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Cognitive science-based enactive theories of perception afford surprising insight onto a less examined component of perceptual experience: perceptual entrainment through the embodied encounter with tools. My analysis of the body/tool/perception nexus in Neal Stephenson's Snow Crash (1992) introduces the concept of perceptual entrainment in two steps: first I explain Alva Noë's claim that perception is virtual—that it takes place as an active process of environmental investigation rather than through computer-processing-like brain activity. I then take Noë's approach to perception a step further by examining how tool use directs and amplifies our perceptual focus. I argue that in Snow Crash, tools contain within them ideologies of repression that emerge precisely at the “technological interface,” moments when characters in the novel engage with tools that interpellate them, enable them to wield power, or blur the boundaries between control and abjection. This article analyzes the novel's computational anxiety—the fear of loss of self identity via an informational/mathematical determinism mapped by the tool that entrains our perception.

Binary diagnosis of coronary artery disease does not preserve the complexity of disease or quantify its severity or its associated risk with death; hence, a quantitative marker of coronary artery disease is warranted. We evaluated a quantitative marker of coronary artery disease derived from probabilities of a machine learning model. In this cohort study, we developed and validated a coronary artery disease-predictive machine learning model using 95 935 electronic health records and assessed its probabilities as in-silico scores for coronary artery disease (ISCAD; range 0 [lowest probability] to 1 [highest probability]) in participants in two longitudinal biobank cohorts. We measured the association of ISCAD with clinical outcomes—namely, coronary artery stenosis, obstructive coronary artery disease, multivessel coronary artery disease, all-cause death, and coronary artery disease sequelae. Among 95 935 participants, 35 749 were from the BioMe Biobank (median age 61 years [IQR 18]; 14 599 [41%] were male and 21 150 [59%] were female; 5130 [14%] were with diagnosed coronary artery disease) and 60 186 were from the UK Biobank (median age 62 [15] years; 25 031 [42%] male and 35 155 [58%] female; 8128 [14%] with diagnosed coronary artery disease). The model predicted coronary artery disease with an area under the receiver operating characteristic curve of 0·95 (95% CI 0·94–0·95; sensitivity of 0·94 [0·94–0·95] and specificity of 0·82 [0·81–0·83]) and 0·93 (0·92–0·93; sensitivity of 0·90 [0·89–0·90] and specificity of 0·88 [0·87–0·88]) in the BioMe validation and holdout sets, respectively, and 0·91 (0·91–0·91; sensitivity of 0·84 [0·83–0·84] and specificity of 0·83 [0·82–0·83]) in the UK Biobank external test set. ISCAD captured coronary artery disease risk from known risk factors, pooled cohort equations, and polygenic risk scores. Coronary artery stenosis increased quantitatively with ascending ISCAD quartiles (increase per quartile of 12 percentage points), including risk of obstructive coronary artery disease, multivessel coronary artery disease, and stenosis of major coronary arteries. Hazard ratios (HRs) and prevalence of all-cause death increased stepwise over ISCAD deciles (decile 1: HR 1·0 [95% CI 1·0–1·0], 0·2% prevalence; decile 6: 11 [3·9–31], 3·1% prevalence; and decile 10: 56 [20–158], 11% prevalence). A similar trend was observed for recurrent myocardial infarction. 12 (46%) undiagnosed individuals with high ISCAD (≥0·9) had clinical evidence of coronary artery disease according to the 2014 American College of Cardiology/American Heart Association Task Force guidelines. Electronic health record-based machine learning was used to generate an in-silico marker for coronary artery disease that can non-invasively quantify atherosclerosis and risk of death on a continuous spectrum, and identify underdiagnosed individuals. National Institutes of Health.

Crohn’s disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn’s disease 1 , 2 , and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment 3 . The risk alleles with the highest effect on Crohn’s disease are loss-of-function mutations in NOD2 4 , 5 , which increase the risk of stricturing 6 . However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14 + peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2- deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid–stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn’s disease, and suggest that gp130 blockade may benefit some patients with Crohn’s disease—potentially as a complement to anti-TNF therapy. NOD2 deficiency drives fibrosis and stricturing complications in Crohn’s disease through dysregulated homeostasis of activated fibroblasts and macrophages, which is ameliorated by gp130 blockade in human cell and zebrafish models.

Tony Blair, prime minister, is set to put an optimistic gloss on the expected agreement by the Nato summit starting today to instruct Iraqi security staff, in spite of France and Germany's reluctance to send their troops into the country as trainers. Mr Blair's official spokesman yesterday played down claims that Britain was angered because the French had vetoed plans to rebadge some of the coalition troops in Iraq under the Nato umbrella. Mr Blair admits in today's FT article that \"the challenges posed by post-Taliban Afghanistan have not been easy for Nato\" and stresses it should be the organisation's top priority. Additional reporting by Judy Dempsey and Joshua Chaffin in Istanbul Tony Blair on Nato's role, Page 17

Dysfunction of microglia is known to play an important role in Alzheimer’s disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aβ in vitro. We characterized the transcriptional profiles of adultmicroglia from APP/PS1mice and identified a role for RIPK1 in regulating the microglial expression of CH25H and Cst7, a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD.

Systemic autoimmune rheumatic diseases (SARDs) can lead to irreversible damage if left untreated, yet these patients often endure long diagnostic journeys before being diagnosed and treated. Machine learning may help overcome the challenges of diagnosing SARDs and inform clinical decision-making. Here, we developed and tested a machine learning model to identify patients who should receive rheumatological evaluation for SARDs using longitudinal electronic health records of 161,584 individuals from two institutions. The model demonstrated high performance for predicting cases of autoantibody-tested individuals in a validation set, an external test set, and an independent cohort with a broader case definition. This approach identified more individuals for autoantibody testing compared with current clinical standards and a greater proportion of autoantibody carriers among those tested. Diagnoses of SARDs and other autoimmune conditions increased with higher model probabilities. The model detected a need for autoantibody testing and rheumatology encounters up to five years before the test date and assessment date, respectively. Altogether, these findings illustrate that the clinical manifestations of a diverse array of autoimmune conditions are detectable in electronic health records using machine learning, which may help systematize and accelerate autoimmune testing. Early diagnosis can significantly improve treatment options and prevent severe organ damage in individuals with autoimmune diseases. Here, the authors develop a machine learning model that uses electronic health records to identify patients with clinical suspicion of autoimmune diseases.

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.Mohammad et al. show that prenatal alcohol exposure increases Kcnn2 activity in the mouse cerebral cortex. Blockade of Kcnn2 improves learning deficits in a mouse model of fetal alcohol spectrum disorders.

Depression and anxiety disorders are increasingly prevalent among university students, making the provision of effective treatment in this population a priority. Whilst campus-based services provide some psychological treatments, many students are treated by routine adult psychological treatment services which have no focus or adaptations to treatment for student populations. We aimed to compare psychological treatment outcomes between university students and young adults (aged 18–25) in employment to explore whether routinely delivered psychological interventions are equally effective for these groups, or whether students report poorer outcomes. A retrospective cohort was formed of 19,707 patients treated by eight National Health Service (NHS) Improving Access to Psychological Therapies (IAPT) services in England. Associations between student status (compared to same-age employed adults) and psychological treatment outcomes were explored using logistic regression models. Models were adjusted for important treatment, clinical and demographic characteristics, and propensity score matching was used to explore the robustness of effects. Students and the employed comparison group were similar on baseline characteristics at assessment, but students were less likely to reliably recover (OR = 0.90 [95% CI = 0.83;0.96]) and reliably improve (OR = 0.91 [95% CI = 0.84;0.98]) by the end of treatment in fully adjusted models. Students and the employed group did not differ regarding the likelihood of deterioration (OR = 0.89 [95% CI = 0.78;1.02]) or treatment dropout (OR = 1.01 [95% CI = 0.93;1.11]). Students appear at risk of poorer outcomes compared to employed younger adults when treated in routine psychological treatment services. Students may require additional support and treatment adaptations that account for student-specific stressors as this might improve psychological treatment outcomes. •Students in this analysis were less likely to reliably recover or improve following routine psychological service treatment•The students were also no more likely to reliably deteriorate or drop out of treatment compared to employed controls•Treatment intensity, frequency, or medium did not moderate findings•Adaptation of care pathways and content to meet student specific needs and may benefit students.

The Shinui council voted on Thursday night to expel Gadi Ben- Shmuel and Gabi Gelber, two loyalists of former Shinui minister Yosef Paritzky, who tried to frame MK Avraham Poraz by taping him offering them trips abroad if they would stop criticizing him in an online party newspaper. Since the story broke last week, it became apparent that the tapes were unclear and Poraz did not try to bribe them. At the council meeting, Lapid called Ben- Shmuel and Belger's act \"abominable\" and accused them of being \"Paritzky's moles.\" Lapid was heckled by activists, who called him a \"totalitarian dictator.\" * Gil Hoffman World Likud officials petitioned the Likud's top internal court on Thursday against Prime Minister Ariel Sharon's nomination of Ra'anana Mayor Ze'ev Bielski as his candidate to head the Jewish Agency. Bielski decided to run as an independent for the position and not challenge former ministers Natan Sharansky and Gideon Patt, who are running for the World Likud's nomination. The World Likud officials asked for a restraining order that would force Sharon to support whoever wins the June 19 race for the World Likud's candidate. They said that if the Likud court turns down their petition they would appeal to district court. * Gil Hoffman

Freshwater harmful algal blooms (HABs) are increasing in number and severity worldwide. These HABs are chiefly composed of one or more species of cyanobacteria, also known as blue-green algae, such as Microcystis and Anabaena. Numerous HAB cyanobacterial species produce toxins (e.g., microcystin and anatoxin—collectively referred to as HAB toxins) that disrupt ecosystems, impact water and air quality, and deter recreation because they are harmful to both human and animal health. Exposure to these toxins can occur through ingestion, inhalation, or skin contact. Acute health effects of HAB toxins have been well documented and include symptoms such as nausea, vomiting, abdominal pain and diarrhea, headache, fever, and skin rashes. While these adverse effects typically increase with amount, duration, and frequency of exposure, susceptibility to HAB toxins may also be increased by the presence of comorbidities. The emerging science on potential long-term or chronic effects of HAB toxins with a particular emphasis on microcystins, especially in vulnerable populations such as those with pre-existing liver or gastrointestinal disease, is summarized herein. This review suggests additional research is needed to define at-risk populations who may be helped by preventative measures. Furthermore, studies are required to develop a mechanistic understanding of chronic, low-dose exposure to HAB toxins so that appropriate preventative, diagnostic, and therapeutic strategies can be created in a targeted fashion.