Urban Education, Ahead of Print. Belonging matters in early childhood. Despite its importance, the majoritarian conceptualization of belonging is seldom problematized. In the US, the politics of belonging draws racialized lines of inclusion and exclusion, (re)inscribing longstanding racialized systems of inequity and injustice. Through critical race and Latina feminist perspectives and methodologies, an immigrant mother and son of Color examined their lived experiences. Finding unveil the urgency of upending formal racialized notions of belonging—for example, citizenship, co naturalized with whiteness. Attending to the palpable consequences of ideological and relational borders that exclude and subjugate immigrants of Color, implications call for abolishing belonging as property and cultivating collective healing.
Owing to clinical success of immune checkpoint blockade, immunotherapy is becoming a cornerstone of modern oncology, and immuno oncology is at the forefront of basic cancer research. This commentary outlines future opportunities for immuno oncology modeling.
As the technical and political challenges of land based carbon dioxide removal (CDR) approaches become more apparent, the oceans may be the new “blue” frontier for carbon drawdown strategies in climate governance. Drawing on lessons learnt from the way terrestrial carbon dioxide removal emerged, we explore increasing overall attention to marine environments and mCDR projects, and how this could manifest in four entwined knowledge systems and governance sectors. We consider how developments within and between these “frontiers” could result in different futures—where hype and over promising around marine carbon drawdown could enable continued time buying for the carbon economy without providing significant removals, or where reforms to modeling practices, policy development, innovation funding, and legal governance could seek co benefits between ocean protection, economy, and climate.
Human Langerhans cells are refractory to HIV‐1 infection due to the expression of the alarmin S100A9 that inhibits reverse transcriptase activity. Dendritic cells (DC) subsets, like Langerhans cells (LC), are immune cells involved in pathogen sensing. They express specific antimicrobial cellular factors that are able to restrict infection and limit further pathogen transmission. Here, we identify the alarmin S100A9 as a novel intracellular antiretroviral factor expressed in human monocyte‐derived and skin‐derived LC. The intracellular expression of S100A9 is decreased upon LC maturation and inversely correlates with enhanced susceptibility to HIV‐1 infection of LC. Furthermore, silencing of S100A9 in primary human LC relieves HIV‐1 restriction while ectopic expression of S100A9 in various cell lines promotes intrinsic resistance to both HIV‐1 and MLV infection by acting on reverse transcription. Mechanistically, the intracellular expression of S100A9 alters viral capsid uncoating and reverse transcription. S100A9 also shows potent inhibitory effect against HIV‐1 and MMLV reverse transcriptase (RTase) activity in vitro in a divalent cation‐dependent manner. Our findings uncover an unexpected intracellular function of the human alarmin S100A9 in regulating antiretroviral immunity in Langerhans cells.
Benign prostatic obstruction (BPO) is associated with sexual dysfunction. Furthermore, numerous BPO interventions may themselves impact sexual function. To perform a systematic review with network meta-analysis to evaluate how BPO interventions affect erectile function. Three databases were searched for randomised controlled trials (RCTs) comparing surgical interventions for BPO. The primary outcome was postoperative International Index of Erectile Function-5 (IIEF-5) score at ten time points up to 72 mo. A random-effects Bayesian network meta-analysis with meta-regression was performed. In comparison to monopolar transurethral resection (mTURP), the mean difference (MD) with 95% credible interval (CrI) and rank probability (rank p) were calculated for interventions. The mean baseline score was studied in meta-regression. τ2 values were used to quantify heterogeneity. A total of 48 papers (33 RCTs, 5159 patients, 16 interventions) were included. Prostatic urethral lift (PUL) ranked highest at 1 mo (MD 3.88, 95% CrI -0.47 to 8.25; rank p = 0.742), 6 mo (MD 2.43, 95% CrI -0.72 to 5.62; rank p = 0.581), 12 mo (MD 2.94, 95% CrI -0.26 to 6.12, rank p = 0.782), and 24 mo (MD 3.63, 95% CrI 0.14 to 7.11; rank p = 0.948), at which point statistical significance was reached. At time points up to 60 mo, there were no statistically significant comparisons for other interventions. Analyses were not possible at 18, 48, or 72 mo. β did not reach statistical significance in meta-regression. τ2 was highest at 1 mo (0.56) and 60 mo (0.55). PUL ranked highly and resulted in erectile function improvement at 24 mo compared to mTURP, but direct evidence is lacking. We did not observe significant differences in erectile function following other interventions up to 60 mo. Owing to heterogeneity, our conclusions are weakest at 1 and 60 mo. Further RCTs comparing sexual function outcomes are recommended, such as PUL versus holmium laser or bipolar enucleation. Different surgical treatments can be used to treat benign enlargement of the prostate causing urinary problems. We compared the effects of various treatments on erectile function at time points up to 5 years after surgery. Compared to surgical removal of some of the prostate gland (transurethral resection of the prostate, TURP), a technique called prostatic urethral lift resulted in better erectile function scores at 24 months. However, other treatments did not differ in their effect on erectile function.
Hundreds of messenger RNAs (mRNAs) are transported into neurites to provide templates for the assembly of local protein networks. These networks enable a neuron to configure different cellular domains for specialized functions. According to current evidence, mRNAs are mostly transported in rather small packages of one to three copies, rarely containing different transcripts. This opens up fascinating logistic problems: how are hundreds of different mRNA cargoes sorted into distinct packages and how are they coupled to and released from motor proteins to produce the observed mRNA distributions? Are all mRNAs transported by the same transport machinery, or are there different adaptors or motors for different transcripts or classes of mRNAs? A variety of often indirect evidence exists for the involvement of proteins in mRNA localization, but relatively little is known about the essential activities required for the actual transport process. Here, we summarize the different types of available evidence for interactions that connect mammalian mRNAs to motor proteins to highlight at which point further research is needed to uncover critical missing links. We further argue that a combination of discovery approaches reporting direct interactions, in vitro reconstitution, and fast perturbations in cells is an ideal future strategy to unravel essential interactions and specific functions of proteins in mRNA transport processes.
Working memory function is severely limited. One key limitation that constrains the ability to maintain multiple items in working memory simultaneously is so-called swap errors. These errors occur when an inaccurate response is in fact accurate relative to a non-target stimulus, reflecting the failure to maintain the appropriate association or "binding" between the features that define one object (e.g., color and location). The mechanisms underlying feature binding in working memory remain unknown. Here, we tested the hypothesis that features are bound in memory through synchrony across feature-specific neural assemblies. We built a biophysical neural network model composed of two one-dimensional attractor networks - one for color and one for location - simulating feature storage in different cortical areas. Within each area, gamma oscillations were induced during bump attractor activity through the interplay of fast recurrent excitation and slower feedback inhibition. As a result, different memorized items were held at different phases of the networks oscillation. These two areas were then reciprocally connected via weak cortico-cortical excitation, accomplishing binding between color and location through the synchronization of pairs of bumps across the two areas. Encoding and decoding of color-location associations was accomplished through rate coding, overcoming a long-standing limitation of binding through synchrony. In some simulations, swap errors arose: "color bumps" abruptly changed their phase relationship with "location bumps". This model, which leverages the explanatory power of similar attractor models, specifies a plausible mechanism for feature binding and makes specific predictions about swap errors that are testable at behavioral and neurophysiological levels.
The organs and metabolic pathways involved in energy metabolism, and the process of ATP production from nutrients, are comparable between humans and Drosophila melanogaster. This level of conservation, together with the power of Drosophila genetics, makes the fly a very useful model system to study energy homeostasis. Here, we discuss the major organs involved in energy metabolism in Drosophila and how they metabolize different dietary nutrients to generate adenosine triphosphate. Energy metabolism in these organs is controlled by cell intrinsic, paracrine, and endocrine signals that are similar between Drosophila and mammals. We describe how these signaling pathways are regulated by several physiological and environmental cues to accommodate tissue , age , and environment specific differences in energy demand. Last, we discuss several genetic and diet induced fly models of obesity and diabetes that can be leveraged to better understand the molecular basis of these metabolic diseases and thereby promote the development of novel therapies.
Journal of Pharmacy Practice, Ahead of Print. Background :Dexmedetomidine is a highly selective α2 adrenoreceptor agonist that produces dose dependent sedation, anxiolysis, and analgesia without respiratory depression. Due to these ideal sedative properties, there has been increased interest in utilizing dexmedetomidine as a first line sedative for critically ill patients requiring light sedation.Objective :To evaluate the ability to achieve goal intensive care unit (ICU) sedation before and after an institutional change of dosing from actual (ABW) to adjusted (AdjBW) body weight in obese patients on dexmedetomidine.Method :This study included patients ≥ 18 years old, admitted to a surgical or medical ICU, required dexmedetomidine for at least 8 hours as a single continuous infusion sedative, and weighed ≥ 120% of ideal body weight. Percentage of RASS measurements within goal range (−1 to +1) during the first 48 hours after initiation of dexmedetomidine as the sole sedative agent or until discontinuation dosed on ABW compared to AdjBW was evaluated.Result :100 patients were included in the ABW cohort and 100 in the AdjBW cohort. The median dosing weight was significantly higher in the ABW group (95.9 vs 82.2 kg; p = 0.001). There was no statistical difference in percent of RASS measurements in goal range (61.5% vs 69.6%, p = 0.267) in patients that received dexmedetomidine dosed based on ABW versus AdjBW.Conclusion :Dosing dexmedetomidine using AdjBW in obese critically ill patients for ongoing ICU sedation resulted in no statistical difference in the percent of RASS measurements within goal when compared to ABW dosing. Further studies are warranted.
Therapeutic Advances in Infectious Disease, Volume 8, Issue , January December 2021. Background :Immunization is an important strategy for controlling the COVID 19 pandemic. COVID 19 vaccination was recently launched in Uganda, with prioritization to healthcare workers and high risk individuals. In this study, we aimed to determine the acceptability of COVID 19 vaccine among persons at high risk of COVID 19 morbidity and mortality in Uganda.Method :Between 29 March and 14 April 2021, we conducted a cross sectional survey consecutively recruiting persons at high risk of severe COVID 19 (diabetes mellitus, HIV and cardiovascular disease) attending Kiruddu National Referral Hospital outpatient clinics. A trained research nurse administered a semi structured questionnaire assessing demographics, COVID 19 vaccine related attitudes and acceptability. Descriptive statistics, bivariate and multivariable analyses were performed using STATA 16.Result :A total of 317 participants with a mean age 51.5 ± 14.1 years were recruited. Of this, 184 (60.5%) were female. Overall, 216 (70.1%) participants were willing to accept the COVID 19 vaccine. The odds of willingness to accept COVID 19 vaccination were four times greater if a participant was male compared with if a participant was female . Participants who agreed (AOR: 0.04, 95% CI: 0.01–0.38, p = 0.003) or strongly agreed (AOR: 0.04, 95% CI: 0.01–0.59, p = 0.005) that they have some immunity against COVID 19 were also significantly less likely to accept the vaccine. Participants who had a history of vaccination hesitancy for their children were also significantly less likely to accept the COVID 19 vaccine (AOR: 0.1, 95% CI: 0.01–0.58, p = 0.016).Conclusion :The willingness to receive a COVID 19 vaccine in this group of high risk individuals was comparable to the global COVID 19 vaccine acceptance rate. Increased sensitization, myth busting and utilization of opinion leaders to encourage vaccine acceptability is recommended.
Aims and Objective The aims of the review are to synthesise current evidence about advanced nurse practitioner clinical autonomy and consider how this may inform clinical practice and research. Background Clinical autonomy is one of the cornerstones of advanced nursing practice globally, yet there is limited synthesis of clinical autonomy in the literature. Design This is a narrative literature review. Data sources The databases Cumulative Index to Nursing and Allied Health Literature, EBSCO host, Cochrane Library, CINAHL and MEDLINE were searched for publications between 2005 and 2020 inclusive. Review methods A systematic approach was used to analyse the literature reviewed. Two reviewers undertook quality appraisal. Result Nineteen articles were selected. Four major themes emerged: (1) ‘ANP Stepping Up’—moving into and accepting advanced nursing practice roles and clinical responsibilities; (2) ‘ANP Living It’—ANPs" ability to act independently including an understanding of task mastery and self‐determination; (3) ‘ANP Bounce‐back ability’—depicted in challenges that threaten their ability to practice clinically autonomously; (4) ‘ANP Setting in Motion’—indirect care activities and service‐level improvements. Conclusion A clearer understanding of advanced nurse practitioner clinical autonomy could help develop more in‐depth knowledge. Research of advanced nurse practitioners" clinical autonomy would improve full utilisation in clinical practice.
Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood-brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.
Big Data & Society, Volume 8, Issue 1, January Jun 2021. Social media platforms’ digital advertising revenues depend considerably on partnerships. Business partnerships are endemic and essential to the business of platforms, yet their role remains relatively underexplored in the literature on platformisation and platform power. This article considers the significance of partnerships in the social media ecosystem to better understand how industry platforms, and the infrastructure they build, mediate and shape platform power and governance. We argue that partners contribute to ‘platformisation’ through their collective development of business to business platform infrastructures. Specifically, we examine how partners have integrated social media platforms with what we call the audience economy – an exceptionally complex global and interconnected marketplace of intermediaries involved in the creation, commodification, analysis, and circulation of data audiences for purposes including but not limited to digital advertising and marketing. We determined which relationships are involved, which are exclusive or shared, and identified key ecosystem partners. Further, we found that partners build and integrate extensive infrastructures for data sourcing and media distribution, surfacing infrastructural and strategic sources and locations, or ‘nodes’, of power in this ecosystem. The empirical findings thus highlight the significance of partnerships and partner integrations and draw attention to the powerful industry players and intermediaries that remain largely invisible.
Theoretical accounts suggest that memories play a role in empathy, but direct evidence of reactivation of autobiographical memories (AM) in empathy is yet to be shown. We addressed this question in one EEG and one fMRI experiment. Participants self‐reported higher empathy for people depicted in situations they had experienced themselves as compared to situations they had not experienced. An EEG pattern classifier showed evidence for AM reactivation when participants were preparing their judgement in the empathy task. Increased activation was observed for AM compared to non‐AM in the brain networks underlying empathy. Together, our study reports behavioural, electrophysiological, and fMRI evidence that robustly supports AM reactivation in empathy. Empathy relies on the ability to mirror and to explicitly infer others" inner states. Theoretical accounts suggest that memories play a role in empathy, but direct evidence of reactivation of autobiographical memories (AM) in empathy is yet to be shown. We addressed this question in two experiments. In Experiment 1, electrophysiological activity (EEG) was recorded from 28 participants. Participants performed an empathy task in which targets for empathy were depicted in contexts for which participants either did or did not have an AM, followed by a task that explicitly required memory retrieval of the AM and non‐AM contexts. The retrieval task was implemented to extract the neural fingerprints of AM and non‐AM contexts, which were then used to probe data from the empathy task. An EEG pattern classifier was trained and tested across tasks and showed evidence for AM reactivation when participants were preparing their judgement in the empathy task. Participants self‐reported higher empathy for people depicted in situations they had experienced themselves as compared to situations they had not experienced. A second independent fMRI experiment replicated this behavioural finding and showed increased activation for AM compared to non‐AM in the brain networks underlying empathy: precuneus, posterior parietal cortex, superior and inferior parietal lobule, and superior frontal gyrus. Together, our study reports behavioural, electrophysiological, and fMRI evidence that robustly supports AM reactivation in empathy.
We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10−8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein–protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
Network similarity measures quantify how and when two networks are symmetrically related, including measures of statistical association such as pairwise distance or other correlation measures between networks or between the layers of a multiplex network, but neither can directly unveil whether there are hidden confounding network factors nor can they estimate when such correlation is underpinned by a causal relation. In this work we extend this pairwise conceptual framework to triplets of networks and quantify how and when a network is related to a second network (of the same number of nodes) directly or via the indirect mediation or interaction with a third network. Accordingly, we develop a simple and intuitive set-theoretic approach to quantify mediation and suppression between networks. We validate our theory with synthetic models and further apply it to triplets (multiplex) of real-world networks, unveiling mediation and suppression effects which emerge when considering different modes of interaction in online social networks and different routes of information processing in the nervous system.