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Functional identification of cis-regulatory long noncoding RNAs at controlled false discovery rates.
Get PDFA key attribute of some long noncoding RNAs (lncRNAs) is their ability to regulate expression of neighbouring genes in cis. However, such 'cis-lncRNAs' are presently defined using ad hoc criteria that, we show, are prone to false-positive predictions. The resulting lack of cis-lncRNA catalogues hinders our understanding of their extent, characteristics and mechanisms. Here, we introduce TransCistor, a framework for defining and identifying cis-lncRNAs based on enrichment of targets amongst proximal genes. TransCistor's simple and conservative statistical models are compatible with functionally defined target gene maps generated by existing and future technologies. Using transcriptome-wide perturbation experiments for 268 human and 134 mouse lncRNAs, we provide the first large-scale survey of cis-lncRNAs. Known cis-lncRNAs are correctly identified, including XIST, LINC00240 and UMLILO, and predictions are consistent across analysis methods, perturbation types and independent experiments. We detect cis-activity in a minority of lncRNAs, primarily involving activators over repressors. Cis-lncRNAs are detected by both RNA interference and antisense oligonucleotide perturbations. Mechanistically, cis-lncRNA transcripts are observed to physically associate with their target genes and are weakly enriched with enhancer elements. In summary, TransCistor establishes a quantitative foundation for cis-lncRNAs, opening a path to elucidating their molecular mechanisms and biological significance
Creating pathways to just and sustainable food systems with citizen assemblies
Get PDFFood systems affect and are affected by the interrelated crises of climate change, biodiversity loss, resource depletion and health, amongst others. Transforming to sustainable approaches is vital, yet entangled with uncertainties, complexity and a great value diversion with stakeholders. Deliberative processes such as citizen assemblies offer a valuable contribution to such a transformation, since the crises and their responses affect everyday life, and therefore inviting individual and collective action. Still, who is included and whose knowledge counts affects outcomes. Theoretically anchored in concepts of environmental justice, our study analyses three nation-wide citizens’ assemblies on climate change and food systems from Western Europe. It assesses (a) how citizens’ assemblies can incorporate a broad set of viewpoints and design more substantive political answers to current crises, and (b) whether citizens’ assemblies include environmental justice aspects to facilitate social change. The paper argues that systematic and methodologically reflected inclusion of various positionalities can inspire decision-making processes in that they incorporate procedural, recognition, and distributional justice to address problems of climate change or modern food systems. It concludes with offering further approaches to include more than scientific knowledge in deliberative processes for a just transformation towards sustainability
Guideline-directed medical therapy assessment in heart failure patients undergoing percutaneous mitral valve repair.
Get PDFAIMS
Achieving optimized guideline-directed medical therapy (GDMT) is recommended prior to transcatheter mitral valve edge-to-edge repair (M-TEER) for secondary mitral regurgitation (SMR). We aimed to propose and validate an easy-to-use score for assessing the quality of GDMT in patients with heart failure with reduced ejection fraction (HFrEF) undergoing M-TEER.
METHODS AND RESULTS
Among the 1641 EuroSMR patients enrolled in the EuroSMR Registry who underwent M-TEER, a total of 1072 patients [median age 74, interquartile range (IQR) 67-79 years, 29% female] had complete data on GDMT and a left ventricular ejection fraction ≤ 40% and were included in the current study. We proposed a GDMT score that considers the dosage levels of three medication classes (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists), with a maximum score of 12 points indicating optimal GDMT. The primary outcome was all-cause mortality. The median GDMT score was 4 points (IQR 3-6). All three domains of the scoring system were associated with all-cause mortality (P < 0.05 for all). The overall GDMT score was associated with all-cause mortality (hazard ratio 0.90, 95% confidence interval 0.86-0.95 for each 1-point increase in the GDMT score). This association remained significant after adjusting for renal function and co-morbidities.
CONCLUSIONS
This study demonstrates the utility of a simple GDMT scoring system for assessing the adequacy of GDMT in HFrEF patients with relevant SMR undergoing M-TEER. The GDMT score has potential applications in guiding the design of future clinical trials and aiding clinical decision-making processes
Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.
Get PDFBACKGROUND AND OBJECTIVES
Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression.
METHODS
CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient.
RESULTS
CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001).
DISCUSSION
CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS
"Until death do us part". A multidisciplinary study on human- Animal co- burials from the Late Iron Age necropolis of Seminario Vescovile in Verona (Northern Italy, 3rd-1st c. BCE).
Get PDFAnimal remains are a common find in prehistoric and protohistoric funerary contexts. While taphonomic and osteological data provide insights about the proximate (depositional) factors responsible for these findings, the ultimate cultural causes leading to this observed mortuary behavior are obscured by the opacity of the archaeological record and the lack of written sources. Here, we apply an interdisciplinary suite of analytical approaches (zooarchaeological, anthropological, archaeological, paleogenetic, and isotopic) to explore the funerary deposition of animal remains and the nature of joint human-animal burials at Seminario Vescovile (Verona, Northern Italy 3rd-1st c. BCE). This context, culturally attributed to the Cenomane culture, features 161 inhumations, of which only 16 included animal remains in the form of full skeletons, isolated skeletal parts, or food offerings. Of these, four are of particular interest as they contain either horses (Equus caballus) or dogs (Canis lupus familiaris)-animals that did not play a dietary role. Analyses show no demographic, dietary, funerary similarities, or genetic relatedness between individuals buried with animals. Isotopic data from two analyzed dogs suggest differing management strategies for these animals, possibly linked to economic and/or ritual factors. Overall, our results point to the unsuitability of simple, straightforward explanations for the observed funerary variability. At the same time, they connect the evidence from Seminario Vescovile with documented Transalpine cultural traditions possibly influenced by local and Roman customs
Rainforest transformation reallocates energy from green to brown food webs.
Get PDFTerrestrial animal biodiversity is increasingly being lost because of land-use change1,2. However, functional and energetic consequences aboveground and belowground and across trophic levels in megadiverse tropical ecosystems remain largely unknown. To fill this gap, we assessed changes in energy fluxes across 'green' aboveground (canopy arthropods and birds) and 'brown' belowground (soil arthropods and earthworms) animal food webs in tropical rainforests and plantations in Sumatra, Indonesia. Our results showed that most of the energy in rainforests is channelled to the belowground animal food web. Oil palm and rubber plantations had similar or, in the case of rubber agroforest, higher total animal energy fluxes compared to rainforest but the key energetic nodes were distinctly different: in rainforest more than 90% of the total animal energy flux was channelled by arthropods in soil and canopy, whereas in plantations more than 50% of the energy was allocated to annelids (earthworms). Land-use change led to a consistent decline in multitrophic energy flux aboveground, whereas belowground food webs responded with reduced energy flux to higher trophic levels, down to -90%, and with shifts from slow (fungal) to fast (bacterial) energy channels and from faeces production towards consumption of soil organic matter. This coincides with previously reported soil carbon stock depletion3. Here we show that well-documented animal biodiversity declines with tropical land-use change4-6 are associated with vast energetic and functional restructuring in food webs across aboveground and belowground ecosystem compartments
What Should “We” Do? Subjects and Scales in the Double-Bind between Energy Transition and Lithium Extraction
Get PDFIt is now broadly accepted that lithium is needed to power the energy transition and address climate change, or, simply stated, “we need lithium to save the planet.” And yet, we are faced with an ethical dilemma. While lithium technologies may allow us to slow climate change and perhaps offer opportunities for lithium-rich countries like Bolivia, extraction has socio-environmental consequences at the local level. How can we exploit the planet to save it? Rather than seeking to resolve this apparent double-bind, we propose to stay with it through an exploration of narratives around lithium and the energy transition. We begin our questioning with a focus on ethics – what should we do? We then approach the dilemma through two ethnographic vignettes, related to Bolivia's Salar de Uyuni. Our approach allows us to reflect on the scales and subjects invoked in this dilemma, and to interrogate homogenizing “we” positions implicit in pervasive narratives. The article ends with a reflection on what we – in our diversity as differently-situated but interrelated people with distinct projects – can do
Specific T-cell subsets have a role in anti-viral immunity and pathogenesis but not viral dynamics or onwards vector transmission of an important livestock arbovirus.
Get PDFINTRODUCTION
Bluetongue virus (BTV) is an arthropod-borne Orbivirus that is almost solely transmitted by Culicoides biting midges and causes a globally important haemorrhagic disease, bluetongue (BT), in susceptible ruminants. Infection with BTV is characterised by immunosuppression and substantial lymphopenia at peak viraemia in the host.
METHODS
In this study, the role of cell-mediated immunity and specific T-cell subsets in BTV pathogenesis, clinical outcome, viral dynamics, immune protection, and onwards transmission to a susceptible Culicoides vector is defined in unprecedented detail for the first time, using an in vivo arboviral infection model system that closely mirrors natural infection and transmission of BTV. Individual circulating CD4+, CD8+, or WC1+ γδ T-cell subsets in sheep were depleted through the administration of specific monoclonal antibodies.
RESULTS
The absence of cytotoxic CD8+ T cells was consistently associated with less severe clinical signs of BT, whilst the absence of CD4+ and WC1+ γδ T cells both resulted in an increased clinical severity. The absence of CD4+ T cells also impaired both a timely protective neutralising antibody response and the production of IgG antibodies targeting BTV non-structural protein, NS2, highlighting that the CD4+ T-cell subset is important for a timely protective immune response. T cells did not influence viral replication characteristics, including onset/dynamics of viraemia, shedding, or onwards transmission of BTV to Culicoides. We also highlight differences in T-cell dependency for the generation of immunoglobulin subclasses targeting BTV NS2 and the structural protein, VP7.
DISCUSSION
This study identifies a diverse repertoire of T-cell functions during BTV infection in sheep, particularly in inducing specific anti-viral immune responses and disease manifestation, and will support more effective vaccination strategies
Intimate Suspects: Politics of fieldwork and intimacy under state surveillance
No full textUncertain and intimidating encounters with state surveillance are not merely scary interruptions or, at best, annoying sideshows to anthropological research. Rather, as anthropologists we need to think through such encounters to deepen our understanding of political power relations and how they shape not only our interlocutors’ lives, but also our own positionality and practices as researchers. Using my own example as a woman researcher in the ‘disputed territory’ of Pakistan-controlled Kashmir, this chapter traces the ambivalent and intimate workings of mistrust and suspicion in the everyday relationships and interactions between the anthropologist and her ‘shadows’. It shows how they become intimate suspects, related through not only political intimacies of everyday life, but also the intimate politics of mistrust and enmity entrenched in Pakistan’s military nationalism
Interventional study to improve pertussis and influenza vaccination uptake in pregnant women.
Get PDFOBJECTIVES
Pertussis and influenza are endemic infections and associated with relevant morbidity and mortality in newborns and young infants. The Swiss Federal Office of Public Health has recommended influenza vaccination since 2011 and pertussis vaccination in pregnancy (ViP) since 2013 and expanded to repetition in each pregnancy since 2017. ViP is safe and effective in preventing severe diseases, but implementation is a challenge. We hypothesized that the proportion of women receiving ViP is persistently low despite existing national recommendations. Our primary objective was to compare the proportion of pertussis and influenza vaccine recommendations for and its acceptance by pregnant women before and after an information campaign tailored to obstetricians. Secondly, we aimed to identify reasons for missing or declining ViP.
STUDY DESIGN
We conducted a prospective, single-center, single-arm implementation study in the maternity ward at the University Women's Hospital Basel. We performed standardized interviews with women hospitalized for postpartum care before (October to December 2019, Phase 1, n = 262) and after an information campaign (October to December 2020, Phase 2, n = 233) and compared categorical variables using chi-squared or Fisher's exact test and continuous variables using Whitney Mann U test.
RESULTS
We found no significant differences in the proportion of recommendation for pertussis ViP (80 % vs. 84 %, p = 0.25) and implementation (76 % vs. 78 %, p = 0.63) between Phase 1 and 2. Main reasons for missing or declining vaccinations were lack of recommendation (62.8 %) and safety concerns regarding the unborn child (17.7 %). In contrast, the proportion of recommendation for influenza ViP (45 % vs. 63 %, p < 0.001) and implementation (29 % vs. 43 %, p < 0.001) increased significantly.
CONCLUSION
Proactive recommendations by obstetricians play a key role in the implementation of ViP but is still insufficient in our setting. We believe that future efforts should aim to explore possible hurdles that impede recommendations by obstetricians for ViP. The focus should be on the needs and experiences of obstetricians in private practice, but also other health care professionals involved in care of pregnant women. Local campaigns do not seem effective enough, therefore national campaigns with new strategies are desirable
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