize different subtypes of asthma and chronic obstructive pulmonary disease (COPD). We previously described serum periostin and chitinase‐3‐like protein 1 (YKL‐40) as useful markers for asthma‐COPD overlap (ACO). MicroRNAs (miRNAs) are now recognized as markers for identifying the pathophysiological features in several diseases. This study aimed to identify circulating miRNAs that could discriminate patients with ACO from patients with asthma or COPD.

Methods

This study included two independent cohorts. First, we screened 84 miRNAs for expression levels in patients with ACO (n = 6) or asthma (n = 6) using a quantitative real‐time PCR array. The miRNAs showing at least a 2‐fold difference in the discovery phase were analyzed in 30 patients each with asthma, COPD, or ACO in the replication phase. The diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC).

Results

Nine miRNAs were identified in the discovery phase. Five of these miRNAs (miR‐148a‐3p, miR‐15b‐5p, miR‐223‐3p, miR‐23a‐3p, and miR‐26b‐5p) had lower levels in ACO patients and could discriminate between ACO patients and patients with either asthma or COPD. miR‐15b‐5p was the most accurate miRNA for the discrimination of patients with ACO (AUROC, 0.71). Moreover, the combined assessment of miR‐15b‐5p, serum periostin, and YKL‐40 (AUROC, 0.80) improved diagnostic accuracy for ACO compared with the combined model of periostin and YKL‐40 (AUROC, 0.69).

Conclusions

Circulating miR‐15b‐5p is a potential marker for identifying patients with ACO. By elucidating the molecular pathways controlled by miRNAs, we may better understand the pathophysiology of ACO.
Trust and well‐being: Evidence from Indonesia
Authors: Nizeyumukiza Emmanuel , Cilik Pierewan Adi , Ndayambaje Edmond , Ayriza Yulia
Published: July 2020

There is a growing empirical scholarship on the benefits of trust for well‐being in the literature. However, few studies have been conducted in the Indonesian context. This study is intended at investigating the association between different measures of trust and well‐being in Indonesia using national representative data from the 5th wave of the Indonesian Family Life Survey on a sample of 27,150 individuals. Multiple regression was performed to calculate the estimates of this relationship. The main findings revealed a small positive relationship of trust in neighbors with life satisfaction and a small positive relationship of trust in police with life satisfaction and happiness beyond the contribution of gender, age, level of education, marital status, personality trait, economic status, and physical and mental health. This study suggests that policies that can forge trustworthiness of neighborhoods and institutions should be developed and prioritized.
Long‐term trends in the distribution, abundance and impact of native “injurious” weeds
Authors: Maskell Lindsay C. , Henrys Peter , Pescott Oliver L. , Smart Simon M.
Published: July 2020

Questions

How can we quantify changes in the distribution and abundance of injurious weed species (Senecio jacobaea,Cirsium vulgare,Cirsium arvense,Rumex obtusifolius,Rumex crispus and Urtica dioica), over long time periods at wide geographical scales? What impact do these species have on plant communities? To what extent are changes driven by anthropogenically induced drivers such as disturbance, eutrophication and management?

Location

Great Britain.

Methods

Data from national surveys were used to assess changes in the frequency and abundance of selected weed species between 1978 and 2007. This involved novel method development to create indices of change, and to relate changes in distribution and abundance of these species to plant community diversity and inferred changes in resource availability, disturbance and management.

Results

Three of the six weed species became more widespread in GB over this period and all of them increased in abundance (in grasslands, arable habitats, roadsides and streamsides). Patterns were complex and varied by landscape context and habitat type. For most of the species, there were negative relationships between abundance, total plant species richness, grassland, wetland and woodland indicators. Each individual species responds to a different combination of anthropogenic drivers but disturbance, fertility and livestock management significantly influenced most species.

Conclusions

The increase in frequency and abundance of weeds over decades has implications for landscape‐scale plant diversity, fodder yield and livestock health. This includes reductions in plant species richness, loss of valuable habitat specialists and homogenisation of vegetation communities. Increasing land‐use intensity, excessive nutrient input, overgrazing, sward damage, poaching and bare ground in fields and undermanagement or too frequent cutting on linear features may have led to increases in weeds. These weeds do have conservation value so we are not advocating eradication, rather co‐existence, without dominance. Land management policy needs to adapt to benefit biodiversity and agricultural productivity.
Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide
Authors: Pecker Lydia H. , Hussain Sarah , Christianson Mindy S. , Lanzkron Sophie
Published: July 2020

The application of modern ovarian reserve measures to women with sickle cell disease (SCD) may help answer longstanding questions about whether SCD or hydroxycarbamide (HC; also known as hydroxyurea) affect women’s reproductive lifespan. Anti‐Müllerian hormone (AMH), an established marker of ovarian reserve, is used to assess the ovarian follicle pool. We used a standard clinical assay to measure AMH in 285 banked samples from 93 female subjects with haemoglobin SS from the historic Multicenter Study of Hydroxyurea (MSH), which led to the United States Food and Drug Administration approval of HC for adults with SCD. No samples from the randomised portion of the MSH remain, so samples from the decade‐long MSH follow‐up studies were analysed. Most subjects were exposed to HC (86/93). The median AMH levels were lower in study subjects than in age‐ and sex‐matched reference values. The median AMH levels consistent with diminished ovarian reserve, a risk factor for infertility, occurred in subjects starting at the age of 25–30 years; in healthy women, this occurs after the age of 40 years. In multivariate analysis, taking HC was independently associated with a low AMH (β = 0·001, 95% confidence interval −0·002 to 0·000; P = 0·006). These results suggest that ovarian reserve is prematurely reduced in women with haemoglobin SS and raise the possibility that HC contributes to this finding.
Oral HPV16 DNA as a screening tool to detect early oropharyngeal squamous cell carcinoma
Authors: Tang Kai D. , Vasani Sarju , Menezes Lilian , Taheri Touraj , Walsh Laurence J. , Hughes Brett G.M. , Frazer Ian H. , Kenny Liz , Scheper Gert C. , Punyadeera Chamindie
Published: July 2020

Given that oropharyngeal squamous cell carcinoma (OPSCC) have now surpassed cervical cancer as the most common human papillomavirus (HPV)‐driven cancer, there is an interest in developing non‐invasive predictive biomarkers to early detect HPV‐driven OPSCC. In total, 665 cancer‐free individuals were recruited from Queensland, Australia. Oral HPV16 DNA positivity in those individuals was determined by our in‐house developed sensitive PCR method. Individuals with (n = 9) or without (n = 12) oral HPV16 infections at baseline were followed for a median duration of 24 mo. Individuals with persistent oral HPV16 infection (≥ 30 mo) were invited for clinical examination of their oral cavity and oropharynx by an otolaryngologist. Oral HPV16 DNA was detected in 12 out of 650 cancer‐free individuals (1.8%; 95% confidence interval [CI]: 1.0‐3.2). Of the 3 individuals with persistent oral HPV16 infection, the first individual showed no clinical evidence of pathology. The second individual was diagnosed with a 2 mm invasive squamous cell carcinoma (T1N0M0) positive for both p16INK4a expression and HPV16 DNA. The third individual was found to have a mildly dysplastic lesion in the tonsillar region that was negative for p16INK4a expression and HPV16 DNA and she continues to have HPV16 DNA in her saliva. Taken together, our data support the value of using an oral HPV16 DNA assay as a potential screening tool for the detection of microscopic HPV‐driven OPSCC. Larger multicenter studies across various geographic regions recruiting populations at a higher risk of developing HPV‐driven OPSCC are warranted to extend and confirm the results of the current investigation.
Gastric cancer deaths by age group in Japan: Outlook on preventive measures for elderly adults
Authors: Asaka Masahiro , Kobayashi Masanobu , Kudo Takahiko , Akino Kozo , Asaka Yuichiro , Fujimori Kenji , Kikuchi Shogo , Kawai Sayo , Kato Mototsugu
Published: July 2020

In February 2013, Japan became the first country in the world to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system. Now that eradication therapy is covered by NHI, its usage has increased dramatically, and gastric cancer deaths have begun to decrease. We undertook a detailed epidemiological analysis to investigate effects of expanded NHI coverage for H. pylori eradication therapy on gastric cancer deaths in specific age groups. Numbers of gastric cancer deaths were determined by referencing data from Ministry of Health, Labour and Welfare reports and “Cancer Statistics in Japan – 2018” published by the Foundation for Promotion of Cancer Research. Gastric cancer deaths across all age groups have been clearly decreasing since 2013, but deaths of people aged 80 years and older are still increasing. The number of gastric cancer deaths in people aged in their 80s was 2 times higher than in people aged in their 70s and 4 times higher than in people aged in their 60s. The number of people in their 80s who had an endoscopy was less than half that of people in their 60s and 70s. The eradication therapy has increased dramatically, and gastric cancer deaths are clearly decreasing in Japan. However, this decrease in deaths has not extended to elderly adults aged in their 80s, which suggests that measures to prevent gastric cancer in people aged 80 years and older will be critical to achieving the mission of eliminating gastric cancer in Japan.
24‐Dehydrocholesterol reductase promotes the growth of breast cancer stem‐like cells through the Hedgehog pathway
Authors: Qiu Ting , Cao Jiawei , Chen Wanzhou , Wang Jieyi , Wang Yaqi , Zhao Lingjie , Liu Min , He Licai , Wu Guang , Li Hongzhi , Gu Haihua
Published: July 2020

Cholesterol is a risk factor for breast cancer. However, it is still unclear whether the cholesterol biosynthesis pathway plays any significant role in breast carcinogenesis. 24‐Dehydrocholesterol reductase (DHCR24) is a key enzyme in the cholesterol synthesis pathway. Although DHCR24 is reported to have different functions in different cancers, it is not clear whether DHCR24 is involved in breast cancer. In this study, we found that DHCR24 expression was higher in breast cancer especially in luminal and HER2 positive breast cancer tissues compared with normal breast. Changes in DHCR24 expression altered cellular cholesterol content without affecting the adherent growth of breast cancer cells. However, DHCR24 knockdown reduced whereas DHCR24 overexpression enhanced breast cancer stem‐like cell populations such as mammosphere and aldehyde dehydrogenase positive cell numbers. In addition, DHCR24 overexpression increased the expression of the Hedgehog pathway‐regulated genes. Treating DHCR24 overexpressing breast cancer cell lines with the Hedgehog pathway inhibitor GANT61 blocked DHCR24‐induced mammosphere growth and increased mRNA levels of the Hedgehog regulated genes. Furthermore, expression of a constitutively activated mutant of Smoothened, a key hedgehog signal transducer, rescued the decreases in mammosphere growth and Hedgehog regulated gene expression induced by knockdown of DHCR24. These results indicate that DHCR24 promotes the growth of breast cancer stem‐like cells in part through enhancing the Hedgehog signaling pathway. Our data suggest that cholesterol contribute to breast carcinogenesis by enhancing Hedgehog signaling and cancer stem‐like cell populations. Enzymes including DHCR24 involved in cholesterol biosynthesis should be considered as potential treatment targets for breast cancer.
Cognitive Stimulation at Home and in Child Care and Children’s Preacademic Skills in Two‐Parent Families
Authors: Cabrera Natasha J. , Jeong Moon Ui , Fagan Jay , West Jerry , Aldoney Daniela
Published: July 2020

This paper used the Early Childhood Longitudinal Study‐Birth Cohort (N = 1,258) to examine the influence of hilevels of cognitive stimulation from mothers, fathers, and childcare providers at 24 months and children’s pre‐academic skills at 48 and 60 months in two parent families. Results from path analysis showed direct positive effects of fathers’ early cognitive stimulation on early reading and math skills at 48 and 60 months. There were also two moderated effects: The effects of high levels of maternal stimulation at 24 months on early math and reading skills at 48 months were largest for children also receiving high levels of cognitive stimulation from their childcare providers. Implications for including fathers in studies of the home cognitive stimulation and strengthening the parent‐childcare connection are discussed.
The Role of Childhood Executive Function in Explaining Income Disparities in Long‐Term Academic Achievement
Authors: Deer LillyBelle K. , Hastings Paul D. , Hostinar Camelia E.
Published: July 2020

This study utilized data from the Avon Longitudinal Study of Parents and Children (N = 14,860) to examine whether early‐life family income (age 0–5) predicted long‐term academic achievement (age 16–18) and to investigate the role of executive function (EF) assessed multiple times across age 7–11 in explaining this association. Task‐based EF was a significant mediator between early‐life family income and later academic achievement in every model. This mediating pathway persisted when adjusting for a comprehensive panel of covariates including verbal IQ, sex, family income at ages 8 and 18, and early‐life temperament. Additionally, teacher‐rated and parent‐rated EF mediated in some models. Overall, these findings suggest that childhood EF may play an important role in perpetuating income‐based educational disparities.