bluuebunny/crossref_metadata_2025 huggingface dataset:
The Reintroduction of Radiotherapy Into the Integrated Management of Kidney Cancer
Authors: Dohopolski Michael , Hannan Raquibul , Wardak Zabi , Hammers Hans , Garant Aurelie
Published: September 2020

The incidence of renal cell carcinoma (RCC) has been increasing, with a moderate subgroup of individuals who later develop metastatic disease. Historically, metastatic RCC has been managed with systemic therapy because RCC was believed to be radioresistant. Local therapies, such as stereotactic body radiation therapy, also known as stereotactic ablative radiotherapy, which utilize focused high-dose-rate radiation delivered over a limited number of treatments, have been successful in controlling local disease and, in some cases, extending survival in patients with intracranial and extracranial metastatic RCC. Stereotactic ablative radiotherapy is highly effective in treating intact disease when patients are not surgical candidates. Stereotactic ablative radiotherapy is well tolerated when used in conjunction with systemic therapy such as tyrosine kinase inhibitors and immune checkpoint inhibitors. These successes have prompted investigators to evaluate the efficacy of stereotactic body radiation therapy in novel settings such as neoadjuvant treatment of advanced RCC with tumor thrombus and oligometastatic/oligoprogressive disease states.
The von Hippel-Lindau Tumor Suppressor Gene
Authors: Elias Roy , Zhang Qing , Brugarolas James
Published: September 2020

The discovery of the von Hippel-Lindau (VHL) gene marked a milestone in our understanding of clear cell renal cell carcinoma (ccRCC) pathogenesis. VHL inactivation is not only a defining feature of ccRCC, but also the initiating event. Herein, we discuss canonical and noncanonical pVHL functions, as well as breakthroughs shaping our understanding of ccRCC evolution and evolutionary subtypes. We conclude by presenting evolving strategies to therapeutically exploit effector mechanisms downstream of pVHL.
Liability of Health Care Professionals and Institutions During COVID-19 Pandemic in Italy: Symposium Proceedings and Position Statement
Authors: Oliva Antonio , Caputo Matteo , Grassi Simone , Vetrugno Giuseppe , Marazza Marco , Ponzanelli Giulio , Cauda Roberto , Scambia Giovanni , Forti Gabrio , Bellantone Rocco , Pascali Vincenzo L.
Published: September 2020

Background

On May 12, 2020, a symposium titled “Liability of healthcare professionals and institutions during COVID-19 pandemic” was held in Italy with the participation of national experts in malpractice law, hospital management, legal medicine, and clinical risk management. The symposium’s rationale was the highly likely inflation of criminal and civil proceedings concerning alleged errors committed by health care professionals and decision makers during the COVID-19 pandemic. Its aim was to identify and discuss the main issues of legal and medicolegal interest and thus to find solid solutions in the spirit of preparedness planning.

Methods

There were 5 main points of discussion: (A) how to judge errors committed during the pandemic because of the application of protocols and therapies based on no or weak evidence of efficacy, (B) whether hospital managers can be considered liable for infected health care professionals who were not given adequate personal protective equipment, (C) whether health care professionals and institutions can be considered liable for cases of infected inpatients who claim that the infection was transmitted in a hospital setting, (D) whether health care institutions and hospital managers can be considered liable for the hotspots in long-term care facilities/care homes, and (E) whether health care institutions and hospital managers can be considered liable for the worsening of chronic diseases.

Results and Conclusion

Limitation of the liability to the cases of gross negligence (with an explicit definition of this term), a no-fault system with statal indemnities for infected cases, and a rigorous methodology for the expert witnesses were proposed as key interventions for successfully facing future proceedings.
Types, Safety, and Efficacy of Limb Distalization for Inadequate Weight Loss After Roux-en-Y Gastric Bypass
Authors: Hamed Hosam , Ali Mahmoud , Elmahdy Youssif
Published: September 2020

Objective:

Comprehensive classification and evaluation of the outcome of limb distalization (LD) for inadequate weight loss after roux-en-y gastric bypass (RYGB)

Background:

Limb distalization is a revisional malabsorptive procedure for the management of inadequate weight loss after RYGB. Multiple studies with small sample sizes reported the outcome of LD. This meta-analysis aims to reach a higher level of evidence regarding the safety and efficacy of the procedure.

Methods:

A systematic search, including all studies on LD for management of inadequate weight loss after RYGB. The search engines included were PubMed, Embase, Web of Science, Cochrane Library, Scopus, and EBSCOhost.

Results:

Fourteen studies were included. The pooled estimates of the mid-term percentage of excess weight loss (%EWL), diabetic, and hypertension remission were 50.8%, 69.9%, and 59.8%, respectively. The rate of surgical revision for the management of protein-energy malnutrition (PEM) was 17.1%. The %EWL was significantly higher with older age and good response to index surgery (P = 0.01, 0.04, respectively). Less total alimentary limb length was not associated with better %EWL (P = 0.9), but it was significantly associated with severe PEM (P = 0.01).

Conclusions:

LD has an encouraging rate of resolution of comorbidities. A judicious patient selection is essential for better weight loss after LD. Type I LD with total alimentary limb length ≥350 cm was associated with less risk of malnutrition. PEM is a life-threatening complication that may require revisional surgery years after LD. Future studies on LD, adopting standardized surgical practice and terminology, will allow a more conclusive assessment of the outcome of the procedure.
Disparity Between United States Adolescent Class II and III Obesity Trends and Bariatric Surgery Utilization, 2015–2018
Authors: Messiah Sarah E. , Xie Luyu , Atem Folefac , Mathew Matthew S. , Qureshi Faisal G. , Schneider Benjamin E. , Cruz-Muñoz Nestor de la
Published: September 2020

Objectives:

Class II (120% > body mass index [BMI] < 140% of the 95th percentile for age and sex) and Class III (BMI >140% of the 95th percentile for age and sex) obesity are the fastest growing subcategories of obesity in the United States pediatric population. Metabolic and bariatric surgery (MBS) is a safe and effective treatment option for with class II/III obesity. The primary objectives of this analysis were to determine the (1) current US MBS utilization rates in those with class II/III obesity and (2) utilization rates and 30-day postoperative outcomes.

Background:

The 2015 to 2018 National Health and Nutrition Examination Survey cross-sectional data (N = 19,225) generated US with class II/III obesity prevalence estimates. The 2015 to 2018 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) longitudinal (30 days) cohort data were used to compare adolescent and adult (N = 748,622) postoperative outcomes and to calculate utilization rates.

Methods:

The 2015 to 2018 youth and adult MBS utilization rates were calculated using MBSAQIP data (numerator) and National Health and Nutrition Examination Survey data (denominator). Two-sample tests of proportions were performed to compare the MBS utilization rates by age, ethnicity, and sex and expressed per 1000.

Results:

Mean age of the analytical MBSAQIP sample was 17.9 (1.15) years in youth (n = 3846) and 45.1 (11.5) in adults (N = 744,776), majority female (77.4%, 80.7%, respectively) and non-Hispanic White (68.5%, 59.4%, respectively). The overall 2015 to 2018 MBS utilization rate for youth was 1.81 per 1000 and 5.56 per 1000 for adults (P < 0.001). Adult patients had slightly higher percentage (4.2%) of hospital readmissions compared to youth (3.4%, P = 0.01) but there were no other post-MBS complication differences. From 2015 to 2018 the US prevalence of youth with class II/III obesity increased in Hispanics and non-Hispanic Blacks (P trend < 0.001), but among youth who did complete MBS non-Hispanic Whites had higher rates of utilization (45.8%) compared to Hispanics (22.7%) and non-Hispanic blacks 14.2% (P = 0.006).

Conclusions:

MBS is an underutilized obesity treatment tool for both youth and adults, and among ethnic minority groups in particular.
TransCarotid Revascularization With Dynamic Flow Reversal Versus Carotid Endarterectomy in the Vascular Quality Initiative Surveillance Project
Authors: Malas Mahmoud B. , Dakour-Aridi Hanaa , Kashyap Vikram S. , Eldrup-Jorgensen Jens , Wang Grace J. , Motaganahalli Raghu L. , Cronenwett Jack L. , Schermerhorn Marc L.
Published: September 2020

Objective:

To compare the outcomes of TCAR with flow reversal to the gold standard CEA using data from the Society for Vascular Surgery Vascular Quality Initiative TCAR Surveillance Project.

Summary of Background Data:

TCAR is a novel minimally invasive procedure for carotid revascularization in high-risk patients that is associated with significantly lower stroke rates compared with carotid artery stenting via the transfemoral approach.

Methods:

Patients in the United States and Canada who underwent TCAR and CEA for carotid artery stenosis (2016-2019) were included. Propensity scores were calculated based on baseline clinical variables and used to match patients in the 2 treatment groups (n = 6384 each). The primary endpoint was the combined outcome of perioperative stroke and/or death.

Results:

No significant differences were observed between TCAR and CEA in terms of in-hospital stroke/death [TCAR, 1.6% vs CEA, 1.6%, RR (95% CI): 1.01 (0.77–1.33), P = 0.945], stroke [1.4% vs 1.4%, RR (95% CI): 1.02 (0.76–1.37), P = 0.881], or death [0.4% vs 0.3%, RR (95% CI): 1.14 (0.64–2.02), P = 0.662]. Compared to CEA, TCAR was associated with lower rates of in-hospital myocardial infarction [0.5% vs 0.9%, RR (95% CI): 0.53 (0.35–0.83), P = 0.005], cranial nerve injury [0.4% vs 2.7%, RR (95% CI): 0.14 (0.08–0.23), P < 0.001], and post-procedural hypertension [13% vs 18.8%, RR (95% CI): 0.69 (0.63–0.76), P < 0.001]. They were also less likely to stay in the hospital for more than 1 day [26.4% vs 30.1%, RR (95% CI): 0.88 (0.82–0.94), P < 0.001]. No significant interaction was observed between procedure and symptomatic status in predicting postoperative outcomes. At 1 year, the incidence of ipsilateral stroke or death was similar between the 2 groups [HR (95% CI): 1.09 (0.87–1.36), P = 0.44].

Conclusions:

This propensity-score matched analysis demonstrated significant reduction in the risk of postoperative myocardial infarction and cranial nerve injury after TCAR compared to CEA, with no differences in the rates of stroke/death.
Streptomyces arboris sp. nov., isolated from Populus euphratica wetland soil
Authors: Liu Panpan , Xia Zhanfeng , Zhang Lili
Published: September 2020

A novel actinobacterial strain (TRM 68085T) was isolated from soil ofPopulus euphraticawetland. A polyphasic approach was used to study the taxonomy of TRM 68085Tand the results showed a range of phylogenetic and chemotaxonomic properties consistent with those of the genusStreptomyces. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain TRM 68085Tshowed the highest similarity value toStreptomyces capitiformicae1H-SSA4T(98.6 %), and phylogenetically clustered withStreptomyces kanasensisZX01T(97.5 %) andStreptomyces ipomoeaeNBRC 13050T(97.4 %). The genomic DNA G+C content of strain TRM 68085Tbased on the genome sequence was 71.4 mol%. The levels of DNA–DNA relatedness between the genome of the isolate and its nearest phylogenetic neighbours,S. capitiformicae1H-SSA4T,S. kanasensisZX01TandS. ipomoeaeNBRC 13050T, were 19.2±0.4, 21.8±0.5 and 19.3±0.6 %, respectively. Chemotaxonomic data revealed that strain TRM 68085Tpossessed MK-9(H6) and MK-9(H8) as the predominant menaquinones.ll-Diaminopimelic acid and a small amount ofmeso-diaminopimelic acid were the diagnostic diamino acids. Ribose, xylose, glucose and galactose were the whole-cell sugars. The major cellular fatty acids were C16 : 0(25.4 %) and iso-C16 : 0(18.3 %). On the basis of these genotypic and phenotypic data, it is concluded that strain TRM 68085Trepresents a novel species of the genusStreptomyces, for which the nameStreptomyces arborissp. nov. is proposed. The type strain is TRM 68085T(=CCTCC AA2019031T=LMG 31492T).
Streptococcus catagoni sp. nov., isolated from the respiratory tract of diseased Chacoan peccaries (Catagonus wagneri)
Authors: Mühldorfer Kristin , Szentiks Claudia A. , Wibbelt Gudrun , van der Linden Mark , Ewers Christa , Semmler Torsten , Akimkin Valerij , Blom Jochen , Rau Jörg , Eisenberg Tobias
Published: September 2020

Novel catalase-negative, Gram-stain-positive, beta-haemolytic, coccus-shaped organisms were isolated from Chacoan peccaries that died from respiratory disease. The initial API 20 Strep profiles suggested

Streptococcus agalactiae

with acceptable identification scores, but the 16S rRNA gene similarity (1548 bp) to available sequences of streptococci was below 98 %. Next taxa of the genus

Streptococcus

, displaying highest similarities to the strains from this study, were

S. bovimastitidis

NZ1587T (97.5 %),

S. iniae

ATCC 29178T (97.5 %),

S. hongkongensis

HKU30T (97.4 %),

S. parauberis

DSM 6631T (97.1 %),

S. penaeicida

CAIM 1838T (97.1 %),

S. pseudoporcinus

DSM 18513T (97.0 %),

S. didelphis

DSM 15616T (96.6 %),

S. ictaluri

707-05T (96.6 %),

S. uberis

JCM 5709T (96.5 %) and

S. porcinus

NCTC 10999T (96.4 %). All other

Streptococcus

species had sequence similarities of below 96.4 %. A sodA gene as well as whole genome-based core genome phylogeny of three representative strains and 145 available

Streptococcus

genomes confirmed the unique taxonomic position. Interstrain average nucleotide identity (ANI) and amino acid identity (AAI) values were high (ANI >96 %; AAI 100%), but for other streptococci clearly below the proposed species boundary of 95–96 % (ANI <75 %; AAI <83 %). Results were confirmed by genome-to-genome distance calculations. Pairwise digital DNA–DNA hybridization estimates were high (>90 %) between the novel strains, but well below the species boundary of 70 % for closely related

Streptococcus

type strains (23.5–19.7 %). Phenotypic properties as obtained from extended biochemical profiles and MALDI-TOF mass spectrometry supported the outstanding rank. Based on the presented molecular and physiological data of the six strains, we propose a novel taxon for which we suggest the name Streptococcus catagoni sp. nov. with the type strain 99-1/2017T (=DSM 110457T=CCUG 74072T) and five reference strains.
Holstein Friesian dairy cattle edited for diluted coat color as adaptation to climate change
Authors: Laible G. , Cole S-A. , Brophy B. , Wei J. , Leath S. , Jivanji S. , Littlejohn M.D. , Wells D.N.
Published: September 2020

High-producing Holstein Friesian dairy cattle have a characteristic black and white coat pattern where black frequently comprises a large proportion of the coat. Compared to a light coat color, black absorbs more solar radiation translating into radiative heat gain which is a contributing factor to heat stress in cattle, negatively impacting on their production levels, fertility and welfare. To better adapt dairy cattle to the rapidly changing climatic conditions with predictions for more frequent and prolonged hot temperature patterns, we aimed to lighten their coat color by genome editing. Using gRNA/Cas9-mediated editing, we introduced a three base pair (bp) deletion in the pre-melanosomal protein 17 gene (PMEL) proposed as the causative variant responsible for the semi-dominant color dilution phenotype seen in Galloway and Highland cattle. Calves generated from cells homozygous for the edited mutation revealed a strong color dilution effect. Instead of the characteristic black and white coat color patterning of control calves generated from unedited parental cells, the edited calves displayed a novel pattern of grey and white markings and absence of any black areas. This, for the first time, verified the causative nature of thePMELmutation for diluting the black coat color in cattle. With these edited animals, it is now possible to dissect the effects of the introgressed edit and other interfering allelic variants that might exist in individual cattle and accurately determine the impact of only the three bp change on important health, welfare and production traits. In addition, our study proved targeted editing as a promising approach for the rapid adaptation of livestock to changing climatic conditions.
Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment
Authors: Fernandes Sandra , Srivastava Neetu , Pedicone Chiara , Sudan Raki , Luke Elizabeth A. , Dungan Otto M. , Pacherille Angela , Meyer Shea T. , Dormann Shawn , Chisholm John D. , Kerr William G.
Published: September 2020

Previously a small molecule SHIP inhibitor, K118, was shown to reverse high-fat diet induced obesity and improve blood glucose regulation in obese mice. K118 treatment was also found to increase the frequency and number of IL-4 producing eosinophils in the visceral fat as well two potent immunoregulatory myeloid cell populations: M2-polarized macrophages and myeloid derived suppressor cells (MDSC) suggesting an immune regulatory mechanism. However, the cell(s) or SHIP paralog that should be targeted to improve metabolic regulation was not defined. Here we extend our understanding of how chemical inhibition of SHIP paralogs improves metabolic regulation during excess caloric intake. Here we compare SHIP inhibitors in an obesity prevention model and find that selective inhibitors for SHIP1 or SHIP2 lack the ability to prevent weight gain and body fat accumulation during increased caloric intake. Surprisingly, only pan-SHIP1/2 inhibitors can prevent diet-induced obesity. We confirm that both SHIP1 and SHIP2 must be targeted by showing that dual treatment with the SHIP1 and SHIP2 selective inhibitors can reduced adiposity caused by excess caloric consumption. We also show that pan-SHIP1/2 inhibitors of two different chemical classes can control diet-induced obesity and improve blood glucose regulation. Intriguingly, we find that both classes of pan-SHIP1/2 inhibitors require an intact eosinophil compartment to prevent diet-related fat accumulation demonstrating pan-SHIP1/2 inhibitors act via the VAT innate immune compartment to control adiposity However, improved blood glucose regulation by pan-SHIP1/2 inhibition is not dependent upon eosinophils, indicating a separate mechanism of action for diet-related loss of glucose regulation.
Ebselen, disulfiram, carmofur, PX-12, tideglusib, and shikonin are non-specific promiscuous SARS-CoV-2 main protease inhibitors
Authors: Ma Chunlong , Hu Yanmei , Townsend Julia Alma , Lagarias Panagiotis I. , Marty Michael Thomas , Kolocouris Antonios , Wang Jun
Published: September 2020

There is an urgent need for vaccines and antiviral drugs to combat the COVID-19 pandemic. Encouraging progress has been made in developing antivirals targeting SARS-CoV-2, the etiological agent of COVID-19. Among the drug targets being investigated, the viral main protease (Mpro) is one of the most extensively studied drug targets. Mprois a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites and it is highly conserved among coronaviruses. In addition, Mprohas a unique substrate preference for glutamine in the P1 position. Taken together, it appears that Mproinhibitors can achieve both broad-spectrum antiviral activity and a high selectivity index. Structurally diverse compounds have been reported as Mproinhibitors, with several of which also showed antiviral activity in cell culture. In this study, we investigated the mechanism of action of six previously reported Mproinhibitors, ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 using a consortium of techniques including FRET-based enzymatic assay, thermal shift assay, native mass spectrometry, cellular antiviral assays, and molecular dynamics simulations. Collectively, the results showed that the inhibition of Mproby these six compounds is non-specific and the inhibition is abolished or greatly reduced with the addition of reducing reagent DTT. In the absence of DTT, these six compounds not only inhibit Mpro, but also a panel of viral cysteine proteases including SARS-CoV-2 papain-like protease, the 2Aproand 3Cprofrom enterovirus A71 (EV-A71) and EV-D68. However, none of the compounds inhibits the viral replication of EV-A71 or EV-D68, suggesting that the enzymatic inhibition potency IC50values obtained in the absence of DTT cannot be used to faithfully predict their cellular antiviral activity. Overall, we provide compelling evidence suggesting that ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 are non-specific SARS-CoV-2 Mproinhibitors, and urge the scientific community to be stringent with hit validation.
DeLTa-Seq: direct-lysate targeted RNA-Seq from crude tissue lysate
Authors: Kashima Makoto , Kamitani Mari , Nomura Yasuyuki , Hirata Hiromi , Nagano Atsushi J.
Published: September 2020

Using current mRNA quantification methods such as RT-qPCR and RNA-Seq, it is very difficult to examine thousands of tissue samples due to cost and labor of RNA extraction and quantification steps. Here, we developed Direct-RT buffer in which homogenization of tissue samples and direct-lysate reverse transcription can be conducted without RNA purification. We showed that appreciate concentration of DTT prevented RNA degradation but not RT in the lysates of several plants’ tissues, yeast, and zebrafish larvae. Using the buffer, direct reverse transcription on the lysates could produce comparable amount of cDNA with that synthesized from purified RNA. Furthermore, we established DeLTa-Seq (Direct-Lysate reverse transcription andTargeted RNA-Seq) method. DeLTa-Seq is a cost-effective, high-throughput and highly-precise quantification method for the expressions of hundreds of genes. It enables us to conduct large-scale studies using thousands of samples such as chemical screening, field experiments and studies focusing on individual variability.
Characterisation of protease activity during SARS-CoV-2 infection identifies novel viral cleavage sites and cellular targets with therapeutic potential
Authors: Meyer Bjoern , Chiaravalli Jeanne , Gellenoncourt Stacy , Brownridge Philip , Bryne Dominic P. , Daly Leonard A. , Grauslys Arturas , Walter Marius , Agou Fabrice , Chakrabarti Lisa A. , Craik Charles S. , Eyers Claire E. , Eyers Patrick A. , Gambin Yann , Jones Andrew R. , Sierecki Emma , Verdin Eric , Vignuzzi Marco , Emmott Edward
Published: September 2020

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic, and responsible for over 170 million infections, and over 3.7 million deaths worldwide. Efforts to test, treat and vaccinate against this pathogen all benefit from an improved understanding of the basic biology of SARS-CoV-2. Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication, and inhibitors targeting proteases have already shown success at inhibiting SARS-CoV-2 in cell culture models. Here, we study proteolytic cleavage of viral and cellular proteins in two cell line models of SARS-CoV-2 replication using mass spectrometry to identify protein neo-N-termini generated through protease activity. We identify previously unknown cleavage sites in multiple viral proteins, including major antigenic proteins S and N, which are the main targets for vaccine and antibody testing efforts. We discovered significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease, and identify 14 potential high-confidence substrates of the main and papain-like proteases, validating a subset within vitroassays. We showed that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication, and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, showed a dose-dependent reduction in SARS-CoV-2 titres. Overall, our study provides a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit SARS-CoV-2 and treat COVID-19.
Efficient production of Moloney murine leukemia virus-like particles pseudotyped with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein
Authors: Roy Sylvie , Ghani Karim , de Campos-Lima Pedro O. , Caruso Manuel
Published: September 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak that started in China at the end of 2019 has rapidly spread to become pandemic. Several investigational vaccines that have already been tested in animals and humans were able to induce neutralizing antibodies against the SARS-CoV-2 spike (S) protein, however protection and long-term efficacy in humans remain to be demonstrated.

We have investigated if a virus-like particle (VLP) derived from Moloney murine leukemia virus (MLV) could be engineered to become a candidate SARS-CoV-2 vaccine amenable to mass production. First, we showed that a codon optimized version of the S protein could migrate efficiently to the cell membrane. However, efficient production of infectious viral particles was only achieved with stable expression of a shorter version of S in its C-terminal domain (ΔS) in 293 cells that express MLV Gag-Pol (293GP). The incorporation of ΔS was 15-times more efficient into VLPs as compared to the full-length version, and that was not due to steric interference between the S cytoplasmic tail and the MLV capsid. Indeed, a similar result was also observed with extracellular vesicles released from parental 293 and 293GP cells. The amount of ΔS incorporated into VLPs released from producer cells was robust, with an estimated 1.25μg/ml S2 equivalent (S is comprised of S1 and S2). Thus, a scalable platform that has the potential for production of pan-coronavirus VLP vaccines has been established. The resulting nanoparticles could potentially be used alone or as a boost for other immunization strategies for COVID-19.

IMPORTANCE

Several candidate COVID-19 vaccines have already been tested in humans, but their protective effect and long-term efficacy are uncertain. Therefore, it is necessary to continue developing new vaccine strategies that could be more potent and/or that would be easier to manufacture in large-scale. Virus-like particle (VLP) vaccines are considered highly immunogenic and have been successfully developed for human papilloma virus as well as hepatitis and influenza viruses. In this study, we report the generation of a robust Moloney murine leukemia virus platform that produces VLPs containing the spike of SARS-CoV-2. This vaccine platform that is compatible with lyophilization could simplify storage and distribution logistics immensely.
Efficient Development of Platform Cell Lines Using CRISPR-Cas9 and Transcriptomics Analysis
Authors: Kwon Andrew Tae-Jun , Mohri Kohta , Takizawa Satoshi , Arakawa Takahiro , Takahashi Maiko , Kaczkowski Bogumil , Furuno Masaaki , Suzuki Harukazu , Tagami Shunsuke , Mukai Hidefumi , Arner Erik
Published: September 2020

Antibody-drug conjugates offers many advantages as a drug delivery platform that allows for highly specific targeting of cell types and genes. Ideally, testing the efficacy of these systems requires two cell types to be different only in the gene targeted by the drug, with the rest of the cellular machinery unchanged, in order to minimize other potential differences from obscuring the effects of the drug. In this study, we created multiple variants of U87MG cells with targeted mutation in theTP53gene using the CRISPR-Cas9 system, and determined that their major transcriptional differences stem from the loss of p53 function. Using the transcriptome data, we predicted which mutant clones would have less divergent phenotypes from the wild type and thereby serve as the best candidates to be used as drug delivery testing platforms. Furtherin vitroandin vivoassays of cell morphology, proliferation rate and target antigen-mediated uptake supported our predictions. Based on the combined analysis results, we successfully selected the best qualifying mutant clone. This study serves as proof-of-principle of the approach and paves the way for extending to additional cell types and target genes.
Tumors Negate the Action of ImpL2 by Elevating Wingless
Authors: Lee Jiae , Ng Katelyn G.-L. , Dombek Kenneth M. , Kwon Young V.
Published: September 2020

Tumors often secrete wasting factors associated with atrophy and degeneration of host tissues. If tumors were affected by the wasting factors, mechanisms allowing tumors to evade the adverse effects of the wasting factors must exist and impairing such mechanisms may attenuate tumors. We usedDrosophilamidgut tumor models to show that tumors upregulate Wingless (Wg) to oppose the growth-impeding effects caused by the wasting factor, ImpL2 (Insulin-like growth factor binding protein (IGFBP)-related protein). Growth of Yorkie (Yki)-induced tumors is dependent on Wg while either elimination ofImpL2or elevation of Insulin/IGF signaling in tumors revokes this dependency. Notably, Wg augmentation could be a general mechanism for supporting the growth of tumors with elevated ImpL2 and exploited to attenuate muscle degeneration during wasting. Our study elucidates the mechanism by which tumors negate the action of ImpL2 and implies that targeting the Wnt/Wg pathway might be an efficient treatment strategy for cancers with elevated IGFBPs.
Open Targets Genetics: An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci
Authors: Mountjoy Edward , Schmidt Ellen M. , Carmona Miguel , Peat Gareth , Miranda Alfredo , Fumis Luca , Hayhurst James , Buniello Annalisa , Schwartzentruber Jeremy , Karim Mohd Anisul , Wright Daniel , Hercules Andrew , Papa Eliseo , Fauman Eric , Barrett Jeffrey C. , Todd John A. , Ochoa David , Dunham Ian , Ghoussaini Maya
Published: September 2020

Genome-wide association studies (GWAS) have identified many variants robustly associated with complex traits but identifying the gene(s) mediating such associations is a major challenge. Here we present an open resource that provides systematic fine-mapping and protein-coding gene prioritization across 133,441 published human GWAS loci. We integrate diverse data sources, including genetics (from GWAS Catalog and UK Biobank) as well as transcriptomic, proteomic and epigenomic data across many tissues and cell types. We also provide systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues and identify 729 loci fine-mapped to a single coding causal variant and colocalized with a single gene. We trained a machine learning model using the fine mapped genetics and functional genomics data using 445 gold standard curated GWAS loci to distinguish causal genes from background genes at the same loci, outperforming a naive distance based model. Genes prioritized by our model are enriched for known approved drug targets (OR = 8.1, 95% CI: [5.7, 11.5]). These results will be regularly updated and are publicly available through a web portal, Open Targets Genetics (OTG,http://genetics.opentargets.org), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.
Response of whole plant water use to limiting light and water conditions are independent of each other in seedlings of seasonally dry tropical forests
Authors: Sunny Ron , Guha Anirban , Jezeera Asmi , Mohan N Kavya , Babu Neha Mohan , Barua Deepak
Published: September 2020

How co-occurring species vary in the utilization of a shared and limited supply of water, especially in the context of other limiting resources like light, is essential for understanding processes that facilitate species coexistence and community assembly. For seedlings in a seasonally dry tropical forest that experience large heterogeny in light and water conditions, how water use, leaf physiology, and subsequently plant growth, is affected by limited water and light availability is still not well understood. In a controlled common garden experiment with four co-existing and commonly occurring dry tropical forest species, we examined how whole plant water uptake, responds to limiting water and light conditions and whether these responses are reflected in leaf physiology, and translated to growth. Water use varied dramatically in seedlings of the four species with a five-fold difference in well-watered plants grown in full sunlight. Species varied in their response to shade, but did not differ in responses to the low water treatment, possibly resulting from the strong selective force imposed by the very low water availability and the long dry period characteristic of these seasonally dry forests. Interestingly, species responses in water use, physiology, and growth in limiting water conditions were independent of light. Thus, species response to both these limiting conditions may evolve independently of each other. Responses in water use were largely congruent with responses in leaf physiology and growth. However, while magnitude of changes in leaf physiology were largely driven by light conditions, changes in whole plant water use and growth were influenced to a greater degree by the water treatment. This highlights the need to measure whole plant water use to better understand plant growth responses in these seasonally dry tropical forests.
Influence of Activating and Inhibitory Killer Immunoglobulin-Like Receptors (KIR) genes on the recurrence rate of ocular toxoplasmosis in Brazil
Authors: Perce-da-Silva Daiana de Souza , Joaquim Thays Euzebio , Aleixo Ana Luisa Quintella do Couto , Motta Juliana , Ribeiro-Alves Marcelo , Oliveira Ferreira Joseli de , Porto Luís Cristóvão de Moraes Sobrino , Banic Dalma Maria , Amendoeira Maria Regina Reis
Published: September 2020

Background

Recurrence is a hallmark of ocular toxoplasmosis (OT), and conditions that influence its occurrence remain a challenge. Natural killer cells (NK) are effectors cells whose primary function is the cytotoxic activity against many parasites, includingToxoplasma gondii. Among the NK cell receptors, immunoglobulin-like receptors (KIR) deserve attention due to their high polymorphism. This study aimed to analyze the influence of KIR gene polymorphism in the course of OT infection and its association with recurrences after an active episode.

Methods

Ninety-six patients from the Ophthalmologic Clinic of the National Institute of Infectology Evandro Chagas (INI/Fiocruz/RJ, Brazil) were followed for up to five years. After DNA extraction, genotyping of the patients was performed by PCR-SSO utilizing Luminex equipment for reading. During follow-up, 57.4% had a recurrence.

Results

We identified 25 KIR genotypes and found a higher frequency of genotypes 1 (31.7%) with worldwide distribution. We note that theKIR2DL2inhibitor gene and the gene activatorKIR2DS2were more frequent in patients without recurrence (P = 0.03 and P = 0.02, respectively). Additionally, we observed one activating gene, KIR2DS1, associated with more than four times faster progression to the development of recurrent ocular toxoplasmosis than individuals without this gene (aRR = 4.6, P = 0.04).

Conclusion

The KIR2DL2 and KIR2DS2 are associated as possible protection markers and the KIR2DS1 acting as a possible susceptibility marker. Additionally, the lower proportion of activating genes observed in individuals with recurrence corroborating with the hypothesis that these individuals are more susceptible to ocular toxoplasmosis recurrence (OTR).
Studies on Forecasting of Incidence of Leaf Mold in Tomato and Fungicide-spray Scheduling
Authors: Lee Mun Haeng
Published: September 2020

Tomato leaves were inoculated with 1×104conidia·mL−1and placed in a dew chamber for 0 to 18hrs at 10 to 25°C. Eighteen days after inoculation, leaf mold incidence appeared in 9hr treatment of leaf wet duration and the proper temperature was 15 to 20°C. In 10 and 25°C treatments, the incidence rate was 0% and 4.2%, respectively. The most important factors regard to leaf mold incidence were leaf wet duration and temperature. Considering the proper tomato growth temperature is 15-25°C, control by leaf wet duration is easier than control by temperature to prevent leaf mold incidence. After leaf mold inoculation, incidence appeared at 20 days and the latency period was estimated as 14-15 days. The leaf mold incidence rate was the highest at 15°C and 20°C. When ‘trihumin’ (triflumizole 30%) was applied at 12 hr of leaf wet duration, the control effect was the highest at 90% up to 168 hr but after 240 hr, it dropped to 60%. When ‘Demani B’ (polyoxin B 50%) was applied at 12 hour of leaf wet duration, the control effect was the highest at 91% up to 144hr but after 240hr, it dropped to 58%, similar to trihumin application treatment. When ‘belqute’ (Iminoctadine tris 40%) was applied at 12 hours of leaf wet duration, the control effect was the highest at 93% up to 144 hr but after 240 hr, it dropped to 65%.
Monthly physical activity and storage time affect enzyme acetylcholinesterase activity in Plasma and Whole blood samples of healthy elderly subjects
Authors: Jovičić Snežana M.
Published: September 2020

Objective

Enzyme Acetylcholinesterase is a potential marker for ageing, disease onset, progression and therapy. Physical activity and storage time affect the variable range, quality data prevalence and variability. The study aims to examine the effect of one and two months of storage time on protein concentration, acetylcholinesterase activity and inhibitor efficacy in subjects subjected to 3 months of physical activity.

Method

The value of AChE activity was measured spectrophotometrically by Elman et al. (1961). The obtained results were processed by the statistical program SPSS v 23.0.

Results

Group of 32 healthy subjects showed a significant difference (P<0.01) for protein concentration and acetylcholinesterase activity in Plasma, inhibitor Eserine efficacy in Plasma and Whole blood before and after physical activity. Based on Age, a significant difference is present for Height (P<0.01), Muscle mass (P<0.01) and protein concentration (P<0.05) in Whole blood after physical activity and storage time. A statistically significant difference between Gender exists for Age (P<0.01), Height (P<0.01), Weight (P<0.05), Muscle mass (P<0.05), protein concentration (P<0.05) in whole blood and acetylcholinesterase activity (P<0.05) in Plasma after physical activity.

Conclusions

Preliminary and descriptive data indicate no difference in acetylcholinesterase activity between Age groups. Physical activity and storage time influence the change of protein concentration, enzyme activity and inhibitor Eserine efficacy in healthy elderly subjects. Future studies should compare disease and healthy participants.
Bio-hybrid soft robots with self-stimulating skeletons
Authors: Guix Maria , Mestre Rafael , Patiño Tania , De Corato Marco , Zarpellon Giulia , Sánchez Samuel
Published: September 2020

Bioinspired hybrid soft robots combining living actuation and synthetic components are an emerging field in the development of advanced actuators and other robotic platforms (i.e. swimmers, crawlers, walkers). The integration of biological components offers unique properties (e.g. adaptability, response to external stimuli) that artificial materials cannot replicate with accuracy, being skeletal and cardiac muscle cells the preferred candidates for providing contractile actuation. Here, we present a skeletal-muscle-based swimming biobot with a 3D-printed serpentine spring skeleton that provides mechanical integrity and self-stimulation during the cell maturation process. The restoring force inherent to the spring system allows a dynamic skeleton compliance upon spontaneous muscle contraction, leading to a novel cyclic mechanical stimulation process that improves the muscle force output without external stimuli. Optimization of the 3D-printed skeletons is carried out by studying the geometrical stiffnesses of different designsviafinite element analysis. Upon electrical actuation of the muscle tissue, two types of motion mechanisms are experimentally observed: i) directional swimming when the biobot is at the liquid-air interface and ii) coasting motion when it is near the bottom surface. The integrated compliant skeleton provides both the mechanical self-stimulation and the required asymmetry for directional motion, displaying its maximum velocity at 5 Hz (800 micrometer second−1, 3 body length second−1). This skeletal muscle-based bio-hybrid swimmer attains speeds comparable to cardiac-based bio-hybrid robots and outperforms other muscle-based swimmers. The integration of serpentine-like structures in hybrid robotic systems allows self-stimulation processes that could lead to higher force outputs in current and future biomimetic robotic platforms.
A solution-free crystal-mounting platform for native SAD
Authors: Yu Jian , Shinoda Akira , Kato Koji , Tanaka Isao , Yao Min
Published: September 2020

The native SAD phasing method uses the anomalous scattering signals from the S atoms contained in most proteins, the P atoms in nucleic acids or other light atoms derived from the solution used for crystallization. These signals are very weak and careful data collection is required, which makes this method very difficult. One way to enhance the anomalous signal is to use long-wavelength X-rays; however, these wavelengths are more strongly absorbed by the materials in the pathway. Therefore, a crystal-mounting platform for native SAD data collection that removes solution around the crystals has been developed. This platform includes a novel solution-free mounting tool and an automatic robot, which extracts the surrounding solution, flash-cools the crystal and inserts the loop into a UniPuck cassette for use in the synchrotron. Eight protein structures (including two new structures) have been successfully solved by the native SAD method from crystals prepared using this platform.
Supply chain communication and cultural compatibility: performance implications in the global manufacturing industry
Authors: Nguyen Hung , Onofrei George , Truong Dothang
Published: September 2020

Purpose

Research has extensively focused on the cultural differences in supply chain collaboration while neglecting the importance of cultural similarities and compatible goals among supply chain members. With the rise of global supply chain network, the choice of supply chain orientation is critical. This study argues that performance differences between these configurations highlight managerial implications for sustainable development.

Design/methodology/approach

Drawing from uncertainty reduction and cognitive social capital theories, this study developed a taxonomy of manufacturing firms based on process alignment between cultural compatibility and supply chain communication. The empirical data used in this study were drawn from the Global Manufacturing Research Group (GMRG) survey project, with data collected from 680 manufacturing companies, across various industry sectors and countries.

Findings

There appeared to be consistent three major configurations: the Proactive, the Initiative and the Reactive. Manufacturers distanced themselves based mainly on communication with customers on events and proprietary information. Communication-cultural compatibility taxonomies influence differently on operations and financial performance. The Initiative, who excelled in communication practices gained significant improvement in efficiency and delivery measures. While Reactive lagged, Proactive aligned in both capabilities to experience higher payoffs in operational and financial measures. The findings offer a step-by-step approach where manufacturers intensify communication with partners for better efficiency and delivery measures, then align cultural practices to obtain financial, quality and innovation performance.

Research limitations/implications

It will be fruitful for future research to examine the evolution of longitudinally. A comparison between developed and developing economies will be of interest.

Practical implications

The findings provide a step-by-step decision-making process for supply chain communication and offer guidance especially for global supply chain managers.

Originality/value

This study adds greater comprehensiveness and richness to the information exchange literature on performance by process aligning to enhance cultural compatibility.
Performance management in social impact bonds: how an outcomes-based approach shapes hybrid partnerships
Authors: Dixon Ruth
Published: September 2020

Purpose

This paper investigates how outcomes-based performance management (PM) regimes operate in the partnerships known as social impact bonds (SIBs), which bring together partners from the public, private and third sectors. The findings are analysed in the light of the different cultural world views of the partners.

Design/methodology/approach

Published evaluations of 25 UK SIBs were analysed by a qualitative multiple case study approach. This study of secondary sources permitted the analysis of a wide range of SIB partnerships from near contemporary accounts.

Findings

Outcomes frameworks led to rigorous PM regimes that brought the cultural differences between partners into focus. While partnerships benefitted from the variety of viewpoints and expertise, the differences in outlook simultaneously led to strains and tensions. In order to mitigate such tensions, some stakeholders conformed to the outlooks of others.

Practical implications

The need to achieve a predefined set of payable outcomes embeds a “linear” view of intervention and effect on the SIB partners and a performance regime in which some partners dominate. In designing accountability systems for partnerships such as SIBs, commissioners should consider how the performance regime will affect the interests of all stakeholders.

Originality/value

This study adds to the cultural theory literature which has rarely considered three-way partnerships embodying hierarchical, individualist and egalitarian world views and how performance regimes operate in such partnerships. Three-way partnerships are thought to be rare and short-lived, but this empirical study shows that they can be successful albeit over a predefined lifespan.
The embedded feelings in local gastronomy: a sentiment analysis of online reviews
Authors: Yu Chung-En , Zhang Xinyu
Published: September 2020

Purpose

This study aims to quantify the underlying feelings of online reviews and discover the role of seasonality in customer dining experiences.

Design/methodology/approach

This study applied sentiment analysis to determine the polarity of a given comment. Furthermore, content analysis was conducted based on the core attributes of the customer dining experiences.

Findings

Positive feelings towards the food and the service do not show a linear relationship, while the overall dining experiences increase in line with the positive feelings on food quality. Moreover, feelings towards the atmosphere of the restaurants are the most positive in peak season.

Practical implications

This study provides guidelines for restaurateurs regarding the aspects that need more attention in different seasons.

Originality/value

The paper contributes to the knowledge of customer feelings in local restaurants/gastronomy and the role seasonality plays in fostering such feelings. In addition, the novel methodological procedures provide insights for tourism research in discovering new dimensions in theories based on big data.