Integrating Ethics into the NLP Curriculum

To raise awareness among future NLP practitioners and prevent inertia in the field, we need to place ethics in the curriculum for all NLP students—not as an elective, but as a core part of their education. Our goal in this tutorial is to empower NLP researchers and practitioners with tools and resources to teach others about how to ethically apply NLP techniques. We will present both high-level strategies for developing an ethics-oriented curriculum, based on experience and best practices, as well as specific sample exercises that can be brought to a classroom. This highly interactive work session will culminate in a shared online resource page that pools lesson plans, assignments, exercise ideas, reading suggestions, and ideas from the attendees. Though the tutorial will focus particularly on examples for university classrooms, we believe these ideas can extend to company-internal workshops or tutorials in a variety of organizations. In this setting, a key lesson is that there is no single approach to ethical NLP: each project requires thoughtful consideration about what steps can be taken to best support people affected by that project. However, we can learn (and teach) what issues to be aware of, what questions to ask, and what strategies are available to mitigate harm

Somaticization, the making and unmaking of minded persons and the fabrication of dementia

This article examines the strategies by which the different and variable signs of failing mental powers become known sufficiently for ‘dementia’ to be made into a stable bio-clinical entity, that can be tested, diagnosed and perhaps one day even treated. Drawing on data from ethnographic observations in memory clinics, together with interviews with associated scientists and clinicians, we document the challenges that clinicians face across the clinical and research domain in making dementia a stable object of their investigation. We illustrate how the pressure for early diagnoses of dementia creates tensions between the scientific representations of early dementia and its diagnosis in the clinic. Our aim is to highlight the extent to which the work of diagnosing dementia involves an intricate process of smoothing out seemingly insurmountable problems, such as the notoriously elusive connections between brain/mind and body/person. Furthermore, we show that a part of this process involves enrolling patients as minded, agentic subjects, the very subjects who are excluded from dementia science research in pursuit of biomarkers for the pre-clinical detection of dementia

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection

TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma

BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma. METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3 RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors. CONCLUSIONS: We generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma

Statistical Multiplicity in Systematic Reviews of Anaesthesia Interventions: A Quantification and Comparison between Cochrane and Non-Cochrane Reviews

BACKGROUND: Systematic reviews with meta-analyses often contain many statistical tests. This multiplicity may increase the risk of type I error. Few attempts have been made to address the problem of statistical multiplicity in systematic reviews. Before the implications are properly considered, the size of the issue deserves clarification. Because of the emphasis on bias evaluation and because of the editorial processes involved, Cochrane reviews may contain more multiplicity than their non-Cochrane counterparts. This study measured the quantity of statistical multiplicity present in a population of systematic reviews and aimed to assess whether this quantity is different in Cochrane and non-Cochrane reviews. METHODS/PRINCIPAL FINDINGS: We selected all the systematic reviews published by the Cochrane Anaesthesia Review Group containing a meta-analysis and matched them with comparable non-Cochrane reviews. We counted the number of statistical tests done in each systematic review. The median number of tests overall was 10 (interquartile range (IQR) 6 to 18). The median was 12 in Cochrane and 8 in non-Cochrane reviews (difference in medians 4 (95% confidence interval (CI) 2.0-19.0). The proportion that used an assessment of risk of bias as a reason for doing extra analyses was 42% in Cochrane and 28% in non-Cochrane reviews (difference in proportions 14% (95% CI -8 to 36). The issue of multiplicity was addressed in 6% of all the reviews. CONCLUSION/SIGNIFICANCE: Statistical multiplicity in systematic reviews requires attention. We found more multiplicity in Cochrane reviews than in non-Cochrane reviews. Many of the reasons for the increase in multiplicity may well represent improved methodological approaches and greater transparency, but multiplicity may also cause an increased risk of spurious conclusions. Few systematic reviews, whether Cochrane or non-Cochrane, address the issue of multiplicity

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement

Objective Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T4). Design Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T4). Methods Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T3), and T4 levels. Results Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64×10−10 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T4 (P=0.023, −0.07 s.d./allele, 95% CI −0.137, −0.01), no association was seen with free T3 (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (−0.068 s.d./allele, 95% CI −0.167, 0.031) and 1994 (−0.07 s.d./allele, 95% CI −0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T4. Conclusion Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on l-T4. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid

'Correction:' Serum transforming growth factor beta-1 (TGF-beta-1) levels in diabetic patients are not associated with pre-existent coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The association between TGF-β1 levels and long-term major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) is controversial. No study specifically addressed patients with CAD and diabetes mellitus (DM). The association between TGF-β1 levels and long-term major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) is controversial. No study specifically addressed patients with CAD and diabetes mellitus (DM).</p> <p>Methods</p> <p>Patients (n = 135, 30–80 years) referred for coronary angiography were submitted to clinical and laboratory evaluation, and the coronary angiograms were evaluated by two operators blinded to clinical characteristics. CAD was defined as the presence of a 70% stenosis in one major coronary artery, and DM was characterized as a fasting glycemia > 126 mg/dl or known diabetics (personal history of diabetes or previous use of anti-hyperglycemic drugs or insulin). Based on these criteria, study patients were classified into four groups: no DM and no CAD (controls, C n = 61), DM without CAD (D n = 23), CAD without DM (C-CAD n = 28), and CAD with DM (D-CAD n = 23). Baseline differences between the 4 groups were evaluated by the χ²test for trend (categorical variables) and by ANOVA (continuous variables, post-hoc Tukey). Patients were then followed-up during two years for the occurrence of MACE (cardiac death, stroke, myocardial infarction or myocardial revascularization). The association of candidate variables with the occurrence of 2-year MACE was assessed by univariate analysis.</p> <p>Results</p> <p>The mean age was 58.2 ± 0.9 years, and 51% were men. Patients with CAD had a higher mean age (p = 0.011) and a higher percentage were male (p = 0.040). There were no significant baseline differences between the 4 groups regarding hypertension, smoking status, blood pressure levels, lipid levels or inflammatory markers. TGF-β1 was similar between patients with or without CAD or DM (35.1 ×/÷ 1.3, 33.6 ×/÷ 1.6, 33.9 ×/÷ 1.4 and 31.8 ×/÷ 1.4 ng/ml in C, D, C-CAD and D-CAD, respectively, p = 0.547). In the 2-year follow-ip, independent predictors of 2-year MACE were age (p = 0.007), C-reactive protein (p = 0.048) and systolic blood pressure (p = 0.008), but not TGF-β1.</p> <p>Conclusion</p> <p>Serum TGF-β1 was not associated with CAD or MACE occurrence in patients with or without DM.</p

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263

Activation loop phosphorylaton of a non-RD receptor kinase initiates plant innate immune signaling

Receptor kinases (RKs) are fundamental for extracellular sensing and regulate development and stress responses across kingdoms. In plants, leucine-rich repeat receptor kinases (LRR-RKs) are primarily peptide receptors that regulate responses to myriad internal and external stimuli. Phosphorylation of LRR-RK cytoplasmic domains is among the earliest responses following ligand perception, and reciprocal transphosphorylation between a receptor and its coreceptor is thought to activate the receptor complex. Originally proposed based on characterization of the brassinosteroid receptor, the prevalence of complex activation via reciprocal transphosphorylation across the plant RK family has not been tested. Using the LRR-RK ELONGATION FACTOR TU RECEPTOR (EFR) as a model, we set out to understand the steps critical for activating RK complexes. While the EFR cytoplasmic domain is an active protein kinase in vitro and is phosphorylated in a ligand-dependent manner in vivo, catalytically deficient EFR variants are functional in antibacterial immunity. These results reveal a noncatalytic role for EFR in triggering immune signaling and indicate that reciprocal transphoshorylation is not a ubiquitous requirement for LRR-RK complex activation. Rather, our analysis of EFR along with a detailed survey of the literature suggests a distinction between LRR-RKs with RD- versus non-RD protein kinase domains. Based on newly identified phosphorylation sites that regulate the activation state of the EFR complex in vivo, we propose that LRR-RK complexes containing a non-RD protein kinase may be regulated by phosphorylation-dependent conformational changes of the ligand-binding receptor, which could initiate signaling either allosterically or through driving the dissociation of negative regulators of the complex

Modeling denitrification in aquatic sediments

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Biogeochemistry 93 (2009): 159-178, doi:10.1007/s10533-008-9270-z.Sediment denitrification is a major pathway of fixed nitrogen loss from aquatic systems. Due to technical difficulties in measuring this process and its spatial and temporal variability, estimates of local, regional and global denitrification have to rely on a combination of measurements and models. Here we review approaches to describing denitrification in aquatic sediments, ranging from mechanistic diagenetic models to empirical parameterizations of nitrogen fluxes across the sediment-water interface. We also present a compilation of denitrification measurements and ancillary data for different aquatic systems, ranging from freshwater to marine. Based on this data compilation we reevaluate published parameterizations of denitrification. We recommend that future models of denitrification use (1) a combination of mechanistic diagenetic models and measurements where bottom waters are temporally hypoxic or anoxic, and (2) the much simpler correlations between denitrification and sediment oxygen consumption for oxic bottom waters. For our data set, inclusion of bottom water oxygen and nitrate concentrations in a multivariate regression did not improve the statistical fit.Financial support for AEG to work on the manuscript came from NSF NSF-DEB-0423565. KF, DB and DDT acknowledge support from NOAA CHRP grant NA07NOS4780191