Incest in the 1990s: reading Anais Nin's 'Father Story'

In the summer of 1933, diarist, author and critic Anaïs Nin joined her father for a short vacation in France. Nin wrote about the trip in her diary afterwards, referring to it as the ‘Father Story.’ In the story, she details how, aged 30, she embarked upon an affair with her father which would last for several months. Rather than displaying the signs of trauma that we have come to expect from the incest narrative such as dissociation, blame and recrimination, the ‘Father Story’ is more ambiguous in its tone. Part-tribute to the father, part-seduction narrative, part-confession, this is a story that resists categorisation – a resistance that has ethical, critical and formal ramifications for our reading of incest narratives. Upon its publication in the early 1990s, critics responded to the ‘Father Story’ as fantastical, excessive and vulgar. These responses form part of a wider American father story during this period; a story about memory, therapy culture, family values and the concealed rules of testimony. This article reads Anaïs Nin’s narrative as a text which raises fundamental questions about why certain father (and daughter) stories are culturally acceptable and others are not

Obesogenic and diabetogenic effects of high-calorie nutrition require adipocyte BK channels:Adipocyte BK protects from overwhelming BW gain

Elevated adipose tissue expression of the Ca2+- and voltage-activated K+ (BK) channel was identified in morbidly obese men carrying a BK gene variant supporting the hypothesis that K+ channels affect metabolic responses of fat cells to nutrients. To establish the role of endogenous BKs for fat cell maturation, storage of excess dietary fat and body-weight (BW) gain we studied a gene-targeted mouse model with a global ablation of the BK channel (BKL1/L1) and adipocyte-specific BK-deficient (adipoqBKL1/L2) mice. Global BK deficiency afforded protection from high-fat-diet (HFD) induced BW gain and excessive fat accumulation. Expansion of white adipose tissue-derived epididymal BKL1/L1 pre-adipocytes and their differentiation to lipid-filled mature adipocytes in vitro, however, were improved. Moreover, BW gain and total fat masses of usually super-obese ob/ob mice were significantly attenuated in the absence of BK together supporting a central or peripheral role for BKs in the regulatory system that controls adipose tissue and weight. Accordingly, HFD-fed adipoqBKL1/L2 mutants presented with a reduced total BW and overall body fat mass, smaller adipocytes and reduced leptin levels. Protection from pathologic weight gain in the absence of adipocyte BKs was beneficial for glucose handling and related to an increase in body core temperature due to higher levels of uncoupling protein 1 as well as low abundance of the proinflammatory interleukin-6 as a common risk factor for diabetes and metabolic abnormalities. This suggests that adipocyte BK activity is at least partially responsible for excessive BW gain under high-caloric conditions suggesting BK channels as promising drug targets for pharmacotherapy of metabolic disorders and obesity

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Genetic mechanisms of critical illness in Covid-19.

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Characterization of cell type specific gene expression in Nicotiana tabacum leaf tissue.

Protoplasts isolated from Nicotiana tabacum leaf tissue were characterized through flow cytometric analysis based on chlorophyll autofluorescence and cell size. For mesophyll protoplasts, a high correlation coefficient (r² = 0.973) was observed between chlorophyll content and flow cytometric measurement of chlorophyll fluorescence. Chlorophyll fluorescence was found to correlate with chloroplast number (r² = 0.992) in protoplasts isolated from a single leaf, however comparison of these same parameters between experiments utilizing different leaves yielded a poor correlation. Cell size measured using pulse-width time-of-flight generated from the chlorophyll autofluorescence signal was highly correlated with cell diameter (r² > 0.99). Comparison of red fluorescence generated pulse-width time-of-flight size measurements with chloroplast number was also highly correlated with r² = 0.986. Fluorescein diacetate fluorochromasia generated pulse-width time-of-flight can be used to separate protoplasts which contain chloroplasts from protoplasts devoid of chloroplasts when analyzed with chlorophyll autofluorescence in a two-parameter histogram. Separation of the population devoid of chloroplasts on the basis of pulse-width time-of-flight provides an accurate means of measuring cell diameter. The purification of homogeneous populations of protooplasts derived from photosynthetic (containing chloroplasts) and nonphotosynthetic (devoid of chloroplasts) tissues was used as a basis to study cell specific gene expression of the cauliflower mosaic virus 35S promoter (CaMV), the chlorophyll a,b/binding protein promoter (cab) and small subunit of ribulose bisphosphate carboxylase promoter (rbcS), each fused to the gene encoding the enzyme beta-glucuronidase. Protoplasts from transgenic plants, each containing one of the three specific constructs, were subjected to flow analysis and sorting to separate cells from photosynthetic and nonphotosynthetic tissue types. Expression of the CaMV gene fusion was found in both cell types, while the expression of the photosynthetic (rbcS and cab) gene fusions occurred predominantly in protoplasts isolated from photosynthetic tissue. A similar pattern of expression was observed in wild-type protoplasts transfected with the same gene fusions. Photooxidation induced by the herbicide Norflurazon had no effect on the expression of the CaMV gene fusion, but reduced the level of expression of both the cab and rbcS gene fusions in both the transgenic and the transfected protoplasts

Transient fluvial incision in the headwaters of the Yellow River, northeastern Tibet, China

We utilize topographic analysis of channel profiles combined with field measurements of erosion rates to explore the distribution of channel incision in the Anyemaqen Shan, a broad mountainous region in the northeastern Tibetan plateau. Tributary channels to the Yellow River display systematic downstream increases in channel gradient associated with convex upward longitudinal profiles. Steep lower reaches of channels are associated with rapid (&gt; 1 m/ ka) incision rates along the Yellow River, while upstream reaches are associated with relatively slow ( 0.05 - 0.1 m/ ka) erosion of soil- mantled uplands. Covariance between erosion rates and channel steepness indices suggest that channels are adjusted to match long- wavelength differential rock uplift across the range. Geologic constraints indicate that rapid incision downstream of the range is associated with excavation of basin fill driven by changes in relative base level farther downstream. The upstream limit of this wave of transient incision is marked by a series of knickpoints that are found at nearly the same elevation throughout the watershed, consistent with knickpoint migration as a kinematic, rather than diffusional, wave. Tributary channel gradients downstream of knickpoints, however, display a progressive adjustment to increased incision rates that may reflect the influence of increased sediment flux. Comparison of observed channel profiles to a stream power model of fluvial behavior reveals that the rate of knickpoint propagation can only be explained if the erosional efficiency coefficient ( K) increases during incision. Our results thus highlight the utility of channel profile analysis to reconstruct the fluvial response to both active tectonism and external changes in base level.</p