bluuebunny/crossref_metadata_2025 huggingface dataset:
Recognition and Outcomes of Pneumococcal Meningitis in 2 Tertiary Pediatric Hospitals Since the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine
Authors: Stevens James Patrick , Lively Austin , Jerris Robert , Yildirim Inci , Lantis Patricia
Published: November 2020

Objectives

The aims of the study were to analyze the demographics, presentation, laboratory findings, and complications of pediatric Streptococcus pneumoniae meningitis since the introduction of the 13-valent pneumococcal conjugate vaccine, to improve recognition, and to minimize patient morbidity and mortality.

Methods

This study used a retrospective analysis of pediatric pneumococcal meningitis cases at 2 tertiary healthcare systems in the Southeastern United States from 2010 to 2018.

Results

We describe 21 cases of pneumococcal meningitis. All patients presented with fever, 95% had altered mental status by history or examination, and 48% had meningeal signs. Forty-three percent had seen another provider within 48 hours of admission. Forty-eight percent had delay in lumbar puncture (LP) of more than 6 hours after antibiotic administration, decreasing rates of positive cerebrospinal fluid cultures from 100% to 40% (P < 0.001). Decision to delay LP was due to either low suspicion for meningitis (n = 4) or clinical instability (n = 6) and was associated with lower rates of meningeal signs (P = 0.014) and higher rates of altered mental status on examination (P = 0.031). Fourteen patients (67%) were up-to-date on pneumococcal immunization. Serotypes were determined in 16 cases, with 2 patients (13%) immunized against the strain that infected them. Primary outcomes included seizures (48%), hearing loss (48%), cranial nerve palsy (33%), and death (5%). Delay in LP with low suspicion for meningitis was associated with longer hospital length of stay approaching statistical significance (P = 0.053).

Conclusions

Pneumococcal meningitis remains a relevant and potentially fatal disease despite widespread use of 13-valent pneumococcal conjugate vaccine. Its diagnosis is often delayed during interactions with physicians, which may put patients at increased risk for poor clinical outcomes.
FDG-Avid Lung Nodule Formation by the Use of Hemostatic Powder
Authors: Oksuzoglu Kevser , Ones Tunc , Bozkurtlar Emine , Bostanci Korkut , Tureli Derya
Published: November 2020

FDG PET/CT is used in the diagnosis and follow-up of various malignant tumors and changes patient management in routine clinical practice. However, inflammatory, infectious, physiological, and technical causes and benign pathological conditions may lead to false-positive FDG uptake. We report a case of a 59-year-old man who was considered having a false-positive FDG-PET pulmonary nodular lesion in favor of metastasis, which was formed by the use of hemostatic powder.
Detection of Dural Metastases Before the Onset of Clinical Symptoms by 16α-[18F]Fluoro-17β-Estradiol PET in a Patient With Estrogen Receptor–Positive Breast Cancer
Authors: Boers Jorianne , Schröder Carolina P. , Hospers Geke A. P. , de Vries Erik F. J. , Glaudemans Andor W. J. M.
Published: November 2020

We offer an illustrative case about estrogen receptor (ER) imaging (also known as 16α-[18F]fluoro-17β-estradiol ([18F]-FES) PET) and the detection of metastatic lesions in the dural region. We present a case of a woman with ER-positive metastatic breast cancer and high [18F]-FES uptake in the dural region on PET imaging, without associated clinical symptoms. These lesions were missed on [18F]-FDG PET because of physiological [18F]-FDG uptake in the brain. This case highlighted some difficulties in the interpretation of imaging of brain metastases and demonstrated the added value of [18F]-FES PET imaging. [18F]-FES PET could be used to prove the presence of ER-positive metastases in the brain.
18F-FDG PET/CT in a Rare Case of Poland Syndrome and Gastric Cancer
Authors: Loharkar Sarvesh , Malhotra Gaurav , Asopa Ramesh V.
Published: November 2020

Poland syndrome is a rare congenital anomaly characterized by unilateral aplasia of the sternoclavicular head of pectoralis major muscle with varying degree of same side upper limb anomalies. A 44-year-old man, with a case of adenocarcinoma of stomach, whose CECT chest revealed complete absence of pectoralis major and minor muscles on the left side, was diagnosed with Poland syndrome without presence of typical ipsilateral limb anomalies. Follow-up PET/CT revealed metabolically active recurrent disease with typical findings of Poland syndrome. It is important to be aware of oncologic association in a patient of Poland syndrome as highlighted in the present case.
Evoked Potentials in Patients With Wilson Disease
Authors: Mihaylova Violeta M. , Kosseva Olga R. , Kotzev Iskren A. , Georgiev Georgi , Kremensky Ivo M. , Todorov Teodor N. , Tournev Ivaylo L.
Published: November 2020

Introduction:

Wilson disease (WD) is an inherited disorder of copper metabolism presenting with a variety of symptoms but commonly as a liver or neuropsychiatric disease. Abnormal evoked responses are constantly found among patients with neurologic manifestations and sometimes in patients with hepatic presentation or in presymptomatic siblings. The aim of our study was to assess visual and brainstem auditory evoked potentials (BAEP) in patients with various presentation of WD.

Methods:

Visual evoked potentials (VEP) were performed in 36 WD patients and BAEP were done in 37 WD patients.

Results:

Brainstem auditory evoked potentials were normal in patients with isolated hepatic presentation, whereas they were abnormal in 93.5% of patients with neurologic symptoms. There was significant prolongation of the latencies of the III and V waves and of the interpeak III–V and I–V latencies in comparison with the healthy controls (T-test P = 0). Abnormal VEP were observed in 81% of the patients including six of seven neurologically asymptomatic patients. The values of N75, P100, and N145 latencies were significantly longer in all patients than in healthy controls (T-test).

Conclusions:

The data showed that VEP and BAEP are more frequently abnormal in WD than previously reported. The abnormal VEP and BAEP even without clinical signs and brain MRI abnormalities point to subclinical involvement of visual and auditory pathways caused by copper toxicity. Because VEP and BAEP are noninvasive and widely available, they should be performed in all patents with WD.
Seroprevalence of hepatitis B, hepatitis C and HIV infection among patients undergoing haemodialysis in Buenos Aires, Argentina
Authors: Pereson Matías J. , Martínez Alfredo P. , Isaac Katia , Laham Gustavo , Ridruejo Ezequiel , Garcia Gabriel H. , Flichman Diego M. , Di Lello Federico A.
Published: November 2020

Introduction. Blood-borne infections are a major cause of harm in individuals on haemodialysis (HD). In particular, knowledge about hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV) status in HD patients is a major concern, since these infections may cause comorbidities in this setting. There is a paucity of data regarding this issue in Argentina.

Hypothesis/Gap Statement. The epidemiological surveillance of HBV, HCV, and HIV is a fundamental tool for planning and implementing health strategies in order to prevent and control viral transmission of these viral agents.

Aim. To determine the seroprevalence of HBV, HCV and HIV infections in HD patients in Buenos Aires, Argentina.

Methodology. Seven hundred and forty-eight HD patients were included in a retrospective cross-sectional study. Serological assays were performed to determine HBV, HCV and HIV status. HBV HBsAg and anti-HBc IgG were analysed using AxSYM (samples before 2010) or the Architect Abbott system (samples since 2010), anti-HCV IgG testing was performed using the anti-HCV enzyme immunoassay AxSYM HCV V3.0 and ARCHITECT anti-HCV, while HIV was tested for using AxSYM HIV 1/2 gO and ARCHITECT HIV Ag/Ab Combination. HCV genotyping was carried out by phylogenetic analysis of the NS5B partial gene.

Results. Infection with one of the viruses was detected in 31.1 % of patients [HBV in 82 (11.0 %), HCV in 179 (23.9 %) and HIV in 6 (0.8 %)]. Thirty-two (4.3 %) patients had 2 virus markers [27 (3.6 %) with HCV/HBV, 4 (0.5 %) with HCV/HIV and 1 (0.13 %) with HBV/HIV]. Finally, a single patient (0.13 %) presented all three markers. Time on dialysis was correlated with HCV but not with HBV infection. The HCV subtype distribution in HD patients was inverted with respect to that observed in the general population (HCV-1a 73.2 % and HCV-1b 26.8 % in HD vs HCV-1a 26.5 % and HCV-1b 73.5 % in the general population, P <0.001).

Conclusion. Despite the implementation of universal precautionary biosafety standards for dialysis, infection with HBV and HCV continues to occur at very high rates in HD patients. The results emphasize the need to carry out proactive tasks for early diagnosis and treatment of infected individuals and to vaccinate those with non-protective antiHBs antibodies in order to reduce morbidity and mortality in HD patients.
Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu
Authors: Goods Brittany A. , Askenase Michael H. , Markarian Erica , Beatty Hannah E. , Drake Riley , Fleming Ira , DeLong Jonathan H. , Philip Naomi H. , Matouk Charles C. , Awad Issam A. , Zuccarello Mario , Hanley Daniel F. , Love J. Christopher , Shalek Alex K. , Sansing Lauren H.
Published: November 2020

Intracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality rate and few treatment options. Discovery of therapeutic interventions has been slow given the challenges associated with studying acute injury, particularly over time, in the human brain. Inflammation induced by exposure of brain tissue to blood appears to be a major part of brain tissue injury. Here we longitudinally profiled blood and cerebral hematoma effluent from a patient enrolled in the Minimally Invasive Surgery with Thrombolysis in Intracerebral Haemorrhage Evacuation (MISTIEIII) trial, offering a rare window into the local and systemic immune responses to acute brain injury. Using single-cell RNA-sequencing, we characterized the local cellular response during ICH in the brain of a living patient at single-cell resolution for the first time. Our analysis revealed rapid shifts in the activation states of myeloid and T cells in the brain over time, suggesting that leukocyte responses are dynamically reshaped by the hematoma microenvironment. Interestingly, the patient had an asymptomatic re-bleed (second local exposure to blood) that our transcriptional data indicated occurred more than 30 hours prior to detection by CT scan. This case highlights the rapid immune dynamics in the brain after ICH and suggests that sensitive methods like scRNA-seq can inform our understanding of complex intracerebral events.
The effects of GC-biased gene conversion on patterns of genetic diversity among and across butterfly genomes
Authors: Boman Jesper , Mugal Carina F. , Backström Niclas
Published: November 2020

Recombination reshuffles the alleles of a population through crossover and gene conversion. These mechanisms have considerable consequences on the evolution and maintenance of genetic diversity. Crossover, for example, can increase genetic diversity by breaking the linkage between selected and nearby neutral variants. Bias in favor of G or C alleles during gene conversion may instead promote the fixation of one allele over the other, thus decreasing diversity. Mutation bias from G or C to A and T opposes GC-biased gene conversion (gBGC). Less recognized is that these two processes may –when balanced– promote genetic diversity. Here we investigate how gBGC and mutation bias shape genetic diversity patterns in wood white butterflies (Leptideasp.). This constitutes the first in-depth investigation of gBGC in butterflies. Using 60 re-sequenced genomes from six populations of three species, we find substantial variation in the strength of gBGC across lineages. When modeling the balance of gBGC and mutation bias and comparing analytical results with empirical data, we reject gBGC as the main determinant of genetic diversity in these butterfly species. As alternatives, we consider linked selection and GC content. We find evidence that high values of both reduce diversity. We also show that the joint effects of gBGC and mutation bias can give rise to a diversity pattern which resembles the signature of linked selection. Consequently, gBGC should be considered when interpreting the effects of linked selection on levels of genetic diversity.
Combinations of maternal-specific repressive epigenetic marks in the endosperm control seed dormancy
Authors: Sato Hikaru , Santos-González Juan , Köhler Claudia
Published: November 2020

Polycomb Repressive Complex 2 (PRC2)-mediated trimethylation of histone H3 on lysine 27 (H3K27me3) and methylation of histone 3 on lysine 9 (H3K9me) are two repressive epigenetic modifications that are typically localized in distinct regions of the genome. For reasons unknown, however, they co-occur in some organisms and special tissue types. In this study, we show that maternal alleles marked by H3K27me3 in the Arabidopsis endosperm were targeted by the H3K27me3 demethylase REF6 and became activated during germination. In contrast, maternal alleles marked by H3K27me3, H3K9me2, and CHGm were protected from REF6 targeting and remained silenced. Our study unveils that combinations of different repressive epigenetic modifications time a key adaptive trait by modulating access of REF6.
A cohort of Caenorhabditis species lacking the highly conserved let-7 microRNA
Authors: Nelson Charles , Ambros Victor
Published: November 2020

let-7 is a highly conserved microRNA with critical functions integral to cell fate specification and developmental progression in diverse animals. In Caenorhabditis elegans, let-7 is a component of the heterochronic (developmental timing) gene regulatory network, and loss-of-function mutations of let-7 result in lethality during the larval to adult transition due to misregulation of the conserved let-7 target, lin-41. To date, no bilaterian animal lacking let-7 has been characterized. In this study, we identify a cohort of nematode species within the genus Caenorhabditis, closely related to C. elegans, that lack the let-7 microRNA, owing to absence of the let-7 gene. Using C. sulstoni as a representative let-7-lacking species to characterize normal larval development in the absence of let-7, we demonstrate that, except for the lack of let-7, the heterochronic gene network is otherwise functionally conserved. We also report that species lacking let-7 contain a group of divergent let-7 orthologs -- also known as the let-7-family of microRNAs -- that have apparently assumed the role of targeting the lin-41 mRNA.

Summary Statement

We have identified a group of Caenorhabditis species that lack let-7a, an otherwise highly conserved and nearly ubiquitous microRNA that was previously thought to be critical to bilaterian animal development.
Sustained ErbB activation causes demyelination and hypomyelination by driving necroptosis of mature oligodendrocytes and apoptosis of oligodendrocyte precursor cells
Authors: Hu Xu , Xiao Guanxiu , He Li , Niu Xiaojie , Li Huashun , Lou Tianjie , Hu Qianqian , Yang Youguang , Xu Qi , Wei Zhengdong , Qiu Mengsheng , Tanaka Kenji F. , Shen Ying , Tao Yanmei
Published: November 2020

Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in maintaining the CNS myelin integrity are largely unknown. Here we overactivate ErbB receptors that mediate signaling of either neuregulin or EGF family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse toolPlp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination prior to these inflammatory pathological events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse toolSox10+/rtTAcaused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By tracing the differentiation states of cells expressing tTA/rtTA-dependent transgene or pulse-labeled reporter proteinsin vitroandin vivo, we found thatPlp-tTA targeted mainly mature oligodendrocytes (MOs), whereasSox10+/rtTAtargeted OPCs and newly-formed oligodendrocytes. The distinct phenotypes of mice with ErbB overactivation induced byPlp-tTA andSox10+/rtTAconsolidated their non-overlapping targeting preferences in the oligodendrocyte lineage, and enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused inflammatory demyelination, whereas in OPCs induced apoptosis that caused non-inflammatory hypomyelination. Early interference with aberrant ErbB activation ceased oligodendrocyte deaths and restored myelin development in both mice. This study suggests that aberrant ErbB activation is an upstream pathogenetic mechanism of demyelinating diseases, providing a potential therapeutic target.

Significance statement

Primary oligodendropathy is one of the etiological mechanisms for multiple sclerosis, and oligodendrocyte necroptosis is a pathological hallmark in the disease. Moreover, the demyelinating disease is now a broad concept that embraces schizophrenia, in which white matter lesions are an emerging feature. ErbB overactivation has been implicated in schizophrenia by genetic analysis and postmortem studies. This study suggests the etiological implications of ErbB overactivation in myelin pathogenesis and elucidates the pathogenetic mechanisms.
Ozone exposure upregulates the expression of host susceptibility protein TMPRSS2 to SARS-CoV-2
Authors: Vo Thao , Paudel Kshitiz , Choudhary Ishita , Patial Sonika , Saini Yogesh
Published: November 2020

Background

SARS-CoV-2, a novel coronavirus, and the etiologic agent for the current global health emergency, causes acute infection of the respiratory tract leading to severe disease and significant mortality. Ever since the start of SARS-CoV-2, also known as COVID-19 pandemic, countless uncertainties have been revolving around the pathogenesis and epidemiology of the SARS-CoV-2 infection. While air pollution has been shown to be strongly correlated to increased SARS-CoV-2 morbidity and mortality, whether environmental pollutants such as ground level ozone affects the susceptibility of individuals to SARS-CoV-2 is not yet established.

Objective

To investigate the impact of ozone inhalation on the expression levels of signatures associated with host susceptibility to SARS-CoV-2.

Methods

We analyzed lung tissues collected from mice that were sub-chronically exposed to air or 0.8ppm ozone for three weeks (4h/night, 5 nights/week), and analyzed the expression of signatures associated with host susceptibility to SARS-CoV-2.

Results

SARS-CoV-2 entry into the host cells requires proteolytic priming by the host-derived protease, transmembrane protease serine 2 (TMPRSS2). The TMPRSS2 protein andTmprss2transcripts were significantly elevated in the extrapulmonary airways, parenchyma, and alveolar macrophages from ozone-exposed mice. A significant proportion of additional known SARS-CoV-2 host susceptibility genes were upregulated in alveolar macrophages and parenchyma from ozone-exposed mice.

Conclusions

Our data indicate that the unhealthy levels of ozone in the environment may predispose individuals to severe SARS-CoV-2 infection. Given the severity of this pandemic, and the challenges associated with direct testing of host-environment interactions in clinical settings, we believe that this mice-ozone-exposure based study informs the scientific community of the potentially detrimental effects of the ambient ozone levels determining the host susceptibility to SARS-CoV-2.
Diversification of CD1 molecules shapes lipid antigen selectivity
Authors: Paterson Nicole M. , Al-Zubieri Hussein , Barber Matthew F.
Published: November 2020

Molecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.
Distinct molecular signatures of fission predict mitochondrial degradation or proliferation
Authors: Kleele Tatjana , Rey Timo , Winter Julius , Zaganelli Sofia , Mahecic Dora , Lambert Hélène Perreten , Ruberto Francesco , Nemir Mohamed , Wai Timothy , Pedrazzini Thierry , Manley Suliana
Published: November 2020

Mitochondrial fission is a highly regulated process which, when disrupted, can alter metabolism, proliferation and apoptosis1–3. The downstream effects have implications for many diseases, from neurodegeneration4–6to cardiovascular disease7,8and cancer9,10. Key components of the fission machinery have been identified: constriction sites are initiated by the endoplasmic reticulum (ER)11and actin12before dynamin-related protein 1 (Drp1)13is recruited to the outer mitochondrial membrane via adaptor proteins14–17, where it drives constriction and scission of the membrane18. In the life cycle of mitochondria, fission is important for the biogenesis of new mitochondria as well as the clearance of dysfunctional mitochondria via mitophagy3,19. Global regulation of fission on the cellular level is insufficient to explain how fate decisions are made at the single organelle level, so it is unknown how those dual functions arise, blocking progress in developing therapies that target mitochondrial activity. However, systematically studying mitochondrial division to uncover fate determinants is challenging, since fission is unpredictable, and mitochondrial morphology is extremely heterogeneous. Furthermore, because their ultrastructure lies below the diffraction limit, the dynamic organization of mitochondria and their interaction partners are hard to study at the single organelle level. We used live-cell structured illumination microscopy (SIM) and instant SIM20for fast multi-colour acquisition of mitochondrial dynamics in Cos-7 cells and mouse cardiomyocytes. We analysed hundreds of fission events, and discovered two functionally and mechanistically distinct types of fission. Mitochondria divide peripherally to shed damaged material into smaller daughter mitochondria that subsequently undergo mitophagy, whereas healthy mitochondria proliferate via midzone division. Both types are Drp1-mediated, but they rely on different membrane adaptors to recruit Drp1, and ER and actin mediated pre-constriction is only involved in midzone fission.
Processing of subjectively and objectively invisible stimuli in human visual cortex
Authors: Stein Timo , Kaiser Daniel , Fahrenfort Johannes J. , van Gaal Simon
Published: November 2020

The study of unconscious processing requires a measure of conscious awareness. Awareness measures can be either subjective (based on participant’s report) or objective (based on perceptual performance). The preferred awareness measure depends on the theoretical position about consciousness, and may influence conclusions about the extent of unconscious processing and about the neural correlates of consciousness. We obtained fMRI measurements from 43 subjects while they viewed masked faces and houses that were either subjectively or objectively invisible. We show that neural representations of objectively invisible faces and houses are limited to visual (shape-related) object properties, while subjectively invisible stimuli are processed up to more abstract, categorical levels of representation. These results demonstrate that the hypothesized extent of unconscious information processing is determined by the measurement approach. Furthermore, our data show that subjective and objective approaches are associated with different neural correlates of consciousness and thus have implications for neural theories of consciousness.
An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance
Authors: Stejskal Lenka , Kalemera Mphatso D. , Palor Machaela , Walker Lucas , Daviter Tina , Lees William D. , Moss David S. , Kremyda-Vlachou Myrto , Kozlakidis Zisis , Rosenberg William , Illingworth Christopher J. R. , Shepherd Adrian J. , Grove Joe
Published: November 2020

E1 and E2 (E1E2), the entry proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Crucially, to allow entry, this mechanism is turned off by host receptor interactions at the cell surface. Thus, HVR-1 is akin to a safety catch on E1E2 activity. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies.
Extracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R
Authors: Dankovich Tal M. , Kaushik Rahul , Petersen Gabriel Cassinelli , Giro Philipp Emanuel , Hadi Hannah Abdul , Bao Guobin , Beuermann Sabine , Cooper Benjamin H. , Dityatev Alexander , Rizzoli Silvio O.
Published: November 2020

The brain extracellular matrix (ECM) assembles around neurons and synapses, and is thought to change only rarely, through proteolysis and renewed protein synthesis. We report here an alternative ECM remodeling mechanism, based on the recycling of ECM molecules. We found that a key ECM protein, Tenascin-R, is frequently endocytosed, and later resurfaces, preferentially near synapses. The TNR molecules complete this cycle within ∼3 days, in an activity-dependent fashion.
A functional pre-screening platform for identifying points of vulnerability in the cell death map of human melanoma tumors
Authors: Dekel-Bird Naama Pnina , Bialik Shani , Itzhaki Orit , Salame Tomer Meir , Yaeli-Slonim Naama , Levin-Salomon Vered , Dasari Santosh Kumar , Besser Michal , Kimchi Adi
Published: November 2020

Targeted drug therapy in melanoma patients carrying theBRAFV600E mutation provides temporary remission, often followed by relapse due to acquired drug resistance. Here we propose a functional approach to circumvent drug resistance by applying a personalized prescreening platform that maps points of vulnerability in each tumor, prior to drug treatment. This platform applies siRNAs targeting 81 apoptosis, autophagy and programmed necrosis genes in patient tumor cell cultures, identifying genes whose targeting maximizes cell killing by short-term BRAF inhibition. Melanoma tumors displayed large heterogeneity in the number and identities of soft-spots, providing different tumor-specific functional death signatures. The soft-spots were targeted by replacing functional siRNAs with small compound inhibitors for long-term treatment in combination with vemurafenib. This strategy reduced the number of drug-tolerant persister cells surviving treatment, and most importantly, the number of drug-resistant foci. Thus, prescreening melanoma tumors for soft-spots within the cell death network may enhance targeted drug therapy before resistance emerges, thereby reducing the odds of developing drug-resistant mutations, and preventing tumor relapse.
Nsp1 of SARS-CoV-2 Stimulates Host Translation Termination
Authors: Shuvalov Alexey , Shuvalova Ekaterina , Biziaev Nikita , Sokolova Elizaveta , Evmenov Konstantin , Egorova Tatiana , Alkalaeva Elena
Published: November 2020

The Nsp1 protein of SARS-CoV-2 regulates the translation of host and viral mRNAs in cells. Nsp1 inhibits host translation initiation by occluding the entry channel of the 40S ribosome subunit. The structural study of SARS-CoV-2 Nsp1-ribosomal complexes reported post-termination 80S complex containing Nsp1 and the eRF1 and ABCE1 proteins. Considering the presence of Nsp1 in the post-termination 80S ribosomal complex simultaneously with eRF1, we hypothesized that Nsp1 may be involved in translation termination. Using a cell-free translation system and reconstitutedin vitrotranslation system, we show that Nsp1 stimulates translation termination in the stop codon recognition stage at all three stop codons. This stimulation targets the release factor 1 (eRF1) and does not affect the release factor 3 (eRF3). The activity of Nsp1 in translation termination is provided by its N-terminal domain and the minimal required part of eRF1 is NM domain. We assume that biological meaning of Nsp1 activity in translation termination is binding with the 80S ribosomes translating host mRNAs and removal them from the pool of the active ribosomes.
Functional and microstructural plasticity following social and interoceptive mental training
Authors: Valk Sofie L , Kanske Philipp , Park Bo-yong , Hong Seok Jun , Böckler Anne , Trautwein Fynn-Mathis , Bernhardt Boris C. , Singer Tania
Published: November 2020

The human brain scaffolds social cognitive functions, including Theory of Mind, empathy and compassion, through its functional and microstructural organization. However, it remains unclear how the learning and refinement of these skills may, in turn, shape brain function and structure. Here we studied if different types of social mental training can lead to plastic changes in brain function and microstructure. We studied a group of 332 healthy adults (197 women, 20-55 years) with repeated multimodal neuroimaging and behavioral testing. Our neuroimaging approach capitalized on the quantification of cortical functional gradients and myelin-sensitive T1 relaxometry, two emerging measures of cortical functional organization and microstructure. Longitudinal analysis indicated marked changes in intrinsic cortical function and microstructure, which varied as a function of social training content. In particular, we observed consistent differential change in function and microstructure between attention-mindfulness and socio-cognitive training in regions functionally associated with attention and interoception, including insular and parietal cortices. Conversely, socio-affective and socio-cognitive training resulted in differential microstructural changes in regions classically implicated in interoceptive and emotional processing, including insular and orbitofrontal areas, but did not result in functional reorganization. Notably, longitudinal changes in cortical function and microstructure were predictive of behavioral change in attention, compassion and perspective-taking, suggesting behavioral relevance. In sum, our work provides evidence for functional and microstructural plasticity after the training of social-interoceptive functions, and provides a causal perspective on the neural basis of behavioral adaptation in human adults.
Force requirements of endocytic vesicle formation
Authors: Abella Marc , Andruck Lynnel , Malengo Gabriele , Skruzny Michal
Published: November 2020

Mechanical forces are integral to many cellular processes, including clathrin-mediated endocytosis, a principal membrane trafficking route into the cell. During endocytosis, forces provided by endocytic proteins and the polymerizing actin cytoskeleton reshape the plasma membrane into a vesicle. Assessing force requirements of endocytic membrane remodelling is essential for understanding endocytosis. Here, we determined forces applied during endocytosis using FRET-based tension sensors integrated into the major force-transmitting protein Sla2 in yeast. We measured force of approx. 10 pN transmitted over Sla2 molecule, hence a total force of 450-1300 pN required for endocytic vesicle formation. Importantly, decreasing cell turgor pressure and plasma membrane tension reduced force requirements of endocytosis. The measurements in hypotonic conditions and mutants lacking BAR-domain membrane scaffolds then showed the limits of the endocytic force-transmitting machinery. Our study provides force values and force profiles critical for understanding the mechanics of endocytosis and potentially other key cellular membrane-remodelling processes.
Temperature affects the repeatability of evolution in the microbial eukaryoteTetrahymena thermophila
Authors: Tarkington Jason A , Zufall Rebecca
Published: November 2020

Evolutionary biologists have long sought to understand what factors affect the repeatability of adaptive outcomes. To better understand the role of temperature in determining the repeatability of adaptive trajectories, we evolved populations of different genotypes of the ciliateTetrahymena thermophilaat low and high temperatures and followed changes in growth rate over 4,000 generations. As expected, growth rate increased with a decelerating rate for all populations; however, there were differences in the patterns of evolution at the two temperatures. The growth rates of the different genotypes converged as evolution proceeded at both temperatures, but this convergence was quicker at the higher temperature. Likewise, we found greater repeatability of evolution, in terms of change in growth rate, among replicates of the same genotype at the higher temperature. Finally, we found no evidence of trade-offs in fitness between temperatures, but did observe asymmetry in the correlated responses, whereby evolution in a high temperature increases growth rate at the lower temperature significantly more than the reverse. These results demonstrate the importance of temperature in determining the repeatability of evolutionary trajectories.
A dominant-negative SOX18 mutant disrupts multiple regulatory layers essential to transcription factor activity
Authors: McCann Alex , Lou Jieqiong , Moustaqil Mehdi , Blum Ailisa , Fontaine Frank , Liu Hui , Luu Winnie , Koopman Peter , Sierecki Emma , Gambin Yann , Meunier Frédéric A. , Liu Zhe , Hinde Elizabeth , Francois Mathias
Published: November 2020

Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged opossum and the human genetic disorder Hypotrichosis-Lymphedema-Telangiectasia-Renal Syndrome. Combing three single-molecule imaging assays in living cells, we found that SOX18RaOpdisrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its chromatin-binding dynamics. The dominant-negative effect is further amplified by recruiting the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular etiology of dominant-negative transcription factor function.
Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response inStentor coeruleus
Authors: Zhang Kevin S. , Blauch Lucas R. , Huang Wesley , Marshall Wallace F. , Tang Sindy K. Y.
Published: November 2020

Background

Wound healing is one of the defining features of life and is seen not only in tissues but also within individual cells. Understanding wound response at the single-cell level is critical for determining fundamental cellular functions needed for cell repair and survival. This understanding could also enable the engineering of single-cell wound repair strategies in emerging synthetic cell research. One approach is to examine and adapt self-repair mechanisms from a living system that already demonstrates robust capacity to heal from large wounds. Towards this end,Stentor coeruleus, a single-celled free-living ciliate protozoan, is a unique model because of its robust wound healing capacity. This capacity allows one to perturb the wounding conditions and measure their effect on the repair process without immediately causing cell death, thereby providing a robust platform for probing the self-repair mechanism.

Results

Here we used a microfluidic guillotine and a fluorescence-based assay to probe the timescales and mechanisms of wound repair inStentor. We found thatStentorrequires ∼100 – 1000 s to close bisection wounds, depending on the severity of the wound. This corresponds to a healing rate of ∼8 – 80 μm2/s, faster than most other single cells reported in the literature. Further, we observed and characterized three distinct mechanical modes of wound repair inStentor: contraction, cytoplasm retrieval, and twisting/pulling. Using chemical perturbations, active cilia were found to be important for only the twisting/pulling mode. Contraction of myonemes, a major contractile fiber inStentor, was surprisingly not important for the contraction mode and was of low importance for the others.

Conclusions

While events local to the wound site have been the focus of many single-cell wound repair studies, our results suggest that large-scale mechanical behaviors may be of greater importance to single-cell wound repair than previously thought. The work here advances our understanding of the wound response inStentor, and will lay the foundation for further investigations into the underlying components and molecular mechanisms involved.
Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaling
Authors: Lawlor Katerina , Marques-Torrejon Maria Angeles , Dharmalingham Gopuraja , El-Azhar Yasmine , Schneider Michael D. , Pollard Steven M. , Rodríguez Tristan A.
Published: November 2020

There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell–cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation.
PDO labels and food preferences: results from a sensory analysis
Authors: Savelli Elisabetta , Bravi Laura , Francioni Barbara , Murmura Federica , Pencarelli Tonino
Published: November 2020

Purpose

The paper aims at investigating whether and how the product designation of origin (PDO) label influences consumers' acceptance, attributes' perception and purchase intention of PDO foods.

Design/methodology/approach

The study employs an experimental lab study based on the affective test of acceptance methodology with a nine-point hedonic scale. Three PDO foods are compared with similar non-PDO samples concerning cheese, cured ham and olive oil categories.

Findings

The presence of PDO labels enhances the consumers' acceptance as well as their perception of sensory attributes. A critical role of the brand name as an enhancer of consumer acceptance also emerges, highlighting the relationship between brand-name and PDO label.

Research limitations/implications

The main limitation is related to the lab study methodology, which employs a small number of participants and occurs far from a “normal” situation of consumption. The acceptance test, moreover, does not provide explanations about motives underlying the differences in consumers' perception and preferences.

Practical implications

Practical implications are suggested for food companies concerning the management of both PDO labels and brand strategies and the product's properties that could improve the sensory perception of consumers and their overall product's acceptance.

Originality/value

The study contributes to the debate on consumer behaviour towards PDO foods by adding evidence about the positive influence of such a certification on individual preferences on the basis of a sensory methodology that has been little employed for studying the domain of product certifications.
Effects of self-affirmation on responses toward graphic cigarette warning labels: testing the mediating role of perceived susceptibility and self-efficacy
Authors: Ma Zexin , Nan Xiaoli , Iles Irina A. , Butler James , Feldman Robert , Wang Min Qi
Published: November 2020

Purpose

The purpose of this study is to examine the effects of self-affirmation on African American smokers' intentions to quit smoking sooner and desire to stop smoking altogether in response to viewing graphic cigarette warning labels. It also tested the mediating role of perceived susceptibility and self-efficacy in explaining the impact of self-affirmation.

Design/methodology/approach

African American smokers (N = 158) were recruited to participate in a controlled experiment. Participants first completed a short questionnaire about their demographic background and smoking-related attitudes and behavior. They were then randomly assigned to engage in either a self-affirmation task or a control task and viewed two graphic cigarette warning labels subsequently. Participants then responded to a questionnaire about their perceived susceptibility to smoking-related diseases, perceived self-efficacy to quit smoking, intentions to quit smoking and desire to stop smoking altogether.

Findings

Results showed that engaging in self-affirmation prior to exposure to graphic cigarette warning labels increased African American smokers' perceived susceptibility to smoking-related diseases, but decreased their perceived self-efficacy to quit smoking. Furthermore, self-affirmation indirectly enhanced smokers' intentions to quit smoking sooner and desire to stop smoking altogether through increased perceived susceptibility. It also had an unexpected negative indirect effect on intentions to quit smoking sooner through decreased self-efficacy.

Originality/value

This study is one of the few studies that investigates the effect of self-affirmation on African American smokers' responses toward graphic cigarette warning labels.
How and when intragroup relationship conflict leads to knowledge hiding: the roles of envy and trait competitiveness
Authors: Peng He , Bell Chris , Li Yiran
Published: November 2020

Purpose

Although studies have demonstrated that knowledge hiding is an important inhibitor of organizational innovation, current research does not clearly address how intragroup relationship conflict influences knowledge hiding. This study aims to identify the underlying mechanism between intra-group relationship conflict and knowledge hiding.

Design/methodology/approach

Drawing on affective events theory (AET), the authors propose a theoretical model and empirically test it by applying hierarchical regression analysis and a bootstrapping approach to data from a multi-wave survey of 224 employees in China.

Findings

Consistent with AET, the empirical results show that envy mediates perceived intragroup relationship conflict and knowledge hiding. As predicted, trait competitiveness moderates the indirect effect of perceived intragroup relationship conflict on knowledge hiding via envy.

Originality/value

The results support an AET perspective whereby knowledge hiding is shaped by relationship conflict, envy and trait competitiveness. This study introduces the novel proposition that relationship conflict and competitiveness influence envy, and consequently knowledge hiding.
An optimized queue management system to improve patient flow in the absence of appointment system
Authors: Safdar Komal Aqeel , Emrouznejad Ali , Dey Prasanta Kumar
Published: November 2020

Purpose

The aim of this research study is to develop a queue assessment model to evaluate the inflow of walk-in outpatients in a busy public hospital of an emerging economy, in the absence of appointment systems, and construct a dynamic framework dedicated towards the practical implementation of the proposed model, for continuous monitoring of the queue system.

Design/methodology/approach

The current study utilizes data envelopment analysis (DEA) to develop a combined queuing–DEA model as applied to evaluate the wait times of patients, within different stages of the outpatients' department at the Combined Military Hospital (CMH) in Lahore, Pakistan, over a period of seven weeks (23rd April to 28th May 2014). The number of doctors/personnel and consultation time were considered as outputs, where consultation time was the non-discretionary output. The two inputs were wait time and length of queue. Additionally, VBA programming in Excel has been utilized to develop the dynamic framework for continuous queue monitoring.

Findings

The inadequate availability of personnel was observed as the critical issue for long wait times, along with overcrowding and variable arrival pattern of walk-in patients. The DEA model displayed the “required” number of personnel, corresponding to different wait times, indicating queue build-up.

Originality/value

The current study develops a queue evaluation model for a busy outpatients' department in a public hospital, where “all” patients are walk-in and no appointment systems. This model provides vital information in the form of “required” number of personnel which allows the administrators to control the queue pre-emptively minimizing wait times, with optimal yet dynamic staff allocation. Additionally, the dynamic framework specifically targets practical implementation in resource-poor public hospitals of emerging economies for continuous queue monitoring.