bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterisation of gene and pathway expression in stabilised blood from children with coeliac disease
Authors: Bragde Hanna Gustafsson , Jansson Ulf , Fredrikson Mats , Grodzinsky Ewa , Söderman Jan 
Published: December 2020

IntroductionA coeliac disease (CD) diagnosis is likely in children with levels of tissue transglutaminase autoantibodies (anti-TG2) >10 times the upper reference value, whereas children with lower anti-TG2 levels need an intestinal biopsy to confirm or rule out CD. A blood sample is easier to obtain than an intestinal biopsy sample, and stabilised blood is suitable for routine diagnostics because transcript levels are preserved at sampling. Therefore, we investigated gene expression in stabilised whole blood to explore the possibility of gene expression-based diagnostics for the diagnosis and follow-up of CD.DesignWe performed RNA sequencing of stabilised whole blood from active CD cases (n=10), non-CD cases (n=10), and treated CD cases on a gluten-free diet (n=10) to identify diagnostic CD biomarkers and pathways involved in CD pathogenesis.ResultsNo single gene was differentially expressed between the sample groups. However, by using gene set enrichment analysis (GSEA), significantly differentially expressed pathways were identified in active CD, and these pathways involved the inflammatory response, negative regulation of viral replication, translation, as well as cell proliferation, differentiation, migration, and survival. The results indicate that there are differences in pathway regulation in CD, which could be used for diagnostic purposes. Comparison between GSEA results based on stabilised blood with GSEA results based on small intestinal biopsies revealed that type I interferon response, defence response to virus, and negative regulation of viral replication were identified as pathways common to both tissues.ConclusionsStabilised whole blood is not a suitable sample for clinical diagnostics of CD based on single genes. However, diagnostics based on a pathway-focused gene expression panel may be feasible, but requires further investigation.
Zika virus infection in pregnancy: a protocol for the joint analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia
Authors: Ades A E , Brickley Elizabeth B , Alexander Neal , Brown David , Jaenisch Thomas , Miranda-Filho Demócrito de Barros , Pohl Moritz , Rosenberger Kerstin D , Soriano-Arandes Antoni , Thorne Claire , Ximenes Ricardo Arraes de Alencar , de Araújo Thalia Velho Barreto , Avelino-Silva Vivian I , Bethencourt Castillo Sarah Esperanza , Borja Aburto Victor Hugo , Brasil Patrícia , Christie Celia D C , de Souza Wayner Vieira , Gotuzzo H Jose Eduardo , Hoen Bruno , Koopmans Marion , Martelli Celina Maria Turchi , Martins Teixeira Mauro , Marques Ernesto T A , Miranda Maria Consuelo , Montarroyos Ulisses Ramos , Moreira Maria Elisabeth , Morris J Glenn , Rockx Barry , Saba Villarroel Paola Mariela , Soria Segarra Carmen , Tami Adriana , Turchi Marília Dalva , Giaquinto Carlo , de Lamballerie Xavier , Wilder-Smith Annelies 
Published: December 2020

IntroductionZika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean.Methods and analysisWe will carry out a centre-by-centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach.Ethics and disseminationEthical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities.
Double-blind RCT of fish oil supplementation in pregnancy and lactation to improve the metabolic health in children of mothers with overweight or obesity during pregnancy: study protocol
Authors: Satokar Vidit V , Cutfield Wayne S , Derraik José G B , Harwood Matire , Okasene-Gafa Karaponi , Beck Kathryn , Cameron-Smith David , O’Sullivan Justin M , Sundborn Gerhard , Pundir Shikha , Mason R Preston , Albert Benjamin B 
Published: December 2020

IntroductionMaternal obesity during pregnancy is associated with adverse changes in body composition and metabolism in the offspring. We hypothesise that supplementation during pregnancy of overweight and obese women may help prevent the development of greater adiposity and metabolic dysfunction in children. Previous clinical trials investigating fish oil supplementation in pregnancy on metabolic outcomes and body composition of the children have not focused on the pregnancies of overweight or obese women.Methods and analysisA double-blind randomised controlled trial of fish oil (providing 3 g/day of n-3 polyunsaturated fatty acids) versus an equal volume of olive oil (control) taken daily from recruitment until birth, and in breastfeeding mothers, further continued for 3 months post partum. Eligible women will have a singleton pregnancy at 12–20 weeks’ gestation and be aged 18–40 years with body mass index ≥25 kg/m2at baseline. We aim to recruit a minimum of 128 participants to be randomised 1:1. Clinical assessments will be performed at baseline and 30 weeks of pregnancy, including anthropometric measurements, fasting metabolic markers, measures of anxiety, physical activity, quality of life and dietary intake. Subsequent assessments will be performed when the infant is 2 weeks, 3 months and 12 months of age for anthropometry, body composition (dual-energy X-ray absorptiometry (DXA)) and blood sampling. The primary outcome of the study is a between-group difference in infant percentage body fatness, assessed by DXA, at 2 weeks of age. Secondary outcomes will include differences in anthropometric measures at each time point, percentage body fat at 3 and 12 months and homeostatic model assessment of insulin resistance at 3 months. Statistical analysis will be carried out on the principle of intention to treat.Ethics and disseminationThis trial was approved by the Northern A Health and Disabilities Ethics Committee, New Zealand Ministry of Health (17/NTA/154). Results will be published in a peer-reviewed journal.Trial registration numberACTRN12617001078347p; Pre-results.
Modelling the impact of presemester testing on COVID-19 outbreaks in university campuses
Authors: Rennert Lior , Kalbaugh Corey Andrew , Shi Lu , McMahan Christopher 
Published: December 2020

ObjectivesUniversities are exploring strategies to mitigate the spread of COVID-19 prior to reopening their campuses. National guidelines do not currently recommend testing students prior to campus arrival. However, the impact of presemester testing has not been studied.DesignDynamic SARS-CoV-2 transmission models are used to explore the effects of three presemester testing interventions.InterventionsTesting of students 0, 1 and 2 times prior to campus arrival.Primary outcomesNumber of active infections and time until isolation bed capacity is reached.SettingWe set on-campus and off-campus populations to 7500 and 17 500 students, respectively. We assumed 2% prevalence of active cases at the semester start, and that one-third of infected students will be detected and isolated throughout the semester. Isolation bed capacity was set at 500. We varied disease transmission rates (R0=1.5, 2, 3, 4) to represent the effectiveness of mitigation strategies throughout the semester.ResultsWithout presemester screening, peak number of active infections ranged from 4114 under effective mitigation strategies (R0=1.5) to 10 481 under ineffective mitigation strategies (R0=4), and exhausted isolation bed capacity within 10 (R0=4) to 25 days (R0=1.5). Mandating at least one test prior to campus arrival delayed the timing and reduced the size of the peak, while delaying the time until isolation bed capacity was reached. Testing twice in conjunction with effective mitigation strategies (R0=1.5) was the only scenario that did not exhaust isolation bed capacity during the semester.ConclusionsPresemester screening is necessary to avert early and large surges of active COVID-19 infections. Therefore, we recommend testing within 1 week prior to and on campus return. While this strategy is sufficient for delaying the timing of the peak outbreak, presemester testing would need to be implemented in conjunction with effective mitigation strategies to significantly reduce outbreak size and preserve isolation bed capacity.
COVID-19 mortality effects of underlying health conditions in India: a modelling study
Authors: Novosad Paul , Jain Radhika , Campion Alison , Asher Sam 
Published: December 2020

ObjectiveTo model how known COVID-19 comorbidities affect mortality rates and the age distribution of mortality in a large lower-middle-income country (India), and to identify which health conditions drive differences with high-income countries.DesignModelling study.SettingEngland and India.ParticipantsIndividual data were obtained from the fourth round of the District Level Household Survey and Annual Health Survey in India, and aggregate data were obtained from the Health Survey for England and the Global Burden of Disease, Risk Factors and Injuries Studies.Main outcome measuresThe primary outcome was the modelled age-specific mortality in each country due to each COVID-19 mortality risk factor (diabetes, hypertension, obesity and respiratory illness, among others). The change in overall mortality and in the share of deaths under age 60 from the combination of risk factors was estimated in each country.ResultsRelative to England, Indians have higher rates of diabetes (10.6% vs 8.5%) and chronic respiratory disease (4.8% vs 2.5%), and lower rates of obesity (4.4% vs 27.9%), chronic heart disease (4.4% vs 5.9%) and cancer (0.3% vs 2.8%). Population COVID-19 mortality in India, relative to England, is most increased by uncontrolled diabetes (+5.67%) and chronic respiratory disease (+1.88%), and most reduced by obesity (−5.47%), cancer (−3.65%) and chronic heart disease (−1.20%). Comorbidities were associated with a 6.26% lower risk of mortality in India compared with England. Demographics and population health explain a third of the difference in share of deaths under age 60 between the two countries.ConclusionsKnown COVID-19 health risk factors are not expected to have a large effect on mortality or its age distribution in India relative to England. The high share of COVID-19 deaths from people under age 60 in low- and middle-income countries (LMICs) remains unexplained. Understanding the mortality risk associated with health conditions prevalent in LMICs, such as malnutrition and HIV/AIDS, is essential for understanding differential mortality.
Non-invasive testing for liver pathology in alpha-1 antitrypsin deficiency
Authors: Abbas Syed Hamza , Pickett Elisha , Lomas David A , Thorburn Douglas , Gooptu Bibek , Hurst John R , Marshall Aileen 
Published: December 2020

BackgroundMany patients with alpha-1 antitrypsin deficiency (A1ATD) receive care in respiratory clinics without access to specialist hepatology expertise. Liver disease can develop asymptomatically, and non-invasive markers of fibrosis may help identify patients who require definitive assessment with liver biopsy. We evaluated the utility of non-invasive markers of liver fibrosis in A1ATD to guide testing in settings without ready access to hepatology expertise.MethodsPatients attending the London A1ATD service undergo assessment using blood tests to calculate the ‘APRI’ and ‘FIB-4’ score, liver ultrasound and Fibroscan. Liver biopsy is offered to patients who have abnormal liver function tests with abnormal liver ultrasound and/or liver stiffness >6 kPa on Fibroscan. Liver biopsies were assessed for the presence of A1AT, steatosis, fibrosis and inflammation.Results75 patients with A1ATD had results for analysis, 56% were female, age 16–82 years. 75% of patients had Fibroscan <6 kPa, 19% had Fibroscan 6–7.9 kPa and 6%>8 kPa. There was a significant correlation between FIB-4 and Fibroscan (r=0.244, p=0.035). Fibroscan >6 kPa corresponded to a FIB-4 score of >1.26. However, FIB-4 >1.26 had poor sensitivity (47%), specificity (32%) and positive-predictive value (PPV; 36%) to identify Fibroscan >6 kPa. The negative-predictive value (NPV) was stronger at 81%. APRI data were similar. Twelve patients underwent liver biopsy, with 11 reports available for analysis. Six had FIB-4 scores<1.26 and five had Fibroscan of <6 kPa. A1AT was present in 64% of biopsies, steatosis in 82%, mild fibrosis in 36%, moderate fibrosis in 9% and severe fibrosis in 9%.ConclusionA combination of liver ultrasound and non-invasive fibrosis tests can help identify patients with A1ATD liver injury. However, APRI and FIB-4 scores alone had poor sensitivity and specificity to justify use as an independent tool for liver pathology in A1ATD.
Detection prospects for the second-order weak decays of $$^{124}$$Xe in multi-tonne xenon time projection chambers
Authors: Wittweg Christian , Lenardo Brian , Fieguth Alexander , Weinheimer Christian 
Published: December 2020

AbstractWe investigate the detection prospects for two-neutrino and neutrinoless second-order weak decays of $$^{124}{\mathrm{Xe}}$$

124

Xe

– double-electron capture ($$0/2\upnu \text {ECEC}$$

0
/
2
ν
ECEC

), electron capture with positron emission ($$0/2\upnu \text {EC}\upbeta ^+$$

0
/
2
ν
EC

β
+

) and double-positron emission ($$0/2\upnu \upbeta ^+\upbeta ^+$$

0
/
2
ν

β
+

β
+

) – in multi-tonne xenon time projection chambers. We simulate the decays in a liquid xenon medium and develop a reconstruction algorithm which uses the multi-particle coincidence in these decays to separate signal from background. This is used to compute the expected detection efficiencies as a function of position resolution and energy threshold for planned experiments. In addition, we consider an exhaustive list of possible background sources and find that they are either negligible in rate or can be greatly reduced using our topological reconstruction criteria. In particular, we draw two conclusions: First, with a theoretical half-life of $$T_{1/2}^{2\upnu \text {EC}\upbeta ^+} = (1.7 \pm 0.6)\cdot 10^{23}\,\text {year}$$

T

1
/
2

2
ν
EC

β
+

=

(
1.7
±
0.6
)

·

10
23

year

, the $$2\upnu \text {EC}\upbeta ^{+}$$

2
ν
EC

β
+

decay of $$^{124}$$

124

Xe will likely be detected in upcoming Dark Matter experiments (e.g. XENONnT or LZ), and their major background will be $$\upgamma $$
γ
-rays from detector construction materials. Second, searches for the $$0\upnu \text {EC}\upbeta ^+$$

0
ν
EC

β
+

decay mode will likely be background-free, and new parameter space may be within reach. To this end we investigate two different scenarios of existing experimental constraints on the effective neutrino mass. The necessary 500 kg-year exposure of $$^{124}$$

124

Xe could be achieved by the baseline design of the DARWIN observatory, or by extracting and using the $$^{124}$$

124

Xe from the tailings of the nEXO experiment. We demonstrate how a combination of $$^{124}$$

124

Xe results with those from $$0\upnu \upbeta ^-\upbeta ^-$$

0
ν

β
-

β
-

searches in $$^{136}$$

136

Xe could help to identify the neutrinoless decay mechanism.
Nicotinic receptor modulation of primary afferent excitability with selective regulation of Aδ-mediated spinal actions
Authors: Shreckengost Jacob , Halder Mallika , Mena-Avila Elvia , Garcia-Ramirez David Leonardo , Quevedo Jorge , Hochman Shawn 
Published: December 2020

Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABAA receptors on afferent terminals. We investigated whether ionotropic nicotinic acetylcholine receptors (nAChRs) also provide modulatory actions, focusing on myelinated afferent excitability in in vitro murine spinal cord nerve-attached models. Primary afferent stimulation-evoked synaptic transmission was recorded in the deep dorsal horn as extracellular field potentials (EFPs), whereas concurrently recorded dorsal root potentials (DRPs) were used as an indirect measure of PAD. Changes in afferent membrane excitability were simultaneously measured as direct current (DC)-shifts in membrane polarization recorded in dorsal roots or peripheral nerves. The broad nAChR antagonist d-tubocurarine (d-TC) selectively and strongly depressed Aδ-evoked synaptic EFPs (36% of control) coincident with similarly depressed A-fiber DRP (43% of control), whereas afferent electrical excitability remained unchanged. In comparison, acetylcholine (ACh) and the nAChR agonists, epibatidine and nicotine, reduced afferent excitability by generating coincident depolarizing DC-shifts in peripheral axons and intraspinally. Progressive depolarization corresponded temporally with the emergence of spontaneous axonal spiking and reductions in the DRP and all afferent-evoked synaptic actions (31%–37% of control). Loss of evoked response was long-lasting, independent of DC repolarization, and likely due to mechanisms initiated by spontaneous C-fiber activity. DC-shifts were blocked with d-TC but not GABAA receptor blockers and retained after tetrodotoxin block of voltage-gated Na+ channels. Notably, actions tested were comparable between three mouse strains, in rat, and when performed in different labs. Thus, nAChRs can regulate afferent excitability via two distinct mechanisms: by central Aδ-afferent actions, and by transient extrasynaptic axonal activation of high-threshold primary afferents. NEW & NOTEWORTHY Primary afferents express many nicotinic ACh receptor (nAChR) subtypes but whether activation is linked to presynaptic inhibition, facilitation, or more complex and selective activity modulation is unknown. Recordings of afferent-evoked responses in the lumbar spinal cord identified two nAChR-mediated modulatory actions: 1) selective control of Aδ afferent transmission and 2) robust changes in axonal excitability initiated via extrasynaptic shifts in DC polarization. This work broadens the diversity of presynaptic modulation of primary afferents by nAChRs.
A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression
Authors: Dong Dezuo , Zhang Weimin , Xiao Wenchang , Wu Qingnan , Cao Yiren , Gao Xiaohan , Huang Lijie , Wang Yan , Chen Jie , Wang Weihu , Zhan Qimin 
Published: December 2020

AbstractEsophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B (FAM135B) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer clinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo, likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAM135B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC.Significance:These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC.
MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells
Authors: Hagiwara Masayuki , Yasumizu Yota , Yamashita Nami , Rajabi Hasan , Fushimi Atsushi , Long Mark D. , Li Wei , Bhattacharya Atrayee , Ahmad Rehan , Oya Mototsugu , Liu Song , Kufe Donald 
Published: December 2020

Abstract

The Brg/Brahma-associated factor (BAF, mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. The oncogenic MUC1-C protein promotes lineage plasticity in the progression of neuroendocrine prostate cancer (NEPC), however, there is no known association between MUC1-C and BAF. We report here that MUC1-C binds directly to the E2F1 transcription factor and that the MUC1-C→E2F1 pathway induces expression of embryonic stem cell–specific BAF (esBAF) components BRG1, ARID1A, BAF60a, BAF155, and BAF170 in castrate-resistant prostate cancer (CRPC) and NEPC cells. In concert with this previously unrecognized pathway, MUC1 was associated with increased expression of E2F1 and esBAF components in NEPC tumors as compared with CRPC, supporting involvement of MUC1-C in activating the E2F1→esBAF pathway with progression to NEPC. MUC1-C formed a nuclear complex with BAF and activated cancer stem cell (CSC) gene signatures and the core pluripotency factor gene network. The MUC1-C→E2F1→BAF pathway was necessary for induction of both the NOTCH1 effector of CSC function and the NANOG pluripotency factor, and collectively, this network drove CSC self-renewal. These findings indicate that MUC1-C promotes NEPC progression by integrating activation of E2F1 and esBAF with induction of NOTCH1, NANOG, and stemness.

Significance:
These findings show that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.