bluuebunny/crossref_metadata_2025 huggingface dataset:
Quartz crystal microbalances (QCM) are suitable for real-time dosimetry in nanotoxicological studies using VITROCELL®Cloud cell exposure systems
Authors: Ding Yaobo , Weindl Patrick , Lenz Anke-Gabriele , Mayer Paula , Krebs Tobias , Schmid Otmar
Published: September 2020

Background

Accurate knowledge of cell−/tissue-delivered dose plays a pivotal role in inhalation toxicology studies, since it is the key parameter for hazard assessment and translation of in vitro to in vivo dose-response. Traditionally, (nano-)particle toxicological studies with in vivo and in vitro models of the lung rely on in silio computational or off-line analytical methods for dosimetry. In contrast to traditional in vitro testing under submerged cell culture conditions, the more physiologic air-liquid interface (ALI) conditions offer the possibility for real-time dosimetry using quartz crystal microbalances (QCMs). However, it is unclear, if QCMs are sensitive enough for nanotoxicological studies. We investigated this issue for two commercially available VITROCELL®Cloud ALI exposure systems.

Results

Quantitative fluorescence spectroscopy of fluorescein-spiked saline aerosol was used to determine detection limit, precision and accuracy of the QCMs implemented in a VITROCELL®Cloud 6 and Cloud 12 system for dose-controlled ALI aerosol-cell exposure experiments. Both QCMs performed linearly over the entire investigated dose range (200 to 12,000 ng/cm2) with an accuracy of 3.4% (Cloud 6) and 3.8% (Cloud 12). Their precision (repeatability) decreased from 2.5% for large doses (> 9500 ng/cm2) to values of 10% and even 25% for doses of 1000 ng/cm2 and 200 ng/cm2, respectively. Their lower detection limit was 170 ng/cm2 and 169 ng/cm2 for the Cloud 6 and Cloud 12, respectively. Dose-response measurements with (NM110) ZnO nanoparticles revealed an onset dose of 3.3 μg/cm2 (or 0.39 cm2/cm2) for both cell viability (WST-1) and cytotoxicity (LDH) of A549 lung epithelial cells.

Conclusions

The QCMs of the Cloud 6 and Cloud 12 systems show similar performance and are highly sensitive, accurate devices for (quasi-) real-time dosimetry of the cell-delivered particle dose in ALI cell exposure experiments, if operated according to manufacturer specifications. Comparison with in vitro onset doses from this and previously published ALI studies revealed that the detection limit of 170 ng/cm2 is sufficient for determination of toxicological onset doses for all particle types with low (e.g. polystyrene) or high mass-specific toxicity (e.g. ZnO and Ag) investigated here. Hence, in principle QCMs are suitable for in vitro nanotoxciological studies, but this should be investigated for each QCM and ALI exposure system under the specific exposure conditions as described in the present study.
Examining fidelity in the INFORM trial: a complex team-based behavioral intervention
Authors: Ginsburg Liane R. , Hoben Matthias , Easterbrook Adam , Andersen Elizabeth , Anderson Ruth A. , Cranley Lisa , Lanham Holly J. , Norton Peter G. , Weeks Lori E. , Estabrooks Carole A.
Published: September 2020

Background

Fidelity in complex behavioral interventions is underexplored. This study examines the fidelity of the INFORM trial and explores the relationship between fidelity, study arm, and the trial’s primary outcome—care aide involvement in formal team communications about resident care.

Methods

A concurrent process evaluation of implementation fidelity was conducted in 33 nursing homes in Western Canada (Alberta and British Columbia). Study participants were from 106 clinical care units clustered in 33 nursing homes randomized to the Basic and Enhanced-Assisted Feedback arms of the INFORM trial.

Results

Fidelity of the INFORM intervention was moderate to high, with fidelity delivery and receipt higher than fidelity enactment for both study arms. Higher enactment teams experienced a significantly larger improvement in formal team communications between baseline and follow-up than lower enactment teams (F(1, 70) = 4.27, p = .042).

Conclusions

Overall fidelity enactment was associated with improvements in formal team communications, but the study arm was not. This suggests that the intensity with which an intervention is offered and delivered may be less important than the intensity with which intervention participants enact the core components of an intervention. Greater attention to fidelity assessment and publication of fidelity results through studies such as this one is critical to improving the utility of published trials.
RETRACTED ARTICLE: IMP3 accelerates the progression of prostate cancer through inhibiting PTEN expression in a SMURF1-dependent way
Authors: Zhang Xiang , Wang Dawei , Liu Boke , Jin Xingwei , Wang Xianjin , Pan Junwei , Tu Weichao , Shao Yuan
Published: September 2020

Background

Insulin-like growth factor 2 (IGF2) messenger RNA binding protein 3 (IMP3) has been testified to be overexpressed in prostate cancer and strongly related to patients’ poor prognosis. However, the functions of IMP3 and the underlying mechanisms in prostate cancer still remain unknown. Therefore, the current study was carried out to reveal the role and molecular mechanism of IMP3 in prostate cancer progression.

Methods

The expression levels of IMP3 in prostate cancer tissues and cells were detected by immunohistochemistry (IHC), western blotting and RT-PCR. CCK-8, clone formation, flow cytometry and in vivo tumor formation assays were used to determine cell growth, clone formation apoptosis and tumorigenesis, respectively. The effect of IMP3 on the expression levels of the key proteins in PI3K/AKT/mTOR signaling pathway, including PIP2, PIP3, p-AKT, AKT, p-mTOR, mTOR, PTEN and BAD activation of was determined by western blotting. IP (Immunoprecipitation) assay was used to evaluate the effects of IMP3 and SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) on the ubiquitination of PTEN protein.

Results

IMP3 expression level was significantly increased in prostate cancer tissues and cell lines (LNCap, PC3 and DU145) as compared with the paracancerous normal tissues and cells (RWPE-1), respectively. High expression of IMP3 apparently promoted cell viability, tumorigenesis and inhibited cell apoptosis in prostate cancer LNCap, DU145 and PC3 cell lines. In mechanism, IMP3 upregulation significantly increased the phosphorylation levels of AKT and mTOR, and elevated PIP3 expression level, while induced significant reductions in the expression levels of BAD, PTEN and PIP2. And, IMP3 overexpression increased SMURF1 expression, which facilitated PTEN ubiquitination. In addition, SMURF1 overexpression enhanced prostate cancer cell viability and inhibited cell apoptosis. Silence of SMURF1 rescued the enhancements in cell proliferation and tumorigenesis and the inhibition in cell apoptosis rates induced by IMP3 in prostate cancer DU145 and LNCap cells.

Conclusion

This study reveals that IMP3 is overdressed in prostate cancer, which accelerates the progression of prostate cancer through activating PI3K/AKT/mTOR signaling pathway via increasing SMURF1-mediated PTEN ubiquitination.
Providing pediatric well-care and sick visits in the COVID-19 pandemic era: the recommendations of the Italian pediatric society
Authors: Agostiniani Rino , Bozzola Elena , Staiano Annamaria , Del Vecchio Antonio , Mazzone Teresa , Greco Luigi , Corsello Giovanni , Villani Alberto
Published: September 2020

Pediatricians have observed a significant decrease in in-person child health visits during the COVID-19 pandemic. In the post lockdown period, the coronavirus trend remains positive in Italy but fears of a second wave have recently grown in Italy due to active hotbeds of contagion. The pandemic may negatively affect the care of pediatric patients and overall children welfare as it may present with severe signs and symptoms or it may complicate. The Italian Pediatric Society recommend to separate well visits from sick ones, to educate families and to promote hygienic strategies to provide an adequate pediatric assistance in case of a second pandemic wave.
Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations
Authors: Flaczyk Adam , Rosovsky Rachel P. , Reed Clay T. , Bankhead-Kendall Brittany K. , Bittner Edward A. , Chang Marvin G.
Published: September 2020

Critically ill patients with COVID-19 are at increased risk for thrombotic complications which has led to an intense debate surrounding their anticoagulation management. In the absence of data from randomized controlled clinical trials, a number of consensus guidelines and recommendations have been published to facilitate clinical decision-making on this issue. However, substantive differences exist between these guidelines which can be difficult for clinicians. This review briefly summarizes the major societal guidelines and compares their similarities and differences. A common theme in all of the recommendations is to take an individualized approach to patient management and a call for prospective randomized clinical trials to address important anticoagulation issues in this population.
EvoMol: a flexible and interpretable evolutionary algorithm for unbiased de novo molecular generation
Authors: Leguy Jules , Cauchy Thomas , Glavatskikh Marta , Duval Béatrice , Da Mota Benoit
Published: September 2020

The objective of this work is to design a molecular generator capable of exploring known as well as unfamiliar areas of the chemical space. Our method must be flexible to adapt to very different problems. Therefore, it has to be able to work with or without the influence of prior data and knowledge. Moreover, regardless of the success, it should be as interpretable as possible to allow for diagnosis and improvement. We propose here a new open source generation method using an evolutionary algorithm to sequentially build molecular graphs. It is independent of starting data and can generate totally unseen compounds. To be able to search a large part of the chemical space, we define an original set of 7 generic mutations close to the atomic level. Our method achieves excellent performances and even records on the QED, penalised logP, SAscore, CLscore as well as the set of goal-directed functions defined in GuacaMol. To demonstrate its flexibility, we tackle a very different objective issued from the organic molecular materials domain. We show that EvoMol can generate sets of optimised molecules having high energy HOMO or low energy LUMO, starting only from methane. We can also set constraints on a synthesizability score and structural features. Finally, the interpretability of EvoMol allows for the visualisation of its exploration process as a chemically relevant tree.
Estimate of the sequenced proportion of the global prokaryotic genome
Authors: Zhang Zheng , Wang Jianing , Wang Jinlan , Wang Jingjing , Li Yuezhong
Published: September 2020

Background

Sequencing prokaryotic genomes has revolutionized our understanding of the many roles played by microorganisms. However, the cell and taxon proportions of genome-sequenced bacteria or archaea on earth remain unknown. This study aimed to explore this basic question using large-scale alignment between the sequences released by the Earth Microbiome Project and 155,810 prokaryotic genomes from public databases.

Results

Our results showed that the median proportions of the genome-sequenced cells and taxa (at 100% identities in the 16S-V4 region) in different biomes reached 38.1% (16.4–86.3%) and 18.8% (9.1–52.6%), respectively. The sequenced proportions of the prokaryotic genomes in biomes were significantly negatively correlated with the alpha diversity indices, and the proportions sequenced in host-associated biomes were significantly higher than those in free-living biomes. Due to a set of cosmopolitan OTUs that are found in multiple samples and preferentially sequenced, only 2.1% of the global prokaryotic taxa are represented by sequenced genomes. Most of the biomes were occupied by a few predominant taxa with a high relative abundance and much higher genome-sequenced proportions than numerous rare taxa.

Conclusions

These results reveal the current situation of prokaryotic genome sequencing for earth biomes, provide a more reasonable and efficient exploration of prokaryotic genomes, and promote our understanding of microbial ecological functions.
Reverse vaccinology assisted designing of multiepitope-based subunit vaccine against SARS-CoV-2
Authors: Tahir ul Qamar Muhammad , Shahid Farah , Aslam Sadia , Ashfaq Usman Ali , Aslam Sidra , Fatima Israr , Fareed Muhammad Mazhar , Zohaib Ali , Chen Ling-Ling
Published: September 2020

Background

Coronavirus disease 2019 (COVID-19) linked with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause severe illness and life-threatening pneumonia in humans. The current COVID-19 pandemic demands an effective vaccine to acquire protection against the infection. Therefore, the present study was aimed to design a multiepitope-based subunit vaccine (MESV) against COVID-19.

Methods

Structural proteins (Surface glycoprotein, Envelope protein, and Membrane glycoprotein) of SARS-CoV-2 are responsible for its prime functions. Sequences of proteins were downloaded from GenBank and several immunoinformatics coupled with computational approaches were employed to forecast B- and T- cell epitopes from the SARS-CoV-2 highly antigenic structural proteins to design an effective MESV.

Results

Predicted epitopes suggested high antigenicity, conserveness, substantial interactions with the human leukocyte antigen (HLA) binding alleles, and collective global population coverage of 88.40%. Taken together, 276 amino acids long MESV was designed by connecting 3 cytotoxic T lymphocytes (CTL), 6 helper T lymphocyte (HTL) and 4 B-cell epitopes with suitable adjuvant and linkers. The MESV construct was non-allergenic, stable, and highly antigenic. Molecular docking showed a stable and high binding affinity of MESV with human pathogenic toll-like receptors-3 (TLR3). Furthermore, in silico immune simulation revealed significant immunogenic response of MESV. Finally, MEV codons were optimized for its in silico cloning into the Escherichia coli K-12 system, to ensure its increased expression.

Conclusion

The MESV developed in this study is capable of generating immune response against COVID-19. Therefore, if designed MESV further investigated experimentally, it would be an effective vaccine candidate against SARS-CoV-2 to control and prevent COVID-19.
Adverse event profiles of dipeptidyl peptidase-4 inhibitors: data mining of the public version of the FDA adverse event reporting system
Authors: Huang Jing , Jia Yuntao , Sun Shusen , Meng Long
Published: September 2020

Background

To describe and analyze the patterns of adverse events associated with dipeptidyl peptidase-4 inhibitors (DPP-4is) (sitagliptin, saxagliptin, linagliptin, vildagliptin, and alogliptin) from the FDA Adverse Event Reporting System (FAERS) and to highlight areas of safety concerns.

Methods

Adverse events spontaneously submitted to the FAERS between 2004 Q1 to 2019 Q2 were included. The online tool OpenVigil 2.1 was used to query the database. The research relied on definitions of preferred terms (PTs) specified by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ). The reporting odds ratio (ROR), with 95% confidence intervals (CIs) was calculated for disproportionality analysis.

Results

Over 16 years, a total of 9706 adverse event reports were identified. Alogliptin was excluded from further analysis due to insufficient sample size. Compared with the non-insulin antidiabetic drugs, the four DPP-4is were all disproportionately associated with four SMQs: “gastrointestinal nonspecific inflammation and dysfunctional conditions,” “hypersensitivity,” “severe cutaneous adverse reactions,” and “noninfectious diarrhoea”. As for PT level analyses, DPP-4is are associated with higher reporting of the gastrointestinal tract, pancreas, malignancies, infection, musculoskeletal disorders, general disorders, hypersensitivity, and skin AEs.

Conclusions

Data mining of the FAERS is useful for examining DPP-4 inhibitors-associated adverse events. The findings of the present study are compatible with clinical experience, and it provides valuable information to decision-makers and healthcare providers in clinical practice.
Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL
Authors: Liu Wen-Hsin , Mrozek-Gorska Paulina , Wirth Anna-Katharina , Herold Tobias , Schwarzkopf Larissa , Pich Dagmar , Völse Kerstin , Melo-Narváez M. Camila , Carlet Michela , Hammerschmidt Wolfgang , Jeremias Irmela
Published: September 2020

Background

Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors, from the vast amount of tumor descriptive expression data.

Methods

We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap.

Results

With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4.

Conclusion

Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.
Biocontrol potential of Streptomyces sp. CACIS-1.5CA against phytopathogenic fungi causing postharvest fruit diseases
Authors: Evangelista-Martínez Zahaed , Contreras-Leal Erika Anahí , Corona-Pedraza Luis Fernando , Gastélum-Martínez Élida
Published: September 2020

Background

Fungi are one of the microorganisms that cause most damage to fruits worldwide, affecting their quality and consumption. Chemical controls with pesticides are used to diminish postharvest losses of fruits. However, biological control with microorganisms or natural compounds is an increasing alternative to protect fruits and vegetables. In this study, the antifungal effect of Streptomyces sp. CACIS-1.5CA on phytopathogenic fungi that cause postharvest tropical fruit rot was investigated.

Main body

Antagonistic activity was evaluated in vitro by the dual confrontation over fungal isolates obtained from grape, mango, tomato, habanero pepper, papaya, sweet orange, and banana. The results showed that antagonistic activity of the isolate CACIS-1.5CA was similar to the commercial strain Streptomyces lydicus WYEC 108 against the pathogenic fungi Colletotrichum sp., Alternaria sp., Aspergillus sp., Botrytis sp., Rhizoctonia sp., and Rhizopus sp. with percentages ranging from 30 to 63%. The bioactive extract obtained from CACIS-1.5 showed a strong inhibition of fungal spore germination, with percentages ranging from 92 to 100%. Morphological effects as irregular membrane border, deformation, shrinkage, and collapsed conidia were observed on the conidia. Molecularly, the biosynthetic clusters of genes for the polyketide synthase (PKS) type I, PKS type II, and NRPS were detected in the genome of Streptomyces sp. CACIS-1.5CA.

Conclusions

This study presented a novel Streptomyces strain as a natural alternative to the use of synthetic fungicides or other commercial products having antagonistic microorganisms that were used in the postharvest control of phytopathogenic fungi affecting fruits.
UndetectableRAS-Mutant Clones in Plasma: Possible Implication for Anti-EGFR Therapy and Prognosis in Patients WithRAS-Mutant Metastatic Colorectal Cancer
Authors: Bouchahda Mohamed , Saffroy Raphael , Karaboué Abdoulaye , Hamelin Jocelyne , Innominato Pasquale , Saliba Faouzi , Lévi Francis , Bosselut Nelly , Lemoine Antoinette
Published: September 2020

PURPOSE

Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with RAS wild-type ( RAS-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with RAS mutation ( RAS-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was RAS-wt.

MATERIALS AND METHODS

The occurrence of Kirsten rat sarcoma viral oncogene homolog ( KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 ( BRAF), and PI3KCA mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed RAS-mt mCRC had disease progression on previous chemotherapy that contained no anti–epidermal growth factor receptor (EGFR). The patients with RAS-wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with RAS-mt ctDNA were treated with the oncologist’s choice of therapy.

RESULTS

Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified RAS-mt in seven patients (44%) and RAS-wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with RAS-wt ctDNA and 17.9% for those with RAS-mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.

CONCLUSION

Patients with RAS-mt mCRC whose plasma biopsies contained RAS-wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.
Inhibition of BRAF Sensitizes Thyroid Carcinoma to Immunotherapy by Enhancing tsMHCII-mediated Immune Recognition
Authors: Zhi Jingtai , Zhang Peitao , Zhang Wei , Ruan Xianhui , Tian Mengran , Guo Shicheng , Zhang Weiyu , Zheng Xiangqian , Zhao Li , Gao Ming
Published: September 2020

Context

Multiple mechanisms play roles in restricting the ability of T-cells to recognize and eliminate tumor cells.

Objective

To identify immune escape mechanisms involved in papillary thyroid carcinoma (PTC) to optimize immunotherapy.

Setting and Design

iTRAQ analysis was conducted to identify proteins differentially expressed in PTC samples with or without BRAFV600E mutation. Molecular mechanisms regulating tumor cell evasion were investigated by in vitro modulations of BRAF/MAPK and related pathways. The pathological significance of identified tumor-specific major histocompatibility complex class II (tsMHCII) molecules in mediating tumor cell immune escape and targeted immune therapy was further evaluated in a transgenic mouse model of spontaneous thyroid cancer.

Results

Proteomic analysis showed that tsMHCII level was significantly lower in BRAFV600E-associated PTCs and negatively correlated with BRAF mutation status. Constitutive activation of BRAF decreased tsMHCII surface expression on tumor cells, which inhibited activation of CD4+ T-cells and led to immune escape. Pathway analysis indicated that the transforming growth factor (TGF)-β1/SMAD3-mediated repression of tsMHCII, which could be reversed by BRAF inhibition (BRAFi). Targeting this pathway with a combined therapy of BRAF inhibitor PLX4032 and anti-PD-1 antibody efficiently blocked tumor growth by increasing CD4+ T-cell infiltration in a transgenic PTC mouse model.

Conclusions

Our results suggest that BRAFV600E mutation in PTC impairs the expression of tsMHCII through the TGF-β1/SMAD3 pathway to enhance immune escape. Combined treatment with PLX4032 and anti-PD-1 antibody promotes recognition and elimination of PTC by the immune system in a pre-clinical mouse model, and therefore offers an effective therapeutic strategy for patients with advanced PTC.
Prenatal Androgenization Alters the Development of GnRH Neuron and Preoptic Area RNA Transcripts in Female Mice
Authors: Burger Laura L , Wagenmaker Elizabeth R , Phumsatitpong Chayarndorn , Olson David P , Moenter Suzanne M
Published: September 2020

Polycystic ovary syndrome (PCOS) is the most common form of infertility in women. The causes of PCOS are not yet understood and both genetics and early-life exposure have been considered as candidates. With regard to the latter, circulating androgens are elevated in mid–late gestation in women with PCOS, potentially exposing offspring to elevated androgens in utero; daughters of women with PCOS are at increased risk for developing this disorder. Consistent with these clinical observations, prenatal androgenization (PNA) of several species recapitulates many phenotypes observed in PCOS. There is increasing evidence that symptoms associated with PCOS, including elevated luteinizing hormone (LH) (and presumably gonadotropin-releasing hormone [GnRH]) pulse frequency emerge during the pubertal transition. We utilized translating ribosome affinity purification coupled with ribonucleic acid (RNA) sequencing to examine GnRH neuron messenger RNAs from prepubertal (3 weeks) and adult female control and PNA mice. Prominent in GnRH neurons were transcripts associated with protein synthesis and cellular energetics, in particular oxidative phosphorylation. The GnRH neuron transcript profile was affected more by the transition from prepuberty to adulthood than by PNA treatment; however, PNA did change the developmental trajectory of GnRH neurons. This included families of transcripts related to both protein synthesis and oxidative phosphorylation, which were more prevalent in adults than in prepubertal mice but were blunted in PNA adults. These findings suggest that prenatal androgen exposure can program alterations in the translatome of GnRH neurons, providing a mechanism independent of changes in the genetic code for altered expression.
Sleep-length differences are associated with altered longevity in the fruit fly Drosophila melanogaster
Authors: Thompson Jacqueline B. , Su Oanh Oanh , Yang Nou , Bauer Johannes H.
Published: September 2020

Sleep deprivation has been shown to negatively impact health outcomes, leading to decreased immune responses, memory loss, increased activity of stress and inflammatory pathways, weight gain, and even behavioral changes. These observations suggest that sleep deprivation substantially interferes with important physiological functions, including metabolic pathways of energy utilization. Many of those phenotypes are correlated with age, suggesting that disrupted sleep may interfere with the aging process. However, little is known about how sleep disruption affects aging and longevity. Here, we investigate this relationship using eight representative fruit fly lines from the Sleep Inbred Panel (SIP). The SIP consists of 39 inbred lines that display extreme short- and long-sleep patterns, and constitutes a crucial Drosophila community resource for investigating the mechanisms of sleep regulation. Our data show that flies with short-sleep periods have ∼16% longer life span, as well as reduced aging rate, compared to flies with long-sleep. In contrast, disrupting normal circadian rhythm reduces fly longevity. Short-sleep SIP flies moreover show slight metabolic differences to long-sleep lines, and to flies with disrupted circadian rhythm. These data suggest that the inbred SIP lines engage sleep mechanisms that are distinct from the circadian clock system.
The ESCRTs – converging on mechanism
Authors: Remec Pavlin Mark , Hurley James H.
Published: September 2020

The endosomal sorting complexes required for transport (ESCRTs) I, -II and –III, and their associated factors are a collection of ∼20 proteins in yeast and ∼30 in mammals, responsible for severing membrane necks in processes that range from multivesicular body formation, HIV release and cytokinesis, to plasma and lysosomal membrane repair. ESCRTs are best known for ‘reverse-topology’ membrane scission, where they act on the inner surface of membrane necks, often when membranes are budded away from the cytosol. These events are driven by membrane-associated assemblies of dozens to hundreds of ESCRT molecules. ESCRT-III proteins form filaments with a variety of geometries and ESCRT-I has now been shown to also form helical structures. The complex nature of the system and the unusual topology of its action has made progress challenging, and led to controversies with regard to its underlying mechanism. This Review will focus on recent advances obtained by structural in vitro reconstitution and in silico mechanistic studies, and places them in their biological context. The field is converging towards a consensus on the broad outlines of a mechanism that is driven by a progressive ATP-dependent treadmilling exchange of ESCRT subunits, as well as compositional change and geometric transitions in ESCRT filaments.
Overexpression of Mdm36 reveals Num1 foci that mediate dynein-dependent microtubule sliding in budding yeast
Authors: Omer Safia , Brock Katia , Beckford John , Lee Wei-Lih
Published: September 2020

The current model for spindle positioning requires attachment of the microtubule (MT) motor cytoplasmic dynein to the cell cortex, where it generates pulling force on astral MTs to effect spindle displacement. How dynein is anchored by cortical attachment machinery to generate large spindle-pulling forces remains unclear. Here, we show that cortical clustering of Num1, the yeast dynein attachment molecule, is limited by its assembly factor Mdm36. Overexpression of Mdm36 results in an overall enhancement of Num1 clustering but reveals a population of dim Num1 clusters that mediate dynein anchoring at the cell cortex. Direct imaging shows that bud-localized, dim Num1 clusters containing around only six Num1 molecules mediate dynein-dependent spindle pulling via a lateral MT sliding mechanism. Mutations affecting Num1 clustering interfere with mitochondrial tethering but do not interfere with the dynein-based spindle-pulling function of Num1. We propose that formation of small ensembles of attachment molecules is sufficient for dynein anchorage and cortical generation of large spindle-pulling forces.

This article has an associated First Person interview with the first author of the paper.
M. tuberculosisinfection of human iPSDM reveals complex membrane dynamics during xenophagy evasion
Authors: Bernard Elliott M. , Fearns Antony , Bussi Claudio , Santucci Pierre , Peddie Christopher J. , Lai Rachel J. , Collinson Lucy M. , Gutierrez Maximiliano G.
Published: September 2020

Xenophagy is an important cellular defence mechanism against cytosol invading pathogens, such as Mycobacterium tuberculosis (Mtb). Activation of xenophagy in macrophages targets Mtb to autophagosomes, however how Mtb is targeted to autophagosomes in human macrophages at a high spatial and temporal resolution is unknown. Here, we use human induced pluripotent stem cell derived macrophages (iPSDM) to study the human macrophage response to Mtb infection induced by the ESX-1 Type-VII secretion system. Using RNA-seq, we identify ESX-1 dependent transcriptional responses in iPSDM after infection with Mtb. This analysis revealed differential inflammatory responses and dysregulated pathways such as Eukaryotic Initiation Factor 2 (eIF2) signalling and protein ubiquitination. Moreover, live cell imaging revealed that Mtb infection in human macrophages induces dynamic ESX-1-dependent, LC3B positive tubulovesicular autophagosomes (LC3-TVS). Through a correlative live cell/FIB SEM approach, we show that upon phagosomal rupture Mtb induces the formation of LC3-TVS, from which it is able to escape to reside in the cytosol. Thus, iPSDM represent a valuable model for studying spatiotemporal dynamics of human macrophage-Mtb interactions and that Mtb is able to evade capture by autophagic compartments.
BCO App: tools for generating BioCompute Objects from next-generation sequencing workflows and computations
Authors: Xiao Nan , Koc Soner , Roberson David , Brooks Phillip , Ray Manisha , Dean Dennis
Published: September 2020

The BioCompute Object (BCO) standard is an IEEE standard (IEEE 2791-2020) designed to facilitate the communication of next-generation sequencing data analysis with applications across academia, government agencies, and industry. For example, the Food and Drug Administration (FDA) supports the standard for regulatory submissions and includes the standard in their Data Standards Catalog for the submission of HTS data. We created the BCO App to facilitate BCO generation in a range of computational environments and, in part, to participate in the Advanced Track of the precisionFDA BioCompute Object App-a-thon. The application facilitates the generation of BCOs from both workflow metadata provided as plaintext and from workflow contents written in the Common Workflow Language. The application can also access and ingest task execution results from the Cancer Genomics Cloud (CGC), an NCI funded computational platform. Creating a BCO from a CGC task significantly reduces the time required to generate a BCO on the CGC by auto-populating workflow information fields from CGC workflow and task execution results. The BCO App supports exporting BCOs as JSON or PDF files and publishing BCOs to both the CGC platform and to GitHub repositories.
The genome of the American groundhog, Marmota monax
Authors: Puiu Daniela , Zimin Aleksey , Shumate Alaina , Ge Yuchen , Qiu Jiabin , Bhaskaran Manoj , Salzberg Steven L.
Published: September 2020

We sequenced the genome of the North American groundhog, Marmota monax, also known as the woodchuck. Our sequencing strategy included a combination of short, high-quality Illumina reads plus long reads generated by both Pacific Biosciences and Oxford Nanopore instruments. Assembly of the combined data produced a genome of 2.74 Gbp in total length, with an N50 contig size of 1,094,236 bp. To annotate the genome, we mapped the genes from another M. monax genome and from the closely related Alpine marmot, Marmota marmota, onto our assembly, resulting in 20,559 annotated protein-coding genes and 28,135 transcripts. The genome assembly and annotation are available in GenBank under BioProject PRJNA587092.
Assessment of the Personnel Potential of Production Masters Using the Method of Identifying Qualification Deficiencies (on the Example of a Study Conducted in JSC «Kuznetsov»)
Authors: Komarov V. , Fedorchenko G.
Published: September 2020

The article describes the study of the personnel potential of the production masters of a large industrial enterprise. Such studies are of great practical importance, because they reveal hidden reserves associated with insufficient use of human resources, and therefore allow you to find additional ways to improve the efficiency of the organization, increase productivity. The main method of assessing the human resources potential in the article is the method of identifying qualification deficits-indicators that reflect not achieving the required level for a specific competence, lack of specific knowledge or skills, a certain skill in the work of certain employees.

In conditions of increasing changes in all spheres of human life, increasing competition of technologies, services, and goods, the ability of an organization to respond quickly to these changes, correctly assess the skill level of its employees, understand what skill deficits are occurring, and take timely measures to eliminate them is of great importance.

Assess workforce capacity and identify the skill deficits is to obtain reliable and objective data reflecting the quality of human resources of the organization, on which to build effective program of individual and group staff development, which in turn will improve the overall efficiency of the organization.

The article describes the research process itself, its stages and their features, and the main results. The novelty of the study is that a new approach is applied to the formation of indicators for assessing human resources potential, which is demonstrated by a specific example.
Intellectual Potential of a Complex-Structured Region as an Object of Management in the Period of Digitalization
Authors: Mahmudova Muhabbat
Published: September 2020

Objective: to assess the state of research potential of the Tyumen region in the conditions of digitalization of the regional economy.

Methods: on the basis of comparative analysis and graphical interpretation of data, modern regional trends in the state and development of intellectual potential are identified.

Results: during the analyzed period, the scientific sector of the regional economy showed trends in increasing the level of activation, as a result of stimulating the growth of the effectiveness of research institutions on the part of local authorities.

Conclusions: the current state of the regional research sector, the intensity and direction of its development, as well as the effectiveness of the functioning of scientific organizations correspond to the level and specialization of the Tyumen region; and for the long-term maintenance of digital transformation, it is necessary to properly support the implementation of the digitalization policy in an unstable economic environment.
The Implementation of the Mechanism of Management of the Strategic and Tactical Planning System of the Enterprise of the Military-Industrial Complex in the Conditions of Diversification
Authors: Krasnikova A.
Published: September 2020

The types of strategies by type of strategic planning are considered. Efficiency criteria and initial parameters of a diversification strategy are defined: market potential, number of competitors, volumes of civilian products, marketing costs, investments, number of types of raw materials and production resources.

Methodological recommendations on the implementation of the mechanism are proposed organizational and economic management of the strategic and tactical planning of the defense industry enterprise in the context of diversification. The practical use of the mechanism of organizational and economic management of the strategic and tactical planning system of the enterprise in the conditions of diversification is considered at the enterprises of JSC "Electric Machine Building Plant" LEPSE "and PJSC" Kirov Plant "Mayak".
„Jesteście w naszej pamięci”
Authors: Hołda Renata
Published: September 2020

“You are in Our Memory”. Polish Murals as Memory Medium and a Popular Form of Patriotism 

The article elaborates on issues of patriotic murals – a phenomenon with its own history, noticeable not only in Poland. From many such paintings, the author chooses those that are dedicated to members of the post-war, anticommunist underground, known today as the Cursed Soldiers. This kind of creativity can be associated with so called popular patriotism. Patriotic murals are examples of a form of collective memory and at the same time materialization of a medium, that contributes to reproduction of a specific version of the past.
Reaktywacja nordyckich bogów
Authors: Banaś Monika
Published: September 2020

Reactivation of the Norse Gods. Neopaganism as a Form of Collective Memory
The article addresses the issue of neopaganism reviving intensively in the Nordic countries at the beginning of the 21st century. By using examples from Denmark and Iceland the author analyses socio-cultural conditions and intercultural relations that enhance reactivation of the Norse gods. Neopaganism with its Nordic face seems to offer an attractive alternative for contemporary secularized societies which still express inclination to believe in power of the nature, power of the human mind or power of the markets.
„Jedenastka”: konstrukcja i re-konstrukcje pamięci samolotu-symbolu
Authors: Mazur Wojciech
Published: September 2020

The PZL-11: Construction and Re-constructions of How an Aeronautical Symbol is Remembered
The PZL-11 fighter plane, almost immediately after its creation in the early 30s of the 20th century, became recognized in Poland to be one of the greatest achievements of native technological know-how; evidence that in a very short period of time it had attained a world-class level. In September 1939, a little dated, it fought the Luftwaffe. After WW2 it was exploited by the historical politics of the ruling communist party: presented as evidence of the failure of the preceding capitalist system. Over time, however, it has become a symbol of persistent struggle against foreign aggression and of heroic resistance, becoming a significant element of Polish cultural heritage.
Research Roundup
Authors: Winter George
Published: September 2020

George Winter provides an overview of recently published articles that are of interest to practice nurses. Should you wish to look at any of the papers in more detail, a full reference is provided.
The future of automation in primary care
Authors: Hancock Dave
Published: September 2020

Recently published research found that around 44% of administrative and clerical tasks performed in general practice could be mostly or completed automated. Dave Hancock looks at what the future holds for technology and AI in healthcare
Coronavirus lockdown, lifestyle and self-care
Authors: Last Rhian
Published: September 2020

The COVID-19 pandemic has the potential to change our daily lives permanently. What does the evidence tell us about our lockdown habits and possible outcomes for the nation's health when the crisis is over?
Decomposing Matter: From literary critique to language creation
Authors: Palmer Helen , Revelles-Benavente Beatriz
Published: September 2020

This article provides a context for the section “Creating Language and Theorizing Literature”. The editors of the section discuss both contemporary and historicalarticulations of the materiality of language from a new materialist perspective. The new materialist project comprises looking for the immanence of language via three realms: its relation, its theorization, and its creation. Therefore, moving away from representationalist practices demands a definition of language as animate, sensory material requiring creative labour for its realisation. The article provides an example of this materialization of language, via the concept of bodywording.
Doing new materialisms: an interview with Maria Tamboukou
Authors: Tamboukou Maria , Revelles Benavente Beatriz
Published: September 2020

Including an interview as part of the special issue responds to one specific question that has to do with the production of scientific knowledge. During the Training School, the context in which the current special issue is framed, we highlighted the importance of creating inter-generational knowledges able to transverse across disciplines and the historicity of matter itself. The interview that we are transcribing in this journal represents this specific moment between Beatriz Revelles-Benavente (co-editor and co-organizer of the Training School together with Ana M. González) and Maria Tamboukou, a recognized scholar on new materialist methodologies.
Implementation Science of Mindfulness in Intellectual and Developmental Disabilities
Authors: Singh Nirbhay N.
Published: September 2020

Implementation science deals with the translation of evidence-based knowledge into practice in the real world. Mindfulness-based programs for people with intellectual and developmental disabilities (IDD) emerged about 20 years ago. Efficacy and effectiveness studies provide the evidence-base for these programs and the field of IDD is moving towards large scale implementation of these programs. This article presents a model for implementing mindfulness-based programs in community settings, including family and group homes, schools, vocational settings, and congregate care facilities. The model is based on the 3-tier positive behavior support (PBS) system commonly used in school, family, and agency settings. Specific mindfulness-based programs can be linked to each of the three tiers to improve the quality of life of people with IDD.
Health Literacy and Health Outcomes Among Children With Developmental Disabilities: A Systematic Review
Authors: Lindly Olivia , Crossman Morgan , Eaves Megan , Philpotts Lisa , Kuhlthau Karen
Published: September 2020

Developmental disabilities (DDs) are prevalent and associated with health disparities among children. Family health literacy of parents and/or children is one modifiable factor associated with child health; however, little is known about family health literacy for children with DDs. This systematic review was conducted to determine evidence on associations of health literacy with health outcomes among children with DDs. Medline, CINAHL, Embase, ERIC, PsycInfo, and Web of Science were searched through August 2018. Of 2,768 unique records, 53 full text articles were reviewed and four articles were included. Associations of family health literacy with health outcomes among children with DDs were mixed. Future research should include more diverse samples, greater breadth in health outcomes assessed, and increased methodological rigor.
Enhanced Fourier-transform method for high-density fringe analysis by iterative spectrum narrowing
Authors: Nakayama Shigeru , Toba Hidemitsu , Fujiwara Naoki , Gemma Takashi , Takeda Mitsuo
Published: September 2020

We propose a model-based fringe analysis technique that enables the Fourier transform method to analyze dense fringe patterns with large phase variations. The conventional Fourier-transform method has a limited dynamic range of measurable phase because the Fourier spectra broadened by large phase variations cannot be separated by the spatial carrier frequency. Our model-based iterative technique effectively narrows the broad spectrum and reduces phase errors. Results of simulations and experiments are presented that demonstrate the validity of the proposed spectrum-narrowing technique for high-density fringe patterns.
Fourier domain diffuse correlation spectroscopy with heterodyne holographic detection
Authors: James Edward , Powell Samuel
Published: September 2020

We present a new approach to diffuse correlation spectroscopy which overcomes the limited light throughput of single-mode photon counting techniques. Our system employs heterodyne holographic detection to allow parallel measurement of the power spectrum of a fluctuating electric field across thousands of modes, at the shot noise limit, using a conventional sCMOS camera. This yields an order of magnitude reduction in detector cost compared to conventional techniques, whilst also providing robustness to the effects of ambient light and an improved signal-to-noise ratio during in vitro experiments. We demonstrate a GPU-accelerated holographic demodulation system capable of processing the incoming data (79.4 M pixels per second) in real-time, and a novel Fourier domain model of diffuse correlation spectroscopy which permits the direct recovery of flow parameters from the measured data. Our detection and modelling strategy are rigorously validated by modulating the Brownian component of an optical tissue phantom, demonstrating absolute measurements of the Brownian diffusion coefficient in excellent agreement with conventional methods. We further demonstrate the feasibility of our system through in vivo measurement of pulsatile flow rates measured in the human forearm.