Central Event Research Articles

Kendra Allen’s Learning & Unlearning

Kendra Allen’s Learning & Unlearning Jalen Eutsey (bio) When You Learn the Alphabet, by Kendra Allen (University of Iowa Press, 2019), 160 pp. Kendra Allen’s literary debut, the essay collection When You Learn the Alphabet, is a relatively short but densely packed portrait of a Black life, a raw rendering of familial relationships inflected by race, gender, trauma, and disability. The book explores grown folks’ business in great detail, business that Allen is caught precariously in the middle of as a child. Allen’s parents’ relationship, her childhood in Dallas, Texas, and the fallout of their coming together, burning out, and pulling apart are the central events that the book orbits. The second essay in the collection, titled “About American Marriages,” details her parents’ seven-year separation and eventual divorce: “This is what happened: What I’ve been told: Which is what always happens: Your husband begins having sex with a woman, who isn’t you and he doesn’t even care enough to hide it well.” The essay goes on to describe the separation that allows her mother to keep hope alive and allows her father to come and go as he pleases, often without seeing Allen. Allen painfully draws out the rising tension as her father builds a life with the other woman and her child in Houston, unbeknownst to her mother, and mandates that she participate in the cover-up. It leads to this heartbreaking culmination: “When my mama finally files for divorce, it feels like she not only divorces my daddy, but every once in a while, when the subject is brought up, it feels like she’s divorced me too.” As the book develops, we learn more and more about this triumvirate. We see moments of physical violence and manifestations of post-traumatic stress disorder—both of Allen’s parents have been diagnosed as disabled veterans, although her father’s diagnosis is “100% disabled veteran” while her mother’s is “90% disabled veteran.” It’s clear that even this diagnosis is not free of the influence of race and gender: “She’s been shooting for 100% for a couple of years now, but even after working at the VA for 28 years, and even after all her apparent symptoms of forcefulness, forgetfulness, and injury, they just won’t let her have it. Her wounds ain’t physical enough. She ain’t pale enough. She ain’t male enough.” We’re never quite on settled ground in When You Learn the Alphabet. [End Page 128] Allen makes all the beautiful and painful contradictions of humanity, of the individual, plain in her essays. One of my favorite examples comes in the titular essay, “When You Learn the Alphabet,” which is presented as an abecedarian, with each new vignette beginning with a subsequent letter of the alphabet. H begins this way: “Horror story: Your childhood friend goes to jail for not snitching.” The section continues by detailing the conditioning, from childhood, that puts the highest priority on not snitching. Yet, the most compelling part of the section is how Allen feels about this life- altering decision: “He was just doing what he was told. But part of you blames him he’s still in a small cell years later for a crime he didn’t commit. Part of you blames him for committing to be loyal only.” But even as Allen makes this point, there is this honest admission: “Part of you that follows the impossible expectations of the hood praises him for being some obscured version of a real nigga.” Allen slips in and out of genres in this collection, from the abecedarian essay to a short section, “Boy Is a White Racist Word,” organized as a contrapuntal poem. All the while, she mixes personal narrative with cultural critique, placing her work invariably in conversation with the work of writers like Hanif Abdurraqib and Kiese Laymon. Allen often references pop culture, most notably music and film. True Blood, Moonlight, Monster’s Ball, The Fresh Prince of Bel-Air, Behind the Music, Jay-Z, Boyz n the Hood, and Everybody Hates Chris (among others), all get a mention. This familiarity with popular media allows her to...

Abstract OT1-18-01: A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study

Abstract Background: Hormone receptor (HR)-positive HER2-negative breast cancers have a lower tumor mutation burden than other types of cancer and triple-negative breast cancer, resulting in relatively low immunogenicity. It is also known that estrogen suppressively regulates immunity through regulatory T cells in the tumor microenvironment. Therefore, the development of immunotherapy in HR-positive and HER2-negative breast cancer is a challenging issues. Anti-VEGF therapy has been shown to improve antigen presentation, local migration of cytotoxic T lymphocytes, and suppressive tumor microenvironment in preclinical and clinical studies of various cancers. Anti-VEGF therapy can be hypothesized to modulate immunotherapy. Methods: JCOG1919E (AMBITION) is a randomized, multicenter, open-label, phase III trial to evaluate efficacy and safety of bevacizumab and paclitaxel in combination with atezolizumab (BEV+PTX+ATZ) comparing to bevacizumab and paclitaxel (BEV+PTX) in patients with HR-positive HER2 negative locally advanced or metastatic breast cancer. The key eligibility criteria are as follows: 1) ECOG PS 0-2, 2) ER and/or PgR positive and HER2-negative breast cancer, 3) endocrine resistance or life-threatening disease, 4) measurable disease, 5) centrally confirmed programmed death-ligand 1 (PD-L1) status on tumor-infiltrating immune cells, 6) no prior chemotherapy for locally advanced or metastatic breast cancer, 7) adequate organ function. Patients will be randomized (staratified by recurrence/de novo, liver metastasis, or PD-L1 status) in a 1:1 ratio, to BEV+PTX arm or BEV+PTX+ATZ arm. Patients in arm A receive PTX (90 mg/m2/day, days 1, 8 and 15, iv) and BEV (10 mg/kg/day, days 1 and 15, iv) on a 28-day cycle. Patients in arm B receive PTX and BEV plus ATZ (840 mg/body/day, days 1 and 15, iv). Treatment in both arms is continued until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) assessed by investigators. The secondary endpoints include overall survival, PFS assessed by blinded independent central review, response rate, adverse events, PFS (PD-L1 positive), and OS (PD-L1 positive). We assumed a median PFS of 16 months in BEV+PTX+ATZ arm and 11 months in BEV+PTX arm. The planned sample size was calculated as a total of 280 patients (140 patients per arm) with a one-sided alpha of 2.5%, power of 80%, an accrual period of 2.5 years, and a follow-up period of 2 years. Translational research also will be conducted accompanying with this trial. Patient accrual was started in January 29, 2021 and 37 patients were enrolled by June 18, 2021. Safety of patients in this study is being monitored by IDMC. For further information on this trial, visit ClinicalTrials.gov (NCT04732598). Citation Format: Fumikata Hara, Makiko Ono, Shigehisa Kitano, Shigehira Saji, Akihiko Shimomura, Takashi Yamanaka, Takayuki Kadoya, Mitsuya Ito, Hiroko Bando, Hiroyuki Yasojima, Keita Sasaki, Tomoko Kataoka, Tadahiko Shien, Kan Yonemori, Hiroji Iwata. A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-01.

Effects of renal denervation on sleep apnea and arrhythmia in rats with myocardial infarction

BackgroundSympathetic hyperactivity and poor sleep quality have been reported in patients with myocardial infarction (MI). Sleep is an important modulator of cardiovascular function. We aimed to evaluate the effects of renal denervation (RDN) on cardiac autonomic activity and disordered sleep patterns in rats with MI. MethodsWireless transmission of polysomnographic recordings was performed in sham and left coronary artery (LCA) ligation male rats during normal daytime sleep before and after RDN. Spectral analyses of electroencephalogram and electromyogram (EMG) recordings were performed to define active waking, quiet sleep, and paradoxical sleep. Cardiac autonomic activity was measured by analyzing the power spectrum of heart rate variability. Central sleep apnea events were measured by analyzing the EMG recordings of the diaphragm. ResultsIn the LCA ligation group, there was a higher low-frequency (LF)/high-frequency (HF) power ratio during sleep; the LF/HF ratio decreased significantly in the rats that underwent RDN in all sleep stages when compared with that in the rats that did not. The frequency of sleep interruptions increased without RDN in the LCA ligation group when compared with that in the sham group. This change was ameliorated and prevented with RDN in the LCA ligation group. ConclusionsOur results demonstrate significant sleep fragmentation with sympathetic hyperactivity after MI and that RDN prevents autonomic dysfunction and disordered sleep. RDN may then reduce sleep apnea and sleep-related sudden cardiac death after MI by restoring autonomic homeostasis.

Asynchronous learning for actor–critic neural networks and synchronous triggering for multiplayer system

In this paper, based on actor–critic neural network structure and reinforcement learning scheme, a novel asynchronous learning algorithm with event communication is developed, so as to solve Nash equilibrium of multiplayer nonzero-sum differential game in an adaptive fashion. From the point of optimal control view, each player or local controller wants to minimize the individual infinite-time cost function by finding an optimal policy. In this novel learning framework, each player consists of one critic and one actor, and implements distributed asynchronous policy iteration to optimize decision-making process. In addition, communication burden between the system and players is effectively reduced by setting up a central event generator. Critic network executes fast updates by gradient-descent adaption while actor network gives event-induced updates using the gradient projection. The closed-loop asymptotic stability is ensured along with uniform ultimate convergence. Then, the effectiveness of the proposed algorithm is substantiated on a four-player nonlinear system, revealing that it can significantly reduce sampling numbers without impairing learning accuracy. Finally, by leveraging nonzero-sum game idea, the proposed learning scheme is also applied to solve the lateral-directional stability of a linear aircraft system, and is further extended to a nonlinear vehicle system for achieving adaptive cruise control.

Altered Mitochondrial Quality Control in Rats with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Induced by High-Fat Feeding.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as the presence of hepatic steatosis in addition to one of three metabolic conditions: overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation. Chronic exposure to excess dietary fatty acids may cause hepatic steatosis and metabolic disturbances. The alteration of the quality of mitochondria is one of the factors that could contribute to the metabolic dysregulation of MAFDL. This study was designed to determine, in a rodent model of MAFLD, the effects of a long-term high-fat diet (HFD) on some hepatic processes that characterize mitochondrial quality control, such as biogenesis, dynamics, and mitophagy. To mimic the human manifestation of MAFLD, the rats were exposed to both an HFD and a housing temperature within the rat thermoneutral zone (28–30 °C). After 14 weeks of the HFD, the rats showed significant fat deposition and liver steatosis. Concomitantly, some important factors related to the hepatic mitochondrial quality were markedly affected, such as increased mitochondrial reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) damage; reduced mitochondrial biogenesis, mtDNA copy numbers, mtDNA repair, and mitochondrial fusion. HFD-fed rats also showed an impaired mitophagy. Overall, the obtained data shed new light on the network of different processes contributing to the failure of mitochondrial quality control as a central event for mitochondrial dysregulation in MAFLD.

Progesterone Inhibits the Establishment of Activation-Associated Chromatin During TH1 Differentiation.

TH1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human TH1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during TH1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.

Holographic imaging of the mitochondrial swelling in the living cells reveals that mitochondrial depolarization occurs before activation of the high-conductance permeability transition pore

Mitochondrial permeability transition is caused by opening of the Cyclosporine A (CSA) dependent calcium-induced pore, Permeability Transition Pore (PTP). PTP activation is the central event in stress-induced cell death. Molecular details of PTP opening remain incompletely understood. PTP makes mitochondrial inner membrane permeable to the molecules up to 1.5 kDa in size and results in high-amplitude mitochondrial swelling. Swelling and solutes equilibration make mitochondria optically transparent—the phenomenon that has been widely used as a bona fide “light-scattering” PTP assay in the isolated mitochondria.

Cryo-EM structures of amyloid-β 42 filaments from human brains

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss of memory and other cognitive functions and the filamentous assembly of Aβ and tau in the brain. The assembly of Aβ peptides into filaments that end at residue 42 is a central event. Yang et al . used electron cryo–electron microscopy to determine the structures of Aβ42 filaments from human brain (see the Perspective by Willem and Fändrich). They identified two types of related S-shaped filaments, each consisting of two identical protofilaments. These structures will inform the development of better in vitro and animal models, inhibitors of Aβ42 assembly, and imaging agents with increased specificity and sensitivity. —SMH

Levofloxacin prophylaxis for pediatric leukemia patients: Longitudinal follow-up for impact on health care-associated infections.

Bloodstream infections (BSIs) cause morbidity and mortality in pediatric patients with leukemia. Antibiotic prophylaxis during periods of chemotherapy-induced neutropenia may reduce the incidence of BSIs. A levofloxacin prophylaxis guideline was implemented for pediatric patients with acute myeloid leukemia and relapsed acute lymphoblastic leukemia. We conducted a retrospective cohort study over 4years (2years pre and 2years post implementation) of the practice guideline to assess the impact on central line-associated bloodstream infections (CLABSI) and BSI events. Secondary outcomes included incidence of Clostridioides difficile-associated diarrhea, bacteremia due to multidrug-resistant organisms (MDRO), and bacteremia due to levofloxacin nonsusceptible organisms. STATA was used for data analysis. Sixty-three and 72 patients met inclusion criteria for the pre- and postimplementation cohorts, respectively. Demographics were similar between the groups. We observed 60 BSI events in the pre-group versus 49 events in the post-group (p=.1). Bacteremia due to Gram-negative rods (risk ratio [RR] 0.37 [0.21, 0.66], p<.001) and National Healthcare Safety Network (NHSN) CLABSIs (RR 0.62 [0.44, 0.89], p=.01) were significantly reduced in the postimplementation group. The incidences of C. difficile-associated diarrhea and MDRO bacteremia were similar between groups. However, we observed an increase in the incidence of BSI due to Gram-negative rods that were nonsusceptible to levofloxacin (RR 3.38 [0.72, 6.65], p<.001). Following implementation of a levofloxacin prophylaxis guideline, we observed a significant decrease in BSIs due to Gram-negative rods and NHSN CLABSIs. Vigilant monitoring of outcomes post guideline implementation is critical to track emergence of resistant organisms.

Plasmodium falciparum Cysteine Rich Secretory Protein uniquely localizes to one end of male gametes

Fertilization is a central event during the life cycle of most eukaryotic organisms and involves gamete recognition and fusion, ultimately resulting in zygote formation. Gamete fertilization in the malaria-causing Plasmodium parasites occurs inside the mosquito midgut and represents a major bottleneck in the life cycle. Cysteine Rich Secretory Proteins (CRISPs) are key molecules involved in fertilization in vertebrates and the presence of a CRISP ortholog in human malaria infective Plasmodium falciparum suggested a possible role in fertilization. Strikingly, P. falciparum CRISP exhibited a unique terminal localization in the male microgamete. Parasites with a CRISP gene deletion (P. falciparum crisp−) proliferated asexually similar to wildtype NF54 parasites and differentiated into gametocytes. Further analysis showed that Plasmodium falciparum crisp− gametocytes underwent exflagellation to form male gametes and no apparent defect in transmission to the mosquito vector was observed. These data show that P. falciparum CRISP is a marker for the apical end of the microgamete and that it might only have an ancillary or redundant function in the male sexual stages.

From a National Meeting to an International Conference: A Scientometric Case Study of a Finnish Computing Education Conference

Computerisation and digitalisation are shaping the world in fundamental and unpredictable ways, which highlights the importance of computing education research (CER). As part of understanding the roots of CER, it is crucial to investigate the evolution of CER as a research discipline. In this paper we present a case study of a Finnish CER conference called Koli Calling, which was launched in 2001, and which has become a central publication venue of CER. We investigate the evolution of Koli Calling&#x2019;s scholarly communities and zoom in on it&#x2019;s publication habits and internalisation process. We explore the narrative of the development and scholarly agenda behind changes in the conference submission categories from the perspective of some of the conference chairs over the years.We then take a qualitative perspective, analysing the conference publications based on a comprehensive bibliometric analysis. The outcomes include classification of important research clusters of authors in the community of conference contributors. Interestingly, we find traces of important events in the historical development of CER. In particular, we find clusters emerging from specific research capacity building initiatives and we can trace how these connect research spanning the world CER community from Finland to Sweden and then further to the USA, Australia and New Zealand. This paper makes an important strategic contribution to the evolution of CER as a research discipline, from the perspective of one central event and publication venue, providing a broad perspective on the role of the conference in connecting research clusters and establishing a truly international research community. This work contributes insights to researchers in one specific CER community and how they shape the future of computing education.

Plasma metallothioneins are potential predictive biomarkers of acute kidney injury in acute-on-chronic liver failure

Background and Aim: Acute kidney injury (AKI) is a central event in acute-on-chronic-liver failure (ACLF) and considerably increases the risk of short-term mortality. However, currently there are no biomarkers to predict AKI in ACLF. Our study aimed at de novo discovery of AKI biomarkers in ACLF.

Quantification of the trans-synaptic partners neurexin-neuroligin in CSF of neurodegenerative diseases by parallel reaction monitoring mass spectrometry

SummaryBackgroundSynaptic proteins are increasingly studied as biomarkers for synaptic dysfunction and loss, which are early and central events in Alzheimer's disease (AD) and strongly correlate with the degree of cognitive decline. In this study, we specifically investigated the synaptic binding partners neurexin (NRXN) and neuroligin (Nlgn) proteins, to assess their biomarker's potential.Methodswe developed a parallel reaction monitoring mass spectrometric method for the simultaneous quantification of NRXNs and Nlgns in cerebrospinal fluid (CSF) of neurodegenerative diseases, focusing on AD. Specifically, NRXN-1α, NRXN-1β, NRXN-2α, NRXN-3α and Nlgn1, Nlgn2, Nlgn3 and Nlgn4 proteins were targeted.FindingsThe proteins were investigated in a clinical cohort including CSF from controls (n=22), mild cognitive impairment (MCI) due to AD (n=44), MCI due to other conditions (n=46), AD (n=77) and a group of non-AD dementia (n=28). No difference in levels of NRXNs and Nlgns was found between AD (both at dementia and MCI stages) or controls or the non-AD dementia group for any of the targeted proteins. NRXN and Nlgn proteins correlated strongly with each other, but only a weak correlation with the AD core biomarkers and the synaptic biomarkers neurogranin and growth-associated protein 43, was found, possibly reflecting different pathogenic processing at the synapse.Interpretationwe conclude that NRXN and Nlgn proteins do not represent suitable biomarkers for synaptic pathology in AD. The panel developed here could aid in future investigations of the potential involvement of NRXNs and Nlgns in synaptic dysfunction in other disorders of the central nervous system.Fundinga full list of funding can be found under the acknowledgments section.

Studying Alzheimer’s Disease Using &amp;lt;i&amp;gt;Drosophila melanogaster&amp;lt;/i&amp;gt; as a Powerful Tool

Background: Alzheimer’s disease (AD) is an increasingly prevalent neurodegenerative disease characterized by protein aggregation in the form of amyloid plaques containing beta-amyloid peptides and neurofibrillary tangles containing hyperphosphorylated tau protein. The central molecular events underlying AD pathogenesis remain controversial and poorly defined. Drosophila melanogaster has emerged as an important genetic resource for studying the pathology of AD. Many AD models have been created using Drosophila, taking advantage of its short generation times, sophisticated genetic tools, and abundance of homologs to human genes. Purpose: This review summarizes different models for studying AD in Drosophila melanogaster, including the full-length APP, C99, Aβ42 and Tau models, explaining how the models were built and what we have learned from them. Conclusion: Four main AD Drosophila models are introduced in this review, which can serve as a future method to investigate genes and drugs that can modify symptoms.

Dietary Hesperidin Suppresses Lipopolysaccharide-Induced Inflammation in Male Mice.

Depressive disorders are partially attributed to chronic inflammation associated with the tryptophan (Trp)-kynurenine (Kyn) pathway. Recent evidence suggests that anti-inflammatory agents may reduce the risk of depression. The present study aimed to elucidate the potential of the citrus flavonoid hesperidin, which exhibits anti-inflammatory activity, in suppressing the Trp-Kyn pathway in the brain, using a lipopolysaccharide (LPS)-induced inflammation mouse model. Dietary hesperidin was found to suppress activation of the Trp-Kyn pathway in the prefrontal cortex. In addition, it reduced systemic LPS-induced signs of illness, such as low skin temperature and enhanced leukocyte count in the blood. However, dietary supplementation with hesperidin did not improve body weight loss, food intake, water intake, or splenic increases in leukocyte numbers in the LPS model. Collectively, the results suggest that dietary hesperidin can partially regulate central and peripheral events linked to inflammation in LPS mouse models.

Global Response: Consent in the Long View

Global Response:Consent in the Long View Elizabeth Fowler These rich essays offer us a glimpse of how fervently medieval western Europe was obsessed with the theme of consent in romance, lyric, fabliau, hagiography, and so many other genres—as well as in legal records, charters, deeds, and all the documentary evidence of signature, property, and contract. Long before Hobbes, Locke, or Rousseau, the topic of consent saturated culture: in Sarah Baechle's phrase, it has "hypersignifying potency" (318). These essays reveal the explosive combination of outrage, wit, pleasure, shame, laughter, and distress evoked by staging medieval consent and its disabilities, infelicities, and misfires. In these centuries sexual relations became a template for the assessment of all political relations. Just as liberty could not have been a central ideological driver of the Enlightenment and all the eighteenth-century revolutions without slavery threatening formulations of justice, issues of consent could not have been a central theme of contract theory itself without medieval writers making rape and its correlates a central plot event. Topics of consent have an uncanny ability to throw us back into the staunch crouch of individualism and even essentialism, a stance that on other topics might seem distasteful, because we tend to confirm the slipperiness and fragility of gender, the ecological diffusion of consciousness, the interpersonal nature of the will, and the polymorphous way that these kinds of constructions are mapped by language. Yet characters in medieval fictions of consent are anything but individuals: they veer toward allegory, distribute agency across a circuit of relationships (Torres, 331), represent social markers rather than individual bodies. As these scholars show collectively, medieval texts like to pitch bodies against social positions, to pressure us to acknowledge injury (Goodrich, Raw) even when they push us to embrace it and reconceive it as grace (Schwebel, Torres). They [End Page 361] understand it as the defining relation between the sexes, mark it by class (Alberghini, Akard), worry about it (all), stage the harms that cluster around consent in the topoi of religious or "racial" conversion or in the relations among incipient nations or peoples. In sum, medieval stories unfailingly ask us to compare consent in sexual acts to consent in other social interactions (Baechle, 318). And so the stories these scholars illuminate show us the political ideals of western democracies under construction. They give us consent as one of the primary instigators of narrative, a launching of the chess game of social stress and struggle. I think this is why such texts speak to us now, because the seventeenth-century scene of social contract that ushered in the Enlightenment is impossible to see without its exclusions of women, children, the unpropertied, the racialized, the alien, though loud voices unashamedly call for the disenfranchisement of their consent. How do we make visible medieval literature's investigation of what is at stake in the construction of modernity? Start here: these scholars bring us vibrant, probing assessments of materials that have lain dormant, though often in plain sight, for centuries—waiting to help us develop sorely needed new approaches to consent. [End Page 362] Elizabeth Fowler University of Virginia Copyright © 2022 The New Chaucer Society, University of Miami

Reconsideration of the historical events of 1985 Palace of Justice siege in Colombia

The subject of this research is the theme of violence in Colombian art as a reflection of political and social conflicts in the country. Political, economic and social problems in the history of Colombia of the XX century are closely intertwined, resulting in a complicated situation of coups d&amp;rsquo;&amp;eacute;tat and terror, which affects different types of art in the country and representatives of the cultural elite. The conflict that stretches since the early XX century is reflected in the Colombian architecture and painting. It is depicted as rather conservatism and alienation from the constituency in architecture, and from the critical perspective in painting. The projects of the Palace of Justice are taken as an example of the changes in architecture. Trends in the visual arts are revealed in the works of Beatriz Gonzalez and Doris Salcedo. One of the central events in the political and social history of Colombia of the XX century &amp;ndash; 1985 Palace of Justice siege &amp;ndash; has found a special place in their art. The novelty of this research lies in using the comparative method of analysis. This is the first Russian-language research to draw the parallel between the architectural changes in the projects of the Palace of Justice in Bogota and the impact of the events of November 6 and 7, 1985 upon Colombian painting based on the works of the two remarkable Colombian artists. It is established that different types of art show different response to the political and social disturbances that take place in the country. This is substantiated by differentiation of the political-social order in various types of art.

Форт №5 в исторической памяти калининградцев

The Königsberg Fort № 5 “Friedrich Wilhelm III”, built in the second half of the 19th century was never used in military operations before the Second World War. But during the storm of Königsberg by the Soviet troops in April, 1945, it had been exposed to the attacks of all kinds of forces of the 3rd Belorussian front for four days and was surrendered by the German command. Later fifteen men were awarded the title of Hero of the Soviet Union for the fort storming. The article is based on the unpublished documents dating from 1970—1980s from the archives of the Kaliningrad Regional Museum of History and Art which are related to the events of the East Prussian invasion. The author studies the process of including the former German fortress in the historical memory of the Soviet Kaliningrad inhabitants. The article identifies the reasons for the museumisation of the fortress among other fortification structures and its formation as a place of memory. Two concept plans of turning the fort into a memorial are described and analyzed in detail: projects by sculptors from the Moscow organization Rosmonumentyskusstvo and by workers of the Regional Museum of History and Art. The conclusion is made about the principles of reconstruction and the limits of what is admissible in the process of adjusting the German monuments to the objectives of the memory policy aimed at filling the historic landscape of the city with the Soviet attributes. The conclusion substantiates the key role of the memorial opened at Fort № 5 as a mediator (media) between the past of the region and the inhabitants of the region to promote the historical narrative about the storming of Königsberg by the Red Army as the central event of the East Prussian operation of 1945.

Histone acetylation of bile acid transporter genes plays a critical role in cirrhosis

Owing to the lack of genetic animal models that adequately recreate key clinical characteristics of cirrhosis, the molecular pathogenesis of cirrhosis has been poorly characterized, and treatments remain limited. Hence, we aimed to better elucidate the pathological mechanisms of cirrhosis using a novel murine model. We report on the first murine genetic model mimicking human cirrhosis induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of non-specific lethal (NSL) and INO80 chromatin-modifier complexes. Using this genetic tool with other mouse models, cell culture and human samples, combined with quantitative proteomics, single nuclei/cell RNA sequencing and chromatin immunoprecipitation assays, we investigated mechanisms of cirrhosis. MCRS1 loss in mouse hepatocytes modulates the expression of bile acid (BA) transporters - with a pronounced downregulation of Na+-taurocholate cotransporting polypeptide (NTCP) - concentrating BAs in sinusoids and thereby activating hepatic stellate cells (HSCs) via the farnesoid X receptor (FXR), which is predominantly expressed in human and mouse HSCs. Consistently, re-expression of NTCP in mice reduces cirrhosis, and genetic ablation of FXR in HSCs suppresses fibrotic marks in mice and invitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts histone deacetylase 1 from its histone H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays decreased nuclear MCRS1 and NTCP expression. Our data reveal a previously unrecognized function of MCRS1 as a critical histone acetylation regulator, maintaining gene expression and liver homeostasis. MCRS1 loss induces acetylation of BA transporter genes, perturbation of BA flow, and consequently, FXR activation in HSCs. This axis represents a central and universal signaling event in cirrhosis, which has significant implications for cirrhosis treatment. By genetic ablation of MCRS1 in mouse hepatocytes, we generate the first genetic mouse model of cirrhosis that recapitulates human features. Herein, we demonstrate that the activation of the bile acid/FXR axis in liver fibroblasts is key in cirrhosis development.

Granulocyte Colony-Stimulating Factor Is Safe and Well Tolerated following Allogeneic Transplantation in Patients with Sickle Cell Disease

Granulocyte colony-stimulating factor (G-CSF) used after hematopoietic stem cell transplantation (HSCT) can enhance neutrophil recovery in patients rendered neutropenic by the preparative regimen. G-CSF is contraindicated in patients with sickle cell disease (SCD), because life-threatening complications can ensue in the presence of sickle vasculopathy. The safety profile of G-CSF after HSCT for SCD has not been described, however. We report clinical outcomes in the first 100 days post-HSCT in 62 patients supported with G-CSF until neutrophil recovery on a clinical trial of reduced- intensity conditioning HSCT for SCD. The patients received G-CSF for a median of 9 days (range, 5 to 33 days) post-transplantation from the best available stem cell source. Preparation for transplantation included a target hemoglobin S level of ≤45%. Neutrophil engraftment (absolute neutrophil count >0.5×103/mL) was achieved at a median of 13 days (range, 10 to 34 days), and platelet engraftment (>50×103/mL) was achieved at a median of 19 days (range, 12 to 71 days). The median duration of inpatient hospitalization following stem cell infusion (day 0) was 21.5 days (range, 11 to 33 days). No patient developed SCD-related complications following G-CSF use. The most common organ toxicities encountered between G-CSF initiation (on day +7) and day +100 were anorexia (n=14), hypertension (n=11), and electrolyte imbalance requiring correction (n=9). Central nervous system-related events were noted in 5 patients, all of whom had preexisting cerebral vasculopathy/moyamoya disease, attributed to reversible posterior leukoencephalopathy syndrome in the presence of calcineurin inhibitor therapy and hypertension. We conclude that G-CSF does not adversely impact SCD HSCT recipients and can be safely used post-transplantation to enhance neutrophil recovery.