bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors and prognostic significance of platelet count abnormalities in children with HIV infection on antiretroviral therapy
Authors: Lubega Joseph , Kim Taylor O. , Airewele Gladstone , Grimes Amanda , Bulsara Shaun , Peckham Erin , Wanless Sebastian R. , Haq Heather , Elyanu Peter , Musoke Philippa , Lumumba Mwita , Kekitiinwa Adeodata , Matshaba Mogomotsi , Scheurer Michael , Despotovic Jenny
Published: September 2022

Objectives:

To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children with HIV infection (CWH).

Design:

A retrospective nested case control study of patients 0–18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004–2014.

Methods:

Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with selected clinical variables. We constructed Kaplan–Meier curves and a Cox proportional hazards model to evaluate the impact of T/T on survival.

Results:

Two thousand, one hundred and nine children were sampled. The incidence density of thrombocytopenia was 1 per 57.9 (95% confidence interval [CI] 50.3–66.8) CWH-years. Thrombocytopenia was higher in children with WHO Stage III/IV, lower in children on zidovudine, and had no association with use of lamivudine or nevirapine, CD4+ suppression, age, and nutrition status. Thrombocytopenia was independently associated with 2.2-fold higher mortality (95% CI 1.62–3.08). The incidence density of thrombocytosis was 1 per 11.4 (95% CI 10.7–12.1) CWH-years. Thrombocytosis was associated with higher CD4+ cell count, younger age, and use of lamivudine or nevirapine, and did not impact survival.

Conclusions:

Platelet count is a clinically valuable biomarker of HIV clinical progression and mortality. Laboratory studies are necessary to elucidate the mechanisms of T/T.
64Cu-DOTA-Rituximab PET/CT of B-Cell Non-Hodgkin Lymphoma for Imaging the CD20 Expression
Authors: Lee Inki , Lim Ilhan , Lee Kyo Chul , Kang Hye Jin , Lim Sang Moo
Published: September 2022

64Cu-DOTA-rituximab PET/CT was performed on a 62-year-old and a 71-year-old men diagnosed with B-cell non-Hodgkin lymphoma. Compared with 18F-FDG PET/CT, lesions could be detected more sensitively, and it was confirmed that there was no discernible 64Cu-DOTA-rituximab uptake in the tumor other than lymphoma. 64Cu-DOTA-rituximab PET/CT could be a powerful tool for the diagnosis and monitoring treatment response of lymphoma because of imaging the CD20 expression.
Monitoring the Progression of a Calcifying Uterine Leiomyoma
Authors: Resto David A. , Park Peter Sang Uk , Werner Thomas J. , Høilund-Carlsen Poul F. , Alavi Abass
Published: September 2022

Uterine leiomyomas (fibroids) are common and benign hormone-dependent tumors of the uterus, often coinciding with atypical menstrual bleeding, urinary incontinence, and lower abdominal pain. The PET tracer 18F-NaF has been used to study metastatic and benign bone disorders, but its potential use in investigating the molecular alterations of extraosseous tissues and tumors has not been fully investigated. In this report, we present a calcifying uterine leiomyoma incidentally detected on 18F-NaF PET/CT scans in a postmenopausal 61-year-old woman and follow-up image 2 years after, highlighting the potential of 18F-NaF in monitoring both the molecular and structural progression of uterine leiomyomas.
A unified framework for linear thermo-visco-elastic wave propagation including the effects of stress-relaxation
Authors: García Neefjes Erik , Nigro David , Gower Artur L. , Assier Raphaël C. , Pinfield Valerie J. , Parnell William J.
Published: September 2022

We present a unified framework for the study of wave propagation in homogeneous linear thermo-visco-elastic (TVE) continua, starting from conservation laws. In free-space such media admit two thermo-compressional modes and a shear mode. We provide asymptotic approximations to the corresponding wavenumbers which facilitate the understanding of dispersion of these modes, and consider common solids and fluids as well as soft materials where creep compliance and stress relaxation are important. We further illustrate how commonly used simpler acoustic/elastic dissipative theories can be derived via particular limits of this framework. Consequently, our framework allows us to: (i) simultaneously model interfaces involving both fluids and solids and (ii) easily quantify the influence of thermal or viscous losses in a given configuration of interest. As an example, the general framework is appliedto the canonical problem of scattering from an interface between two TVE half spaces in perfect contact. To illustrate, we provide results for fluid–solid interfaces involving air, water, steel and rubber, paying particular attention to the effects of stress relaxation.
Microbe Profile: Wigglesworthia glossinidia: the tsetse fly’s significant other
Authors: Weiss Brian L. , Rio Rita V. M. , Aksoy Serap
Published: September 2022

Wigglesworthia glossinidia

is an obligate, maternally transmitted endosymbiont of tsetse flies. The ancient association between these two organisms accounts for many of their unique physiological adaptations. Similar to other obligate mutualists,

Wigglesworthia

’s genome is dramatically reduced in size, yet it has retained the capacity to produce many B-vitamins that are found at inadequate quantities in the fly’s vertebrate blood-specific diet. These

Wigglesworthia

-derived B-vitamins play essential nutritional roles to maintain tsetse’s physiological homeostasis as well as that of other members of the fly’s microbiota. In addition to its nutritional role,

Wigglesworthia

contributes towards the development of tsetse’s immune system during the larval period. Tsetse produce amidases that degrade symbiotic peptidoglycans and prevent activation of antimicrobial responses that can damage

Wigglesworthia

. These amidases in turn exhibit antiparasitic activity and decrease tsetse’s ability to be colonized with parasitic trypanosomes, which reduce host fitness. Thus, the

Wigglesworthia

symbiosis represents a fine-tuned association in which both partners actively contribute towards achieving optimal fitness outcomes.
Exact global alignment using A* with chaining seed heuristic and match pruning
Authors: Groot Koerkamp Ragnar , Ivanov Pesho
Published: September 2022

Motivation

Sequence alignment has been at the core of computational biology for half a century. Still, it is an open problem to design a practical algorithm for exact alignment of a pair of related sequences in linear-like time (Medvedev, 2022b).

Methods

We solve exact global pairwise alignment with respect to edit distance by using the A* shortest path algorithm. In order to efficiently align long sequences with high divergence, we extend the recently proposedseed heuristic(Ivanovet al., 2022) withmatch chaining, gap costs, andinexact matches. We additionally integrate the novelmatch pruningtechnique and diagonal transition (Ukkonen, 1985) to improve the A* search. We prove the correctness of our algorithm, implement it in the A*PA aligner, and justify our extensions intuitively and empirically.

Results

On random sequences of divergenced=4% and lengthn, the empirical runtime of A*PA scales near-linearly with length (best fitn1.06,n≤107bp). A similar scaling remains up tod=12% (best fitn1.24,n≤107bp). Forn=107bp andd=4%, A*PA reaches >500× speedup compared to the leading exact aligners EDLIB and BIWFA. The performance of A*PA is highly influenced by long gaps. On long (n>500 kbp) ONT reads of a human sample it efficiently aligns sequences withd<10%, leading to 3× median speedup compared to EDLIB and BIWFA. When the sequences come from different human samples, A*PA performs 1.7× faster than EDLIB and BIWFA.

Availability

github.com/RagnarGrootKoerkamp/astar-pairwise-aligner

Contact

ragnar.grootkoerkamp@inf.ethz.ch,pesho@inf.ethz.ch
Myonuclear alterations associated with exercise are independent of age in humans
Authors: Battey E. , Ross J.A , Hoang A. , Wilson D.G.S. , Han Y. , Levy Y. , Pollock R.D. , Kalakoutis M. , Pugh J.N. , Close G.L. , Ellison-Hughes G. M. , Lazarus N.R. , Iskratsch T. , Harridge S.D.R. , Ochala J. , Stroud M.J.
Published: September 2022

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with nuclear lamina protein Lamin A regulating nuclear shape, nuclear mechanics, and ultimately gene expression. Defective Lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals. Complementary to this, exercise resulted in increased levels of Lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan.

Key points

The nucleus plays an active role in translating forces into biochemical signals

Myonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function.

Here, we present striking differences in myonuclear shape and mechanics associated with exercise, in both young and old humans.

Myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals.

We conclude that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan.
Structural basis of bacteriophage T5 infection trigger and E. coli cell wall perforation
Authors: Linares Romain , Arnaud Charles-Adrien , Effantin Grégory , Darnault Claudine , Epalle Nathan Hugo , Erba Elisabetta Boeri , Schoehn Guy , Breyton Cécile
Published: September 2022

The vast majority of bacteriophages (phages) - bacterial viruses - present a tail that allows host recognition, cell wall perforation and safe channelling of the viral DNA from the capsid to the cytoplasm of the infected bacterium. The majority of tailed phages bears a long flexible tail (Siphoviridae) at the distal end of which a tip complex, often called baseplate, harbours one or more Receptor Binding Protein·s (RBPs). Interaction between the RBPs and the host surface triggers cell wall perforation and DNA ejection, but little is known on these mechanisms for Siphoviridae. Here, we present the structure of siphophage T5 tip at high resolution, determined by electron cryo-microscopy, allowing to trace most of its constituting proteins, including 35 C-terminal residues of the Tape Measure Protein. We also present the structure of T5 tip after interaction with its E. coli receptor FhuA reconstituted into nanodisc. It brings out the dramatic conformational changes underwent by T5 tip upon infection, i.e. bending of the central fibre on the side, opening of the tail tube and its anchoring to the membrane, and formation of a transmembrane channel. These new structures shed light on the mechanisms of host recognition and activation of the viral entry for Siphoviridae.
Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans
Authors: Ridley Amanda JL , Ou Yaqing , Karlsson Richard , Pun Nabina , Birchenough Holly L , Jowitt Thomas A , Lawless Craig , Miller Rebecca L , Dyer Douglas P
Published: September 2022

Chemokine driven leukocyte recruitment is a key component of the immune response and is central to a wide range of diseases. However, there has yet to be a clinically successful therapeutic approach that targets the chemokine system during inflammatory disease; possibly due to the supposed redundancy of the chemokine system. A range of recent studies have demonstrated that the chemokine system is in fact based on specificity of function. Here we have generated a resource to analyse chemokine gene (ligand and receptor) expression across different species, tissues and diseases; revealing complex expression patterns whereby multiple chemokine ligands that mediate recruitment of the same leukocyte type are expressed in the same context, e.g. the CXCR3 ligands CXCL9, 10 and 11. We use biophysical approaches to show that CXCL9, 10 and 11 have very different interactions with extracellular matrix glycosaminoglycans (GAGs) which is exacerbated by specific GAG sulphation. Finally, in vivo approaches demonstrate that GAG-binding is critical for CXCL9 driven recruitment of specific T cell subsets (e.g. CD4+) but not others (e.g. CD8+), independent of CXCR3 expression. Our data demonstrate that chemokine expression is complex and that multiple ligands are likely needed for robust leukocyte recruitment across tissues and diseases. We also demonstrate that ECM GAGs facilitate decoding of these complex chemokine signals so that they are either primarily presented on GAG-coated cell surfaces or remain more soluble. Our findings represent a new mechanistic understanding of chemokine mediated immune cell recruitment and identify novel avenues to target specific chemokines during inflammatory disease.
Single-cell analysis of megakaryopoiesis in peripheral CD34+ cells: insights into ETV6-related thrombocytopenia
Authors: Bigot Timothée , Gabinaud Elisa , Hannouche Laurent , Sbarra Véronique , Andersen Elisa , Bastelica Delphine , Falaise Céline , Ibrahim-Kosta Manal , Loosveld Marie , Saultier Paul , Payet-Bornet Dominique , Alessi Marie-Christine , Potier Delphine , Poggi Marjorie
Published: September 2022

Expansion of human megakaryoblasts from peripheral blood-derived CD34+ cells is commonly used to characterize inherited or acquired thrombocytopenia and evaluate defects in megakaryocyte (MK) differentiation, MK maturation and proplatelet formation. We applied single-cell RNA sequencing to understand local gene expression changes during megakaryopoiesis (days 6 and 11 of differentiation) in peripheral CD34+ cells from healthy controls and patients with ETV6-related thrombocytopenia.

Analysis of gene expression and regulon activity revealed distinct clusters partitioned into seven major cell stages: hematopoietic stem/progenitor cells (HSPC), common-myeloid progenitors (CMP), MK-primed CMP, granulocyte-monocyte progenitors, megakaryocyte-erythroid progenitors (MEP), MK progenitor /mature MK (MKP/MK) and platelets. We observed a subpopulation of MEP that arose directly from HSPC, deviating from the canonical MK differentiation pathway.

ETV6 deficiency was characterized by an increase in HSPC, a decrease in MKP/MK, and a lack of platelets. ETV6 deficiency also led to the development of aberrant MEP and MKP/MK cell populations. Genes involved in “mitochondrial” and “DNA repair” pathways were downregulated, while genes involved in “translation” pathways were upregulated. Analysis of patient samples and hematopoietic cell lines transduced with an ETV6 variant revealed increased translation in MK. Ribosomal protein small 6 (RPS6) levels in MK, platelets and peripheral blood mononuclear cells was consistent with the translation findings.

Our results provide a framework to understand peripheral CD34+ cell-derived megakaryocytic cultures. Our observations also shed light on ETV6-variant pathology and reveal potential targets for diagnostic and therapeutic purposes.

Key points

-

scRNAseq gain insight into in vitro megakaryopoiesis, identify MK-primed CMP, and a differentiation trajectory that bypasses the CMP.

-

ETV6 variants led to the development of aberrant MEP and MK cell populations.
Staining of human skin with RGB trichrome unveils a proteoglycan-enriched zone in the hair dermal sheath
Authors: Serrano-Garrido Clara , Gaytán Francisco
Published: September 2022

The skin is the largest organ in the body and plays several essential functions acting as a barrier that protects us from physical and chemical insults, prevents the entrance of pathogens and the loss of water, besides playing an esential role in the regulation of body temperature. The skin displays a high regenerative capacity, evidenced by its self-renewing activity and the process of wound healing, driven by the existence of several resident stem cell populations. Due to the high prevalence of skin pathology, and their anatomical accessibility, skin biopsies and their subsequent microscopic observation constitute a powerfull tool for the study of primary skin diseases, as well as cutaneous manifestations of systemic diseases. This gave rise to dermatopathology as a specific discipline that unifies dermatology and pathology. In this setting, staining with hematoxylin and eosin constitutes the gold standard method for microscopic observation and diagnosis. Yet, several additional stains are used for specific purposes, such as trichrome stains for the staining of collagens in the extracellular matrix. We have applied a recently developed stain (RGB trichrome, acronym for picrosirius Red, fast Green and alcian Blue) to human samples to assess the staining outcomes in normal skin tissues. RGB staining provides a high contrasted interface between epidermis and dermis, and a comprehensible staining of the different dermal structures such as blood vessels, nerves, and sweat and sebaceous glands. The specific staining of collagens by picrosirius red can be useful for the objective quantification of these proteins under polarized light microscopy. In hair follicles, RGB staining resulted in specific staining of the epidermal sheaths and the encasing connective tissue (i.e., dermal sheath). Interestingly, the dermal sheath show two domains in which blue predominates over red staining, thus indicating that proteoglycans prevail in these areas. These two zones are the dermal papilla and an uncharacterized zone located at the upper isthmus, that we have denominated as proteoglycan-enriched belt (PEB). While the role of the papilla in the induction and regulation of hair growth is clearly established, the possible role of PEB remains to be determined and merits additional investigation.
Golden Standard: A complete standard, portable, and interoperative MoClo tool for model and non-model bacterial hosts
Authors: Blázquez Blas , Torres-Bacete Jesús , Leon David San , Kniewel Ryan , Martinez Igor , Sordon Sandra , Wilczak Aleksandra , Salgado Sergio , Huszcza Ewa , Popłoński Jarosław , Prieto M. Auxiliadora , Nogales Juan
Published: September 2022

Modular cloning assembly has become a benchmark technology in synthetic biology. However, there is a mismatch between its impressive development and the standardization required to promote interoperability between the different systems available. The full development of the field is thus hampered by a surge of oftentimes incompatible organism-specific systems. To overcome these issues, we present Golden Standard (GS), a Type IIS assembly method underpinned by the Standard European Vector Architecture (SEVA). GS unlocks modular cloning applications with any type of microorganism and delivers consistent combinatorial multi-part assembly of standardized genetic elements to create genetic circuits of up to twenty transcription units. Reliance on the Golden Gate syntax renders GS fully compatible with many existing tools and it sets the path towards efficient reusability of available part libraries and assembled TUs. GS was fully validated in terms of DNA assembly performance, portability and phenotype engineering in model and non-model bacteria. In order to facilitate the widespread adoption and future community-driven development of GS, we provide a web-portal featuring: i) a repository of parts and vectors, ii) a SBOLHub for exchange and analysis of constructs and iii) Wizard and Setup tools to guide the design of constructs using stored and user-specific parts.
Plasmodiuminfection disrupts the T follicular helper cell response to heterologous immunization
Authors: Fontana Mary F. , Saphire Erica Ollmann , Pepper Marion
Published: September 2022

Naturally acquired immunity to malaria develops only after many years and repeated exposures, raising the question of whetherPlasmodiumparasites, the etiological agents of malaria, suppress the ability of dendritic cells (DCs) to activate optimal T cell responses. We demonstrated recently that B cells, rather than DCs, are the principal activators of CD4+ T cells in murine malaria. In the present study, we further investigated factors that might prevent DCs from primingPlasmodium-specific T helper cell responses. We found that DCs were significantly less efficient at taking up infected red blood cells (iRBCs) compared to soluble antigen, whereas B cells more readily bound iRBCs. To assess whether DCs retained the capacity to present soluble antigen during malaria, we measured responses to a heterologous protein immunization administered to naïve mice or mice infected withP. chabaudi. Antigen uptake, DC activation, and expansion of immunogen-specific T cells were intact in infected mice, indicating DCs remained functional. However, polarization of the immunogen-specific response was dramatically altered, with a near-complete loss of germinal center T follicular helper cells specific for the immunogen, accompanied by significant reductions in antigen-specific B cells and antibody. Our results indicate that DCs remain competent to activate T cells duringPlasmodiuminfection, but that T cell polarization and humoral responses are severely disrupted. This study provides mechanistic insight into the development of bothPlasmodium-specific and heterologous adaptive responses in hosts with malaria.
A neural mechanism of cognitive reserve: The case of bilingualism
Authors: Stevens W. Dale , Khan Naail , Anderson John A. E. , Grady Cheryl L. , Bialystok Ellen
Published: September 2022

Cognitive Reserve (CR) refers to the preservation of cognitive function in the face of age-or disease-related neuroanatomical decline. While bilingualism is known to contribute to CR, the extent to which, and what particular aspect of, second language experience contributes to CR are debated, and the underlying neural mechanism(s) unknown. Intrinsic functional connectivity reflects experience-dependent neuroplasticity that occurs across timescales ranging from minutes to decades, and may be a neural mechanism underlying CR. To test this hypothesis, we used voxel-based morphometry and resting-state functional connectivity analyses of MRI data to compare structural and functional brain integrity between bilingual and monolingual older adults, matched on cognitive performance using a rigorous propensity score matching technique, and across levels of second language proficiency measured as a continuous variable. Bilingualism, and degree of second language proficiency in particular, were associated with lower grey matter integrity in a hub of the default mode network – a region that is particularly vulnerable to decline in aging and dementia – but preserved functional network organization that resembled the young adult brain. Our findings confirm that lifelong bilingualism contributes to CR through experience-dependent maintenance of optimal functional network structure of the domain-general attentional control network across the lifespan.
Fake it to break it: mimicking superinfection exclusion disrupts alphavirus infection and transmission in the yellow fever mosquito Aedes aegypti
Authors: Reitmayer Christine M , Levitt Emily , Basu Sanjay , Atkinson Barry , Fragkoudis Rennos , Merits Andres , Lumley Sarah , Larner Will , Diaz Adriana V , Rooney Sara , Thomas Callum J E , von Wyschetzki Katharina , Rausalu Kai , Alphey Luke
Published: September 2022

Multiple viruses cause a phenomenon termed superinfection exclusion whereby a currently infected cell is resistant to secondary infection by the same or a closely related virus. In alphaviruses, this process is thought to be mediated, at least in part, by the viral protease (nsP2) which is responsible for processing the non-structural polyproteins (P123 and P1234) into individual proteins (nsP1-nsP4), forming the viral replication complex. Taking a synthetic-biology approach, we mimicked this naturally occurring phenomenon by generating a superinfection exclusion-like state in Aedes aegypti mosquitoes, rendering them refractory to alphavirus infection. By artificially expressing Sindbis virus (SINV) and chikungunya virus (CHIKV) nsP2 in mosquito cells and transgenic mosquitoes, we demonstrated a reduction in both SINV and CHIKV viral replication rates in cells following viral infection as well as reduced infection prevalence, viral titres and transmission potential in mosquitoes.
Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair
Authors: Alghoul Emile , Paloni Matteo , Takedachi Arato , Urbach Serge , Barducci Alessandro , Gaillard Pierre-Henri , Basbous Jihane , Constantinou Angelos
Published: September 2022

SLX4, disabled in Fanconi anemia group P, is a scaffolding protein that coordinates the action of structure-specific endonucleases and other proteins involved in replication-coupled repair of DNA interstrand crosslinks (ICLs). Here we show that SLX4 dimerization and SUMO-SIM interactions drive the assembly of SLX4 membraneless compartments in the nucleus called condensates. Super-resolution microscopy reveals that SLX4 forms chromatin-bound clusters of nanocondensates. We report that SLX4 compartmentalizes the SUMO-RNF4 signaling pathway. SENP6 and RNF4 regulate the assembly and disassembly of SLX4 condensates, respectively. SLX4 condensationper setriggers the selective modification of proteins by SUMO and ubiquitin. Specifically, SLX4 condensation induces ubiquitylation and chromatin extraction of topoisomerase 1 DNA-protein cross-links. SLX4 condensation also induces the nucleolytic degradation of newly replicated DNA. We propose that the compartmentalization of proteins by SLX4 through site-specific interactions ensures the spatiotemporal control of protein modifications and nucleolytic reactions during DNA repair.
Small molecule inhibition of multiple RNA binding proteins underlies Musashi-2 independent phenotypes
Authors: Walters Kathryn , Sajek Marcin Piotr , Issaian Aaron , Baldwin Amber , Harrison Evan , Murphy Elisabeth , Daniels Miles , Haines Julie , Hansen Kirk , D’Alessandro Angelo , Mukherjee Neelanjan
Published: September 2022

RNA binding proteins (RBPs) are key regulators of gene expression. Small molecules targeting these RBP-RNA interactions are a rapidly emerging class of therapeutics for treating a variety of diseases. Ro-08-2750 (Ro) is a small molecule inhibitor identified as a competitive inhibitor of Musashi(MSI)-RNA interactions. Here we show Ro potently inhibits adrenocortical steroidogenesis and viability independent of MSI2 in multiple cell lines. We identified Ro-interacting proteins using an unbiased proteome-wide approach and discovered it is broadly targeting RBPs. To confirm this finding, we leveraged the large-scale ENCODE data and found a subset of RBPs whose depletion phenocopies Ro inhibition. We conclude that Ro is a promiscuous inhibitor of multiple RBPs, many containing RRM1 domains. Moreover, we provide a general framework for validating the specificity and identifying targets of RBP inhibitors in a cellular context.
Mitochondrial protein import clogging as a mechanism of disease
Authors: Coyne Liam P. , Wang Xiaowen , Song Jiyao , de Jong Ebbing , Schneider Karin , Massa Paul T. , Middleton Frank A. , Becker Thomas , Chen Xin Jie
Published: September 2022

Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria is disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in adenine nucleotide translocase 1 (Ant1), and its yeast ortholog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of Ant1’s nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/Ant1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger Ant1 variant led to an age-dependent dominant myopathy that phenocopies Ant1-induced human disease, suggesting clogging as a mechanism of disease. We propose that secondary structures of mitochondrial preproteins play an essential role in preventing clogging and disease.
Multi-Dimensional Structure and Dynamics Landscape of Proteins in Mammalian Cells Revealed by In-cell NMR
Authors: Kadavath Harindranath , Prymaczok Natalia , Eichmann Cédric , Riek Roland , Gerez Juan
Published: September 2022

Governing function, half life and subcellular localization, the 3D structure and dynamics of proteins are in nature constantly changing in a tightly regulated manner to fulfill the physiological and adaptive requirements of the cells. To find evidence for this hypothesis, we applied in-cell NMR to three folded model proteins and propose that the splitting of cross peaks are due to distinct structural states that arise from multiple target binding co-existing inside mammalian cells as a result of subcellular localisation including distinct cell compartments. In addition to peak splitting, we observed NMR signal intensity attenuations indicative of transient interactions with other molecules and dynamics on the microsecond to millisecond time scale.
The effect of 18 months lifestyle intervention on brain age assessed with resting-state functional connectivity
Authors: Levakov Gidon , Kaplan Alon , Meir Anat Yaskolka , Rinott Ehud , Tsaban Gal , Zelicha Hila , Blüher Matthias , Ceglarek Uta , Stumvoll Michael , Shelef Ilan , Avidan Galia , Shai Iris
Published: September 2022

Obesity negatively impacts multiple bodily systems, including the central nervous system. Retrospective studies that estimated chronological age from neuroimaging have found accelerated brain aging in obesity, but it is unclear how this estimation would be affected by lifestyle intervention. In a sub-study of 102 participants of the DIRECT-PLUS (dietary-intervention-randomized-controlled-trial polyphenol-unprocessed) trial, we tested the effect of 18 months of lifestyle intervention on predicted brain age, based on MRI-assessed resting-state functional connectivity (RSFC). We further examined how dynamics in multiple health factors, including anthropometric measurements, blood biomarkers, and fat deposition, can account for changes in brain age. To establish our method, we first demonstrated that our model could successfully predict chronological age from RSFC in three cohorts (n=291;358;102). We then found that among the DIRECT-PLUS participants, 1% of body weight loss resulted in an 8.9 months attenuation of brain age. Attenuation of brain age was significantly associated with improved liver biomarkers, decreased liver fat, and visceral and deep subcutaneous adipose tissues after 18m of intervention. Finally, we showed that lower consumption of processed food, sweets, and beverages were associated with attenuated brain age. These results suggest that lifestyle intervention has beneficial effects on the trajectory of brain aging.
Exploring the relationship between job characteristics and infection: Application of a COVID-19 Job Exposure Matrix to SARS-CoV-2 infection data in the United Kingdom
Authors: Rhodes Sarah , Beale Sarah , Wilkinson Jack , van Veldhoven Karin , Basinas Ioannis , Mueller William , Henge Karen Oude , Burdorf Alex , Peters Susan , Stokholm Zara A , Schlünssen Vivi , Kolstad Henrik , Pronk Anjoeka , Pearce Neil , Hayward Andrew , van Tongeren Martie
Published: September 2022

Objectives

To assess whether workplace exposures as estimated via a COVID-19 Job Exposure Matrix (JEM) are associated with SARS-CoV-2.

Methods

Data on 244,470 participants were available from the ONS Coronavirus Infection Survey (CIS) and 16,801 participants from the Virus Watch Cohort, restricted to workers aged 20 to 64. Analysis used logistic regression models with SARS-CoV-2 as the dependent variable for eight individual JEM domains (number of workers, nature of contacts, contact via surfaces, indoor or outdoor location, ability to social distance, use of face covering, job insecurity, migrant workers) with adjustment for age, sex, ethnicity, Index of Multiple Deprivation (IMD), region, household size, urban vs rural area, and health conditions. Analyses were repeated for three time periods (i) February 2020 (Virus Watch)/April 2020 (CIS) to May 2021), (ii)June 2021 to November 2021, (iii) December 2021 to January 2022.

Results

Overall, higher risk classifications for the first six domains tended to be associated with an increased risk of infection, with little evidence of a relationship for domains relating to proportion of workers with job insecurity or migrant workers. By time there was a clear exposure-response relationship for these domains in the first period only. Results were largely consistent across the two cohorts.

Conclusions

An exposure-response relationship exists in the early phase of the COVID-19 pandemic for number of contacts, nature of contacts, contacts via surfaces, indoor or outdoor location, ability to social distance and use of face coverings. These associations appear to have diminished over time.
Active disturbance rejection control for optoelectronic stabilized platform based on model-assisted double extended state observers
Authors: Gao Peng , Su Xiuqin , Zhang Wenbo
Published: September 2022

Purpose

This study aims to promote the anti-disturbance and tracking accuracy of optoelectronic stabilized platforms, which ensure that optical detectors accurately track targets and acquire high-quality images.

Design/methodology/approach

An improved active disturbance rejection control (ADRC) strategy based on model-assisted double extended state observers (MDESOs) is proposed in this paper. First, by establishing an auxiliary model, the total disturbances are separated into two parts: inner and external disturbances. Then, MDESOs are designed to estimate the two parts by separately using two parallel ESOs, by which the controlled plant is adjusted to the ideal pure integral series. Simultaneously, combined with the nonlinear state error feedback, an overall control strategy is established.

Findings

Compared with the conventional ADRC and proportional derivative, the improved ADRC (IADRC) has stronger robustness and adaptability and effectively reduces the requirements for model accuracy and the gain of the ESO. The error of the auxiliary model is tolerated to exceed 50%, and the parameter values of the MDESOs are reduced by 90%.

Originality/value

The total disturbance rejection rate of the proposed strategy is only 3.11% under multiple disturbances, which indicates that the IADRC strategy significantly promotes anti-disturbance performance.
Dynamics of PPP investment in energy and country governance: evidence from Sub-Saharan Africa
Authors: Ahmed Abdullahi Baba , Musonda Innocent , Pretorius J.H.C.
Published: September 2022

Purpose

This paper intends to investigate the empirical link between governance and energy investment in PPP. To succinctly account for biases in the fixed effects (FE) model, the authors adopted different bias-corrected techniques. The majority of these techniques provided evidence that PPP investments in energy are boosted by increasing the desire for accountability, prioritising the voice of the masses and disabusing the rule of laws. This study could not find any positive influence from the control of corruption to PPP investment in energy.

Design/methodology/approach

The acute shortage of power supply in SSA has attracted PPP investments in the energy subsector of the economy, leading to the recent debate on governance and public, private investment. The authors contributed to this argument by examining the impact of country governance on PPP investment in energy using a sample of countries in SSA.

Findings

Therefore, the authors concluded that low control of corruption is responsible for the inadequate volume of PPP investments. In the light of this, the government should redefine the anti-corruption bill of their sovereignty to accommodate severe sanctions when necessary.

Originality/value

This paper uses the fixed effects (FE) model by introducing batteries of nonlinear panel models to capture the relationship between the impacts of country governance on PPP investment in energy.
Conflicting or co-existing logics – doing action research within the framework of a project in a university
Authors: Jałocha Beata , Bogacz-Wojtanowska Ewa , Góral Anna , Jedynak Piotr , Prawelska-Skrzypek Grażyna
Published: September 2022

Purpose

The aim of the study was to illustrate how three different institutional logics, present in the implementation of action research, interact in a formalised project, in a traditional university setting.

Design/methodology/approach

The article is empirical in nature and the research method used is an instrumental case study. The case was the implementation of action research within the framework of an educational project co-financed by EU funds, conducted in a Polish public university. The research process was conducted from September 2017 to November 2019. The following techniques were used: document analysis, in-depth interviews, participatory observation during the project. Constant comparative analysis was used as an analytical approach.

Findings

The study indicates that action research, project management and university management follow different “logics”. The dominant logic of action research is problem-solving, of project management is efficiency and of university management is compliance. These different logics and the relationship between them is explained in the paper.

Originality/value

The research enriches the ongoing discussion on logic multiplicity and project management in a new context – that of the university environment and combines the issue of the implementation of action research with broader conversations on institutional logics.
The role of situational normality, swift guanxi, and perceived effectiveness of social commerce institutional mechanisms: an uncertainty reduction perspective
Authors: Chen Xiayu , Wang Jiawen , Wei Shaobo
Published: September 2022

Purpose

The success of social commerce depends on the actual transactions of consumers, which will be prevented in the presence of high uncertainty. However, attention paid to the uncertainty reduction strategies in social commerce is limited, especially from a unified theoretical framework. Based on uncertainty reduction theory (URT), this paper aims to investigate how three uncertainty reduction strategies (i.e. situational normality, perceived effectiveness of social commerce institutional mechanisms (PESIM) and swift guanxi) affect perceived uncertainty in social commerce, which in turn affects buyers' purchase intention and purchase behavior. The moderating effects of PESIM on the relationships between the other two strategies and perceived uncertainty were also tested.

Design/methodology/approach

In this study longitudinal data from 211 buyers who have usage experience of Xiaohongshu were collected to test the proposed model and hypotheses.

Findings

Results show that the three uncertainty reduction strategies significantly reduce perceived uncertainty. PESIM negatively moderates the relationships between situational normality and perceived uncertainty, swift guanxi and perceived uncertainty. Perceived uncertainty is negatively related to purchase intention. Purchase intention positively affects purchase behavior.

Originality/value

This study focuses on the role of uncertainty reduction mechanisms in promoting purchase behavior through uncertainty reduction and sheds light on the relationships among situational normality, PESIM, swift guanxi and perceived uncertainty based on URT, which have not been extensively studied from a theoretical perspective in social commerce contexts. Besides, this study investigates the moderating role of PESIM, which improves the understanding of the role of swift guanxi and situational normality in reducing perceived uncertainty under the boundary condition of PESIM.
Severity assessment and the early warning mechanism of public events based on the comparison of microblogging characteristics
Authors: Chen Miaomiao , An Lu , Li Gang , Yu Chuanming
Published: September 2022

Purpose

The purpose of the study is to evaluate the severity of public events in real time from the perspective of social media and to construct the early warning mechanism of public events.

Design/methodology/approach

This study constructed the severity assessment system of public events from the dimensions of the netizens' role, the Internet media's role, the spread of public events and the attitudes and feelings of netizens. The method of analyzing the influence tendency of the public event severity indicators was proposed. A total of 1,107,308 microblogging entries regarding four public events were investigated. The severity of public events was divided into four levels.

Findings

It is found that serious public events have higher indicator values than medium level events on the microblogging platform. A quantitative severity classification standard for public events was established and the early warning mechanism of public events was built.

Research limitations/implications

Microblogging and other social media platforms provide rich clues for the real-time study and judgment of public events. This study only investigated the Weibo platform as the data source. Other social media platforms can also be considered in future.

Originality/value

Different from the ex-post evaluation method of judging the severity of public events based on their physical loss, this study constructed a quantitative method to dynamically determine the severity of public events according to the clues reflected by social media. The results can help the emergency management departments judge the severity of public events objectively and reduce the subjective negligence and misjudgment.
Analysis of barriers to organic farming adoption in developing countries: a grey-DEMATEL and ISM approach
Authors: Dixit Aasheesh , Suvadarshini Pinakhi , Pagare Dewang Vijay
Published: September 2022

Purpose

Farmers in India are hesitant to adopt organic farming (OF) despite high demand for organic products and favorable policy measures to encourage the practice. Therefore, this study aims to assess the OF adoption barriers faced by Indian farmers using a systematic method of multi-criteria decision making (MCDM).

Design/methodology/approach

The authors explored eighteen barriers to OF adoption by conducting a literature survey and discussion with experts on OF. Then the authors used a combined method of Grey Decision Making Trial and Evaluation Laboratory (DEMATEL) and Interpretive Structural Modeling (ISM) methodology to rank the barriers and analyze their interactions.

Findings

The analysis reveals that “Lack of knowledge and information,” “lack of financial capacity of farmers’ and “lack of institutional support” are the cause (independent) barriers that significantly impact other barriers. The top three effect (dependent) barriers are “lack of availability of organic inputs,” “personal characteristics such as age, attitudes and beliefs” and “lack of premium pricing,” which are affected by the other barriers.

Research limitations/implications

This research work will help the decision makers understand the barriers to OF adoption in India and their interrelationships. The proposed framework enables them to focus on the high-priority independent barriers, which will subsequently impact the other dependent barriers.

Originality/value

Previous research on OF adoption barriers lacked a multifaceted scientific approach, which is necessary because OF is a complex system and needs a thorough investigation to assess the interaction between the barriers. The research attempts to fill this gap and addresses the complex nature of adoption barriers.
Towards an understanding of learning within the Norwegian fire and rescue services – focusing on tunnel fire safety
Authors: Bjørnsen Gabriela , Dettweiler Ulrich , Njå Ove , Knudsen Knud
Published: September 2022

Purpose

The purpose of this paper is to study how learning within the fire and rescue services may be conceptualized, with special attention paid to tunnel fire safety. Previous studies have developed a model to understand learning in emergency response work. The concept of learning is extended from observed changes in relevant settings to also encompass confirmation of existing knowledge and comprehension of existing practices. We are interested in investigating the properties of the learning model and identifying the mechanisms that influence fire and rescue personnel’s experiences of change, confirmation and/or comprehension.

Design/methodology/approach

This study relies on quantitative data obtained from a questionnaire answered by 939 Norwegian fire and rescue personnel. Multivariate methods have been used to identify the measurement model and the structural relations of the factors.

Findings

The results confirm the theoretical model and indicate that the outcome of learning is influenced by elements of content, context, commitment, decision-making and response and reflection, and that the influence of content and commitment on the outcome of learning is partially indirect and mediated through reflection.

Originality/value

To date, no systematic analysis has been conducted to investigate the factorial structure, as well as the interactions and relationship between the model’s components. This study makes an important contribution to a detailed understanding of learning within the fire and rescue services.