bluuebunny/crossref_metadata_2025 huggingface dataset:
YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation
Authors: He Lizhi , Pratt Henry , Wei Fengxiang , Gao Mingshi , Weng Zhiping , Struhl Kevin
Published: February 2021

The YAP and TAZ paralogues are transcriptional co-activators recruited to target sites, primarily by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB and STAT3, key factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, co-occupy many target sitesin vivovia AP-1 and (to a lesser extent) STAT3 sequence motifs, and stimulate transcriptional activation by AP-1 proteins. A few target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes. YAP/TAZ, JUNB, and STAT3 directly regulate a common set of target genes that overlap, but are distinct from, those regulated by YAP/TAZ and TEADs. The set of genes regulated by YAP/TAZ, STAT3, and JUNB is associated with poor survival in breast cancer patients with the triple-negative form of the disease.
Rotavirus as an Expression Platform of the SARS-CoV-2 Spike Protein
Authors: Philip Asha A. , Patton John T.
Published: February 2021

Rotavirus, a segmented double-stranded RNA virus, is a major cause of acute gastroenteritis in young children. The introduction of live oral rotavirus vaccines has reduced the incidence of rotavirus disease in many countries. To explore the possibility of establishing a combined rotavirus-SARS-CoV-2 vaccine, we generated recombinant (r)SA11 rotaviruses with modified segment 7 RNAs that contained coding sequences for NSP3 and FLAG-tagged portions of the SARS-CoV-2 spike (S) protein. A 2A translational element was used to drive separate expression of NSP3 and the S product. rSA11 viruses were recovered that encoded the S-protein S1 fragment, N-terminal domain (NTD), receptor-binding domain (RBD), extended receptor-binding domain (ExRBD), and S2 core (CR) domain (rSA11/NSP3-fS1, -fNTD, -fRBD, -fExRBD, and -fCR, respectively). Generation of rSA11/fS1 required a foreign-sequence insertion of 2.2-kbp, the largest such insertion yet made into the rotavirus genome. Based on isopycnic centrifugation, rSA11 containing S sequences were denser than wildtype virus, confirming the capacity of the rotavirus to accommodate larger genomes. Immunoblotting showed that rSA11/-fNTD, -fRBD, -fExRBD, and -fCR viruses expressed S products of expected size, with fExRBD expressed at highest levels. These rSA11 viruses were genetically stable during serial passage. In contrast, rSA11/NSP3-fS1 failed to express its expected 80-kDa fS1 product, for unexplained reasons. Moreover, rSA11/NSP3-fS1 was genetically unstable, with variants lacking the S1 insertion appearing during serial passage. Nonetheless, these results emphasize the potential usefulness of rotavirus vaccines as expression vectors of portions of the SARS-CoV-2 S protein (e.g., NTD, RBD, ExRBD, and CR) with sizes smaller than the S1 fragment.

Importance

Among the vaccines administered to children in the US and many other countries are those targeting rotavirus, a segmented double-stranded RNA virus that is a major cause of severe gastroenteritis. In this study, we have examined the feasibility of modifying the rotavirus genome by reverse genetics, such that the virus could serve as an expression vector of the SARS-CoV-2 spike protein. Results were obtained showing that recombinant rotaviruses can be generated that express domains of the SARS CoV-2 spike protein, including the receptor-binding domain (RBD), a common target of neutralizing antibodies produced in individuals infected by the virus. Our findings raise the possibility of creating a combined rotavirus-COVID-19 vaccine that could be used in place of current rotavirus vaccines.
Induction of specific antibodies, IgG-secreting plasmablasts and memory B cells following BCG vaccination
Authors: Bitencourt Julia , Wilkie Morven , Alvarez Marco Polo Peralta , Jacobs Ashley , Wright Daniel , Harris Stephanie A. , Smith Steven G. , Elias Sean , White Andrew , Sharpe Sally , O’Shea Matthew K. , McShane Helen , Tanner Rachel
Published: February 2021

Many tuberculosis (TB) vaccine candidates are designed as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does protect may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterised, little is known about the B cell and antibody response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titres in serum versus plasma with modestly higher titres in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a potential contribution of the antibody response to BCG vaccine-mediated control of mycobacterial growthin vitro. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.
Burst coding despite unimodal interval distributions
Authors: Williams Ezekiel , Payeur Alexandre , Gidon Albert , Naud Richard
Published: February 2021

The burst coding hypothesis posits that the occurrence of sudden high-frequency patterns of action potentials constitutes a salient syllable of the neural code. Many neurons, however, do not produce clearly demarcated bursts, an observation invoked to rule out the pervasiveness of this coding scheme across brain areas and cell types. Here we ask how identifiable spike-timing patterns have to be to preserve potent transmission of information. Should we expect that neurons avoid ambiguous patterns that are neither clearly bursts nor isolated spikes? We addressed these questions using information theory and computational simulations. By quantifying how information transmission depends on firing statistics, we found that the information transmitted is not strongly influenced by the presence of clearly demarcated modes in the interspike interval distribution, a feature often used to identify the presence of burst coding. Instead, we found that neurons having unimodal interval distributions were still able to ascribe different meanings to bursts and isolated spikes. In this regime, information transmission depends on properties of the synapses as well as the length and relative frequency of bursts. Furthermore, we found that common metrics used to quantify burstiness were also unable to predict the degree with which bursts could be used to carry information. Our results provide guiding principles for the implementation of coding strategies based on spike-timing patterns, and show that even unimodal firing statistics can be consistent with a bivariate neural code.
Macromolecular Regulators Have Matching Effects on the Phase Equilibrium and Interfacial Tension of Biomolecular Condensates
Authors: Mazarakos Konstantinos , Zhou Huan-Xiang
Published: February 2021

The interfacial tension of phase-separated biomolecular condensates affects their fusion and multiphase organization, and yet how this important property depends on the composition and interactions of the constituent macromolecules is poorly understood. Here we use molecular dynamics simulations to determine the interfacial tension and phase equilibrium of model condensate-forming systems. The model systems consist of binary mixtures of Lennard-Jones particles or chains of such particles. We refer to the two components as drivers and regulators; the former has stronger self-interactions and hence a higher critical temperature (Tc) for phase separation. In previous work, we have shown that, depending on the relative strengths of driver-regulator interactions and driver-driver interactions, regulators can either promote or suppress phase separation (i.e., increase or decreaseTc). Here we find that the effects of regulators onTcquantitatively match the effects on interfacial tension (γ). This important finding means that, when a condensate-forming system experiences a change in macromolecular composition or a change in intermolecular interactions (e.g., by mutation or posttranslational modification, or by variation in solvent conditions such as temperature, pH, or salt), the resulting change inTccan be used to predict the change inγand vice versa. We also report initial results showing that disparity in intermolecular interactions drives multiphase coexistence. These findings provide much needed guidance for understanding how biomolecular condensates mediate cellular functions.
The effect of hydrophobic gases on the water fleaDaphnia magna
Authors: Robledo-Sánchez K. Carlo Martín , Ruiz-Suárez J. C.
Published: February 2021

It is well known that some hydrophobic atomic and molecular gases provoke anaesthetic effects in mammal animals. Depending on the gas, there is a Minimum Alveolar Concentration (MAC) to produce anaesthesia. The gas enters in the lungs, dissolve in the blood and reaches the brain. Where are the targets and which are the action mechanisms are subjects not fully understood yet. Very recently, we reported the effects of local anaesthetics on the swimming behaviour of the water fleaDaphnia magna(STOTEN691, 278-283, 2019). Our aim now is to report new studies on the behaviour of this aquatic invertebrate in the presence of three hydrophobic gases: xenon, nitrous oxide and krypton. However, if local anaesthetics easily dissolve in water, these gases do not. Therefore, we designed a chamber to dissolve the gases using pressures up to 50 atmospheres. Simultaneously, we were able to measure in real time the response of the animals through transparent windows able to support such high pressures. Xenon and nitrous oxide effectively induce lack of movement in the daphnids. The effective pressures EP50for xenon and nitrous oxide were and 5.2 atmospheres, respectively. Krypton does not present clear effects on the motile suppression, even after the exposure to 44 atmospheres. Our findings provide insight on the physiological effects important gases used in human medicine produce in aquatic invertebrate animals considered as potential models to study anesthesia.
Strongyloides RNA-seq Browser: a web-based software platform for on-demand bioinformatics analyses of Strongyloides species
Authors: Bryant Astra S. , DeMarco Stephanie F. , Hallem Elissa A.
Published: February 2021

Soil-transmitted gastrointestinal parasitic nematodes infect approximately 1 billion people worldwide, predominantly in low-resource communities. Skin-penetrating gastrointestinal nematodes in the genus Strongyloides are emerging as model systems for mechanistic studies of soil-transmitted helminths due to the growing availability of functional genomics tools for these species. To facilitate future genomics studies of Strongyloides species, we have designed a web-based application, the Strongyloides RNA-seq Browser, that provides an open source, user-friendly portal for accessing and analyzing Strongyloides genomic expression data. Specifically, the Strongyloides RNA-seq Browser takes advantage of alignment-free read mapping tools and R-based transcriptomics tools to re-analyze publicly available RNA sequencing datasets from four Strongyloides species: Strongyloides stercoralis, Strongyloides ratti, Strongyloides papillosus, and Strongyloides venezuelensis. This application permits on-demand exploration and quantification of gene expression across life stages without requiring previous coding experience. Here, we describe this interactive application and demonstrate how it may be used by nematode researchers to conduct a standard set of bioinformatics queries.
The heart rate discrimination task: a psychophysical method to estimate the accuracy and precision of interoceptive beliefs
Authors: Legrand Nicolas , Nikolova Niia , Correa Camile , Brændholt Malthe , Stuckert Anna , Kildahl Nanna , Vejlø Melina , Fardo Francesca , Allen Micah
Published: February 2021

Interoception - the physiological sense of our inner bodies - has risen to the forefront of psychological and psychiatric research. Much of this research utilizes tasks that attempt to measure the ability to accurately detect cardiac signals. Unfortunately, these approaches are confounded by well-known issues limiting their validity and interpretation. At the core of this controversy is the role of subjective beliefs about the heart rate in confounding measures of interoceptive accuracy. Here, we recast these beliefs as an important part of the causal machinery of interoception, and offer a novel psychophysical “heart rate discrimination“ method to estimate their accuracy and precision. By applying this task in 223 healthy participants, we demonstrate that cardiac interoceptive beliefs are more biased, less precise, and are associated with poorer metacognitive insight relative to an exteroceptive control condition. Our task, provided as an open-source python package, offers a robust approach to quantifying cardiac beliefs.

Highlights

Current interoception tasks conflate cardiac beliefs with accuracy.

We introduce a Bayesian method for estimating cardiac belief accuracy and precision.

Individuals underestimate their heart rate by -7 BPM (95% CI [-8.6 -5.3]) on average.

Cardiac beliefs are associated with reduced precision and metacognitive insight.

The task and modelling tools are provided in the Python Cardioception Package.
Platinum nanoparticles inhibit intracellular ROS generation and protect against Cold Atmospheric Plasma-induced cytotoxicity
Authors: Gunes Sebnem , He Zhonglei , Malone Renee , Cullen Patrick J , Curtin James F
Published: February 2021

Platinum nanoparticles (PtNPs) have been investigated for their antioxidant abilities in a range of biological and other applications. The ability to reduce off-target CAP cytotoxicity would be useful in Plasma Medicine, however, little has been published to date about the ability of PtNPs to reduce or inhibit the effects of CAP. Here we investigate whether PtNPs can protect against CAP-induced cytotoxicity in cancerous and non-cancerous cell lines. PtNPs were shown to dramatically reduce intracellular reactive species (RONS) production in human U-251 MG cells. However, RONS generation was unaffected by PtNPs in medium without cells. PtNPs protect against CAP induced mitochondrial membrane depolarization, but not cell membrane permeabilization which is a CAP-induced RONS-independent event. PtNPs act as potent intracellular scavengers of reactive species and can protect both cancerous U-251 MG cells and non-cancerous HEK293 cells against CAP induced cytotoxicity. PtNPs may be useful as a catalytic antioxidant for healthy tissue and for protecting against CAP-induced tissue damage.

Graphical Abstract

PtNPs are potent catalase and superoxide dismutase mimetics which makes them strong antioxidant candidates for the protection of cells against oxidative stress. CAP was generated using a Dielectric Barrier Device (DBD) system with a voltage output of 75 kV at a frequency of 50 Hz. A range of concentrations of 3nm uncoated PtNPs combined with CAP were examined in human U-251 MG Glioblastoma (GBM) cells and non-cancerous human embryonic kidney HEK293 cells. The protective effects of PtNPs against CAP were explored using several biochemical indicators of oxidative stress and cytotoxicity.
A Neural Signature of Regularity in Sound is Reduced in Older Adults
Authors: Herrmann Björn , Maess Burkhard , Johnsrude Ingrid S.
Published: February 2021

Sensitivity to repetitions in sound amplitude and frequency is crucial for sound perception. As with other aspects of sound processing, sensitivity to such patterns may change with age, and may help explain some age-related changes in hearing such as segregating speech from background sound. We recorded magnetoencephalography to characterize differences in the processing of sound patterns between younger and older adults. We presented tone sequences that either contained a pattern (made of a repeated set of tones) or did not contain a pattern. We show that auditory cortex in older, compared to younger, adults is hyperresponsive to sound onsets, but that sustained neural activity in auditory cortex, indexing the processing of a sound pattern, is reduced. Hence, the sensitivity of neural populations in auditory cortex fundamentally differs between younger and older individuals, overresponding to sound onsets, while underresponding to patterns in sounds. This may help to explain some age-related changes in hearing such as increased sensitivity to distracting sounds and difficulties tracking speech in the presence of other sound.
Analysis of the blood microbiome in a porcine model of fecal-induced peritonitis
Authors: Hyun Hwi , Lee Min Seok , Park Inwon , Ko Hwa Soo , Yun Seungmin , Jang Dong-Hyun , Kim Seonghye , Kim Hajin , Kang Joo H. , Lee Jae Hyuk , Kwon Taejoon
Published: February 2021

Background

Recent studies have proposed the existence of a blood microbiome, even in the healthy host. However, we do not know how the blood microbiome changes when a bloodstream infection (BSI) occurs. Here, we analyzed the dynamics of the blood microbiome in a porcine model of polymicrobial bacteremia induced by fecal peritonitis. Serial blood samples were taken over 12 hours post-induction of fecal peritonitis, and BSI was validated by conventional blood culture and assessment of clinical symptoms.

Results

The bacterial populations in the blood microbiome were retained throughout the experimental period. However, there were significant taxonomic differences between the profile in the fecal and blood microbiomes, reflecting tropism for the blood environment. We also confirmed that the microbiota we detected was not contaminated by low mass bacteria in the bloodstream. However, at the same time, we noted a slight increase in Bacteroidetes, which is a major component of the gut microbiome, as sepsis developed. Comparison of the functional pathways in the blood and fecal microbiomes revealed upregulation of pathways involved in environmental interactions, and downregulation of those related to cell proliferation, in the former. Based on the enriched biological pathways, we concluded that communication and stress management pathways are essential for the survival of the blood microbiome under harsh conditions.

Conclusion

This study suggests that the microbiota can be stably retained in the bloodstream over time. Although further investigation in humans is required, we suggest that the blood microbiome may be another factor to be considered in the context of BSI and subsequent sepsis.
Transcriptomic and metabolomic responses to carbon and nitrogen sources in Methylomicrobium album BG8
Authors: Sugden Scott , Lazic Marina , Sauvageau Dominic , Stein Lisa Y.
Published: February 2021

Methanotrophs use methane as their sole carbon and energy source and represent an attractive platform for converting single-carbon feedstocks into value-added compounds. Optimizing these species for biotechnological applications involves choosing an optimal growth substrate based on an understanding of cellular responses to different nutrients. Although many studies of methanotrophs have examined growth rate, yield, and central carbon flux in cultures grown with different carbon and nitrogen sources, few studies have examined more global cellular responses to different media. Here, we evaluated global transcriptomic and metabolomic profiles of Methylomicrobium album BG8 when grown with methane or methanol as the carbon source and nitrate or ammonium as the nitrogen source. We identified five key physiological changes during growth on methanol: M. album BG8 cultures upregulated transcripts for the Entner-Doudoroff and pentose phosphate pathways for sugar catabolism, produced more ribosomes, remodeled its phospholipid membrane, activated various stress response systems, and upregulated glutathione-dependent formaldehyde detoxification. When using ammonium, M. album BG8 upregulated haoAB hydroxylamine dehydrogenase and the overall central metabolic activity; whereas when using nitrate, cultures upregulated genes for nitrate assimilation and conversion. Overall, we identified several nutrient source-specific responses that could provide a valuable basis for future research on the biotechnological optimization of these species.

IMPORTANCE

Methanotrophs are gaining increasing interest for their biotechnological potential to convert single-carbon compounds into value-added products such as industrial chemicals, fuels, and bioplastics. Optimizing these species for biotechnological applications requires a detailed understanding of how cellular activity and metabolism varies across different growth substrates. Although each of the two most commonly used carbon sources (methane or methanol) and nitrogen sources (ammonium or nitrate) in methanotroph growth media have well-described advantages and disadvantages in an industrial context, their effects on global cellular activity remain poorly characterized. Here, we comprehensively describe the transcriptomic and metabolomic changes that characterize the growth of an industrially promising methanotroph strain on multiple combinations of carbon and nitrogen sources. Our results represent a more holistic evaluation of cellular activity than previous studies of core metabolic pathways and provide a valuable basis for the future biotechnological optimization of these species.
Heavy-tailed abundance distributions from stochastic Lotka-Volterra models
Authors: Descheemaeker Lana , Grilli Jacopo , de Buyl Sophie
Published: February 2021

Microbial communities found in nature are composed of many rare species and few abundant ones, as reflected by their heavy-tailed abundance distributions. How a large number of species can coexist in those complex communities and why they are dominated by rare species is still not fully understood. We show how heavy-tailed distributions arise as an emergent property from large communities with many interacting species in population-level models. To do so we rely on stochastic logistic and generalized Lotka-Volterra models for which we introduce a global maximal capacity. This maximal capacity accounts for the fact that communities are limited by available resources and space. In a parallel ‘ad-hoc’ approach, we obtain heavy-tailed abundance distributions from non-interacting models through specific distributions of the parameters. We expect both mechanisms, interactions between many species and specific parameter distributions, to be relevant to explain the observed heavy tails.
A small RNA is linking CRISPR-Cas and zinc transport
Authors: Märkle Pascal , Maier Lisa-Katharina , Maaß Sandra , Hirschfeld Claudia , Bartel Jürgen , Becher Dörte , Voß Björn , Marchfelder Anita
Published: February 2021

The function and mode of action of small regulatory RNAs is currently still understudied in archaea. In the halophilic archaeonH. volcaniia plethora of sRNAs have been identified, however, in-depth functional analysis is missing for most of them. We selected a small RNA (s479) fromH. volcaniifor detailed characterization. The sRNA gene is encoded between a CRISPR RNA locus and the Cas protein gene cluster, the s479 deletion strain is viable and was characterized in detail. Transcriptome studies of wild typeHaloferaxcells and the deletion mutant revealed up-regulation of six genes in the deletion strain, showing that the sRNA has a clearly defined function. Three of the six up-regulated genes encode potential zinc transporter proteins (ZnuA1, ZnuB1, ZnuC1) suggesting involvement of s479 in regulation of zinc transport. Upregulation of these genes in the deletion strain was confirmed by northern blot and proteome analyses. Furthermore, electrophoretic mobility shift assays demonstrate a direct interaction of s479 with the targetznuC1 mRNA. Proteome comparison of wild type and deletion strains further expanded the regulon of s479 deeply rooting this sRNA within the metabolism ofH. volcaniiespecially the regulation of transporter abundance. Interestingly, s479 is not only encoded next to CRISPR-casgenes but the mature s479 contains a crRNA-like 5’ handle and experiments with Cas protein deletion strains indicate maturation by Cas6 and interaction with Cas proteins. Together this might suggest that the CRISPR-Cas system is involved in s479 function.
Identification of novel, clonally stable, somatic mutations targeting transcription factors PAX5 and NKX2-3, the epigenetic regulator LRIF1, and BRAF in a case of atypical B-cell chronic lymphocytic leukemia harboring a t(14;18)(q32;q21)
Authors: Burlet Bénédicte , Ramla Selim , Fournier Cyril , Abrey-Recalde Maria Jimena , Sauter Camille , Chrétien Marie-Lorraine , Rossi Cédric , Duffourd Yannis , Ragot Sylviane , Buriller Céline , Tournier Benjamin , Chapusot Caroline , Nadal Nathalie , Racine Jessica , Guy Julien , Bailly François , Martin Laurent , Casasnovas Olivier , Bastie Jean-Noël , Caillot Denis , Albuisson Juliette , Broccardo Cyril , Thieblemont Catherine , Delva Laurent , Maynadié Marc , Aucagne Romain , Callanan Mary B.
Published: February 2021

Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) is usually straightforward, involving clinical, immunophenotypic (Matutes score), and (immuno)genetic analyses (to refine patient prognosis for treatment). CLL cases with atypical presentation (e.g., Matutes ≤ 3) are also encountered, and for these diseases, biology and prognostic impact are less clear. Here we report the genomic characterization of a case of atypical B-CLL in a 70-yr-old male patient; B-CLL cells showed a Matutes score of 3, chromosomal translocation t(14;18)(q32;q21) (BCL2/IGH), mutated IGHV, deletion 17p, and mutations in BCL2, NOTCH1 (subclonal), and TP53 (subclonal). Quite strikingly, a novel PAX5 mutation that was predicted to be loss of function was also seen. Exome sequencing identified, in addition, a potentially actionable BRAF mutation, together with novel somatic mutations affecting the homeobox transcription factor NKX2-3, known to control B-lymphocyte development and homing, and the epigenetic regulator LRIF1, which is implicated in chromatin compaction and gene silencing. Neither NKX2-3 nor LRIF1 mutations, predicted to be loss of function, have previously been reported in B-CLL. Sequencing confirmed the presence of these mutations together with BCL2, NOTCH1, and BRAF mutations, with the t(14;18)(q32;q21) translocation, in the initial diagnostic sample obtained 12 yr prior. This is suggestive of a role for these novel mutations in B-CLL initiation and stable clonal evolution, including upon treatment withdrawal. This case extends the spectrum of atypical B-CLL with t(14;18)(q32;q21) and highlights the value of more global precision genomics for patient follow-up and treatment in these patients.
Threefold helical assembly via hydroxy hydrogen bonds: the 2:1 co-crystal of bicyclo[3.3.0]octane-endo-3,endo-7-diol and bicyclo[3.3.0]octane-endo-3,exo-7-diol
Authors: Chan Isa Y. H. , Bhadbhade Mohan M. , Bishop Roger
Published: February 2021

Reduction of bicyclo[3.3.0]octane-3,7-dione yields a mixture of the endo-3,endo-7-diol and endo-3, exo-7-diol (C8H14O2) isomers (5 and 6). These form (5)2·(6) co-crystals in the monoclinic P21/n space group (with Z = 6, Z′ = 1.5) rather than undergoing separation by means of fractional recrystallization or column chromatography. The molecule of 5 occupies a general position, whereas the molecule of 6 is disordered over two orientations across a centre of symmetry with occupancies of 0.463 (2) and 0.037 (2). Individual diol hydroxy groups associate around a pseudo-threefold screw axis by means of hydrogen bonding. The second hydroxy group of each diol behaves in a similar manner, generating a three-dimensional hydrogen-bonded network structure. This hydrogen-bond connectivity is identical to that present in three known helical tubuland diol–hydroquinone co-crystals, and the new crystal structure is even more similar to two homologous aliphatic diol co-crystals.
Second distinct conformation of the phosphohistidine loop in succinyl-CoA synthetase
Authors: Huang Ji , Fraser Marie E.
Published: February 2021

Succinyl-CoA synthetase (SCS) catalyzes a reversible reaction that is the only substrate-level phosphorylation in the citric acid cycle. One of the essential steps for the transfer of the phosphoryl group involves the movement of the phosphohistidine loop between active site I, where CoA, succinate and phosphate bind, and active site II, where the nucleotide binds. Here, the first crystal structure of SCS revealing the conformation of the phosphohistidine loop in site II of the porcine GTP-specific enzyme is presented. The phosphoryl transfer bridges a distance of 29 Å between the binding sites for phosphohistidine in site I and site II, so these crystal structures support the proposed mechanism of catalysis by SCS. In addition, a second succinate-binding site was discovered at the interface between the α- and β-subunits of SCS, and another magnesium ion was found that interacts with the side chains of Glu141β and Glu204β via water-mediated interactions. These glutamate residues interact with the active-site histidine residue when it is bound in site II.
Crystal structures of adenylylated and unadenylylated PIIprotein GlnK fromCorynebacterium glutamicum
Authors: Grau Florian C. , Burkovski Andreas , Muller Yves A.
Published: February 2021

PIIproteins are ubiquitous signaling proteins that are involved in the regulation of the nitrogen/carbon balance in bacteria, archaea, and some plants and algae. Signal transductionviaPIIproteins is modulated by effector molecules and post-translational modifications in the PIIT-loop. Whereas the binding of ADP, ATP and the concomitant binding of ATP and 2-oxoglutarate (2OG) engender two distinct conformations of the T-loop that either favor or disfavor the interaction with partner proteins, the structural consequences of post-translational modifications such as phosphorylation, uridylylation and adenylylation are far less well understood. In the present study, crystal structures of the PIIprotein GlnK fromCorynebacterium glutamicumhave been determined, namely of adenylylated GlnK (adGlnK) and unmodified unadenylylated GlnK (unGlnK). AdGlnK has been proposed to act as an inducer of the transcription repressor AmtR, and the adenylylation of Tyr51 in GlnK has been proposed to be a prerequisite for this function. The structures of unGlnK and adGlnK allow the first atomic insights into the structural implications of the covalent attachment of an AMP moiety to the T-loop. The overall GlnK fold remains unaltered upon adenylylation, and T-loop adenylylation does not appear to interfere with the formation of the two major functionally important T-loop conformations, namely the extended T-loop in the canonical ADP-bound state and the compacted T-loop that is adopted upon the simultaneous binding of Mg-ATP and 2OG. Thus, the PII-typical conformational switching mechanism appears to be preserved in GlnK fromC. glutamicum, while at the same time the functional repertoire becomes expanded through the accommodation of a peculiar post-translational modification.
Marketing advantages and sustainable competitiveness through branding for the supply chain of Islamic country
Authors: Shahbaz Muhammad Saeed , Javaid Mudaser , Alam Kazmi Syed Hasnain , Abbas Qamar
Published: February 2021

Purpose

Branding plays a vital role in the success of every organization and even industry. In Islamic countries, every organization must consider Sharia rules while strategy making. Nowadays, the supply chain is considered a major tool of branding and marketing. After an extensive literature review, it has been found that the studies that test the marketing advantages (MAs) and sustainable competitiveness through branding are scarce. The purpose of this study is to empirically examine the relationship between branding and MAs and mediating the role of sustainable competitiveness.

Design/methodology/approach

This is a quantitative study. An instrument was adopted, and data were collected. The researchers tested the hypotheses from the survey data from 179 electronic organizations. The data ware analyzed through structural equation modeling to examine the proposed hypothesis of this study.

Findings

The findings indicate that the relationship among dimensions of branding attitude and MAs were supported (expect reliability). Additionally, this study also revealed that a sustainable competitive variable plays a substantial role as a mediating variable in those relationships.

Research limitations/implications

This study is a cross-sectional survey. Consequently, the limited sample size from the electric industry may affect the power of generalizability. The next study may be demonstrated for other industries to respect the nature of the branding and MAs among the managerial staff of other industries.

Practical implications

This study will help managers to understand how to use the supply chain as branding for their MAs through sustainable competitiveness.

Originality/value

This study adds practical value to the literature on sustainable competitive, branding and MA and supply chain. The study shows that sustainable competitiveness has varying mediating effects on industry value.
Family experiences of caregiving to patients with Alzheimer
Authors: Al-Zyoud Eman , Maharmeh Mahmoud , Ahmad Muayyad
Published: February 2021

Purpose

This paper aims to describe and understand the family experience of caregiving to their Alzheimer patients and to explore the impact of caregiving on the family’s caregiver well-being.

Design/methodology/approach

The study involved eight family caregivers from the outpatient department, specifically from the neurology-medical clinic. A descriptive phenomenological approach was used for data collection through in-depth semi-structured interviews.

Findings

Four themes emerged: caregiver perception, tension, the sense of duty and commitment and altruism and sacrifice. The experience of family caregivers was different from their experiences with other chronic illnesses.

Originality/value

The family caregivers experience new life when providing care to their patients with Alzheimer's. The impact of the process of caregiving on whole life appeared in both positive and negative aspects. The perception and awareness of family caregivers toward Alzheimer’s disease were poor.
Effectiveness, safety and acceptability of no‐test medical abortion (termination of pregnancy) provided via telemedicine: a national cohort study
Authors: Aiken ARA , Lohr PA , Lord J , Ghosh N , Starling J
Published: February 2021

Objective

To compare outcomes before and after implementation of medical abortion (termination of pregnancy) without ultrasound via telemedicine.

Design

Cohort analysis.

Setting

The three main abortion providers.

Population or sample

Medical abortions at home at ≤69 days’ gestation in two cohorts: traditional model (in‐person with ultrasound, n = 22 158) from January to March 2020 versus telemedicine‐hybrid model (either in person or via telemedicine without ultrasound, n = 29 984, of whom 18 435 had no‐test telemedicine) between April and June 2020. Sample (n = 52 142) comprises 85% of all medical abortions provided nationally.

Methods

Data from electronic records and incident databases were used to compare outcomes between cohorts, adjusted for baseline differences.

Main outcome measures

Treatment success, serious adverse events, waiting times, gestation at treatment, acceptability.

Results

Mean waiting time from referral to treatment was 4.2 days shorter in the telemedicine‐hybrid model and more abortions were provided at ≤6 weeks’ gestation (40% versus 25%, P < 0.001). Treatment success (98.8% versus 98.2%, P > 0.999), serious adverse events (0.02% versus 0.04%, P = 0.557) and incidence of ectopic pregnancy (0.2% versus 0.2%, P = 0.796) were not different between models. In the telemedicine‐hybrid model, 0.04% were estimated to be over 10 weeks’ gestation at the time of the abortion; all were completed safely at home. Within the telemedicine‐hybrid model, effectiveness was higher with telemedicine than in‐person care (99.2% versus 98.1%, P < 0.001). Acceptability of telemedicine was high (96% satisfied) and 80% reported a future preference for telemedicine.

Conclusions

A telemedicine‐hybrid model for medical abortion that includes no‐test telemedicine and treatment without an ultrasound is effective, safe, acceptable and improves access to care.

Tweetable abstract

Compelling evidence from 52 142 women shows no‐test telemedicine abortion is safe, effective and improves care.
Computed tomography findings of metabolic syndrome in patients with acute colonic diverticulitis
Authors: Anderson Mark A , Kordbacheh Hamed , Joseph Evita , Bennett Susan E , Stanford Fatima Cody , Kambadakone Avinash
Published: February 2021

Introduction

Many factors associated with colonic diverticulitis are also part of the clinical definition of the metabolic syndrome. Computed tomography (CT) is commonly performed in symptomatic patients, such as those with suspected or known acute diverticulitis, and could add additional value for the health of these patients by identifying and reporting CT biomarkers of metabolic syndrome, if present and detectable. The purpose of this study was to identify CT biomarkers of metabolic syndrome in patients with acute colonic diverticulitis.

Methods

We retrospectively reviewed 243 patients (mean‐60 yrs, M:F:126:117) diagnosed with colonic diverticulitis on CT between March 2015 and March 2017 for hepatic steatosis, vascular calcifications, abdominal diameters and fat volumes. Criteria of metabolic syndrome were obtained from medical records. Differences in imaging biomarkers were compared using chi‐square comparisons stratified by metabolic syndrome, abdominal diameter and fat volume.

Results

Of 243 patients, 33% demonstrated hepatic steatosis and 71% atherosclerotic vascular calcifications on CT. 28% met criteria for metabolic syndrome. Patients with metabolic syndrome had higher occurrence of hepatic steatosis, sagittal diameter ≥ 35 cm, visceral fat > 5000 cm3 and subcutaneous fat > 8300 cm3 (P < 0.05), but not vascular calcifications (P > 0.05).

Conclusions

CT biomarkers of metabolic syndrome are commonly encountered in patients with acute diverticulitis. Recognizing and reporting these findings can guide towards further evaluation for metabolic syndrome.
Pulmonary large cell carcinoma, highly positive for PD‐L1, shows marked response to pembrolizumab: A case report
Authors: Okabe Naoyuki , Mine Hayato , Takagi Hironori , Watanabe Masayuki , Muto Satoshi , Matsumura Yuki , Shio Yutaka , Suzuki Hiroyuki
Published: February 2021

Pulmonary large cell carcinoma (LCC) is classified as a poorly defined entity among non‐small cell lung cancers (NSCLCs). At present, there are no effective anticancer drugs, such as molecular targeted drugs, for LCC, and it has been reported that patient prognosis is poor. Recently, the development of immune checkpoint inhibitors (ICIs) has changed the therapeutic strategies for patients with NSCLC. Here, we present a case of LCC successfully treated with pembrolizumab. A 58‐year‐old man who was a former smoker was diagnosed with LCC. The postoperative stage was T3N2M0. During postoperative adjuvant chemotherapy, swelling of the supraclavicular lymph node was observed and the patient was diagnosed with recurrence. The patient was treated with two regimens of conventional cytotoxic chemotherapy; however, he experienced some hoarseness. Imaging confirmed swelling of the hilar and mediastinal lymph nodes and the patient was subsequently diagnosed with disease progression. Previous surgical specimens when immunostained showed that a high proportion of the tumor cells were positive for expression of programmed death‐ligand 1 (PD‐L1), and it was decided to commence treatment with pembrolizumab. This treatment resulted in rapid regression of the hilar and mediastinal lymph nodes, and a progression‐free period maintained for at least 24 treatment cycles. The patient's hoarseness improved, and the lymph nodes decreased in size. Immunotherapy targeting PD‐1/PD‐L1 may be an option for patients with PD‐L1 positive LCC. This case report suggests that treatment with ICIs may be important in the selection of treatment for not only LCC but also relatively rare NSCLC with high PD‐L1 expression.
Robust ecological analysis of camera trap data labelled by a machine learning model
Authors: Whytock Robin C. , Świeżewski Jędrzej , Zwerts Joeri A. , Bara‐Słupski Tadeusz , Koumba Pambo Aurélie Flore , Rogala Marek , Bahaa‐el‐din Laila , Boekee Kelly , Brittain Stephanie , Cardoso Anabelle W. , Henschel Philipp , Lehmann David , Momboua Brice , Kiebou Opepa Cisquet , Orbell Christopher , Pitman Ross T. , Robinson Hugh S. , Abernethy Katharine A.
Published: February 2021

Ecological data are collected over vast geographic areas using digital sensors such as camera traps and bioacoustic recorders. Camera traps have become the standard method for surveying many terrestrial mammals and birds, but camera trap arrays often generate millions of images that are time‐consuming to label. This causes significant latency between data collection and subsequent inference, which impedes conservation at a time of ecological crisis. Machine learning algorithms have been developed to improve the speed of labelling camera trap data, but it is uncertain how the outputs of these models can be used in ecological analyses without secondary validation by a human.

Here, we present our approach to developing, testing and applying a machine learning model to camera trap data for the purpose of achieving fully automated ecological analyses. As a case‐study, we built a model to classify 26 Central African forest mammal and bird species (or groups). The model generalizes to new spatially and temporally independent data (n = 227 camera stations, n = 23,868 images), and outperforms humans in several respects (e.g. detecting ‘invisible’ animals). We demonstrate how ecologists can evaluate a machine learning model's precision and accuracy in an ecological context by comparing species richness, activity patterns (n = 4 species tested) and occupancy (n = 4 species tested) derived from machine learning labels with the same estimates derived from expert labels.

Results show that fully automated species labels can be equivalent to expert labels when calculating species richness, activity patterns (n = 4 species tested) and estimating occupancy (n = 3 of 4 species tested) in a large, completely out‐of‐sample test dataset. Simple thresholding using the Softmax values (i.e. excluding ‘uncertain’ labels) improved the model's performance when calculating activity patterns and estimating occupancy but did not improve estimates of species richness.

We conclude that, with adequate testing and evaluation in an ecological context, a machine learning model can generate labels for direct use in ecological analyses without the need for manual validation. We provide the user‐community with a multi‐platform, multi‐language graphical user interface that can be used to run our model offline.
A meta‐analysis of the relationship between parental death in childhood and subsequent psychiatric disorder
Authors: McKay Michael T. , Cannon Mary , Healy Colm , Syer Sarah , O’Donnell Laurie , Clarke Mary C.
Published: February 2021

Objective

To systematically review evidence for an association between parental death in childhood, and the subsequent development of an anxiety, affective or psychotic disorder.

Methods

Electronic databases (Scopus, Medline (for Ovid), EMBASE and PsychINFO) were searched for peer‐reviewed, cohort studies in the English language. Meta‐analyses were performed for studies reporting hazard ratios, incidence rate ratios and odds ratios. Two studies reported risk ratios, and these were included in an overall pool of odds, risk and incidence rate ratios. Sensitivity analyses were performed (removal of one study at a time) for all meta‐analyses, and study quality assessed using the Newcastle‐Ottawa Scale.

Results

Fifteen studies were retained, and where required, data were averaged in advance of pooling. Significant results were observed in studies reporting hazard ratios (k = 4, 1.48 [95% CI = 1.32–1.66]), incidence rate ratios (k = 3, 1.37 [95% CI = 1.01–1.85]), but not odds ratios (k = 4, 0.87 [95% CI = 0.72, 1.05]). However, the overall pooled effect (using odds, incidence rate and risk ratios) was statistically significant (k = 9, 1.22 [95% CI = 1.03–1.44]).

Conclusion

Overall, the evidence suggests that there is a positive association between the death of a parent before age 18, and the subsequent development of an anxiety, affective or psychotic disorder. The lack of a significant pooled effect in studies reporting results as odds ratios is likely an artefact of study design.

Limitations

Data were clustered in four countries making generalizability uncertain. Studies adjusted for a variety of possible confounders, and follow‐up after death varied considerably.
Age‐related height loss and health‐related quality of life in a nationwide Korean survey
Authors: Hwang In Cheol , Ahn Hong Yup
Published: February 2021

Objective

This study examined the association between self‐reported height loss and health‐related quality of life (HRQoL) among Korean adults older than 50 years.

Methods

Analyses were based on pooled cross‐sectional data from 6,123 participants over 50 years of age in the Korean National Health and Nutrition Examination Survey between 2008 and 2011. HRQoL was measured using the EuroQol five‐dimensional (EQ‐5D) instrument. Height loss was calculated as the difference between the recalled tallest height in participants’ past and their currently measured height.

Results

The inverse association between height loss and HRQoL was dose‐dependent and strongest for mobility and usual activity dimensions. Fully adjusted EQ‐5D index scores were lower in the height‐loss group than in the no height‐loss group, and these trends were most notable among men or participants with co‐morbid conditions.

Conclusion

Height loss is associated with poor HRQoL among Korean adults.
Congenital melanocytic naevi: An up‐to‐date overview
Authors: Farabi Banu , Akay Bengu Nisa , Goldust Mohamad , Wollina Uwe , Atak Mehmet Fatih , Rao Babar
Published: February 2021

Congenital melanocytic naevi are hamartomas of the neuroectoderm caused by genetic mosaicism. Congenital melanocytic naevi are seen in 1‐6% of all live births and commonly classified based on the projected size in adults. Congenital melanocytic naevi appear in different colours, shapes, and sizes, and occasionally present with complications. In this review, we sought to evaluate congenital melanocytic naevi, their clinical, dermatoscopic, and reflectance confocal microscopic features, behavioural pattern over time, new trends in classification, underlying genetic factors and their influence on clinical manifestations and management, associated risks, complications, magnetic resonance imaging findings and their management in the light of recent literature.