bluuebunny/crossref_metadata_2025 huggingface dataset:
Ambulatory Heart Rate Variability Monitoring: Comparisons Between the Empatica E4 Wristband and Holter Electrocardiogram
Authors: Van Voorhees Elizabeth E. , Dennis Paul A. , Watkins Lana L. , Patel Tapan A. , Calhoun Patrick S. , Dennis Michelle F. , Beckham Jean C.
Published: September 2021

Objective

Heart rate variability (HRV) is a useful index of psychological and physiological stress. Although several wristband devices have purported to measure HRV, none have demonstrated reliability when compared with the criterion-standard Holter monitor. We evaluated the reliability of HRV readings from the Empatica E4 wristband compared with a Holter monitor over a 24-hour period of simultaneous monitoring.

Methods

Agreement between the monitors was assessed by examining correlations and intraclass correlations (ICCs) for fixed sets in 13 individuals in a treatment trial for posttraumatic stress disorder (4 women; mean [standard deviation] age = 51.92 [6.17] years). Agreement was calculated at 1-second and 5-minute intervals for interbeat intervals (IBIs) and for 5-minute intervals of the root mean square of successive differences between normal heartbeats (RMSSD) and standard deviation of all normal R-R intervals (SDNN). Agreement across the entire 24-hour observation period was also measured. Frequency-domain measures of HRV could not be calculated because of too much missing data from the E4.

Results

Although high interdevice correlations and ICCs were observed between the E4 and Holter monitors for IBIs at 1-second (median r = 0.88; median ICC = 0.87) and 5-minute (median r = 0.94; median ICC = 0.94) intervals, reliabilities for 5-minute RMSSD (median r = −0.09; median ICC = −0.05) and 5-minute SDNN (median r = 0.48; median ICC = 0.47) were poor. Agreement between the devices on 24-hour measures of HRV was satisfactory (IBI: r = 0.97, ICC = 0.97; RMSSD: r = 0.77, IBI = 0.76; SDNN: r = 0.92, IBI = 0.89).

Conclusions

Findings suggest that the low reliability of Empatica E4 as compared with the Holter monitor does not justify its use in ambulatory research for the measurement of HRV over time periods of 5 minutes or less.
A Case of Brown Tumor on 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT
Authors: Yao Xilan , Ou Xiaohong
Published: September 2021

A 50-year-old man presented with right chest pain and persistent increased parathyroid hormone after parathyroidectomy for parathyroid carcinoma. 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT were performed consecutively for restaging to determine subsequent treatment strategy. An osteolytic lesion on the right sixth rib showed increased uptake on both 68Ga-DOTATATE and 18F-FDG PET/CT. Subsequent biopsy confirmed it to be a brown tumor.
68Ga-FAPI-04 PET/CT Imaging for Fibrous Dysplasia of the Bone
Authors: Wang Yingwei , Wu Junhao , Liu Lin , Peng DengSai , Chen Yue
Published: September 2021

68Ga-labeled quinoline-based fibroblast activation protein inhibitors (68Ga-FAPIs) are promising agents for tumor imaging. However, some nonneoplastic lesions can also cause increased FAPI uptake. We report a case of a patient with polyostotic fibrous dysplasia who showed widespread and intense metabolic activity on 68Ga-FAPI PET/CT. Physicians should be aware that fibrous dysplasia can also cause elevated FAPI activity.
Pattern of variation in DNA methylation during pregnancy among mothers who delivered preterm in the GARBH-Ini cohort
Authors: Das Jagyashila , Bagchi Indranil , Ghosh Shekhar , Wadhwa Nitya , Nachu Uma Chadramouli , Thiruvengadam Ramachandran , Kshetrapal Pallavi , Bhatnagar Shinjini , Majumder Partha P. , Maitra Arindam ,   GARBH-Ini Team
Published: September 2021

Background

DNA methylation (DNAm) may play an important role in birth outcomes.

Material and Methods

Genome wide DNAm was analysed in peripheral blood DNA of women at multiple time points during gestation. A novel empirical method was used to identify CpG sites with high temporal variance in methylation associating with preterm birth.

Results

High variability at 1296 CpG sites from the promoter regions of 1197 genes significantly associated with PTB. These genes belonged to pathways involved in signalling by platelet derived growth factor, platelet homeostasis, collagen degradation, extracellular matrix and circadian clock.

Conclusions

The findings provide novel information which might help in development of predictive biomarkers of preterm birth outcome.
Antenatal care policy in high-income countries with a universal health system: a scoping review
Authors: Goncalves Andreia Soares , Ferreira Isabel Maria , Pestana-Santos Márcia , McCourt Christine , Prata Ana Paula
Published: September 2021

The availability, effectiveness, and access to antenatal care are directly linked with good maternal and neonatal outcomes, making antenatal care an important determinant in health. But to be effective, care must always be appropriate, not excessive, not insufficient. Perinatal outcomes vary within and between countries, raising questions about practices, the use of best evidence in clinical decisions and the existence of clear and updated guidance.

Through a scoping review methodology, this study aimed to map the available antenatal care policies for low-risk pregnant women in high-income countries with a universal health system founded on the Beveridge Model.

Following searches on the main databases and grey literature, the authors identified and analysed ten antenatal care policies: Australia, Denmark, Finland, Iceland, Italy, Norway, Portugal, Spain, Sweden and the United Kingdom. Some policies were over 10 years old, some recommendations did not present a rationale or context, others were outdated, or were simply different approaches in the absence of strong evidence. Whilst some recommendations were ubiquitous, others differed either in the recommendation provided, the timing, or the frequency. Similarly, we found wide variation in the methods/strategy used to support the recommendations provided. These results confirms that best evidence is not always assimilated into policies and clinical guidance. Further research crossing these differences with perinatal outcomes and evaluation of cost could be valuable to optimise guidance on antenatal care. Similarly, some aspects of care need further rigorous studies to obtain evidence of higher quality to inform recommendations.
Urgency disrupts cognitive control of human action
Authors: Poth Christian H.
Published: September 2021

Intelligent behavior requires cognitive control, the ability to act directed by goals despite competing action tendencies triggered by stimuli in the environment. For eye movements, it has recently been discovered that cognitive control is briefly disrupted in urgent situations (Salinas et al., 2019). In a time-window before an urgent response, participants could not help but look at a suddenly appearing visual stimulus, even though their goal was to look away from it. Urgency seemed to provoke a new visual-oculomotor phenomenon: A period in which saccadic eye movements are dominated by external stimuli, and uncontrollable by current goals. This period was assumed to arise from brain mechanisms controlling eye movements and spatial attention, such as those of the frontal eye field. Here, we show that the phenomenon is more general than previously thought. We found that urgency disrupted cognitive control also in well-investigated manual tasks, so that responses were dominated by goal-conflicting stimulus features. This dominance of behavior followed established trial-to-trial signatures of cognitive control that replicate across a variety of tasks. Thus together, these findings reveal that urgency temporarily impairs cognitive control in general, not only at brain mechanisms controlling eye movements.
A new framework for analysis of three-dimensional shape and architecture of human skeletal muscles
Authors: Bolsterlee Bart
Published: September 2021

A new framework is presented for comprehensive analysis of the three-dimensional shape and architecture of human skeletal muscles from magnetic resonance and diffusion tensor imaging data. The framework comprises three key features: (1) identification of points on the surface of and inside a muscle that have a correspondence to points on and inside another muscle, (2) reconstruction of average muscle shape and average muscle fibre orientations, and (3) utilization of data on between-muscle variation to visualize and make statistical inferences about changes or differences in muscle shape and architecture. The general use of the framework is demonstrated by its application to three datasets. Analysis of data obtained before and after eight weeks of strength training revealed there was little regional variation in hypertrophy of the vastus medialis and vastus lateralis, and no systematic change in pennation angle. Analysis of passive muscle lengthening revealed heterogeneous changes in shape of the medial gastrocnemius, and confirmed the ability of the methods to detect subtle changes in muscle fibre orientation. Analysis of the medial gastrocnemius of children with unilateral cerebral palsy showed that muscles in the more-affected limb were shorter, thinner and less wide than muscles in the less-affected limb, and had slightly more pennate muscle fibres in the central and proximal part of the muscle. Amongst other applications, the framework can be used to explore the mechanics of muscle contraction, investigate adaptations of muscle architecture, build anatomically realistic computational models of skeletal muscles, and compare muscle shape and architecture between species.
Durable Immunity to Ricin Toxin Elicited by a Thermostable, Lyophilized Subunit Vaccine
Authors: Novak Hayley , Doering Jennifer , Ehrbar Dylan , Donini Oreola , Mantis Nicholas J.
Published: September 2021

The development of vaccines against biothreat toxins like ricin (RT) is considered an integral component of the United States national security efforts. RiVax® is a thermostable, lyophilized RT subunit vaccine adsorbed to aluminum salt adjuvant intended for use by military personnel and first responders. Phase 1 studies indicated that RiVax is safe and immunogenic, while a three dose, intramuscular vaccination regimen in non-human primates elicited protection against lethal dose RT challenge by aerosol. Here we investigated, in a mouse model, the durability of RiVax-induced antibody responses and corresponding immunity to lethal dose RT challenge. Groups of mice were subcutaneously administered 3 or 1 μg of RiVax on days 0 and 21 and challenged with 10 × LD50 RT by injection at six different intervals over the course of twelve months. Serum antibody titers and epitope-specific competition assays were determined prior to each challenge. We report that the two-dose, 3 μg regimen conferred near complete protection against RT challenge on day 35 and complete protection thereafter (challenge days 65, 95, 125, 245, and 365). The two-dose, 3 μg regimen was superior to the 1 μg regimen as revealed by slight differences in survival and morbidity scores (e.g., hypoglycemia, weight loss) on challenge days 35 and 365. In separate experiments, a single 3 μg RiVax vaccination proved only marginally effective at eliciting protective immunity to RT, underscoring the necessity of a prime-boost regimen to achieve full and long-lasting protection against RT.

IMPORTANCE

Ricin toxin (RT) is a notorious biothreat, as exposure to even trace amounts via injection or inhalation can induce organ failure and death within a matter of hours. In this study, we advance the preclinical testing of a candidate RT vaccine known as RiVax®. RiVax is a recombinant non-toxic derivative of RT’s enzymatic subunit that has been evaluated for safety in Phase I clinical trials and efficacy in a variety of animal models. We demonstrate that two doses of RiVax is sufficient to protect mice from lethal dose RT challenge for up to one year. We describe kinetics and other immune parameters of the antibody response to RiVax and discuss how these immune factors may translate to humans.
Cortical dopamine reduces the impact of motivational biases governing automated behaviour
Authors: Scholz Vanessa , Hook Roxanne W. , Kandroodi Mojtaba Rostami , Algermissen Johannes , Ioannidis Konstantinos , Christmas David , Valle Stephanie , Robbins Trevor W. , Grant Jon E. , Chamberlain Samuel R. , den Ouden Hanneke EM
Published: September 2021

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n=35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomized, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.
A broad-specificity O-glycoprotease that enables improved analysis of glycoproteins and glycopeptides containing intact complex O-glycans
Authors: Vainauskas Saulius , Guntz Hélène , McLeod Elizabeth , McClung Colleen , Ruse Cristian , Shi Xiaofeng , Taron Christopher H.
Published: September 2021

Analysis of mucin type O-glycans linked to serine/threonine of glycoproteins is technically challenging, in part, due to a lack of effective enzymatic tools that enable their analysis. Recently, several O-glycan-specific endoproteases that can cleave the protein adjacent to the appended glycan have been described. Despite significant progress in understanding the biochemistry of these enzymes, known O-glycoproteases have specificity constrains, such as inefficient cleavage of glycoproteins bearing sialylated O-glycans, high selectivity for certain type of glycoproteins or protein sequence bias, that limit their analytical application. In this study, we examined the capabilities of an immunomodulating metalloprotease (IMPa) from Pseudomonas aeruginosa. The peptide substrate sequence selectivity and its impact on IMPa activity was interrogated using an array of synthetic peptides and their glycoforms. We show that IMPa has no specific P1 residue preference and can tolerate most amino acids at the P1 position, except aspartic acid. The enzyme does not cleave between two adjacent O-glycosites, indicating that O-glycosylated serine/threonine is not allowed at position P1. Glycopeptides with as few as two amino acids on either side of an O-glycosite were specifically cleaved by IMPa. Finally, IMPa efficiently cleaved peptides and proteins carrying sialylated and asialylated O-glycans of varying complexity. We present the use of IMPa in a one-step O-glycoproteomics workflow for glycoprofiling of individual purified glycoproteins granulocyte colony-stimulating factor (G-CSF) and receptor-type tyrosine-protein phosphatase C (CD45) without the need for glycopeptide enrichment. In these examples, IMPa enabled identification of O-glycosites and the range of complex O-glycan structures at each site.
Trans-cellular tunnels induced by the fungal pathogen Candida albicans facilitate invasion through successive epithelial cells without host damage
Authors: Lachat Joy , Pascault Alice , Thibaut Delphine , Le Borgne Rémi , Verbavatz Jean-Marc , Weiner Allon
Published: September 2021

The opportunistic fungal pathogen Candida albicans is normally commensal, residing in the mucosa of most healthy individuals. In susceptible hosts, its filamentous hyphal form can invade epithelial layers leading to superficial or severe systemic infection. Invasion is mainly intracellular, though it causes no apparent damage to host cells. We investigated the invasive lifestyle of C. albicans in vitro using live-cell imaging and the damage-sensitive reporter galectin-3. Quantitative single cell analysis showed that invasion can result in host membrane breaching at different stages of invasion and cell death, or in traversal of host cells without membrane breaching. Membrane labelling and three-dimensional “volume” electron microscopy revealed that hyphae can traverse several host cells within trans-cellular tunnels that are progressively remodelled and may undergo ‘inflations’ linked to host glycogen stores, possibly during nutrient uptake. Thus, C. albicans invade epithelial tissues by either inflicting or avoiding host damage, the latter facilitated by trans-cellular tunnelling.
Long-term persistence of viral RNA and inflammation in the CNS of macaques exposed to aerosolized Venezuelan equine encephalitis virus
Authors: Ma Henry , Albe Joseph R. , Gilliland Theron , McMillen Cynthia M. , Gardner Christina L. , Boyles Devin A. , Cottle Emily L. , Dunn Matthew D. , Lundy Jeneveve D. , Salama Noah , O’Malley Katherine J. , Pandrea Ivona , Teichert Tobias , Barrick Stacey , Klimstra William B. , Hartman Amy L. , Reed Douglas S.
Published: September 2021

Venezuelan equine encephalitis virus (VEEV) is a positively-stranded RNA arbovirus of the genus Alphavirus that causes encephalitis in humans. Cynomolgus macaques are a relevant model of the human disease caused by VEEV and are useful in exploring pathogenic mechanisms and the host response to VEEV infection. Macaques were exposed to small-particle aerosols containing virus derived from an infectious clone of VEEV strain INH-9813, a subtype IC strain isolated from a human infection. VEEV-exposed macaques developed a biphasic fever after infection similar to that seen in humans. Maximum temperature deviation correlated with the inhaled dose, but fever duration did not. Neurological signs, suggestive of virus penetration into the CNS, were predominantly seen in the second febrile period. Electroencephalography data indicated a statistically significant decrease in all power bands and circadian index during the second febrile period that returned to normal after fever resolved. Intracranial pressure increased late in the second febrile period. On day 6 post-infection macaques had high levels of MCP-1 and IP-10 chemokines in the CNS, as well as a marked increase of T lymphocytes and activated microglia. More than four weeks after infection, viral genomic RNA was found in the brain, cerebrospinal fluid and cervical lymph nodes. Pro-inflammatory cytokines & chemokines, infiltrating leukocytes and pathological changes were seen in the CNS tissues of macaques euthanized at these times. These data are consistent with persistence of virus replication and/or genomic RNA and potentially, inflammatory sequelae in the central nervous system after resolution of acute VEEV disease.
Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses
Authors: Maynard Stephanie A , Rostaing Philippe , Schaefer Natascha , Gemin Olivier , Candat Adrien , Dumoulin Andréa , Villmann Carmen , Triller Antoine , Specht Christian G
Published: September 2021

Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy (SR-CLEM). We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs μm-2at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in theoscillatormouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.
Global population genomics of two subspecies ofCryptosporidium hominisduring 500 years of evolution
Authors: Tichkule Swapnil , Cacciò Simone M. , Robinson Guy , Chalmers Rachel M. , Mueller Ivo , Emery-Corbin Samantha J. , Eibach Daniel , Tyler Kevin M. , van Oosterhout Cock , Jex Aaron R.
Published: September 2021

Cryptosporidiosis is a major global health problem and a primary cause of diarrhoea, particularly in young children in low- and middle-income countries (LMICs). The zoonoticCryptosporidium parvumand anthroponoticC. hominiscause most human infections. Here, we present a comprehensive whole-genome study ofC. hominis, comprising 114 isolates from 16 countries within five continents. We detect two lineages with distinct biology and demography, which diverged circa 500 years ago. We consider these lineages two subspecies and propose the namesC. hominis hominisandC. hominis aquapotentis(gp60subtype IbA10G2). In our study,C. h. hominisis almost exclusively represented by isolates from LMICs in Africa and Asia and appears to have undergone recent population contraction. In contrast,C. h. aquapotentiswas found in high-income countries, mainly in Europe, North America and Oceania, and appears to be expanding. Notably,C. h. aquapotentisis associated with high rates of direct human-to-human transmission, which may explain its success in countries with well-developed environmental sanitation infrastructure. Intriguingly, we detected genomic regions of introgression following secondary contact between the subspecies. This resulted in high diversity and divergence in genomic islands of putative virulence genes (GIPVs), includingmuc5(CHUDEA2_430) and a hypothetical protein (CHUDEA6_5270). This diversity is maintained by balancing selection, suggesting a coevolutionary arms race with the host. Lastly, we find that recent gene flow fromC. h. aquapotentistoC. h. hominis, likely associated with increased human migration, may be driving evolution of more virulentC. hominisvariants.
Simultaneous Triple-Parametric Optical Mapping of Transmembrane Potential, Intracellular Calcium and NADH for Cardiac Physiology Assessment
Authors: George Sharon A , Lin Zexu , Efimov Igor R
Published: September 2021

Investigation of the complex relationships and dependencies of multiple cellular processes that govern cardiac physiology and pathophysiology requires simultaneous dynamic assessment of multiple parameters. In this study, we introduce triple-parametric optical mapping to simultaneously image metabolism, electrical excitation, and calcium signaling from the same field of view and demonstrate its application in the field of drug testing and cardiovascular research. We applied this metabolism-excitation-contraction coupling (MECC) methodology to test the effects of blebbistatin, 4-aminopyridine and verapamil on cardiac physiology. While blebbistatin and 4-aminopyridine alter multiple aspects of cardiac function suggesting off-target effects, the effects of verapamil were on-target and it altered only one of ten tested parameters. Triple-parametric optical mapping was also applied during ischemia and reperfusion; and we identified that metabolic changes precede the effects of ischemia on cardiac electrophysiology.
Targeting the Cx26/NANOG/Focal Adhesion Kinase Complex via Cell-Penetrating Peptides in Triple-Negative Breast Cancers
Authors: Mulkearns-Hubert Erin E. , Rhoades Emily Esakov , Ben-Salem Salma , Bharti Rashmi , Hajdari Nicole , Johnson Sarah , Myers Alex , Smith Iris Nira , Bandyopadhyay Smarajit , Eng Charis , Downs-Kelly Erinn , Lathia Justin D. , Reizes Ofer
Published: September 2021

Triple-negative breast cancer (TNBC) represents the most lethal and treatment-resistant breast cancer subtype with limited treatment options. We previously identified a protein complex unique to TNBC cancer stem cells composed of the gap junction protein connexin 26 (Cx26), the pluripotency transcription factor NANOG, and focal adhesion kinase (FAK). We sought to determine whether a peptide mimetic of Cx26 designed to target the complex attenuated tumor growth in pre-clinical models. Histological assessment was employed to verify expression of complex members. We designed peptides based on Cx26 juxtamembrane domains and performed binding experiments with NANOG and FAK using surface plasmon resonance. Peptides with high affinity were engineered with a cell-penetrating sequence and assessed in functional assays including cell proliferation, self-renewal, and in vivo tumor growth, and downstream signaling changes were measured. Binding studies revealed that the Cx26 C-terminal tail and intracellular loop bound to NANOG and FAK with submicromolar-to-micromolar affinity and that a 5-amino acid sequence in the C-terminal tail of Cx26 (RYCSG) was sufficient for binding. The Cx26 C-terminal tail was tagged with an antennapedia cell-penetrating peptide sequence and intracellular localization was confirmed. The cell-penetrating Cx26 peptide (aCx26-pep) disrupted self-renewal as assessed by tumorsphere formation assay while reducing nuclear FAK and NANOG and inhibiting NANOG target gene expression in TNBC cells but not luminal mammary epithelial cells. In vivo, aCx26-pep reduced tumor growth and proliferation and induced cell death. We provide proof-of-concept that a Cx26 peptide-based strategy inhibits growth and alters NANOG activity in TNBC.
Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity
Authors: Barsi Szilvia , Papp Henrietta , Urbelz Alberto Valdeolivas , Tóth Dániel J. , Kuczmog Anett , Madai Mónika , Hunyady László , Várnai Péter , Saez-Rodriguez Julio , Jakab Ferenc , Szalai Bence
Published: September 2021

Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous.

To address this question, we analysed gene expression data fromin vitroSARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment within vitroeffective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity - and not inverse similarity - between drug and infection-induced gene expression signatures, we were able to predict thein vitroantiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by severalin vitroeffective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed thein vitroantiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism.

Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.

Abstract Figure
The reaction of thiourea and 1,3-dimethylthiourea towards organoiodines: oxidative bond formation and halogen bonding
Authors: Peloquin Andrew J. , Ragusa Arianna C. , McMillen Colin D. , Pennington William T.
Published: September 2021

By varying the halogen-bond-donor molecule, 11 new halogen-bonding cocrystals involving thiourea or 1,3-dimethylthiourea were obtained, namely, 1,3-dimethylthiourea–1,2-diiodo-3,4,5,6-tetrafluorobenzene (1/1), C6F4I2·C3H8N2S, 1, thiourea–1,3-diiodo-2,4,5,6-tetrafluorobenzene (1/1), C6F4I2·CH4N2S, 2, 1,3-dimethylthiourea–1,3-diiodo-2,4,5,6-tetrafluorobenzene (1/1), C6F4I2·C3H8N2S, 3, 1,3-dimethylthiourea–1,3-diiodo-2,4,5,6-tetrafluorobenzene–methanol (1/1/1), C6F4I2·C3H8N2S·CH4O, 4, 1,3-dimethylthiourea–1,3-diiodo-2,4,5,6-tetrafluorobenzene–ethanol (1/1/1), C6F4I2·C3H8N2S·C2H6O, 5, 1,3-dimethylthiourea–1,4-diiodo-2,3,5,6-tetrafluorobenzene (1/1), C6F4I2·C3H8N2S, 6, 1,3-dimethylthiourea–1,3,5-trifluoro-2,4,6-triiodobenzene (1/1), C6F3I3·C3H8N2S, 7, 1,3-dimethylthiourea–1,1,2,2-tetraiodoethene (1/1), C6H16N4S2·C2I4, 8, [(dimethylamino)methylidene](1,2,2-triiodoethenyl)sulfonium iodide–1,1,2,2-tetraiodoethene–acetone (1/1/1), C5H8I3N2S+·I−·C3H6O·C2I4, 9, 2-amino-4-methyl-1,3-thiazol-3-ium iodide–1,1,2,2-tetraiodoethene (2/3), 2C4H7N2S+·2I−·3C2I4, 10, and 4,4-dimethyl-4H-1,3,5-thiadiazine-3,5-diium diiodide–1,1,2,2-tetraiodoethene (2/3), 2C5H12N4S2+·4I−·3C2I4, 11. When utilizing the common halogen-bond-donor molecules 1,2-, 1,3-, and 1,4-diiodotetrafluorobenzene, as well as 1,3,5-trifluoro-2,4,6-triiodobenzene, bifurcated I...S...I interactions were observed, resulting in the formation of isolated rings, chains, and sheets. Tetraiodoethylene (TIE) provided I...S...I cocrystals as well, but further yielded a sulfonium-containing product through the reaction of the S atom with TIE. This particular sulfonium motif is the first of its kind to be structurally characterized, and is stabilized in the solid state through a three-dimensional I...I halogen-bonding network. Thiourea reacted with acetone in the presence of TIE to provide two novel heterocyclic products, again stabilized in the solid state through I...I halogen bonding.
Synthesis, structure and magnetocaloric properties of a new two-dimensional gadolinium(III) coordination polymer based on azobenzene-2,2′,3,3′-tetracarboxylic acid
Authors: Wei Wen-Wen , Lu Li-Ping , Feng Si-Si , Zhu Miao-Li , Englert Ulli
Published: September 2021

A new Gd3+ coordination polymer (CP), namely, poly[diaqua[μ4-1′-carboxy-3,3′-(diazene-1,2-diyl)dibenzene-1,2,2′-tricarboxylato]gadolinium(III)], [Gd(C16H7N2O8)(H2O)2]
n
, (I), has been synthesized hydrothermally from Gd(NO3)3·6H2O and azobenzene-2,2′,3,3′-tetracarboxylic acid (H4abtc). The target solid has been characterized by single-crystal and powder X-ray diffraction, elemental analysis, IR spectroscopy and susceptibility measurements. CP (I) crystallizes in the monoclinic space group C2/c. The structure features a 4-connected topology in which Gd3+ ions are connected by carboxylate groups into a linear chain along the monoclinic symmetry direction. Adjacent one-dimensional aggregates are bridged by Habtc3− ligands to form a two-dimensional CP in the (10\overline{1}) plane. A very short hydrogen bond [O...O = 2.4393 (4) Å] links neighbouring layers into a three-dimensional network. A magnetic study revealed antiferromagnetic Gd...Gd coupling within the chain direction. CP (I) displays a significant magnetocaloric effect (MCE), with a maximum −ΔS
m of 27.26 J kg−1 K−1 for ΔH = 7 T at 3.0 K. As the MCE in (I) exceeds that of the commercial magnetic refrigerant GGG (Gd3Ga5O12, −ΔS
m = 24 J kg−1 K−1, ΔH = 30 kG), CP (I) can be regarded as a potential cryogenic material for low-temperature magnetic refrigeration.
Women and Alcohol Consumption in Fascist Italy
Authors: Ferris Kate
Published: September 2021

This article examines discourses and practices around women's drinking in Fascist Italy. The history of alcohol production and consumption in Italy during the fascist dictatorship has only recently received attention; alcohol's gendered dimensions, especially women's drinking, have been hitherto overlooked. While the production of legislation, rhetoric and propaganda on alcohol consumption was dominated by men, women were identified as key constituents whose alcohol‐related practices could make or break the causes of fascist propagandists, ‘anti‐alcohol’ campaigners and alcohol industry associations. The article explains how Italian women were imagined and addressed by regime propagandists, alcohol industry producers and temperance campaigners as (a) simultaneously the principal victims of and responsibility bearers for male excess alcohol consumption, (b) potential ‘crisis‐women’ whose unpatriotic drinking choices (whether English tea, French champagne or American cocktails) denoted their prioritising of fashion over fascist values and (c) gatekeepers of family alcohol consumer practices and consumers of alcohol in their own right. It then moves to examine sources left by interwar Italian women to explore what, how and when they drank. Ultimately, it argues that despite attempts to construct women's drinking in archly nationalistic terms, the discourses and actual practices of Italian women around alcohol consumption operated within profoundly transnational frames.
Cardiac geometry, function, and remodeling patterns in patients under maintenance hemodialysis and peritoneal dialysis treatment
Authors: Alexandrou Maria‐Eleni , Sarafidis Pantelis , P. Theodorakopoulou Μarieta , Sachpekidis Vasileios , Papadopoulos Christodoulos , Loutradis Charalampos , Kamperidis Vasileios , Boulmpou Aristi , Bakaloudi Dimitra‐Rafailia , Faitatzidou Danai , Pateinakis Panagiotis , Papagianni Aikaterini
Published: September 2021

Cardiovascular disease is the leading cause of mortality in patients with end‐stage‐kidney disease. Evidence on the possible echocardiographic differences between hemodialysis and peritoneal dialysis (PD) is scarce. This study aimed to evaluate differences in left (LA) and right atrial (RA), left (LV) and right ventricular (RV) geometry, systolic and diastolic function in hemodialysis, and PD patients. Thirty‐eight hemodialysis and 38 PD patients were matched for age, sex, and dialysis vintage. Two‐dimensional and tissue‐Doppler echocardiography, and lung ultrasound were performed during an interdialytic day in hemodialysis and before a programmed follow‐up visit in PD patients. Vena cava diameter (11.09 ± 4.53 vs. 14.91 ± 4.30 mm; p < 0.001) was significantly lower in hemodialysis patients. Indices of LA, RA, LV, and RV dimensions were similar between the two groups. LVMi (116.91 [38.56] vs. 122.83 [52.33] g/m2; p = 0.767) was similar, but relative wall thickness was marginally (0.40 [0.14] vs. 0.45 [0.15] cm; p = 0.055) lower in hemodialysis patients. LV hypertrophy prevalence was similar between groups (73.7% vs. 71.1%; p = 0.798), but hemodialysis patients presented eccentric and PD patients concentric LVH. Regarding ventricular systolic function, stroke volume (p = 0.030) and cardiac output (p = 0.036) were higher in hemodialysis, while RV systolic pressure (RVSP) (20.37 [22.54] vs. 27.68 [14.32] mm Hg; p = 0.009) was higher in PD. No significant differences were evidenced in diastolic function indices and lung water excess between the two groups. A moderate association was noted between ultrasound B‐lines score and LA volume index (r = 0.465, p < 0.001), RVSP (r = 0.431, p < 0.001), and E/e′ ratio (r = 0.304, p = 0.009). Hemodialysis and PD patients present largely similar echocardiographic indices reflecting cardiac geometry, systolic, and diastolic function, but different patterns of abnormal LV remodeling.
The impact of primary human papillomavirus screening on negative loop excision histology following biopsy‐proven high‐grade cervical intra‐epithelial lesions: A review from a large tertiary colposcopy unit
Authors: Xie Huan , Morton Rhett , Balendran Jananie , Philp Shannon , Saidi Samir , Farrell Rhonda , Anderson Lyndal , Pather Selvan
Published: September 2021

Background

The renewed National Cervical Screening Program incorporating primary human papillomavirus (HPV) screening was implemented in Australia in December 2017. In a previous study conducted in the UK, primary HPV screening was found to be associated with a 25% reduction in the incidence of negative histology following loop electrosurgery excision procedure (LEEP).

Aim

To examine the change in incidence and associated risk factors for a negative LEEP with introduction of primary HPV screening.

Materials and Methods

A retrospective review of the records of all patients undergoing a LEEP excision for biopsy‐proven high‐grade cervical intra‐epithelial lesions between 1 January 2014 and 30 June 2019 in a specialised centre.

Results

There were 1123 patients who underwent a LEEP included in the analysis. The incidence of a negative LEEP specimen was 7.5% (59/784) and 5.3% (18/339) in the pre‐ and post‐HPV screening cohort. More patients in the post‐HPV screening group had low‐grade cytology on referral (P < 0.001), smaller cervical lesions on colposcopy (P = 0.012) and longer biopsy to treatment interval (P = 0.020). Primary HPV screening was associated with a significant reduction in the incidence of a negative LEEP specimen in a propensity matched cohort (11.2% to 5.1%, P = 0.006) and a 41% (P = 0.045) decreased relative risk of a negative LEEP on multivariate analysis.

Conclusions

Primary HPV screening results in a lower incidence of negative LEEP histology, despite a longer biopsy to treatment wait time and higher proportion of low‐grade cytology at triage.
Better performance of medical students on pharmacotherapy knowledge and skills tests is associated with practising with e‐learning program P‐scribe
Authors: Kalfsvel Laura , Versmissen Jorie , van Doorn Adriaan , van den Broek Walter , van der Kuy Hugo , van Rosse Floor
Published: September 2021

Aims

Junior doctors write most hospital prescriptions, yet are more than twice as likely to make an error in their prescriptions compared to senior doctors. A possibility to enhance pharmacotherapy education is through the use of e‐learning modules. The aim of this study was to determine whether P‐scribe, as the chosen e‐learning resource, helps students in passing their pharmacotherapy assessments.

Methods

This retrospective study was undertaken in the Erasmus Medical Center, the Netherlands. All 270 medical students who started their master's curriculum in the academic session of 2017–2018 were included. Data were analysed to identify the frequency of student's use per e‐learning module, total time students spent on e‐learning modules and timing of the use of e‐learning modules in relation to their assessments. The results of the assessments were analysed to identify possible correlations between the time students spent using P‐scribe, their timing of use and their assessment results.

Results

Students who passed their knowledge‐based assessment first time had a mean practice time of five more hours than students who did not pass first time (P < .05, 95% CI: 3.4–6.6). These students practised on average six e‐learning modules more (P < .05, 95% CI: 4.1–7.0) than students who failed their first attempt. Students who passed their skill‐based prescription test first time, practised on average five more e‐learning modules (P = .006, 95% CI: 1.4–8.3) than students who failed their first attempt.

Conclusion

Students who passed their pharmacotherapy assessments first time spent more time, and practised more frequently, with e‐learning modules.
Primary mediastinal germ cell tumours: an immunohistochemical and molecular diagnostic approach
Authors: Fichtner Alexander , Richter Annika , Filmar Simon , Kircher Stefan , Rosenwald Andreas , Küffer Stefan , Nettersheim Daniel , Oing Christoph , Marx Alexander , Ströbel Philipp , Bremmer Felix
Published: September 2021

Aims

Primary mediastinal germ cell tumours (PMGCTs) are rare mediastinal neoplasms, and their diagnosis can be challenging, owing to small biopsy samples. The aim of this study was to develop a diagnostic algorithm using immunohistochemical staining, with a focus on novel markers, and molecular analysis of isochromosome 12p [i(12p)].

Methods and results

Paraffin‐embedded tissues of 32 mediastinal tumours were analysed with immunohistochemical staining for sal‐like transcription factor 4 (SALL4), Lin‐28 homologue A (LIN28), octamer‐binding transcription factor 3/4 (OCT3/4), D2‐40, cluster of differentiation 117 (CD117), sex‐determining region Y‐box 17, sex‐determining region Y‐box 2 (SOX2), cluster of differentiation 30, the β‐subunit of human chorionic gonadotropin (β‐hCG), GATA‐binding protein 3 (GATA3), forkhead box protein A2 (FOXA2), glypican‐3 (GPC3), α‐fetoprotein (AFP), terminal deoxynucleotidyl transferase (TdT), nuclear protein of the testis (NUT), and pan‐cytokeratin. Quantitative real‐time polymerase chain reaction was performed to investigate the i(12p) status. Fifteen seminomas, seven teratomas, one yolk sac tumour, one choriocarcinoma and seven mixed PMGCTs were diagnosed. Each entity had different immunohistochemical staining patterns, which helped to distinguish them: OCT3/4, D2‐40, CD117 and TdT for seminoma; OCT3/4 and SOX2 for embryonal carcinoma; FOXA2, GPC3 and AFP for yolk sac tumour; and β‐hCG and GATA3 for choriocarcinoma. Mature teratomas stained positively for pan‐cytokeratin in epithelial components and focally for SALL4, SOX2, GATA3, D2‐40, and FOXA2. Furthermore, a NUT carcinoma mimicking a PMGCT was diagnosed, showing strong nuclear SOX2 staining and speckled nuclear NUT staining. i(12p) was detected in 24 of 27 PMGCTs (89%).

Conclusion

A diagnostic algorithm is of great importance for a reliable diagnosis of PMGCT in, usually small, tissue biopsy samples. Therefore, a combination of three to four antibodies to identify the correct histological subtype is usually necessary, in addition to morphological features. The i(12p) status serves as an additional option to indicate a germ cell origin in selected cases.
Intracortical surface‐based MR diffusivity to investigate neurologic and psychiatric disorders: a review
Authors: Sampedro Frederic , Kulisevsky Jaime
Published: September 2021

Diffusion tensor imaging (DTI) allows the quantification of water diffusivity within the cerebral cortex. Alterations in cortical mean diffusivity (MD) have been suggested to reflect microstructural damage. Interestingly, microstructural changes can be detected in the absence of macrostructural alterations such as cortical thinning or gray matter volume loss. However, volume‐based neuroimaging techniques for the study of cortical MD have shown some limitations in terms of intersubject registration, partial volume correction, and smoothing artifacts. In this review, we summarize how a surface‐based approach for the assessment of intracortical MD has not only overcome these technical limitations, but also provided important contributions to the fields of neurology and psychiatry. Since its proposal in 2018, the use of this neuroimaging technique has revealed cortical microstructural alterations in a wide range of clinical contexts, including Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and primary progressive aphasia. In most cases, the detection of early intracortical MD alterations preceded the identification of macrostructural changes. Importantly, microstructural damage significantly correlated with cognitive performance and biomarker measures, suggesting a potential role for its use in clinical trials as a sensitive imaging marker of neurodegeneration. Given that DTI is a widely available imaging modality, these encouraging results motivate further research using this novel neuroimaging metric in other clinical contexts. Overall, this technique has shed light into the key role of early cortical degeneration in many diseases where cortical involvement was previously thought to have limited clinical and biological significance.
Mothers' Influence on the Body Dissatisfaction and Weight Loss Behaviors of their Preschool‐ to Junior‐High‐School‐Level Daughters: The Case of Japan
Authors: Suzuki Tomohiro
Published: September 2021

This study examined young girls enrolled in preschool to junior high school in Japan to clarify their mothers' influence on their body dissatisfaction and weight loss behaviors. The survey participants comprised 790 Japanese women aged 20 to 55 years (mean age 37.5 years, SD = 6.28 years) with daughters aged 3–14 years enrolled in preschool to junior high school. Results indicated that a mother's pressure affected her daughter's body dissatisfaction and ultimately her weight loss behavior. The association was confirmed in a wide range of ages from preschoolers to junior high school students. It can be suggested that the message from their mothers over a long period may lead to girls' body dissatisfaction and consequently weight loss behavior from a young age. Intervention for body dissatisfaction is needed for mothers and children starting at a very early age stage.
Farmer Suicide in Wisconsin: A Qualitative Analysis
Authors: Kohlbeck Sara , Schramm Andrew , deRoon‐Cassini Terri , Hargarten Stephen , Quinn Katherine
Published: September 2021

Purpose

There is a need to address suicide among farmers in the United States and understand what contributes to suicide among American farmers. The purpose of this qualitative study is to analyze narrative data to uncover circumstances that were present in the lives of farmers who died by suicide.

Methods

This study leverages data available in the National Violent Death Reporting System. For this study, we examined all suicides that occurred in Wisconsin between the years 2012 and 2016 and were extracted from the Wisconsin Violent Death Reporting System. Decedents were manually sorted by the “usual occupation” variable in order to identify farmers.

Findings

During the study period, 73 farmers died, most of whom were White, non‐Hispanic males. Four themes were identified in the thematic analysis: stymied by physical health issues, grief from loss of relationships, ready access to firearms in rural Wisconsin, and the burden of farming and the farm.

Conclusions

The findings from this study demonstrate how unique contextual factors lead to suicide among farmers. This study has implications for suicide prevention among farmers. Primarily, there is a need to address the accessibility of firearms, as their availability in a time of crisis has lethal consequences. However, suicide prevention programming that addresses access to lethal means must take the sociocultural context of rural America into consideration. These findings should also be considered as applied to health care providers that serve rural communities. Suicide risk assessment and management should consider stressors unique to farmers.