bluuebunny/crossref_metadata_2025 huggingface dataset:
[123I]Iomazenil SPECT Detects a Reversible Lesion of the Left Medial Temporal Lobe in a Case of Global Autobiographical Amnesia
Authors: Sehara Yoshihide , Ando Yoshihito , Minezumi Takumi , Funayama Nozomi , Kawai Kensuke , Sawada Mikio
Published: March 2021

Global autobiographical amnesia is a rare disorder that is characterized by a sudden loss of autobiographical memories covering many years of an individual’s life. Generally, routine neuroimaging studies such as CT and MRI yield negative findings in individuals with global autobiographical amnesia. However, in recent case reports, functional analyses such as SPECT and fMRI have revealed changes in activity in various areas of the brain when compared with controls. Studies using iomazenil (IMZ) SPECT with individuals with global autobiographical amnesia have not been reported. We report the case of a 62-year-old Japanese woman with global autobiographical amnesia who had disappeared for ∼4 weeks. [123I]-IMZ SPECT showed reduced IMZ uptake in her left medial temporal lobe and no significant reduction on N-isopropyl-[123I] p-iodoamphetamine (IMP) SPECT in the identical region. Because IMZ binds to the central benzodiazepine receptor, this dissociation between IMZ and IMP SPECT was thought to reflect the breakdown of inhibitory neurotransmission in the left medial temporal lobe. Moreover, when the woman recovered most of her memory 32 months after fugue onset, the IMZ SPECT-positive lesion had decreased in size. Because the woman had long suffered verbal abuse from her former husband’s sister and brother, which can also cause global autobiographical amnesia, it is difficult to conclude whether the IMZ SPECT-positive lesion in the left medial temporal lobe was the cause or the result of her global autobiographical amnesia. Although only one case, these observations suggest that IMZ SPECT may be useful in uncovering the mechanisms underlying global autobiographical amnesia.
Histopathological assessments reveal retinal vascular changes, inflammation and gliosis in patients with lethal COVID-19
Authors: Jidigam Vijay K. , Singh Rupesh , Batoki Julia C. , Milliner Caroline , Sawant Onkar B. , Bonilha Vera L. , Rao Sujata
Published: February 2021

Purpose

To assess for histopathological changes within the retina and the choroid and determine the long-term sequelae of the SARS-CoV-2 infection.

Design

Comparative analysis of human eyes.

Subjects

Eleven donor eyes from COVID-19 positive donors and similar age-matched donor eyes from patients with a negative test for SARS-CoV-2 were assessed.

Methods

Globes were evaluated ex-vivo with macroscopic, SLO and OCT imaging. Macula and peripheral regions were processed for epon-embedding and immunocytochemistry

Main Outcome Measures

Retinal thickness and histopathology, detection of SARS-CoV-2 Spike protein, changes in vascular density, gliosis, and degree of inflammation.

Results

Fundus analysis shows hemorrhagic spots and increased vitreous debris in several of the COVID-19 eyes compared to the control. OCT based measurements indicated an increased trend in retinal thickness in the COVID-19 eyes, however the difference was not statistically significant. Histology of the retina showed presence of hemorrhages and central cystoid degeneration in several of the donors. Whole mount analysis of the retina labeled with markers showed changes in retinal microvasculature, increased inflammation, and gliosis in the COVID-19 eyes compared to the controls. The choroidal vasculature displayed localized changes in density and signs of increased inflammation in the COVID-19 samples.

Conclusions

In situ analysis of the retinal tissue suggested that there are severe subclinical abnormalities that could be detected in the COVID-19 eyes. This study provides a rationale for evaluating the ocular physiology of patients that have recovered from COVID-19 infections to further understand the long-term effects caused by this virus.
Murine norovirus capsid plasticity – Glycochenodeoxycholic acid stabilizes P-domain dimers and triggers escape from antibody recognition
Authors: Creutznacher Robert , Maaß Thorben , Dülfer Jasmin , Feldmann Clara , Hartmann Veronika , Knickmann Jan , Westermann Leon Torben , Smith Thomas J. , Uetrecht Charlotte , Mallagaray Alvaro , Peters Thomas , Taube Stefan
Published: February 2021

The murine norovirus (MNV) capsid protein is the target for various neutralizing antibodies binding to distal tips of its protruding (P)-domain. The bile acid glycochenodeoxycholic acid (GCDCA), an important co-factor for murine norovirus (MNV) infection, has recently been shown to induce conformational changes in surface-loops and a contraction of the virion. Here, we employ protein NMR experiments using stable isotope labeled MNV P-domains to shed light on underlying molecular mechanisms. We observe two separate sets of NMR resonance signals for P-domain monomers and dimers, permitting analysis of the corresponding exchange kinetics. Unlike human norovirus GII.4 P-dimers, which exhibit a half-life in the range of several days, MNV P-dimers are very short lived with a half-life of about 17 s. Addition of GCDCA shifts the equilibrium towards the dimeric form by tightly binding to the P-dimers. In MNV virions GCDCA-mediated stabilization of the dimeric arrangement of P-domains generates a more ordered state, which in turn may entropically assist capsid contraction. Numerous long-range chemical shift perturbations (CSPs) upon addition of GCDCA reflect allosteric conformational changes as a feature accompanying dimer stabilization. In particular, CSPs indicate rearrangement of the E’F’ loop, a target for various neutralizing antibodies. Indeed, treating MNV virions with GCDCA prior to neutralizing antibody exposure abolishes neutralization. These findings advance our understanding of GCDCA-induced structural changes of MNV capsids and experimentally support an intriguing viral immune escape mechanism relying on GCDCA-triggered conformational changes of the P-dimer.

Significance Statement

This study sheds light on the role of glycochenodeoxycholic acid (GCDCA) in promoting murine norovirus (MNV) infection and immune escape. Binding of GCDCA to the dimeric P-domain has been well characterized by crystallography and cryo EM studies, showing that upon GCDCA binding, a 90° rotation of the P-domain occurs, which results in its collapse onto the underlying shell of the virus. Our NMR experiments now reveal P-dimer stability as a new dimension of plasticity of MNV capsids and suggest that capsid contraction is entropically assisted. Conformational changes as a feature of P-dimer stabilization eliminate recognition by neutralizing antibodies, no longer being able to prevent infection. These findings highlight key differences between human and MNV capsid structures, promote our understanding of MNV infection on a molecular level, and reveal a novel immune escape mechanism.
Comprehensive Profiling of Plasma Exosomes Using Data-Independent Acquisitions – New Tools for Aging Cohort Studies
Authors: Patel Sandip K. , Bruderer Roland , Basisty Nathan , Bons Joanna , Desprez Pierre-Yves , Neri Francesco , Reiter Lukas , Campisi Judith , Schilling Birgit
Published: February 2021

Aging is a complex biological process associated with progressive loss of physiological function and susceptibility to several diseases, such as cancer and neurodegeneration. Exosomes are involved in many cellular signaling pathways, and their cargo may serve as promising disease or aging biomarkers. These membrane-bound extracellular vesicles facilitate the transport of intracellular contents to proximal and distal cells in the body. Here, we investigated two omics approaches for exosome analysis. To overcome the challenges of plasma exosome contamination with abundant soluble plasma proteins, we developed a high-throughput method to isolate highly purified exosomes from human plasma by sequential size-exclusion chromatography and ultrafiltration. First, we used data-dependent acquisitions from offline high-pH reversed-phase fractions of exosome lysate to generate a deep spectral library comprising ∼2,300 exosome proteins. Second, in a pilot aging study, we used comprehensive data-independent acquisitions to compare plasma exosomes from young (20–26 yrs) and old (60–66 yrs) individuals. We quantified 1,318 exosome proteins, and levels of 144 proteins were significantly different in young and old plasma groups (Q<0.05 and >1.5-fold change). We also analyzed exosome miRNA cargo and detected 331 miRNAs. Levels of several were significantly different in young and old individuals. In addition, 88 and 17 miRNAs were unique to old and young individuals, respectively. Plasma exosome biomarkers have great potential for translational studies investigating biomarkers of aging and age-related diseases and to monitor therapeutic aging interventions.
Neuronal activity patterns regulate BDNF expression in cortical neurons via synaptic connections and calcium signaling
Authors: Miyasaka Yumi , Yamamoto Nobuhiko
Published: February 2021

During development, cortical circuits are remodeled by spontaneous and sensory-evoked activity via alteration of the expression of wiring molecules. An intriguing question is how physiological neuronal activity modifies the expression of these molecules in developing cortical networks. Here, we addressed this issue, focusing on brain-derived neurotrophic factor (BDNF), one of the factors underlying cortical wiring. Real-time imaging of Bdnf promoter activity in organotypic slice cultures revealed that patterned stimuli differentially regulated the increase and the time course of the promoter activity in upper layer neurons. Calcium imaging further demonstrated that stimulus-dependent increases in the promoter activity were roughly proportional to the increase in intracellular Ca2+concentration per unit time. Finally, optogenetic stimulation showed that the promoter activity was increased efficiently by patterned stimulation in defined cortical circuits. These results suggest that physiological stimulation patterns differentially tune activity-dependent gene expression in developing cortical neurons via cortical circuits, synaptic responses, and alteration of intracellular calcium signaling.
Knowledge syntheses in medical education: Examining author gender, geographic location, and institutional affiliation
Authors: Maggio Lauren A. , Ninkov Anton , Costello Joseph A. , Driessen Erik W. , Artino Anthony R.
Published: March 2021

Purpose

Authors of knowledge syntheses make many subjective decisions during their review process. Those decisions, which are guided in part by author characteristics, can impact the conduct and conclusions of knowledge syntheses, which assimilate much of the evidence base in medical education. Therefore, to better understand the evidence base, this study describes the characteristics of knowledge synthesis authors, focusing on gender, geography, and institution.

Method

In 2020, the authors conducted a case study of authors of 963 knowledge syntheses published between 1999 and 2019 in 14 core medical education journals using a publicly accessible dataset.

Results

The authors of the present study identified 4,110 manuscript authors across all authorship positions. On average there were 4.3 authors per knowledge synthesis (SD=2.51, Median=4, Range=1-22); 79 knowledge syntheses (8%) were single-author publications. Over time, the average number of authors per synthesis increased (M=1.80 in 1999; M=5.34 in 2019). Knowledge syntheses were authored by slightly more females (n=2047; 50.5%) than males (n=2005; 49.5%) across all author positions (Pearson X2=22.02, p<.001). Authors listed affiliations in 58 countries, and 58 knowledge syntheses (6%) included authors from low- or middle-income countries (LMIC). Authors from the United States (n=366; 38%), Canada (n=233; 24%), and the United Kingdom (n=180; 19%) published the most knowledge syntheses. Authors listed affiliation at 617 unique institutions, and first authors represented 362 unique institutions with greatest representation from the University of Toronto (n=55, 6%) and the Mayo Clinic (n=31, 3%). Across all authorship positions, the large majority of knowledge syntheses (n=753; 78%) included authors at top 200 ranked institutions.

Conclusions

Knowledge synthesis author teams have grown over the past 20 years, and while there is near gender parity across all author positions, authorship has been dominated by North American researchers located at highly ranked institutions. This suggests a potential overrepresentation of certain authors with particular characteristics, which may impact the conduct and conclusions of knowledge syntheses in medical education.
Accounting for health inequities in the design of contact tracing interventions: a rapid review
Authors: Mathevet Isadora , Ost Katarina , Traverson Lola , Zinszer Kate , Ridde Valéry
Published: March 2021

Context

Contact tracing has been a central COVID-19 transmission control measure. However, without the consideration of the needs of specific populations, public health interventions can exacerbate health inequities.

Purpose

The purpose of this rapid review was to determine if and how health inequities were included in the design of contact tracing interventions in epidemic settings.

Method

We conducted a search of the electronic databases MEDLINE and Web of Science. Our inclusion criteria included articles that: (i) described the design of contact tracing interventions, (ii) have been published between 2013 and 2020 in English, French, Spanish, Chinese, or Portuguese, (iii) and included at least 50% of empiricism, according to the Automated Classifier of Texts on Scientific Studies (ATCER) tool. We relied on various tools to extract data.

Result

Following the titles and abstracts screening of 230 articles, 39 articles met the inclusion criteria. Only seven references were retained after full text review. None of the selected studies considered health inequities in the design of contact tracing interventions.

Conclusion

The use of tools/concepts for incorporating health inequities, such as the REFLEX-ISS tool, and “proportionate universalism” when designing contact tracing interventions, would enable practitioners, decision makers, and researchers to better consider health inequities.
Targeted Next Generation Sequencing of environmental DNA improves detection and quantification of invasive European green crab (Carcinus maenas)
Authors: Westfall Kristen Marie , Therriault Thomas W. , Abbott Cathryn L.
Published: March 2021

In the northeast Pacific Ocean there is high interest in developing eDNA-based survey methods to aid management of invasive populations of European green crab (Carcinus maenas). Expected benefits are improved sensitivity for early detection of secondary spread and quantification of abundances to assess the outcome of eradication efforts. A new eDNA-based approach we term ‘Targeted Next Generation Sequencing (tNGS)’ is introduced here and shown to improve detection relative to qPCR at low eDNA concentrations, as is characteristic of founding or spreading populations. tNGS is based on the premise that the number of NGS reads from non-normalized (i.e. equal volumes) targeted PCR amplicons will approximate the starting DNA amount. Standard DNA concentrations that were 10-to 100-times lower than the qPCR limit of detection returned significant numbers of sequencing reads, which in our field assessments translated to a 7% - 10% increase in crab detection probability from tNGS relative to qPCR at low abundances. We also found that eDNA concentration was highly correlated with crab abundance, as measured from traditional trapping methods, for both assays; however, tNGS data had greater precision and less error than qPCR. When partitioning the sources of variation in each assay we identified greater between-site variability for tNGS relative to qPCR, suggesting the former may offer more power for detecting spatial variation in eDNA concentration. When applying this assay in management programs, we suggest including a panel of eDNA samples from sites with trapping data as standards to estimate relative abundance at sites with no a priori information. Results presented here indicate the tNGS approach has great promise for surveillance of green crab and could easily be adopted for surveillance of any species of high interest to management, including endangered species, new incursions of invasive species, and species with low eDNA shedding rates. Pros and cons of this approach compared to qPCR are discussed.
Pericentromeric heterochromatin impacts genome compartmentalization and sex chromosome evolution in a fish
Authors: Xue Lingzhan , Gao Yu , Wu Meiying , Fan Haiping , Huang Yongji , Huang Zhen , Li Dapeng , Xu Luohao
Published: March 2021

Compartmentalization is one of the principles of chromosome 3D organization and has been suggested to be driven by the attraction of heterochromatin. The extent to which the pericentromeric heterochromatin (PCH) impacts chromosome compartmentalization is yet unclear. Here we produced a chromosome-level and fully phased diploid genome of an aquaculture fish, zig-zag eel (Mastacembelus armatus), and identified the centromeric and pericentromeric regions in the majority of chromosomes of both haploid genomes. The PCH is on average 4.2 Mb long, covering 17.7% of the chromosomes, and is the major target of histone 3 lysine 9 trimethylation (H3K9me3). In nearly half of the chromosomes, the PCH drives the chromosomes into two or three megascale chromatin domains with the PCH being a single one. We further demonstrate that PCH has a major impact in submetacentric, metacentric and small telocentric chromosomes in which the PCH drives the distribution of active and inactive compartments along the chromosomes. Additionally, we identified the young and homomorphic XY sex chromosomes that are submetacentric with the entire short-arm heterochromatinized. Interestingly, the sex-determining region seems to arise within the PCH that has been in place prior to the X-Y divergence and recombination suppression. Together, we demonstrate that the PCH can cover a considerably large portion of the chromosomes, and when it does so, it drives chromosome compartmentalization; and we propose a new model for the origin and evolution of homomorphic sex chromosomes in fish.
Strong and Significant Associations of Single Nucleotide Variants (SNVs) in the Promoter and 3’-Untranslated Region (3’-UTR) ofVascular Endothelial Growth Factor(VEGF) Gene with Head and Neck Cancers
Authors: Ajaz Sadia , Muneer Rabbia , Siddiqa Aisha , Memon Muhammad Ali , Firasat Sadaf , Abid Aiysha , Khaliq Shagufta
Published: March 2021

Background

Vascular Endothelial Growth Factor (VEGF) has a potent role in tumorigenesis and metastasis. However, data for the role of common single nucleotide variants (SNVs) in the highly polymorphicVEGFgene in head and neck cancers (HNCs) is limited in general and unavailable in South Asian populations.

The present study addresses this shortfall. It investigates the association of twoVEGFSNVs, −2578 C/A (rs699947) in the promoter region and +936 C/T (rs3025039) in 3’-UTR, with the risk of HNCs and tumour characteristics.

Methods

The study comprised 323 participants with 121 HNC patients and 202 controls. Germline DNA was isolated from peripheral blood samples. PCR-RFLP methods were optimized and validated by Sanger sequencing. After Hardy-Weinberg evaluation, the independent associations were analyzed by applying genetic models. The χ2test of independence or Fisher’s Exact test (significant p-values at <0.05) were performed and ORs (odds ratios) with 95% confidence interval were tabulated.

Results

VEGF−2578 A-allele, A-carrier and AA genotypes had significant protective association against HNCs. The respective ORs were: 0.651 (0.469 – 0.904), 0.613 (0.381 – 0.985), and 0.393 (0.193 – 0.804).VEGF+936 T-allele, CT and T-carrier genotypes had significantly increased susceptibility for HNCs. The respective ORs were 1.882 (1.001 – 3.536), 2.060 (1.035 – 4.102), and 2.023 (1.032 – 3.966). Additionally,VEGF+936 CT and T-carrier genotypes showed significant associations with higher tumour grade (p-value <0.029, and <0.037, respectively).

Conclusion

The present study is the foremost report of independent and unique associations of the investigatedVEGFSNVs with HNCs.
Searching for prognostic biomarkers of Parkinson’s Disease development in the Spanish EPIC cohort through a multiplatform metabolomics approach
Authors: Gonzalez-Riano Carolina , Saiz Jorge , Barbas Coral , Bergareche Alberto , Huerta José Ma , Ardanaz Eva , Konjevod Marcela , Mondragon Elisabet , Erro ME , Chirlaque M. Dolores , Abilleira Eunate , Goñi-Irigoyen Fernando , Amiano Pilar
Published: March 2021

Objective

The lack of knowledge about the onset and progression of Parkinson’s disease (PD) hampers its early diagnosis and treatment. Our aim was to determine the biochemical remodeling induced by PD in a really early and pre-symptomatic stage and unveiling early potential diagnostic biomarkers adopting a multiplatform (LC-MS, GC-MS, CE-MS) untargeted metabolomics approach.

Methods

41,437 healthy volunteers from the European Prospective Study on Nutrition and Cancer (EPIC)-Spain cohort were followed for around 15 years to ascertain incident PD. For this study, baseline pre-clinical plasma samples of 39 randomly selected individuals (46% females, 41– 69 years old) that developed PD (Pre-PD group) and the corresponding control group (n=39, 46% females, 41–69 years old) were analyzed. The metabolic differences were investigated by univariate and multivariate data analyses, followed by pathway-based metabolite analyses to obtain possible clues on biological functions.

Results

Our results exposed significantly lower levels of seven free fatty acids in the pre-PD subjects, together with alterations in other metabolite classes. Our finding revealed alterations in fatty acids metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation.

Conclusions

Although the biological purpose of these events is still unknown, the mechanisms involved in the remodelling of the suggested metabolic pathways seem to appear long before the development of PD hallmarks. These findings might be considered as worthy potential markers whose alteration might lead to the development of PD hallmarks in the future. Consequently, this study is of inestimable value since this is the first study conducted with samples collected many years before the disease development.
Meeting experiments at the diffraction barrier: anin-silicowidefield fluorescence microscopy
Authors: Mahajan Subhamoy , Tang Tian
Published: March 2021

Fluorescence microscopy allows the visualization of live cells and their components, but even with advances in super- resolution microscopy, atomic resolution remains unattainable. On the other hand, molecular simulations (MS) can easily access atomic resolution, but comparison with experimental microscopy images has not been possible. In this work, a novelin-silicowidefield fluorescence microscopy is proposed, which reduces the resolution of MS to generate images comparable to experiments. This technique will allow cross-validation and compound the knowledge gained from experiments and MS. We demonstrate thatin-silicoimages can be produced with different optical axis, object focal planes, exposure time, color combinations, resolution, brightness and amount of out-of-focus fluorescence. This allows the generation of images that resemble those obtained from widefield, confocal, light-sheet, two-photon and super-resolution microscopy. This technique not only can be used as a standalone visualization tool for MS, but also lays the foundation for otherin-silicomicroscopy methods.
Role of BRCA2 DNA-binding and C-terminal domain on its mobility and conformation in DNA repair
Authors: Paul Maarten W. , Sidhu Arshdeep , Liang Yongxin , van Rossum-Fikkert Sarah E. , Odijk Hanny , Zelensky Alex N. , Kanaar Roland , Wyman Claire
Published: March 2021

BRCA2 is an essential protein in genome maintenance, homologous recombination and replication fork protection. Its function includes multiple interaction partners and requires timely localization to relevant sites in the nucleus. We investigated the importance of the highly conserved DNA binding domain (DBD) and C-terminal domain (CTD) of BRCA2. We generated BRCA2 variants missing one or both domains in mouse ES cells and defined their contribution in HR function and dynamic localization in the nucleus, by single particle tracking of BRCA2 mobility. Changes in molecular architecture of BRCA2 induced by binding partners of purified BRCA2 was determined by scanning force microscopy. BRCA2 mobility and DNA damage-induced increase in the immobile fraction was largely unaffected by C- terminal deletions. The purified proteins missing CTD and/or DBD were defective in architectural changes correlating with reduced homologous recombination function in cells. These results emphasize BRCA2 activity at sites of damage beyond promoting RAD51 delivery.
PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
Authors: Fowle Holly , Zhao Ziran , Xu Qifang , Wang Xinru , Adeyemi Mary , Feiser Felicity , Kurimchak Alison , Kettenbach Arminja N. , Page Rebecca , Peti Wolfgang , Dunbrack Roland L. , Graña Xavier
Published: March 2021

Protein phosphorylation is a reversible post-translation modification essential in cell signaling. This study addresses a long-standing question as to how the most abundant serine/threonine Protein Phosphatase 2 (PP2A) holoenzyme, PP2A/B55α, specifically recognizes substrates and presents them to the enzyme active site. Here, we show how the PP2A regulatory subunit B55α recruits p107, a pRB-related tumor suppressor and B55α substrate. Using molecular and cellular approaches, we identified a conserved region 1 (R1, residues 615-626) encompassing the strongest p107 binding site. This enabled us to identify an “HxRVxxV619-625” short linear motif (SLiM) in p107 as necessary for B55α binding and dephosphorylation of the proximal pSer-615in vitroand in cells. Numerous B55α/PP2A substrates, including TAU, contain a related SLiM C-terminal from a proximal phosphosite, “p[ST]-P-x(5-10)-[RK]-V-x-x-[VI]-R”. Mutation of conserved SLiM residues in TAU dramatically inhibits dephosphorylation by PP2A/B55α, validating its generality. A data-guided computational model details the interaction of residues from the conserved p107 SLiM, the B55α groove, and phosphosite presentation. Altogether these data provide key insights into PP2A/B55α mechanisms of substrate recruitment and active site engagement, and also facilitate identification and validation of new substrates, a key step towards understanding PP2A/B55〈 role in multiple cellular processes.
State-Transition Analysis of Time-Sequential microRNA Expression Predicts Development of Acute Myeloid Leukemia
Authors: Frankhouser D. E. , O’Meally D. , Branciamore S. , Uechi L. , Qin H. , Wu X. , Carlesso N. , Marcucci G. , Rockne R. C. , Kuo Ya-Huei
Published: March 2021

MicroRNAs (miRNAs) are small non-coding RNA molecules involved in post-transcriptional regulation of gene expression and have been shown to hold prognostic value in a variety of settings, including acute myeloid leukemia (AML). However, the temporal dynamics of miRNA expression profiles as it relates to AML initiation and progression is poorly understood. Using serial samples from a mouse model of AML, we show that the miRNA transcriptome undergoes state-transition during AML initiation and progression. The AML state-transition was visualized and modeled by constructing an AML state-space from singular value decomposition of the time-series miRNA sequencing data. Within the AML state-space, we identified critical points of AML development characterized by unique differentially expressed miRNAs compared to healthy controls at critical points of leukemogenesis (early, transition, and late). Interestingly, we observed that changes in miRNA expression during leukemogenesis followed two patterns: 1) a monotonic pattern with continuously increasing or decreasing expression; and 2) a non-monotonic pattern with a local maximum or minimum at the transition critical point which was the “point of no-return” from health to AML. We validated the AML state-space and dynamics in an independent cohort of mice and demonstrated the state-transition model accurately predicted time to AML. Of note, we show that the miRNA-derived state-transition model produced a state-space and critical points that were strikingly similar, but not identical to that produced by the coding (i.e., messenger [m]RNA-based) transcriptome. This indicates that while both miRNA and mRNA expression may provide similar information, they also capture independent features of AML state-transition.

Significance

We show that the microRNA transcriptome undergoes a global state transition during the initiation and progression of acute myeloid leukemia, and accurately predicts time to disease development.
Compositional analysis of ALS-linked stress granule-like structures reveals factors and cellular pathways dysregulated by mutant FUS under stress
Authors: An Haiyan , Litscher Gioana , Wei Wenbin , Watanabe Naruaki , Hashimoto Tadafumi , Iwatsubo Takeshi , Buchman Vladimir L. , Shelkovnikova Tatyana A.
Published: March 2021

Formation of cytoplasmic RNA-protein structures called stress granules (SGs) is a highly conserved cellular response to stress. Abnormal metabolism of SGs may contribute to the pathogenesis of (neuro)degenerative diseases such as amyotrophic lateral sclerosis (ALS). Many SG proteins are affected by mutations causative of these conditions, including fused in sarcoma (FUS). Mutant FUS variants have high affinity to SGs and also spontaneously formde novocytoplasmic RNA granules. Mutant FUS-containing assemblies (mFAs), often called “pathological SGs”, are proposed to play a role in ALS-FUS pathogenesis. However, global structural differences between mFAs and physiological SGs remain largely unknown, therefore it is unclear whether and how mFAs may affect cellular stress responses. Here we used affinity purification to characterise the protein and RNA composition of normal SGs and mFAs purified from stressed cells. Comparison of the SG and mFA proteomes revealed that proteasome subunits and certain nucleocytoplasmic transport factors are depleted from mFAs, whereas translation elongation, mRNA surveillance and splicing factors as well as mitochondrial proteins are enriched in mFAs, as compared to SGs. Validation experiments for a hit from our analysis, a splicing factor hnRNPA3, confirmed its RNA-dependent sequestration into mFAs in cells and into pathological FUS inclusions in a FUS transgenic mouse model. Furthermore, silencing of theDrosophilahnRNPA3 ortholog dramatically enhanced FUS toxicity in transgenic flies. Comparative transcriptomic analysis of SGs and mFAs revealed that mFAs recruit a significantly less diverse spectrum of RNAs, including reduced recruitment of transcripts encoding proteins involved in protein translation, DNA damage response, and apoptotic signalling. However mFAs abnormally sequester certain mRNAs encoding proteins involved in stress signalling cascades. Overall, our study establishes molecular differences between physiological SGs and mFAs and identifies the spectrum of proteins, RNAs and respective cellular pathways affected by mFAs in stressed cells. In conclusion, we show that mFAs are compositionally distinct from SGs and that they cannot fully substitute for SG functions while gaining novel, potentially toxic functions in cellular stress response. Results of our study support a pathogenic role for stress-induced cytoplasmic FUS assemblies in ALS-FUS.
« Idol with feet of clay »: reliable predictions of forest ecosystem functioning require flawless climate forcings
Authors: Jourdan M. , François C. , Delpierre N. , Martin St-Paul N. , Dufrêne E.
Published: March 2021

Climate change affects various aspects of the functioning of ecosystem, especially photosynthesis, respiration and carbon storage. We need accurate modelling approaches (impact models) to simulate the functioning, vitality and provision of ecosystem services of forests in a warmer world. These impact models require climate data as forcings, which are often produced by climate models comparing more or less well with observational climate data. The bias percentage of the climate forcings propagates throughout the modeling chain from the climate model to the impact model.

In this study, we aimed to quantify these bias percentage, addressing three questions: (1) Do the impact model predictions vary when forcing it with different climate models, and how do the predictions under climate model vs. observational climate forcing differ? (2) Does the variability in the impact climate simulations caused by climate forcings fade out at large spatial scale? (3) How the fact of using simulated climatic data affects the process-based model predictions in the case of stressful events?

To answer these questions, we present results obtained over the historical period (e.g. 1970-2010) with the CASTANEA ecophysiological forest model and use the data from three climate models. Our analysis focuses on French forests, studying European beech (Fagus sylvatica), temperate deciduous oaks (Quercus roburandQ. petraea), Scots pine (Pinus sylvestris) and spruce (Picea abies) monospecific stands.

We show that prediction of photosynthesis, respiration and wood growth highly depends on the climate model used, whether debiased or not, and also on species and region considered. Overall, we observed an improvement of prediction after a monthly mean bias or monthly quantile mapping correction for three model considered, but not with the same success. Then we highlighted a large variability in the processes simulated by the impact model under different climate forcings when considering the plot (i.e. scale of a few hectares) scale. This variability fades out at larger scale (e.g. the scale of an ecological region, i.e. 100 km2), owing to an aggregation effect. Moreover, process predictions obtained under different climate forcings are more variable during driest years. These results highlight the necessity to quantify bias and uncertainties in climate forcings before predicting fluxes dynamics with process-based model.
Understanding self‐affirmation effects: The moderating role of self‐esteem
Authors: Zhu Xuan , Yzer Marco
Published: February 2021

Objectives

Whether people benefit from self‐affirmation in overcoming resistance to health messages may depend on their level of self‐esteem. However, extant theories offer rival hypotheses about the role of self‐esteem. We pitted these hypotheses against each other, building on the argument that how self‐esteem shapes self‐affirmation effects may depend on how and when people self‐affirm.

Design

A 3 (Self‐affirmation type: value essay, attribute scale, control task) by 2 (Timing: pre‐message, post‐message) plus 1 (message‐only) experimental, between‐subjects design.

Methods

Participants (N = 422) completed a value essay, an attribute scale, a control task, or no task, either before or after reading a message about health risks of excessive drinking. Participants then completed defensiveness and message acceptance measures.

Results

Self‐esteem moderated self‐affirmation effects across different types and timing of self‐affirmation. While participants with relatively high self‐esteem consistently benefited from self‐affirmation, participants with relatively low self‐esteem experienced adverse effects from self‐affirmation. Self‐affirmed participants with high self‐esteem showed lower psychological discomfort, lower personal risk discounting, and higher message acceptance than unaffirmed participants, while self‐affirmed participants with low self‐esteem showed higher psychological discomfort, higher personal risk discounting, and lower message acceptance than unaffirmed participants.

Conclusions

These findings support the proposition that self‐esteem serves as affirmational resources, which implies that self‐affirmation interventions to reduce defensiveness to health messages may be beneficial for people with high self‐esteem but less so for people with lower self‐esteem. Similar to much other self‐esteem research, self‐esteem was negatively skewed, which warrants caution in generalization of the findings across all levels of self‐esteem.
Helicobacterpylori inhibits autophagic flux and promotes its intracellular survival and colonization by down‐regulating SIRT1
Authors: Wang Xin , Wang Bo , Gao Wei , An Yifei , Dong Guoying , Jia Jihui , Yang Qing
Published: February 2021

Helicobacter pylori (H. pylori) is the strong risk factor for a series of gastric pathological changes. Persistent colonization of H. pylori leading to chronic infection is responsible for gastritis and malignancy. Autophagy is an evolutionary conserved process which can protect cells and organisms from bacterial infection. Here, we demonstrated that H. pylori infection induced autophagosome formation but inhibited autophagic flux. SIRT1, a class III histone deacetylase, was down‐regulated at both mRNA and protein levels by H. pylori infection in gastric cells. Further investigation showed that the transcriptional factor RUNX3 accounted for down‐regulation of SIRT1 in H. pylori‐infected gastric cells. SIRT1 promoted autophagic flux in gastric cells and activation of SIRT1 restored the autophagic flux inhibited by H. pylori infection. Furthermore, SIRT1 exerted inhibitory effects on intracellular survival and colonization of H. pylori. And activation of autophagic flux in SIRT1‐inhibited gastric cells could significantly reduce intracellular load of H. pylori. Moreover, the relationship between H. pylori infection and SIRT1 expression was identified in clinical specimen. Our findings define the importance of SIRT1 in compromised autophagy induced by H. pylori infection and bacterial intracellular colonization. These results provide evidence that SIRT1 can serve as a therapeutic target to eradicate H. pylori infection.
A mixed‐methods study to evaluate the acceptability of information leaflets for breast cancer screening
Authors: Fernández‐Feito Ana , Canga‐Gutiérrez Carlos , Paz‐Zulueta María
Published: March 2021

Aims and objectives

To obtain feedback regarding the comprehension and acceptability of an information leaflet on breast cancer screening among women.

Background

Women usually receive a leaflet inviting them to participate in breast cancer screening programmes for early detection of breast cancer. These leaflets include relevant information about mammograms to aid with decision‐making. It is important to know how the target population perceives these leaflets, as this may influence the attitude towards breast cancer screening.

Design

A mixed‐methods study (concurrent triangulation design).

Methods

Participants were 41 women aged between 40–60 years in the north of Spain. The leaflet included information about breast cancer, mammograms, benefits/risks of screening, and the breast cancer mortality and survival rates in relation to screening. Three written methods were used to assess the leaflet: a readability assessment (Flesch Index) and two comprehension assessments (Cloze and multiple‐choice questions). In addition, 26 semi‐structured interviews were conducted to explore the women's opinions regarding comprehension, acceptability and the contribution of the leaflet as a decision aid. The COREQ checklist was used to guarantee the quality and rigour of the qualitative study.

Results

Overall, women found the leaflet fairly easy to read and most understood the content. Some women found the information on mortality alarming, difficult to understand and a cause for rejection. The leaflet was viewed as a decision aid, although further information was requested on mammograms, the need for complementary tests and the risks and symptoms of breast cancer.

Conclusion

The leaflet was accepted by women and, overall, easy to understand. The participation of the target population enabled the content and format of the leaflet to be adjusted to their needs.

Relevance for clinical practice

Nurses can contribute towards improving the breast cancer screening leaflets, considering women's perceptions surrounding screening.
ACCOUNTING FOR GROWTH IN HISTORY
Authors: Prados de la Escosura Leandro , Vonyó Tamás , Voskoboynikov Ilya B.
Published: February 2021

The contributions to this Special Issue present the state of the art of growth accounting in economic history, exhibiting its strengths and weaknesses. Three set of articles compose the issue: comparative papers that discuss the challenges ahead, long‐run perspectives on Britain since the Industrial Revolution, Japan, Italy and Spain from the late‐19th century, and Latin America during the 200 years since independence, and post‐World War II episodes under Soviet and Fabian socialism and the transition to market economies in Eastern Europe and India. The papers reveal how sensitive the interpretation of results is to the quality of output and inputs and the growth accounting procedure employed and the need to adopt the new developments in growth accounting to improve economic history narrative.
Multifocal skeletal tuberculosis with mycobacteremia after kidney transplantation: A case report
Authors: Ramírez‐Sánchez Isabel Cristina , García Karen , Nieto‐Ríos John Fredy
Published: March 2021

Solid organ transplant recipients have a higher risk of active Mycobacterium tuberculosis infection (TB) compared to the general population. Recognized risk factors are immunosuppressant use, graft dysfunction, diabetes mellitus, liver disease caused by the hepatitis C virus, and co‐infections by other opportunists. Most of the active TB cases reported in solid organ transplant recipients occur in kidney transplant patients, especially if they come from M tuberculosis‐endemic areas. Extrapulmonary and disseminated TB are among the wide spectrum of clinical presentations found, but the lungs are the most common organ affected. Disseminated disease occurs in up to a third of the affected population, however, multifocal osteoarticular TB with mycobacteremia is unusual. We report the case of a kidney transplant patient with disseminated M tuberculosis infection, who presented with multifocal skeletal TB.
Imagen militar, capitales en juego y tanatopolítica
Authors: Clavijo Poveda Jairo , Mc Allister Andrade Juan Camilo
Published: March 2021

A partir del estudio de la imagen de sí y del enemigo de la sociedad en los márgenes del Estado, este artículo presenta un análisis de la lógica militar en torno a las nociones de lo humano y del orden en la serie televisiva Hombres de honor. La serie expone a un ejército comprometido con la población civil, especialmente en las llamadas zonas de conflicto, y muestra el carácter humano de los militares más allá del rol de soldados entrenados para la guerra. El análisis de la serie nos permite comprender tanto el campo del poder, como la tanatopolítica que enmarca la lógica de las acciones bélicas en la imagen. Para este análisis, se determinaron los capitales en juego y su jerarquía en el campo militar, y desde allí se exploró la estructuración binaria y narrativas sobre la fuerza pública y los enemigos de la sociedad. En este contexto, la superioridad del ejército legitima desde el biopoder los valores militares como modelo moral para toda la sociedad.
Temperature Effects in a Laminar Compressible-Fluid Boundary Layer Along a Flat Plate
Authors: Emmons H. W. , Brainerd J. G.
Published: March 2021

In this paper the two-dimensional boundary-layer problem of the steady laminar flow of a perfect gas along a thin flat insulated plate has been solved for a wide range of gas velocities and properties. It is found that compressibility and Prandtl number do not introduce any new phenomena, but do alter the drag on the plate, the equilibrium temperature of the plate, and the velocity and temperature distribution through the boundary layer. The drag coefficient for the plate is given by Equation [24] together with Fig. 2. The temperature of the plate is given by Equation [27 a or b], and approximately by Equation [26] or by Figs. 3 or 4. Typical velocity and temperature distributions are given in Figs. 5 to 10, inclusive.
Analysis of Longitudinal Motions in Trains of Several Cars
Authors: Dudley Winston M.
Published: March 2021

Heretofore, longitudinal motions in trains have usually been studied by assuming that the train can be replaced by a bar whose mass and elasticity are uniformly distributed. By means of a long-neglected branch of mathematics known as “difference equations,” it is easy to solve motion problems for trains of concentrated masses connected by springs.

Motion curves are given for a train of five uniform cars, also for one of five nonuniform cars, following a bump at one end. A motion curve is given for the uniform train when constant forces are applied in succession to the cars. The methods shown make it possible to find the effect of any ordinary force system in far less time than by older procedures.

The velocity of waves of force in a train is discussed. It is shown that the elastic-bar assumption gives large errors for this speed. A better approximation is suggested.
Torsional and Flexural Buckling of Bars of Thin-Walled Open Section Under Compressive and Bending Loads
Authors: Goodier J. N.
Published: March 2021

The observed behavior of torsionally weak columns in buckling by twisting rather than, or as well as, bending is analyzed in this paper on the basis of a hypothesis due to Wagner. The theory is simplified, and extended to the general section, where results simpler than some already obtained by Kappus are given. It is further extended to bars, restrained by flexible sheets, and bars with constrained axes of rotation. Wagner’s hypothesis is applied to the problem of lateral buckling, where it yields the accepted theory for symmetrical sections, but indicates results of novel form for unsymmetrical cases. Similar results are obtained in the problem of eccentric thrust, whatever the section.
Computer‐Aided Diagnosis Research of a Lung Tumor Based on a Deep Convolutional Neural Network and Global Features
Authors: Lu Huiling
Published: February 2021

Based on the better generalization ability and the feature learning ability of the deep convolutional neural network, it is very significant to use the DCNN on the computer‐aided diagnosis of a lung tumor. Firstly, a deep convolutional neural network was constructed according to the fuzzy characteristics and the complexity of lung CT images. Secondly, the relation between model parameters (iterations, different resolution) and recognition rate is discussed. Thirdly, the effects of different model structures for the identification of a lung tumor were analyzed by changing convolution kernel size, feature dimension, and depth of the network. Fourthly, the different optimization methods on how to influence the DCNN performance were discussed from three aspects containing pooling methods (maximum pooling and mean pooling), activation function (sigmoid and ReLU), and training algorithm (batch gradient descent and gradient descent with momentum). Finally, the experimental results verified the feasibility of DCNN used on computer‐aided diagnosis of lung tumors, and it can achieve a good recognition rate when selecting the appropriate model parameters and model structure and using the method of gradient descent with momentum.