bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative modelling of reported case numbers and seroprevalence reveals time-dependent test efficiency and infectious contacts
Authors: Contento Lorenzo , Castelletti Noemi , Raimúndez Elba , Le Gleut Ronan , Schälte Yannik , Stapor Paul , Hinske Ludwig Christian , Hoelscher Michael , Wieser Andreas , Radon Katja , Fuchs Christiane , Hasenauer Jan ,   the KoCo19 study group
Published: October 2021

Mathematical models have been widely used during the ongoing SARS-CoV-2 pandemic for data interpretation, forecasting, and policy making. However, most models are based on officially reported case numbers, which depend on test availability and test strategies. The time dependence of these factors renders interpretation difficult and might even result in estimation biases.

Here, we present a computational modelling framework that allows for the integration of reported case numbers with seroprevalence estimates obtained from representative population cohorts. To account for the time dependence of infection and testing rates, we embed flexible splines in an epidemiological model. The parameters of these splines are estimated, along with the other parameters, from the available data using a Bayesian approach.

The application of this approach to the official case numbers reported for Munich (Germany) and the seroprevalence reported by the prospective COVID-19 Cohort Munich (KoCo19) provides first estimates for the time dependence of the under-reporting factor. Furthermore, we estimate how the effectiveness of non-pharmaceutical interventions and of the testing strategy evolves over time. Overall, our results show that the integration of temporally highly resolved and representative data is beneficial for accurate epidemiological analyses.
Neural Correlates of Eye Contact and Social Function in Autism Spectrum Disorder
Authors: Hirsch Joy , Zhang Xian , Adam Noah J. , Dravida Swethasri , Naples Adam , Tiede Mark , Wolf Julie M. , McPartland James C.
Published: October 2021

Reluctance to make eye contact during natural interactions is a central diagnostic criterion for autism spectrum disorder (ASD). However, the underlying neural correlates for natural eye contacts in ASD are unknown, and diagnostic biomarkers are active areas of investigation. Here, neuroimaging, eye-tracking, and pupillometry data were acquired simultaneously using two-person functional near-infrared spectroscopy (fNIRS) during live eye-to-eye contact and eye-gaze at a video face in typically developed (TD) and ASD participants to identify the neural correlates of live eye-to-eye contact in both groups. Direct comparisons between ASD and TD participants showed decreased right dorsal parietal activity and increased right ventral temporal-parietal activity for ASD relative to TD during live eye-to-eye contact (p≤0.05, FDR-corrected) consistent with the hypothesis of alternative neural systems for live eye contact. The additional hypothesis that hypoactivity of the right dorsal-parietal regions during eye contact is associated with social performance in ASD was supported by the correlation of right dorsal parietal activity with individual measures of social function: ADOS-2, Autism Diagnostic Observation Schedule, 2nd Edition (r = -0.69); and SRS-2, Social Responsiveness Scale, Second Edition (r = -0.58). That is, as social ability decreased, the neural responses in the right dorsal parietal region to real eye-contact also decreased consistent with a neural correlate for social characteristics in ASD.
Spatial distribution of erector spinae activity is related to task-specific pain-related fear during a repetitive object lifting task
Authors: Liechti Melanie , Von Arx Michael , Eichelberger Patric , Bangerter Christian , Meier Michael L. , Schmid Stefan
Published: October 2021

Fear-avoidance beliefs, particularly the fear of lifting an object with a flexed spine, were shown to be associated with reduced spinal motion during object lifting in both individuals with and without low back pain (LBP). LBP patients thereby also showed potentially clinically relevant changes in the spatial distribution of back muscle activity, but it remains unknown whether such associations are also present in pain-free individuals. The aim of this study was therefore to investigate the relationship between fear-avoidance beliefs and the change in spatial distribution of lumbar paraspinal muscle activity in pain-free individuals during a repetitive object lifting task. Thirty participants completed two pain-related fear questionnaires and performed 25 repetitions of lifting a 5kg-box from a lower to an upper shelf and back, while multi-channel electromyographic signals were recorded bilaterally from the lumbar erector spinae muscles. Changes in spatial distribution were determined by calculating the differences in vertical position of the weighted centroids of muscle activity (centroid shift) between the first and last few repetitions. Multiple linear regression analyses were performed to examine the relationship between the centroid shift and fear-avoidance belief scores. The analyses showed that the fear of lifting an object with a flexed spine was negatively associated with erector spinae activity centroid shift (R2 adj. = 0.1832; p = 0.045), which might be an expression of behavioral alterations in order to prevent the back from possible harm.
ViralFlow: an automated workflow for SARS-CoV-2 genome assembly, lineage assignment, mutations and intrahost variants detection
Authors: Dezordi Filipe Zimmer , de Lima Campos Túlio , Carneiro Jeronimo Pedro Miguel , Aksenen Cleber Furtado , Almeida Suzana Porto , Wallau Gabriel Luz
Published: October 2021

The COVID-19 pandemic, a disease caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), emerged in 2019 and quickly spread worldwide. Genomic surveillance has become the gold standard methodology to monitor and study this emerging virus. The current deluge of SARS-CoV-2 genomic data being generated worldwide has put additional pressure on the urgent need for streamlined bioinformatics workflows for data analysis. Here, we describe a workflow developed by our group to process and analyze large-scale SARS-CoV-2 Illumina amplicon sequencing data. This workflow automates all the steps involved in SARS-CoV-2 genomic analysis: data processing, genome assembly, PANGO lineage assignment, mutation analysis and the screening of intrahost variants. The workflow presented here (https://github.com/dezordi/ViralFlow) is available through Docker or Singularity images, allowing implementation in laptops for small scale analyses or in high processing capacity servers or clusters. Moreover, the low requirements for memory and CPU cores makes it a versatile tool for SARS-CoV-2 genomic analysis.
New insights into the architecture and dynamics of archaella
Authors: Gambelli Lavinia , Isupov Michail N. , Conners Rebecca , McLaren Mathew , Bellack Annett , Gold Vicki , Rachel Reinhard , Daum Bertram
Published: October 2021

Archaea swim by means of a unique molecular machine called the archaellum. The archaellum consists of an ATP-powered intracellular motor that drives the rotation of an extracellular filament, allowing the cell to rapidly propel itself through liquid media.

The archaellum filament comprises multiple copies of helically organised subunits named archaellins. While in many species several archaellin homologs are encoded in the same operon, structural studies conducted to date have suggested that archaella consist of only one protein species. Thus, the role of the remaining archaellin genes remains elusive.

Here we present the structure of the Methanocaldococcus villosus archaellum filament at 3.08 Å resolution. We find that the filament is composed of two alternating archaellins - ArlB1 and ArlB2, suggesting that the architecture and assembly of archaella is more complex than previously thought. Moreover, we identify two major structural elements that enable the archaellum filament to move.

Our findings provide new insights into archaeal motility and challenge the current view on the archaellum architecture and assembly.
Alkaline phosphatase activity of serum affects osteogenic differentiation cultures
Authors: Ansari Sana , Ito Keita , Hofmann Sandra
Published: October 2021

Fetal bovine serum (FBS) is a widely used supplement in cell culture medium, despite its known variability in composition which greatly affects cellular function and consequently the outcome of studies. In bone tissue engineering, the deposited mineralized matrix is one of the main outcome parameters, but using different brands of FBS can result in large variations. Alkaline phosphatase (ALP) is present in FBS. Not only is ALP used to judge the osteogenic differentiation of bone cells, it may affect deposition of mineralized matrix. The present study focused on the enzymatic activity of ALP in FBS of different suppliers and its contribution to mineralization in osteogenic differentiation cultures. It was hypothesized that culturing cells in a medium with high intrinsic ALP activity of FBS will lead to higher mineral deposition compared to media with lower ALP activity. The used FBS types were shown to have significant differences in enzymatic ALP activity. Our results indicate that the ALP activity of the medium not only affected the deposited mineralized matrix but also the osteogenic differentiation of cells as measured by a changed cellular ALP activity of human bone marrow derived mesenchymal stromal cells (hBMSC). In media with low inherent ALP activity, the cellular ALP activity was increased and played the major role in the mineralization process; while, in media with high intrinsic ALP activity contribution from the serum, less cellular ALP activity was measured and the ALP activity of the medium also contributed to mineral formation substantially. Our results highlight the diverse effects of ALP activity intrinsic to FBS on osteogenic differentiation and matrix mineralization and how FBS can determine the experimental outcomes, in particular for studies investigating matrix mineralization. Once again, the need to replace FBS with more controlled and known additives is highlighted.

Graphical abstract
Synthetic glabridin derivatives mitigate steatohepatitis in a diet-induced biopsy-confirmed non-alcoholic steatosis hepatitis mouse model through paraoxonase-2
Authors: Shin Gu-Choul , Lee Hyeong Min , Kim Na Yeon , Yoo Sang-Ku , Park Yun Sun , Park Hyung Soon , Ryu Dongryeol , Kim Kwang Pyo , Kim Kyun-Hwan
Published: October 2021

Limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH), a common immunometabolic disease that can progress to hepatic cirrhosis and cancer. Glabridin and its derivatives are potential therapeutics for some metabolic diseases. However, the therapeutic effects of glabridin and its derivatives on NASH and their biological functions are unclear. This study demonstrated the role of synthetic glabridin derivatives (SGDs) in alleviating hepatic steatosis and inflammation in a biopsy-confirmed rodent NASH model. SGDs exerted therapeutic effects by activating autophagy and the antioxidant defense system, which mitigate NASH pathogenesis. The cellular target of HSG4112, an SGD, was paraoxonase 2. These findings will enable the development of novel therapeutics for NASH in the future.
JADE family proteins regulate proteasome abundance and activity
Authors: Ebert Lena Kathrin , Bargfrede Sebastian , Bohl Katrin , Müller Roman-Ulrich , Benzing Thomas , Schermer Bernhard
Published: October 2021

JADE family proteins (JADE1/2/3) have been implicated in diverse cellular functions and signaling pathways ranging from WNT signaling and cell cycle control to cell death and complex transcriptional regulation through histone acetyl-transferase complexes. JADE proteins show a high degree of sequence similarity and share two PHD zinc finger domains. JADE1 interacts with cilia-associated proteins and has been implicated in cilia-related genetic disorders with kidney phenotypes. However, the function of the widely expressed JADE proteins at the molecular level is still elusive. Here we show that JADE proteins regulate proteasome abundance and activity. Using kidney cells as a model, we demonstrate that loss of either JADE protein resulted in increased expression of almost all components of the 26S proteasome. Regulation occurred at the post-translational level and was not the consequence of transcriptional activation. Consistent with a role for JADE proteins in regulating overall proteasomal abundance, proteasomal activity was elevated in Jade-deficient cells, while exogenous expression of JADE1/2/3 decreased the level of proteasome activity. Coimmunoprecipitation experiments confirmed the interaction of proteasomal subunits with Jade1 suggesting a direct role of JADE proteins in regulating turnover, stability and abundance of the 26s proteasome. These data may now explain the plethora of cellular roles that have been attributed to JADE proteins.
The Human STAT2 Coiled-Coil Domain Contains a Degron for Zika Virus Interferon Evasion
Authors: Parisien Jean-Patrick , Lenoir Jessica J. , Alvarado Gloria , Horvath Curt M.
Published: October 2021

The ability of viruses to evade the host antiviral immune system determines their level of replication fitness, species specificity, and pathogenic potential. Flaviviruses rely on the subversion of innate immune barriers including the type I and type III IFN antiviral systems. Zika virus infection induces the degradation of STAT2, an essential component of the IFN stimulated gene transcription factor, ISGF3. The mechanisms that lead to STAT2 degradation by Zika virus are poorly understood, but it is known to be mediated by the viral NS5 protein that binds to STAT2 and targets it for proteasome-mediated destruction. To better understand how NS5 engages and degrades STAT2, functional analysis of the protein interactions that lead to Zika virus and NS5-dependent STAT2 proteolysis were investigated. Data implicate the STAT2 coiled-coil domain as necessary and sufficient for NS5 interaction and proteasome degradation after Zika virus infection. Molecular dissection reveals that the first two α-helices of the STAT2 coiled-coil contain a specific targeting region for IFN antagonism. These functional interactions provide a more complete understanding of the essential protein-protein interactions needed for Zika virus evasion of the host antiviral response, and identifies new targets for antiviral therapeutic approaches.

Importance

Zika virus infection can cause mild fever, rash, and muscle pain, and in rare cases lead to brain or nervous system diseases including Guillain–Barré syndrome. Infections in pregnant women can increase the risk of miscarriage or serious birth defects including brain anomalies and microcephaly. There are no drugs or vaccines for Zika disease. Zika virus is known to break down the host antiviral immune response, and this research project reveals how the virus suppresses interferon signaling, and may reveal therapeutic vulnerabilities.
Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma
Authors: Guetta-Terrier Charlotte , Karambizi David , Akosman Bedia , Chen Jia-Shu , Kamle Suchitra , Fajardo Eduardo , Fiser Andras , Singh Ritambhara , Toms Steven A. , Lee Chun Geun , Elias Jack A. , Tapinos Nikos
Published: October 2021

Chi3l1 (Chitinase 3-like 1) is a secreted protein highly expressed in glioblastoma. Here, we show that exposure of glioma stem cells (GSCs) to Chi3l1 reduces the CD133+/SOX2+ cells and increases the CD44+/Chi3l1+ cells. Chi3l1 binds to CD44 and induces phosphorylation and nuclear translocation of beta-catenin, Akt and STAT3. Single cell RNA-seq and RNA velocity following incubation of GSCs with Chi3l1 show significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq reveals that Chi3l1 increases accessibility of promoters containing MAZ transcription factor footprint. Inhibition of MAZ directly regulates genes with highest expression in cellular clusters exhibiting significant cell state transitions. Finally, targeting Chi3l1 in vivo with a blocking antibody, resets the transcriptomic profile of glioblastoma and inhibits tumor growth. Our work implicates Chi3l1 as modulator of GSC cellular states and demonstrates pre-clinical efficacy of anti-Chi3l1 antibody treatment.
Neutrophils contribute to ER stress in lung epithelial cells in the pristane-induced diffuse alveolar hemorrhage mouse model
Authors: Tumurkhuu Gantsetseg , Laguna Duygu Ercan , Moore Richard E. , Contreras Jorge , De Los Santos Gabriela , Akaveka Luisa , Montano Erica N. , Wang Yizhou , Ishimori Mariko , Venuturupalli Swamy , Forbess Lindsy , Stripp Barry R. , Wallace Daniel J. , Jefferies Caroline A.
Published: October 2021

Diffuse alveolar hemorrhage (DAH), although rare, is a life-threatening complication of systemic lupus erythematosus (SLE). Little is known about the pathophysiology of DAH in humans, although increasingly neutrophils, NETosis and inflammatory monocytes have been shown to play an important role in the pristane-induced model of SLE which develops lung hemorrhage and recapitulates many of the pathologic features of human DAH. Using this experimental model, we asked whether endoplasmic reticulum (ER) stress played a role in driving the pathology of pulmonary hemorrhage and what role infiltrating neutrophils had in this process. Analysis of lung tissue from pristane-treated mice showed genes associated with ER stress and NETosis were increased in a time-dependent manner and reflected the timing of CD11b+Ly6G+ neutrophil accumulation in the lung. Using precision cut lung slices from untreated mice we observed that neutrophils isolated from the peritoneal cavity of pristane-treated mice could directly induce the expression of genes associated with ER stress, namely Chop and Bip. Mice which had myeloid-specific deletion of PAD4 were generated and treated with pristane to assess the involvement of PAD4 and PAD4-dependent NET formation in pristane-induced lung inflammation. Specific deletion of PAD4 in myeloid cells resulted in decreased expression of ER stress genes in the pristane model, with accompanying reduction in IFN-driven genes and pathology. Lastly, coculture experiments of human neutrophils and human lung epithelial cell line (BEAS-2b) showed neutrophils from SLE patients induced significantly more ER stress and interferon-stimulated genes in epithelial cells compared to healthy control neutrophils. These results support a pathogenic role of neutrophils and NETs in lung injury during pristane-induced DAH through the induction of ER stress response and suggest that overactivation of neutrophils in SLE and NETosis may underlie development of DAH.
Molecular structure and conformation of stereocilia tip-links elucidated by cryo-electron tomography
Authors: Elferich Johannes , Clark Sarah , Ge Jingpeng , Goehring April , Matsui Aya , Gouaux Eric
Published: October 2021

Mechanosensory transduction (MT), the conversion of mechanical stimuli into electrical signals, underpins hearing and balance and is carried out within hair cells in the inner ear. Hair cells harbor actin-filled stereocilia, arranged in rows of descending heights, where the tips of stereocilia are connected to their taller neighbors by a filament composed of protocadherin 15 (PCDH15) and cadherin 23 (CDH23), deemed the ‘tip-link’. Tension exerted on the tip-link opens an ion channel at the tip of the shorter stereocilia, thus converting mechanical force into an electrical signal. While biochemical and structural studies have provided insights into the molecular composition and structure of isolated portions of the tip-link, the architecture, location and conformational states of intact tip-links, on stereocilia, remains unknown. Here we report in situ cryo-electron microscopy imaging of the tip-link in mouse stereocilia. We observe individual PCDH15 molecules at the tip and shaft of stereocilia and determine their stoichiometry, conformational heterogeneity, and their complexes with CDH23. The PCDH15/CDH23 complexes occur in clusters, frequently with more than one copy of PCDH15 at the tip of stereocilia, suggesting that tip-links might consist of more than one copy of the PCDH15/CDH23 heterotetramer and by extension, might include multiple MT complexes.
Potential of breadfruit cultivation to contribute to climate-resilient low latitude food systems
Authors: Yang Lucy , Zerega Nyree , Montgomery Anastasia , Horton Daniel E.
Published: October 2021

The number of people in food crisis around the world is increasing, exacerbated by the challenges of COVID-19 and a rapidly changing climate. Major crop yields are projected to decrease in low-latitude regions due to anthropogenic climate change, making tropical and sub-tropical food systems particularly vulnerable to climate shocks. Increased cultivation of breadfruit (Artocarpus altilis), often categorized as a neglected and underutilized species (NUS), has been suggested as an agricultural adaptation pathway for food insecure tropical and subtropical regions, due to its potential to enhance climate resilience and overall sustainability of low-latitude agricultural systems. To better understand breadfruit’s cultivation suitability and geographic range in current and future climates, we employ a diverse set of observations and models to delineate the current climatically viable breadfruit range and assess the climatically viable breadfruit range in the future (2061-2080) under stabilization and high emission scenarios. We find that the area of suitable breadfruit range within the tropics and subtropics is projected to decrease ~4.4% in the stabilization scenario and ~4.5% in the high emission scenario. In Southeast Asia and the Pacific Islands, yield quality and consistency show minimal decreases under the high emission scenario, with increases in total suitable area under both scenarios. In contrast, in Latin America and the Caribbean, the current range of breadfruit suitability is projected to contract ~10.1-11.5% (stabilization-high emission). Present and future model suitability outputs suggest that opportunities to successfully expand breadfruit cultivation over the next several decades exist in sub-Saharan Africa, where food insecurity is coincidentally high. However, in all regions, high emission scenario conditions reduce the overall consistency and quality of breadfruit yields compared to the stabilization scenario. Our results have the potential to inform global food security adaptation planning and highlight breadfruit as an ideal NUS to incorporate in food security adaptation strategies in a changing climate.
Relating genome completeness to functional predictions
Authors: Liu Jessica , Williams Tre’Andice , Burns John A.
Published: October 2021

Genome and transcriptome assemblies vary in their quality in terms of the connectedness of the assemblies and the amount of biological information captured. Interpreting de novo assemblies from new, poorly characterized, organisms in the context of complex traits can be challenging because, in the absence of a reference, it is difficult to know how much information is enough to claim the presence or absence of a trait. This study uses randomly downsampled proteome files to compare a genome completeness metric, BUSCO, to functional predictions of the complex trait of phagocytosis in known phagocytotic organisms broadly across the eukaryotic tree of life. We find that as additional proteins are added, BUSCO scores increase incrementally, while the phagocytosis prediction follows a sigmoidal curve. Generalizing our findings, we suggest a threshold of the number of BUSCOs detected above which one would expect an accurate prediction, positive or negative, of the complex trait of phagocytosis. While these findings are specific to a single trait, the methods can be extended to consider additional functional traits and predictive frameworks.
Bioorthogonal Functionalization of Material Surfaces with Bioactive Molecules
Authors: Hast Kern , Stone M. Rhia L. , Jia Zhaojun , Baci Melih , Aggarwal Tushar , Izgu Enver Cagri
Published: October 2021

The functionalization of material surfaces with biologically active molecules is crucial for enabling technologies in life sciences, biotechnology, and medicine. However, achieving biocompatibility and bioorthogonality with current synthetic methods remains a challenge. We report herein a novel surface functionalization method that proceeds chemoselectively and without a free transition metal catalyst. In this method, a coating is first formed via the tyrosinase-catalyzed putative polymerization of a tetrazine-containing catecholamine (DOPA-Tet). One or more types of molecule of interest containing trans-cyclooctene are then grafted onto the coating via tetrazine ligation. The entire process proceeds under physiological conditions and is suitable for grafting bioactive molecules with diverse functions and structural complexities. Utilizing this method, we functionalized material surfaces with enzymes (alkaline phosphatase, glucose oxidase, horseradish peroxidase), a cyclic peptide (cyclo[Arg-Gly-Asp-D-Phe-Lys], or c(RGDfK)), and an antibiotic (vancomycin). Colorimetric assays confirmed the maintenance of the biocatalytic activities of the grafted enzymes on the surface. We established the mammalian cytocompatibility of the functionalized materials with fibroblasts. Surface functionalization with c(RGDfK) showed improved fibroblast cell adhesion and cytoskeletal organization. Microbiological studies with Staphylococcus aureus indicated that surfaces coated using DOPA-Tet inhibit the formation of biofilms. Vancomycin-grafted surfaces additionally display significant inhibition of planktonic S. aureus growth.
OXPHOS Promotes Apoptotic Resistance and Persistence in TH17 cells
Authors: Hong Hanna S. , Mbah Nneka E. , Shan Mengrou , Loesel Kristen , Lin Lin , Sajjakulnukit Peter , Andren Anthony , Hayashi Atsushi , Magnuson Brian , Li Zhaoheng , Xie Yuying , Zhang Li , Lei Yu Leo , Opipari Anthony W. , Argüello Rafael J. , Kryczek Ilona , Kamada Nobuhiko , Zou Weiping , Franchi Luigi , Lyssiotis Costas A.
Published: October 2021

Apoptotic cell death is a cell-intrinsic, immune tolerance mechanism that regulates the magnitude and resolution of T cell-mediated responses. Evasion of apoptosis is critical for the generation of memory T cells, as well as autoimmune T cells, and knowledge of the mechanisms that enable resistance to apoptosis will provide insight into ways to modulate their activity during protective and pathogenic responses. IL-17-producing CD4 T cells (TH17s) are long-lived, memory cells. These features enable their role in host defense, chronic inflammatory disorders, and anti-tumor immunity. A growing number of reports now indicate that TH17s in vivo require mitochondrial oxidative phosphorylation (OXPHOS), a metabolic phenotype that is poorly induced in vitro. To elucidate the role of OXPHOS in TH17 processes, we developed a system to polarize TH17s that metabolically resembled their in vivo counterparts. We discovered that directing TH17s to use OXPHOS promotes mitochondrial fitness, glutamine anaplerosis, and an anti-apoptotic phenotype marked by high BCL-XL and low BIM. Through competitive co-transfer experiments and tumor studies, we further revealed how OXPHOS protects TH17s from cell death while enhancing their persistence in the periphery and tumor microenvironment. Together, our work demonstrates a non-classical role of metabolism in regulating TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.
A mycobacterial glycine-rich protein governs actin-based motility
Authors: Hill Norbert S. , Welch Matthew D.
Published: October 2021

Mycobacterium marinum, a close relative of the significant human pathogen Mycobacterium tuberculosis, polymerizes host actin at the bacterial surface to drive intracellular movement and cell-to-cell spread during infection. Here, we report the identification and characterization of MirA, the M. marinum actin-based motility factor. MirA is a member of the glycine-rich PE_PGRS family of ESX-5-secreted proteins. MirA uses an amphipathic helix to anchor into the mycobacterial outer membrane and, surprisingly, also the surface of host lipid droplet organelles. The glycine-rich PGRS domain in MirA directly binds and activates host N-WASP to stimulate actin polymerization through the Arp2/3 complex, directing both bacterial and lipid droplet actin- based motility. MirA is dissimilar to known N-WASP activating ligands and may represent a new class of microbial and host actin regulator. Additionally, the MirA-N-WASP interaction represents a model to understand how the enigmatic PE_PGRS proteins contribute to mycobacterial pathogenesis.
High Spatial Resolution MALDI Imaging Mass Spectrometry of Fresh-Frozen Bone
Authors: Good Christopher J. , Neumann Elizabeth K. , Butrico Casey E. , Cassat James E. , Caprioli Richard M. , Spraggins Jeffrey M.
Published: October 2021

Bone and bone marrow are vital to mammalian structure, movement, and immunity. These tissues are also commonly subjected to molecular alterations giving rise to debilitating diseases like rheumatoid arthritis, osteoporosis, osteomyelitis, and cancer. Technologies such as matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) enable the discovery of spatially resolved chemical information in biological tissue samples to help elucidate the complex molecular processes underlying pathology. Traditionally, preparation of native osseous tissue for MALDI IMS has been difficult due to the mineralized composition and heterogenous morphology of the tissue, and compensation for these challenges with decalcification and fixation protocols can remove or delocalize molecular species. Here, sample preparation methods were advanced to enable multimodal MALDI IMS of undecalcified, fresh-frozen murine femurs allowing the distribution of endogenous lipids to be linked to specific tissue structures and cell types. Adhesive-bound bone sections were mounted onto conductive glass slides with a microscopy-compatible glue and freeze-dried to minimize artificial bone marrow damage. Subliming matrix does not induce further bone marrow cracking, and recrystallizing the deposited matrix improves lipid signal. High spatial resolution (10 μm) MALDI IMS was employed to characterize lipid distributions in fresh-frozen bone, and use of complementary microscopy modalities aided tissue and cell assignments. For example, various phosphatidylcholines localize to bone marrow, adipose tissue, marrow adipose tissue, and muscle. Further, sphingomyelin(42:1) was abundant in megakaryocytes, whereas sphingomyelin(42:2) was diminished in this cell type. These data reflect the vast molecular and cellular heterogeneity indicative of the bone marrow and the soft tissue surrounding the femur. Multimodal MALDI IMS has the potential to advance bone-related biomedical research by offering deep molecular coverage with spatial relevance in a preserved native bone microenvironment.
Cross‐National Research: Realised and Potential Contributions
Authors: Lillard Dean R.
Published: October 2021

The HILDA Survey is one of a small but growing number of household‐based, country‐specific longitudinal studies that share similar designs and data on individual and household social and economic wellbeing. All track outcomes over time as individuals dynamically form and dissolve personal and professional relationships. The similarities of the data invite researchers to study, compare and contrast social and economic outcomes of Australians with outcomes of residents of other countries. This review summarises published comparative research that uses HILDA data, notes how HILDA contributes, and highlights how and on what topics scholars might use HILDA data to generate additional insights.
Fragmentation of the Inner Circle of Power: Circulation between the Finnish Elites in 1991–2021
Authors: Ruostetsaari Ilkka
Published: October 2021

The study outlines the changes that have taken place in the Finnish elite structure regarding elite circulation from 1991 to 2021. The study first explores the changes in the openness of the elite structure by analysing vertical circulation (i.e., maintenance and accumulation of elite positions), and second, in the coherence of the elite structure by analysing changes in horizontal circulation, (i.e., mobility between the elites). In terms of methodology and data, the study was based on the positional approach, where the elite members were identified on the grounds of previous studies and public documents as individuals who held the highest ranking positions of influential organisations within seven sectors of society. The findings were interpreted in the light of elite structure typology. As regards vertical elite circulation from 1991 to 2021, the maintenance of elite positions and the accumulation elite positions among same individuals decreased. Concurrently, the horizontal elite circulation reduced as a result of decreased mobility of individuals between various elites. Consequently, the elite structure moved slightly towards a fragmented elite structure type since the early 1990s.
How big can a walking fish be? A theoretical inference based on observations on four land‐dwelling fish genera of South Vietnam
Authors: KUZNETSOV Alexander N.
Published: October 2021

Comparative study of terrestrial locomotion of 4 fish genera including Anabas, Channa, Clarias, and Monopterus, was performed in experimental setting with the substrate surface of wet clay. No special adaptations for terrestrial locomotion were found. Every fish uses for propulsion on land what it already has. Eel‐shaped Monopterus crawls by body undulations in a serpentine or sidewinding technique, the latter of which was not previously observed beyond snakes. The other 3 fish genera walk by body oscillations using stiff appendages as propulsors. When they are located anteriorly, as the serrate operculum in Anabas and the preaxial spine of the pectoral fin in Clarias, the propulsion is termed prolocomotor, when posteriorly, as the spiny anal fin in Channa—metalocomotor. Channa is the heaviest fish walking out of water in our days, quite comparable in size with first Devonian tetrapods Acanthostega and Tulerpeton. A theoretical calculation is suggested for the upper size limit of a fish capable of terrestrial walking without special locomotor adaptations. It should be roughly 20 cm in the vertical dimension of the trunk, which is just a little above the known size of Devonian tetrapodomorph fishes Panderichthys and Elpistostege. The metalocomotor walking technique of Channa is suggested as the closest extant model for terrestrial locomotion at the fish‐tetrapod transition. The major difference is that the metalocomotor propulsor in Channa is represented by the anal fin, while in tetrapodomorphs by the pelvic fins. The sprawled pelvic fins were advantageous in respect of reduced requirement for side‐to‐side tail swinging.
Hemoglobin A1c level is a prognostic factor for locoregional recurrence in stage III non‐small cell lung cancer patients treated with radiotherapy
Authors: Kong Moonkyoo , Lim Yu Jin
Published: October 2021

Background

The level of hemoglobin A1c (HbA1c) might be associated with the severity of tumor hypoxia in patients with cancer. Here, we evaluated the association between the level of HbA1c and survival outcome in stage III non‐small cell lung cancer patients treated with radical radiotherapy.

Methods

We retrospectively analysed the clinical data of 104 patients with lung cancer treated with radiotherapy. The HbA1c levels of all patients were checked 1 week before the start of radiotherapy. Survival outcomes were analysed according to the HbA1c level.

Results

The 1‐, 2‐, and 3‐year locoregional recurrence‐free survival rates were 88.3%, 68.8%, and 63.0%, respectively, in the patient group with HbA1c levels ≤6% and 75.5%, 54.4%, and 41.8%, respectively, in the patient group with HbA1c levels >6% (p = 0.015). The HbA1c level remained a significant prognostic factor for locoregional recurrence‐free survival on multivariable analysis (hazard ratio = 2.014, 95% confidence interval = 1.088–3.726, p = 0.026).

Conclusions

Pretreatment HbA1c level is a significant prognostic factor for locoregional recurrence‐free survival in patients with stage III non‐small cell lung cancer treated with radical radiotherapy. Routine monitoring of pretreatment HbA1c levels and aggressive glycemic control may be considered to prevent the development of locoregional recurrence in these patients.
Tramadol versus codeine and the short‐term risk of cardiovascular events in patients with non‐cancer pain: A population‐based cohort study
Authors: Ou Linda B. , Azoulay Laurent , Reynier Pauline , Platt Robert W. , Yoon Sarah , Grad Roland , Filion Kristian B.
Published: October 2021

Aims

The effect of tramadol on the cardiovascular system is largely unknown. There is concern that, with its multimodal mechanism of action to increase serotonin and norepinephrine levels in the body, it could increase the risk of arterial ischaemia and cardiovascular events. We aimed to compare the short‐term risk of cardiovascular events with the use of tramadol to that of codeine among patients with non‐cancer pain.

Methods

We conducted a retrospective population‐based cohort study using data from the Clinical Practice Research Datalink (CPRD) with new users of tramadol or codeine from April 1998 to March 2017. Exposure was defined using an approach analogous to an intention‐to‐treat, with a maximum follow‐up of 30 days. The primary endpoint was myocardial infarction, and secondary endpoints were unstable angina, ischaemic stroke, coronary revascularization, cardiovascular death and all‐cause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusted for high‐dimensional propensity score.

Results

The final cohort included 123 394 tramadol users and 914 333 codeine users. When tramadol was compared to codeine, the adjusted hazard ratio (HR) of myocardial infarction was 1.00 (95% CI 0.81–1.24). There was also no evidence of elevated risks of unstable angina (0.92; 95% CI 0.67–1.27), ischaemic stroke (0.98; 95% CI 0.82–1.17), coronary revascularization (0.97; 95% CI 0.69–1.38), cardiovascular death (1.07; 95% CI 0.93–1.23) or all‐cause mortality (1.03; 95% CI 0.94–1.14) when tramadol was compared to codeine.

Conclusions

Short‐term use of tramadol, compared with codeine, was not associated with an increased risk of cardiac events among patients with non‐cancer pain.
Superior outcomes with paediatric protocols in adolescents and young adults with aggressive B‐cell non‐Hodgkin lymphoma
Authors: Gupta Sumit , Alexander Sarah , Pole Jason D. , Sutradhar Rinku , Crump Michael , Nagamuthu Chenthila , Baxter Nancy N. , Nathan Paul C.
Published: October 2021

Survival disparities by locus of care (LOC; paediatric versus adult) among adolescents and young adults (AYA) with acute lymphoblastic leukaemia (ALL) are well documented. Whether similar disparities exist among AYA with aggressive mature B‐cell non‐Hodgkin lymphoma (B‐NHL) is unknown. We identified all Ontario, Canada AYA aged 15–21 years at diagnosis of B‐NHL between 1992 and 2012. Demographic, disease, treatment and outcome data were chart abstracted. The impact of LOC on event‐free (EFS) and overall survival (OS) were determined, adjusted for patient and disease covariates. Among 176 AYA with B‐NHL, 62 (35·2%) received therapy at paediatric centres. The 5‐year EFS and OS [± standard error (SE)] for the overall cohort were 72·2 [3·4]% and 76·1 [3·2]% respectively. Both EFS and OS were superior among paediatric centre AYA [EFS (± SE) 82·2 (4·9)% vs. 66·7 (4·4)%, P = 0·02; OS 85·5 (4·5)% vs. 71·1 (4·3)%, P = 0·03]. Adjusted for histology, stage and time period, adult centre AYA had inferior EFS [hazard ratio (HR) 2·4, 95% confidence interval (CI) 1·1–4·9, P = 0·02] and OS (HR 2·5, 95% CI 1·1–5·7, P = 0·03). Sensitivity analyses restricted to the latest time period, when most adult centre AYA received rituximab, demonstrated similar disparities. Similar to AYA with ALL, AYA with B‐NHL may benefit from being treated with paediatric protocols. Studies prospectively validating these results are warranted.
Bacterial growth dynamics and pharmacokinetic–pharmacodynamic relationships of rifampicin and bedaquiline in BALB/c mice
Authors: Muliaditan Morris , Della Pasqua Oscar
Published: October 2021

Background and Purpose

Translational efforts in the evaluation of novel anti‐tubercular drugs demand better integration of pharmacokinetic–pharmacodynamic data arising from preclinical protocols. However, parametric approaches that discriminate drug effect from the underlying bacterial growth dynamics have not been fully explored, making it difficult to translate and/or extrapolate preclinical findings to humans. This analysis aims to develop a drug‐disease model that allows distinction between drug‐ and system‐specific properties.

Experimental Approach

Given their clinical relevance, rifampicin and bedaquiline were used as test compounds. A two‐state model was used to describe bacterial growth dynamics. The approach assumes the existence of fast‐ and slow‐growing bacterial populations. Drug effect on the growth dynamics of each subpopulation was characterised in terms of potency (EC50‐F and EC50‐S) and maximum killing rate.

Key Results

The doubling time of the fast‐ and slow‐growing population was estimated to be 25 h and 42 days, respectively. Rifampicin was more potent against the fast‐growing (EC50‐F = 4.8 mg·L−1), as compared with the slow‐growing population (EC50‐S = 60.2 mg·L−1). Bedaquiline showed higher potency than rifampicin (EC50‐F = 0.19 mg·L−1; EC50‐S = 3.04 mg·L−1). External validation procedures revealed an effect of infection route on the apparent potency of rifampicin.

Conclusion and Implications

Model parameter estimates suggest that nearly maximum killing rate is achieved against fast‐growing, but not against slow‐growing populations at the tested doses. Evidence of differences in drug potency for each subpopulation may facilitate the translation of preclinical findings and improve the dose rationale for anti‐tubercular drugs in humans.
Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability
Authors: Bony Anuja R. , McArthur Jeffrey R. , Finol‐Urdaneta Rocio K. , Adams David J.
Published: October 2021

Background and Purpose

Activation of GIRK channels via G protein‐coupled GABAB receptors has been shown to attenuate nociceptive transmission. The analgesic α‐conotoxin Vc1.1 activates GABAB receptors resulting in inhibition of Cav2.2 and Cav2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic α‐conotoxins on recombinant and native GIRK‐mediated K+ currents and on neuronal excitability.

Experimental Approach

The effects of analgesic α‐conotoxins, Vc1.1, RgIA, and PeIA, were investigated on inwardly‐rectifying K+ currents in HEK293T cells recombinantly co‐expressing either heteromeric human GIRK1/2 or homomeric GIRK2 subunits, with GABAB receptors. The effects of α‐conotoxin Vc1.1 and baclofen were studied on GIRK‐mediated K+ currents and the passive and active electrical properties of adult mouse dorsal root ganglion neurons.

Key Results

Analgesic α‐conotoxins Vc1.1, RgIA, and PeIA potentiate inwardly‐rectifying K+ currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABAB receptors. GABAB receptor‐dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin‐sensitive G protein and is inhibited by the selective GABAB receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABAB receptor‐dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability.

Conclusions and Implications

This is the first report of GIRK channel potentiation via allosteric α‐conotoxin Vc1.1‐GABAB receptor agonism, leading to decreased neuronal excitability. Such action potentially contributes to the analgesic effects of Vc1.1 and baclofen observed in vivo.
Central histaminergic signalling, neural excitability and epilepsy
Authors: Yang Lin , Wang Yi , Chen Zhong
Published: October 2021

Epilepsy is a common neurological disorder characterized by repeated and spontaneous epileptic seizures and is not well controlled by current medication. Traditional theory suggests that epilepsy results from an imbalance of excitatory glutamate neurons and inhibitory GABAergic neurons. However, new evidence from clinical and preclinical research suggests that histamine in the CNS plays an important role in the modulation of neural excitability and in the pathogenesis of epilepsy. Many histamine receptor ligands have achieved curative effects in animal epilepsy models, among which the histamine H3receptor antagonist pitolisant has shown anti‐epileptic effects in clinical trials. Recent studies, therefore, have focused on the potential action of histamine receptors to control and treat epilepsy. In this review, we summarize the findings from animal and clinical epilepsy research on the role of brain histamine and its receptors. We also identify current gaps in the research and suggest where further studies are most needed.
Disrupted affective communication characterizes mothers of infants with disorganized but also ambivalent attachments: An Israeli study
Authors: Ariav‐Paraira Inbar , Oppenheim David , Sagi‐Schwartz Abraham
Published: October 2021

This study examined whether maternal disrupted communication, which is associated with disorganized infant attachment, also characterizes mothers of ambivalent infants. The study, conducted in Israel, included a Jewish sample (N = 163; 68 Girls) from diverse socioeconomic status, collected between 1991 and 1993 in an earlier study. The sample over‐represented ambivalent and disorganized attachments. Attachment was assessed in the Strange Situation Procedure (SSP) at 12 months and disrupted communication was coded from the SSP using the Atypical Maternal Behavior Instrument for Assessment and Classification (AMBIANCE; Lyons‐Ruth et al., 1999). Mothers of ambivalent infants showed higher disrupted communication than mothers of secure, avoidant, and disorganized infants. The findings shed further light on the correlates of ambivalent attachment and call for research regarding maternal and infant characteristics that differentiate ambivalent versus disorganized attachment.
‘Can you hear me?’ An exploratory study investigating the representation and impact of children’s views in multi‐agency meetings
Authors: Mitchell Kerry L. , Colville Tracey
Published: October 2021

The study explored parent and professional perceptions of the representation of children's views in multi‐agency meetings in Scottish schools. Online survey (134 responses) and educational documents provided data sources that were subject to thematic and documentary analysis. The findings highlight the importance of professional beliefs around child capacity and their understanding of what constitutes a competent view. In turn, they influence the extent to which professionals find representations of children's views worthwhile. Implications for practice include raising professional awareness of evolving ontologies around the representation of children's views in multi‐agency meetings in line with policy and legislation.