bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal coordination at the maternal-fetal interface promotes trophoblast invasion and vascular remodeling in the first half of human pregnancy
Authors: Greenbaum Shirley , Averbukh Inna , Soon Erin , Rizzuto Gabrielle , Baranski Alex , Greenwald Noah F. , Kagel Adam , Bosse Marc , Jaswa Eleni G. , Khair Zumana , Kwok Shirley , Warshawsky Shiri , Piyadasa Hadeesha , Miller Geneva , Schwartz Morgan , Graf Will , Van Valen David , Winn Virginia D. , Hollmann Travis , Keren Leeat , van de Rijn Matt , Angelo Michael
Published: September 2021

Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels left with a thin, discontinuous smooth muscle layer and partially lined with EVTs. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodeling (SAR). However, it remains a matter of debate which immune and stromal cell types participate in these interactions and how this process evolves with respect to gestational age. Here, we used a multiomic approach that combined the strengths of spatial proteomics and transcriptomics to construct the first spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody panel to analyze ∼500,000 cells and 588 spiral arteries within intact decidua from 66 patients between 6-20 weeks of gestation, integrating this with coregistered transcriptomic profiles. Gestational age substantially influenced the frequency of many maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, Galectin-9, and IDO-1 increasingly enriched and colocalized at later time points. In contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting unique monotonic and biphasic trends. Lastly, we developed an integrated model of SAR supporting an intravasation mechanism where invasion is accompanied by upregulation of pro-angiogenic, immunoregulatory EVT programs that promote interactions with vascular endothelium while avoiding activation of immune cells in circulating maternal blood. Taken together, these results support a coordinated model of decidualization in which increasing gestational age drives a transition in maternal decidua towards a tolerogenic niche conducive to locally regulated, EVT-dependent SAR.
scBasset: Sequence-based modeling of single cell ATAC-seq using convolutional neural networks
Authors: Yuan Han , Kelley David R
Published: September 2021

1

Single cell ATAC-seq (scATAC) shows great promise for studying cellular heterogeneity in epigenetic landscapes, but there remain significant challenges in the analysis of scATAC data due to the inherent high dimensionality and sparsity. Here we introduce scBasset, a sequence-based convolutional neural network method to model scATAC data. We show that by leveraging the DNA sequence information underlying accessibility peaks and the expressiveness of a neural network model, scBasset achieves state-of-the-art performance across a variety of tasks on scATAC and single cell multiome datasets, including cell type identification, scATAC profile denoising, data integration across assays, and transcription factor activity inference.
Myelination deficits in the auditory brainstem of a mouse model of Fragile X Syndrome, a possible mechanism for auditory phenotypes
Authors: Lucas Alexandra , Poleg Shani , Klug Achim , McCullagh Elizabeth
Published: September 2021

1

Auditory symptoms are one of the most frequent sensory issues described in people with Fragile X Syndrome (FXS), the most common genetic form of intellectual disability. However, the mechanisms that lead to these symptoms are under explored. In this study, we examined whether alterations in myelination in auditory brainstem circuitry contribute to auditory impairments in FXS mice. Specifically, we studied myelinated fibers that terminate in the Calyx of Held, which encode temporally precise sound arrival time, and are some of the most heavily myelinated axons in the brain. We measured anatomical myelination characteristics using coherent anti-stokes Raman spectroscopy (CARS) and electron microscopy (EM) in a FXS mouse model in the medial nucleus of the trapezoid body (MNTB) where the Calyx of Held synapses. We measured number of mature oligodendrocytes (OL) and oligodendrocyte precursor cells (OPCs) to determine if changes in myelination were due to changes in the number of myelinating or immature glial cells. The two microscopy techniques (EM and CARS) showed a decrease in fiber diameter in FXS mice. Additionally, EM results indicated reductions in myelin thickness and axon diameter, and an increase in g-ratio, a measure of structural and functional myelination. Lastly, we showed an increase in both OL and OPCs in MNTB sections of FXS mice suggesting that the myelination phenotype is not due to an overall decrease in number of myelinating OLs. This is the first study to show that a potential myelination mechanism can explain alterations seen in FXS at the level of the auditory brainstem.
Characterization of apicomplexan amino acid transporters (ApiATs) in the malaria parasite Plasmodium falciparum
Authors: Wichers Jan Stephan , van Gelder Carolina , Fuchs Gwendolin , Ruge Julia Mareike , Pietsch Emma , Ferreira Josie L. , Safavi Soraya , von Thien Heidrun , Burda Paul-Christian , Mesén-Ramirez Paolo , Spielmann Tobias , Strauss Jan , Gilberger Tim-Wolf , Bachmann Anna
Published: September 2021

During the symptomatic human blood phase, malaria parasites replicate within red blood cells. Parasite proliferation relies on the uptake of nutrients, such as amino acids, from the host cell and the blood plasma, requiring transport across multiple membranes. Amino acids are delivered to the parasite through the parasite surrounding vacuolar compartment by specialized nutrient-permeable channels of the erythrocyte membrane and the parasitophorous vacuole membrane (PVM). However, further transport of amino acid across the parasite plasma membrane (PPM) is currently not well characterized. In this study, we focused on a family of Apicomplexan amino acid transporters (ApiATs) that comprises five members in Plasmodium falciparum. First, we localized four of the PfApiATs at the PPM using endogenous GFP-tagging. Next, we applied reverse genetic approaches to probe into their essentiality during asexual replication and gametocytogenesis. Upon inducible knockdown and targeted gene disruption a reduced asexual parasite proliferation was detected for PfApiAT2 and PfApiAT4. Functional inactivation of individual PfApiATs targeted in this study had no effect on gametocyte development. Our data suggest that individual PfApiATs are partially redundant during asexual in vitro proliferation and fully redundant during gametocytogenesis of P. falciparum parasites.

IMPORTANCE

Malaria parasites live and multiply inside cells. To facilitate their extremely fast intracellular proliferation they hijack and transform their host cells. This also requires the active uptake of nutrients, such as amino acids, from the host cell and the surrounding environment through various membranes that are the consequence of the parasite’s intracellular lifestyle. In this manuscript we focus on a family of putative amino acid transporters termed ApiAT. We show expression and localization of four transporters in the parasite plasma membrane of Plasmodium falciparum-infected erythrocytes that represent one interface of the pathogen to its host cell. We probed into the impact of functional inactivation of individual transporters on parasite growth in asexual and sexual blood stages of P. falciparum and reveal that only two of them show a modest but significant reduction in parasite proliferation but no impact on gametocytogenesis pointing towards redundancy within this transporter family.
How do inter-organisational electronic health records affect hospital physician and pharmacist decisions? A scoping review
Authors: Scott Philip , Nakkas Haythem , Roderick Paul
Published: September 2021

Objective

To provide an overview of the effects of inter-organisational electronic health records on inpatient diagnosis and treatment decisions by hospital physicians and pharmacists.

Materials and Methods

Five-stage scoping review, using distributed cognition and the information value chain as guiding conceptual models. Eligibility criteria: empirical studies addressing how shared health records were used in inpatient clinical decision-making, published 2008-18. Sources: Healthcare Databases Advanced Search, covering nine sources including PubMed. Charting methods: data extraction form completed by one author, with inter-rater reliability assessment at title and abstract review.

Results

Quantitative studies (n=14) often reported relatively low usage of shared records (6.8% to 37.1% of cases). Usage is associated with reduction in diagnostic testing and readmission and variable effects on admissions and overall costs. Qualitative studies (n=6) reported avoidance of duplicate diagnostics, changing clinical decisions, the value of historical laboratory results and optimising the timeliness of care. We found no explicit use of explanatory theoretical models, but there is implicit evidence of an information value chain. We found only one study specifically about pharmacists.

Discussion

Relatively low usage is due to clinical judgement whether “extra” data is needed, given current knowledge of the presenting condition and relative complexity. We suggest that extensive EHRs need recommender systems to highlight (sometimes unexpected) relevant content, in parallel with professional guidance on indications for consulting shared records.

Conclusions

Clinicians only consult shared health records when they must. Mixed effects on process outcomes are due to the hidden variables of patient complexity, clinician judgement and organisational context.
Re-evaluating the role of nucleosomal bivalency in early development
Authors: Shah Rohan N. , Grzybowski Adrian T. , Elias Jimmy , Chen Zhonglei , Hattori Takamitsu , Lechner Carolin C. , Lewis Peter W. , Koide Shohei , Fierz Beat , Ruthenburg Alexander J.
Published: September 2021

Nucleosomes, composed of DNA and histone proteins, represent the fundamental repeating unit of the eukaryotic genome1; posttranslational modifications of these histone proteins influence the activity of the associated genomic regions to regulate cell identity2–4. Traditionally, trimethylation of histone 3-lysine 4 (H3K4me3) is associated with transcriptional initiation5–10, whereas trimethylation of H3K27 (H3K27me3) is considered transcriptionally repressive11–15. The apparent juxtaposition of these opposing marks, termed “bivalent domains”16–18, was proposed to specifically demarcate of small set transcriptionally-poised lineage-commitment genes that resolve to one constituent modification through differentiation, thereby determining transcriptional status19–22. Since then, many thousands of studies have canonized the bivalency model as a chromatin hallmark of development in many cell types. However, these conclusions are largely based on chromatin immunoprecipitations (ChIP) with significant methodological problems hampering their interpretation. Absent direct quantitative measurements, it has been difficult to evaluate the strength of the bivalency model. Here, we present reICeChIP, a calibrated sequential ChIP method to quantitatively measure H3K4me3/H3K27me3 bivalency genome-wide, addressing the limitations of prior measurements. With reICeChIP, we profile bivalency through the differentiation paradigm that first established this model16,18: from naïve mouse embryonic stem cells (mESCs) into neuronal progenitor cells (NPCs). Our results cast doubt on every aspect of the bivalency model; in this context, we find that bivalency is widespread, does not resolve with differentiation, and is neither sensitive nor specific for identifying poised developmental genes or gene expression status more broadly. Our findings caution against interpreting bivalent domains as specific markers of developmentally poised genes.
Prevention of Drug-Induced Lung Fibrosis via Inhibition of the MRTF/SRF Transcription Pathway
Authors: Pawelec Kendell M. , Varnum Megan , Harkema Jack R. , Auerbach Bruce , Larsen Scott D. , Neubig Richard R.
Published: September 2021

Drug-induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality. A number of drugs can cause fibrosis, many of which are used to treat cancer, including chemotherapy agents and immune checkpoint inhibitors. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG-257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC50s of 4 and 15 μM, respectively. The ability of CCG-257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of chemotherapy-induced lung fibrosis. Animals were given intraperitoneal bleomycin for four weeks, and concurrently dosed with CCG-257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti-fibrotic (nintedanib), or clinical standard of care (prednisolone). Mice treated with 100 mg/kg CCG-257081 gained weight vs. vehicle-treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG-257081 were not significantly different from naive tissue, indicating successful prevention. Measures of tissue fibrosis were comparable between CCG-257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor-1 (PAI-1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. Prednisolone led to marked increases in lung fibrosis. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent drug-induced lung fibrosis in a clinically relevant model of drug-induced disease.
Phomoarcherin B as a novel HIV-1 reverse transcriptase RNase H activity inhibitor: conclusions from comprehensive computational analysis
Authors: Abdul Ghafoor Naeem , Baysal Ömür , Süzek Barış Ethem , Silme Ragıp Soner
Published: September 2021

The HIV epidemic has claimed more than 32.7 million live since its emergence in 1981, while many ART and HAART therapies are available and provide relief and control for patients, most of these therapeutics come with long-term side effects, resistance, socio-economical barriers, and other obstacles. In this study, genomic analysis was performed on 98 HIV-1 genomes to determine the most coherent target that could be utilized to restrict and cease the viral replication, the reverse transcriptase enzyme. Following the identification of the target protein, the RNase H activity of the reverse transcriptase was nominated as the potent target given the limited research associated with it. A library of 94 thousand small molecule inhibitors was generated and virtual screening was performed to identify hits, based on the reproducibility of the screening results, 4 compounds with the best scores were considered and their interaction within the active site was analyzed. Subsequently, all-atom molecular dynamics simulations and MM-PBSA was performed to validate the stability and binding free energy of the hits within the RNase H active. In silico ADMET assays were performed on the hit compounds to analyze their drug-likeness, physicochemical and pharmacological properties. Phomoarcherin B, a pentacyclic aromatic sesquiterpene naturally found in the endophytic fungus Phomopsis archeri, known for its anticancer properties scored the best in all the experiments and was nominated as a potential inhibitor of the HIV-1 reverse transcriptase RNase H activity.

Author Summary

The Human immunodeficiency virus 1 (HIV-1) has remained a global public health issue for the past 4 decades with millions of patients around the globe affected. Long years of research in the field of anti-viral therapies had introduced several drugs to combat the viral infection, however, most of these drugs come with their shortcomings. In this study, computational drug discovery approaches were utilized to research novel drugs that could be used as anti-viral agents against the former virus, the results had revealed Phomoarcherin B, a natural compound from an endophytic fungus to hold promising therapeutic potentials.
Spectral Separation of Evoked and Background Cortical Activity – Application to Short Latency Median Nerve Evoked Potentials
Authors: Fischer G. , Baumgarten D. , Kofler M.
Published: September 2021

Background

Spectral analysis of repeatedly evoked potentials (EPs) is challenging since recordings contain a superposition of evoked signals and background activity. We developed a novel approach, N-interval Fourier Transform Analysis (N-FTA), which allows for reliable separation and accurate assessment of evoked and background spectral components. We applied this approach to spectral analysis of median nerve short latency EPs for identifying spectral bands of clinical relevance.

Methods

We performed right median nerve stimulation in two volunteers at 2.46 Hz and 3.95 Hz stimulation rate (600 and 1000 repetitions respectively). We applied N-FTA for splitting the periodically repeated evoked components from irregular background activity and investigated spectral components in the low, medium and high frequency (LF-, MF-, HF-) bands. We present a signal processing approach, which allows for accurately extracting diagnostically relevant features (signal morphology, latency and amplitude) using an 18 Hz to 240 Hz bandwidth.

Results

In the LF-band < 10 Hz, evoked-to-background ratio (EBR) was below −15 dB due to the high level near DC background activity (1/f-activity, eye blinks, θ-band). Highest EBR was near −5 dB and obtained at a few tens of Hz. Relatively broad continuous segments of evoked activity were detected in the MF band. These frequencies of a few hundred Hz were linked to the signal segment between the N20 and P25 peaks in the time domain. High frequency oscillations (HFOs) near 600 Hz were approximately −25 dB below the background level and near the limit of the sensitivity of N-FTA. By subtracting stimulation artifacts and applying zero-phase filters it was possible to extract diagnostically relevant short latency EP features (signal morphology, latency and amplitude) only from the MF-band with a similar accuracy as a routinely used broad-band setting. HFOs displayed amplitudes of a few tenths of µV.

N-FTA allows for accurate, simultaneous spectral analysis of evoked and background activity in individual trials. The approach allowed for identifying target frequency bands of high evoked activity and for tailoring signal processing such, that morphology and latency can be obtained at a significantly reduced bandwidth. This should allow for development of more robust and faster recording techniques in the near future.
Spontaneous alpha-band oscillations bias subjective contrast perception
Authors: Balestrieri Elio , Busch Niko A.
Published: September 2021

Perceptual decisions depend both on the features of the incoming stimulus and on the ongoing brain activity at the moment the stimulus is received. Specifically, trial-to-trial fluctuations in cortical excitability have been linked to fluctuations in the amplitude of pre-stimulus alpha oscillations (≈8-13 Hz), which are in turn are associated with fluctuations in subjects’ tendency to report the detection of a stimulus. It is currently unknown whether alpha oscillations bias post-perceptual decision making, or even bias subjective perception itself. To answer this question, we used a contrast discrimination task in which subjects reported which of two gratings – one in each hemifield – was perceived as having a stronger contrast. Our EEG analysis showed that subjective contrast was reduced for the stimulus in the hemifield represented in the hemisphere with relatively stronger pre-stimulus alpha amplitude, reflecting reduced cortical excitability. Furthermore, the strength of this spontaneous hemispheric lateralization was strongly correlated with the magnitude of individual subjects’ biases, suggesting that the spontaneous patterns of alpha lateralization play a role in explaining the intersubject variability in contrast perception. These results indicate that spontaneous fluctuations in cortical excitability, indicted by patterns of pre-stimulus alpha amplitude, affect perceptual decisions by altering the phenomenological perception of the visual world.

Significance Statement

Our moment to moment perception of the world is shaped by the features of the environment surrounding us, as much as by the constantly evolving states that characterize our brain activity. Previous research showed how the ongoing electrical activity of the brain can influence whether a stimulus has accessed conscious perception. However, evidence is currently missing on whether these electrical brain states can be associated to the subjective experience of a sensory input. Here we show that local changes in patterns of electrical brain activity preceding visual stimulation can bias our phenomenological perception. Importantly, we show that the strength of these variations can help explaining the great inter-individual variability in how we perceive the visual environment surrounding us.
Evolutionary transition from a single RNA replicator to a multiple replicator network
Authors: Mizuuchi Ryo , Furubayashi Taro , Ichihashi Norikazu
Published: September 2021

In prebiotic evolution, self-replicating molecules are believed to have evolved into complex living systems by expanding their information and functions open-endedly. Theoretically, such evolutionary complexification could occur through successive appearance of novel replicators that interact with one another to form replication networks. Here we performed long-term evolution experiments using an RNA that replicates by a self-encoded RNA replicase. The RNA diversified into multiple coexisting host and parasite lineages, whose frequencies in the population initially fluctuated and gradually stabilized. The final population, comprising five RNA lineages, forms a replicator network with diverse interactions, including cooperation to help the replication of all other members. These results support the capability of molecular replicators to spontaneously develop complexity through Darwinian evolution, a critical step for the emergence of life.
The VarA-CsrA regulatory pathway influences cell shape in Vibrio cholerae
Authors: Rocha Leonardo F. Lemos , Peters Katharina , Depelteau Jamie S. , Briegel Ariane , Vollmer Waldemar , Blokesch Melanie
Published: September 2021

Despite extensive studies on the curve-shaped bacterium Vibrio cholerae, the causative agent of the diarrheal disease cholera, its virulence-associated regulatory two-component signal transduction system VarS/VarA is not well understood. This pathway, which mainly signals through the downstream protein CsrA, is highly conserved among gamma-proteobacteria, indicating there is likely a broader function of this system beyond virulence regulation. In this study, we investigated the VarA-CsrA signaling pathway and discovered a previously unrecognized link to the shape of the bacterium. We observed that varA-deficient V. cholerae cells showed an abnormal spherical morphology during late-stage growth. Through peptidoglycan (PG) composition analyses, we discovered that these mutant bacteria contained an increased content of disaccharide dipeptides and reduced peptide crosslinks, consistent with the atypical cellular shape. The spherical shape correlated with the CsrA-dependent overproduction of aspartate ammonia lyase (AspA) in varA mutant cells, which likely depleted the cellular aspartate pool; therefore, the synthesis of the PG precursor amino acid meso-diaminopimelic acid was impaired. Importantly, this phenotype, and the overall cell rounding, could be prevented by means of cell wall recycling. Collectively, our data provide new insights into how V. cholerae use the VarA-CsrA signaling system to adjust its morphology upon unidentified external cues in its environment.

Significance Statement

Responsible for the diarrheal disease cholera, the bacterium Vibrio cholerae tightly regulates its virulence program according to external stimuli. Here, we discovered that a sensing-response mechanism involved in the regulation of virulence also controls bacterial shape. We show that V. cholerae lacking this system lose their normal comma shape and become spherical due to an abnormal cell wall composition caused by metabolic changes that reduce available cell wall building blocks. Our study therefore sheds new light on how V. cholerae modulates its morphology based on environmental changes.
Diversity and dynamics of the CRISPR-Cas systems associated withBacteroides fragilisin human population
Authors: Lam Tony J. , Mortensen Kate , Ye Yuzhen
Published: September 2021

CRISPR-Cas systems are adaptive immune systems commonly found in prokaryotes that provide sequence-specific defense against invading mobile genetic elements (MGEs). The memory of these immunological encounters are stored in CRISPR arrays, where spacer sequences record the identity and history of past invaders. Analyzing such CRISPR arrays provide insights into the dynamics of CRISPR-Cas systems and the adaptation of their host bacteria to rapidly changing environments such as the human gut. In this study, we utilized 601Bacteroides fragilisgenome isolates from 12 healthy individuals, 6 of which include longitudinal observations, and 222 availableB. fragilisreference genomes to update the understanding ofB. fragilisCRISPR-Cas dynamics and their differential activities. Analysis of longitudinal genomic data showed that some CRISPR array structures remained relatively stable over time whereas others involved radical spacer acquisition during some periods, and diverse CRISPR arrays (associated with multiple isolates) co-existed in the same individuals with some persisted over time. Furthermore, features of CRISPR adaptation, evolution, and microdynamics were highlighted through an analysis of host-MGE network, such as modules of multiple MGEs and hosts, reflecting complex interactions betweenB. fragilisand its invaders mediated through the CRISPR-Cas systems. This work demonstrates the power of using culture-based population genomics to reveal the activities and evolution of the CRISPR-Cas systems associated with gut bacteria in human population. We made available of all annotated CRISPR-Cas systems and their target MGEs, and their interaction network as a web resource athttps://omics.informatics.indiana.edu/CRISPRone/Bfragilis.
PAEP and cilia gene splicing changes in endometrial glands during the implantation window in women with recurrent pregnancy loss
Authors: Pearson-Farr J.E. , Wheway G , Jongen M.S.A , Goggin P. , Lewis R.M. , Cheong Y. , Cleal J.K.
Published: September 2021

Endometrial glands are essential for fertility, consisting of ciliated and secretory cells that facilitate a suitable uterine environment for embryo implantation. This study sought to determine whether an endometrial gland specific transcriptome and splicing profile are altered in women with recurrent pregnancy loss. Our data provide a comprehensive catalogue of cilia and PAEP gene isoforms and relative exon usage in endometrial glands. We report a previously unannotated endometrial gland cilia transcript GALNT11 and its susceptibility to exon skipping. Key endometrial receptivity gene transcripts are also reported to change in endometrial glands of women with recurrent pregnancy loss. The endometrial gland cilia and PAEP targets identified in this study could be used to identify a perturbed endometrium, isolate causes of recurrent pregnancy loss and develop targeted therapies in personalised medicine.
HIF-dependent CKB expression promotes breast cancer metastasis, whereas cyclocreatine therapy impairs cellular invasion and improves chemotherapy efficacy
Authors: Krutilina Raisa I. , Playa Hilaire , Brooks Danielle L. , Schwab Luciana P. , Parke Deanna N. , Oluwalana Damilola , Layman Douglas R. , Fan Meiyun , Johnson Daniel L. , Yue Junming , Smallwood Heather , Seagroves Tiffany N.
Published: September 2021

The oxygen-responsive Hypoxia Inducible Factor (HIF)-1 promotes several steps of the metastatic cascade. A hypoxic gene signature is enriched in triple negative breast cancers (TNBCs) and correlates with poor patient survival. Since inhibiting the HIF transcription factors with small molecules is challenging, we sought to identify genes downstream of HIF-1 that could be targeted to block invasion and metastasis. Creatine kinase brain isoform (CKB) was identified as a highly differentially expressed gene in a screen of HIF-1 wild type and knockout mammary tumor cells derived from a transgenic model of metastatic breast cancer. CKB is a cytosolic enzyme that reversibly catalyzes the phosphorylation of creatine, generating phosphocreatine (PCr) in the forward reaction, and regenerating ATP in the reverse reaction. Creatine kinase activity is inhibited by the creatine analog cyclocreatine (cCr). Loss and gain of function genetic approaches were used in combination with cCr therapy to define the contribution of CKB expression or creatine kinase activity to cell proliferation, migration, invasion, and metastasis in ER-negative breast cancers. CKB was necessary for cell invasion in vitro and strongly promoted tumor growth and metastasis in vivo. Similarly, cyclocreatine therapy repressed cell migration, cell invasion, formation of invadopodia, and lung metastasis. Moreover, in common TNBC cell line models, the addition of cCr to conventional cytotoxic chemotherapy agents was either additive or synergistic to repress tumor cell growth.
Antigen-derived peptides directly engage the unfolded-protein sensor IRE1α to curb cross-presentation by dendritic cells
Authors: Guttman Ofer , Thomas Adrien Le , Marsters Scot , Lawrence David A. , Gutgesell Lauren , Harnoss Jonathan M. , Haag Simone M. , Murthy Aditya , Strasser Geraldine , Modrusan Zora , Wu Thomas , Mellman Ira , Ashkenazi Avi
Published: September 2021

Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER) and upload onto major histocompatibility type I (MHC-I) protein complexes for cell-surface transport and cross-presentation. Perplexingly, DCs often exhibit activation of the ER-stress sensor IRE1α in the absence of classical ER stress—leaving the underlying mechanism unexplained. Here we show that antigen-derived hydrophobic peptides directly engage ER-resident IRE1α by masquerading as unfolded proteins. Furthermore, IRE1α activation depletes MHC-I heavy-chain mRNAs through regulated IRE1α-dependent decay (RIDD), thereby curtailing antigen cross-presentation. In tumor-bearing mice, IRE1α disruption increased MHC-I expression on tumor-infiltrating DCs, and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1α inhibition synergized with anti-PD-L1 antibody treatment to cause tumor regression. Our findings elucidate the mechanism and consequence of antigen-driven IRE1α activation in DCs, yielding a promising combination strategy for cancer immunotherapy.
Ferromagnetoelectric phases of hexaferrites: a group-theoretical analysis
Authors: Shirokov Vladimir Borisovich , Razumnaya Anna Grigoryevna , Mikheykin Alexey Sergeevich
Published: September 2021

A symmetry-guided approach for designing and tailoring magnetoelectric and multiferroic hexaferrites is proposed. A group-theoretical study of the magnetoferroelectric structures of a hexagonal ferrite was carried out. The results were applied to M-, W- and Z-type hexaferrites. It is shown that the magnetic structure cannot be collinear in the main magnetic phase, with the direction of the magnetic moment along the hexagonal axis. Magnetic sublattices are shown in which cation substitution should lead to the formation of a multiferroic state. A thermodynamic model of a hexagonal ferroelectric ferrimagnet was constructed, in which isostructural phase transitions were observed.
Risk factors for the rice crop farming community in China: a documentary analysis of the challenges during post COVID-19
Authors: Niaz Ahsan , Asad Muhammad Mujtaba , Abdulmuhsin Amir. A. , Shavanov Musa , Churi Prathamesh
Published: September 2021

Purpose

Pandemics always have an impact on everything; for wildlife it is somehow positive and for human health and safety it is negative. But yet there is not any critique on its impact on the agriculture sector and farmer community. The world is not aware of the hazards which will be caused by crop loss. On the globe the largest country by population is China, where natives in China consume rice as staple food. In past few years, it was among the highest rice producing and consuming countries. Rice is planted in February to May mostly in China, and rice crop production is strongly dependent on preplanting activates which farmers are unable to perform because of the coronavirus disease 2019 (COVID-19) spread and the need to follow safety measures. So, the purpose of this documentary analysis is to indicate the impact of coronavirus disease on the agricultural sector in China specifically for rice production.

Design/methodology/approach

In this article, a documentary analysis approach has been utilized. Moreover, due to the new and latest issue, not much research has been published in the context of the COVID-19 pandemic impact on the agriculture industry in China. Whereas, several online reports and expert reviews have been reviewed which have been published in online platforms and blogs websites. A total of 45 resources (journal articles, expert reviews) have been downloaded from reputed databases such as Scopus and Web of Science, out of which 31 of them were more relevant and related to the context of study.

Findings

The outcome based on this study has indicated that the rice cultivators and farmers are in uncertainty and not comfortable to work in their fields without proper safety measures due to the pandemic situation which will badly affect their lives and the economy of the country. Therefore, this study suggests that to overcome this issue, a proper safety framework is needed to be developed which can be implemented and which can facilitate the rice farming community.

Practical implications

Agriculture is important in so many ways including providing employment to the bulk of the population and providing the basic necessity of life and also contributing to the national economy. The outcome of this study will facilitate the agricultural scientist, economist and seasonal crop production stakeholders to indicate the most problematic domain and upcoming challenges faced by the rice farming community in China due to the COVID-19 pandemic.

Originality/value

This is the first documentary analysis which is addressing the current issues due to the COVID-19 pandemic in the agriculture industry and specifically in the rice cultivation and producing community safety concerns and issues in China which is the first and most affected nation due to the coronavirus.
Entrepreneurial intention of academic students in the time of COVID-19 pandemic
Authors: Krichen Kamel , Chaabouni Haithem
Published: September 2021

Purpose

The purpose of this study was to investigate the consequences of the economic shock caused by the COVID-19 pandemic on the entrepreneurial intentions of academic students. In addition, this research examined whether the pandemic reinforces the tendency to operate new businesses or represents a barrier to the pursuit of entrepreneurial opportunities.

Design/methodology/approach

This study was conducted with a sample of university students. Risk perception and contextual variables were measured. Information was collected from 308 university students enrolled at the University of Sfax (Tunisia) who participated by responding to a structured questionnaire distributed in electronic form by email.

Findings

The results show that university students perceive higher levels of personal entrepreneurial risk than other types of entrepreneurial risks (financial risk and social risk). Perceived financial risk only has a significant effect on entrepreneurial intention for students who view the COVID-19 crisis as an opportunity. Regarding perceived contextual support, only perceived educational support has a significant and positive effect on entrepreneurial intention.

Research limitations/implications

The results have important practical implications for identifying entrepreneurial intentions. They indicate that universities have an essential role in providing educational support for students by implementing awareness and training programs for entrepreneurship. Furthermore, they reveal the differentiated effect of the COVID-19 crisis on the risk perceptions of participants according to their views of the crisis as a threat or as an opportunity.

Originality/value

This is one of few studies that have examined the impact of the COVID-19 pandemic (positive or negative) on the entrepreneurial intention of academic students.
Impacts of management at a local and landscape scale on pollinators in semi‐natural grasslands
Authors: Larkin Michelle , Stanley Dara A.
Published: September 2021

Managing farmland to benefit biodiversity is becoming increasingly necessary to combat biodiversity declines and maintain ecosystem services. Results‐based agri‐environmental schemes are a tool used to achieve this by paying farmers based on environmental results delivered. These schemes often utilise plant indicator species to assess results at field scale; however, it is unknown if focusing on enhancing a subset of one biodiversity group within results‐based schemes impacts wider biodiversity, and whether local‐scale implementation of results‐based schemes or/and the wider landscape are more important drivers of biodiversity patterns.

Insect pollinators provide important pollination services for many crop and wild plants, and as mobile organisms often experience landscape at large spatial scales. We tested whether insect pollinators are affected at local scale by a results‐based scheme scored based on plant indicators, or if landscape management is more important, and whether there were different responses between taxon‐specific groups. Bumblebees, solitary bees, hoverflies and butterflies were sampled using transects and pan traps in 23 fields with varying scores assigned by the scheme, situated in high‐intensity (≥65% improved grassland) or low‐intensity (≥65% semi‐natural grassland) landscapes.

Results indicate taxon‐specific responses to local and landscape management in semi‐natural grasslands. Bumblebees responded positively to local‐scale management in fields with higher floral diversity, whereas hoverflies and butterflies responded positively to low‐intensity landscape management.

Synthesis and applications. Using plant species as indicators for biodiversity in agri‐environment schemes can have indirect benefits for non‐target taxa like bumblebees, but broader indicators should be developed to incorporate other pollinator groups. Pollinator groups respond differently to local and landscape management in semi‐natural grasslands. Agri‐environmental management should consider a range of different management measures and landscape scale approaches where possible, to maximise benefits for a range of pollinator taxa.
Tracking wildlife energy dynamics with unoccupied aircraft systems and three‐dimensional photogrammetry
Authors: Shero Michelle R. , Dale Julian , Seymour Alexander C. , Hammill Mike O. , Mosnier Arnaud , Mongrain Samuel , Johnston David W.
Published: September 2021

We present a novel application using unoccupied aircraft systems (UAS; drones) for structure‐from‐motion three‐dimensional (3‐D) photogrammetry of multiple, free‐living animals simultaneously. Pinnipeds reliably haul out on shore for pupping and breeding each year, accompanied by dramatic female‐to‐pup mass transfer over a short lactation period and males lose mass while defending mating territories. This provides a tractable study system for validating the use of UAS as a non‐invasive tool for tracking energy dynamics in wild populations.

UAS imagery of grey seals Halichoerus grypus was collected at Saddle Island, Nova Scotia. A multirotor UAS was piloted in 360‐degree orbits around relatively dense animal aggregations and georeferenced images were used for construction of a 3‐D point cloud, orthomosaic and Digital Surface Model for animal volumetric measurements. Directly following UAS survey, a subset of adult females were hand‐measured (morphometrics, blubber depth, n = 21 handlings [15 were unique animals]) and female–pup pairs were weighed (adult females: n = 32 [24]; pups: n = 33 [23]) to validate that UAS 3‐D photogrammetric models provided accurate animal volume and mass estimates.

UAS two‐dimensional body length measurements were sensitive to animal recumbency and posture. The new UAS 3‐D photogrammetric method overcame these constraints, and aerial‐derived body volume measurements were equivalent to those collected from the ground. UAS body volume measurements precisely predicted ‘true’ body mass (mean absolute error, adult female: 3.8 kg, 2.1% body mass; pup: 4.1 kg, 9.8%), and exhibited a stronger relationship with total body mass than with blubber volume.

The method was applied to 673 free‐living animals to characterize volume and mass dynamics across lactation and breeding for a much larger sample size than would be possible using traditional ground methods. Indeed, 1–46 animals (M ± SE: 9.2 ± 1.2) were modelled concurrently within the focal area of a UAS flight. Application of the method also captured significant inter‐annual variation in body volume/mass dynamics, and female‐to‐pup energy transfer efficiencies were lower when there was low sea ice extent. The UAS 3‐D photogrammetric method presented in this study is likely to be broadly applicable to other species, and the ability to measure whole groups of free‐living animals at once makes strides towards ‘weighing populations’.
Rural broadband speeds and business startup rates
Authors: Deller Steven , Whitacre Brian , Conroy Tessa
Published: September 2021

Using 2014 U.S. nonmetropolitan county‐level data, we explore the relationship between broadband speeds and business startup rates. Rural development policy discussions have presumed that access to broadband has become a necessary, although not sufficient, condition for economic growth and development. The relationship between broadband access on business startups, which are vital to local economic vibrancy, may be key to understanding the link between broadband and growth. In this study, we explore how qualitative features of broadband influence startup rates across different types of industries. To refine our insights into these relationships, we look at broadband by speed (both download and upload coverage across four speed categories). We also consider the importance of mobile broadband availability, which is often ignored in empirical studies. Because of the presence of spatial dependency within the data and the fact that data on business startup rates is limited to the minority of establishments that have employees, we use a Bayesian spatial Tobit estimator. After controlling for a host of variables likely to influence economic growth, we find that broadband coverage does matter and that download speeds tend to be more important than upload speeds. This pattern holds for mobile coverage as well. Perhaps the most important finding is that the results vary across business type: what matters for new businesses in one industry may not matter for other industry classifications. In the end, our results reaffirm the policy notion that access to broadband is increasingly relevant to rural entrepreneurship.
Are we ‘gritty’ enough? The importance of ‘grit’ in O&G training: Association of passion and perseverance with burnout, thriving and career progression
Authors: Lucky Tarana , Lowe Belinda , Arafat Yasser , Rathbone Evelyne , Angstetra Donald
Published: September 2021

Background

Objective assessment of grit and its association with burnout in obstetrics and gynaecology (O&G) training is underexplored.

Aim

This study utilises the Short Grit Scale and the Oldenburg Burnout Inventory to investigate the association of grit with burnout, thriving and career progression among O&G trainees and Fellows in Australia/New Zealand.

Materials and Methods

A cross‐sectional survey of the RANZCOG (Royal Australian and New Zealand College of Obstetricians and Gynaecologists) members was conducted. Participants were categorised by seniority level (core trainees, advanced trainees and Fellows). Mean grit and burnout scores were compared with one‐way analyses of variance. Correlation between grit and burnout was estimated using Pearson’s correlation coefficient. Logistic regression models were used to determine factors associated with high vs low burnout. Grit was categorised as low/medium/high for regression models.

Results

A total of 751 (26%) participants completed the survey. Fellows reported higher mean grit than core (P = 0.02) and advanced trainees (P = 0.03), and lower mean burnout than core trainees (P < 0.001). Moderate negative correlation was demonstrated between grit and burnout scores (r = −0.34). In the multivariable model, only seniority (adjusted adds ratio (OR): 0.40 for Fellows vs core trainees, P = 0.008) and grit levels (adjusted OR:4.52 for low versus high, P < 0.001; 2.32 for low vs medium, P = 0.001) were significantly associated with burnout.

Conclusion

This study demonstrates the protective role of grit in combating burnout among RANZCOG trainees and Fellows. While further well‐designed studies are warranted, findings from our study are expected to help the College in developing targeted interventions and subsequently minimise burnout‐related adverse outcomes in high‐risk groups.
Letter: universal screening for hepatitis C in pregnant women, children and adolescents
Authors: Garrido Isabel , Macedo Guilherme
Published: September 2021

LINKED CONTENT

This article is linked to Indolfi et al and Indolfi & Lucenteforte papers. To view these articles, visit https://doi.org/10.1111/apt.16037 and https://doi.org/10.1111/apt.16577