Discovering Many Diverse Solutions with Bayesian Optimization

Bayesian optimization (BO) is a popular approach for sample-efficient optimization of black-box objective functions. While BO has been successfully applied to a wide range of scientific applications, traditional approaches to single-objective BO only seek to find a single best solution. This can be a significant limitation in situations where solutions may later turn out to be intractable. For example, a designed molecule may turn out to violate constraints that can only be reasonably evaluated after the optimization process has concluded. To address this issue, we propose Rank-Ordered Bayesian Optimization with Trust-regions (ROBOT) which aims to find a portfolio of high-performing solutions that are diverse according to a user-specified diversity metric. We evaluate ROBOT on several real-world applications and show that it can discover large sets of high-performing diverse solutions while requiring few additional function evaluations compared to finding a single best solution

A comparison of curated gene sets versus transcriptomics-derived gene signatures for detecting pathway activation in immune cells

Background: Despite the significant contribution of transcriptomics to the fields of biological and biomedical research, interpreting long lists of significantly differentially expressed genes remains a challenging step in the analysis process. Gene set enrichment analysis is a standard approach for summarizing differentially expressed genes into pathways or other gene groupings. Here, we explore an alternative approach to utilizing gene sets from curated databases. We examine the method of deriving custom gene sets which may be relevant to a given experiment using reference data sets from previous transcriptomics studies. We call these data-derived gene sets, "gene signatures" for the biological process tested in the previous study. We focus on the feasibility of this approach in analyzing immune-related processes, which are complicated in their nature but play an important role in the medical research. Results: We evaluate several statistical approaches to detecting the activity of a gene signature in a target data set. We compare the performance of the data-derived gene signature approach with comparable GO term gene sets across all of the statistical tests. A total of 61 differential expression comparisons generated from 26 transcriptome experiments were included in the analysis. These experiments covered eight immunological processes in eight types of leukocytes. The data-derived signatures were used to detect the presence of immunological processes in the test data with modest accuracy (AUC = 0.67). The performance for GO and literature based gene sets was worse (AUC = 0.59). Both approaches were plagued by poor specificity. Conclusions: When investigators seek to test specific hypotheses, the data-derived signature approach can perform as well, if not better than standard gene-set based approaches for immunological signatures. Furthermore, the data-derived signatures can be generated in the cases that well-defined gene sets are lacking from pathway databases and also offer the opportunity for defining signatures in a cell-type specific manner. However, neither the data-derived signatures nor standard gene-sets can be demonstrated to reliably provide negative predictions for negative cases. We conclude that the data-derived signature approach is a useful and sometimes necessary tool, but analysts should be weary of false positives. © 2020 The Author(s)

Wirtschaftskrise: Wie können die Folgen für den Arbeitsmarkt abgefedert werden?

Olaf Scholz, Bundesminister für Arbeit und Soziales, erläutert die Politik der Regierung und unterstreicht die Relevanz der Sozialpartnerschaft: "Der gemeinsame Einsatz für Arbeit von Bundesregierung, Arbeitgebern und Gewerkschaften wirkt und verhindert Schlimmeres. Das zeigt: Wir können mit Sozialpartnerschaft durch die Krise kommen und die schlechten Prognosen schlagen." Johann Eekhoff, Universität zu Köln, warnt davor, der Krise mit Versuchen, Beschäftigte mit öffentlichen Mitteln dazu zu bewegen, vorzeitig in den Ruhestand zu gehen, wie beispielsweise mit der geförderten Altersteilzeit und der Frühverrentung ohne Abschläge, begegnen zu wollen. Vielmehr sollten die Steuer- und Abgabesysteme verbessert und Arbeitszeitregelungen gelockert werden. Axel Deeke, Institut für Arbeitsmarkt- und Berufsforschung, Nürnberg, sieht in der Kurzarbeit den Grund dafür, dass die befürchteten Auswirkungen der Krise auf den Arbeitsmarkt bislang ausgeblieben sind. Nach Ansicht von Wilhelm Adamy, DGB-Vorstandsmitglied, ist die Kurzarbeit zwar kurzfristig sehr erfolgreich, kann aber einen krisenbedingten Arbeitsplatzabbau allenfalls verschieben. Diese "gewonnene Zeit" sollte genutzt werden, um, beispielsweise durch Sicherung gefährdeter Arbeitsplätze, Anhebung des Qualifikationsniveaus, Abbau von sozialer Ungleichheit und angemessene Einkommenssicherung, Beschäftigung zu sichern. Stefan Sell, Fachhochschule Koblenz, sieht die derzeitige Stabilisierung der Funktionalitäten in der Arbeitslosenversicherung nur als eine kurzfristige Strategie. Mittel- und langfristig müsse es um die Weiterentwicklung in Richtung auf eine "Beschäftigungsversicherung" gehen. Heike Bruch und David Maus, Universität St. Gallen, stellen ihr Konzept "Einsatz der problemorientierten Führung" vor, dessen Anwendung es auch in Krisenzeiten ermögliche, die Mitarbeiter zu mobilisieren.Wirtschaftskrise, Arbeitsmarkt, Kurzarbeit, Arbeitsmarktpolitik, Unternehmen, Beschäftigung, Krise Armut, Deutschland

S100A9 is indispensable for survival of pneumococcal pneumonia in mice

S100A8/A9 has important immunomodulatory roles in antibacterial defense, but its relevance in focal pneumonia caused by Streptococcus pneumoniae (S. pneumoniae) is understudied. We show that S100A9 was significantly increased in BAL fluids of patients with bacterial but not viral pneumonia and correlated with procalcitonin and sequential organ failure assessment scores. Mice deficient in S100A9 exhibited drastically elevated Zn$^{2+}$ levels in lungs, which led to bacterial outgrowth and significantly reduced survival. In addition, reduced survival of S100A9 KO mice was characterized by excessive release of neutrophil elastase, which resulted in degradation of opsonophagocytically important collectins surfactant proteins A and D. All of these features were attenuated in S. pneumoniae-challenged chimeric WT→S100A9 KO mice. Similarly, therapy of S. pneumoniae-infected S100A9 KO mice with a mutant S100A8/A9 protein showing increased half-life significantly decreased lung bacterial loads and lung injury. Collectively, S100A9 controls central antibacterial immune mechanisms of the lung with essential relevance to survival of pneumococcal pneumonia. Moreover, S100A9 appears to be a promising biomarker to distinguish patients with bacterial from those with viral pneumonia. Trial registration: Clinical Trials register (DRKS00000620)

The lysosomal proteome of senescent cells contributes to the senescence secretome

Senescent cells accumulate in tissues over time, favoring the onset and progression of multiple age-related diseases. Senescent cells present a remarkable increase in lysosomal mass and elevated autophagic activity. Here, we report that two main autophagic pathways macroautophagy (MA) and chaperone-mediated autophagy (CMA) are constitutively upregulated in senescent cells. Proteomic analyses of the subpopulations of lysosomes preferentially engaged in each of these types of autophagy revealed profound quantitative and qualitative changes in senescent cells, affecting both lysosomal resident proteins and cargo proteins delivered to lysosomes for degradation. These studies have led us to identify resident lysosomal proteins that are highly augmented in senescent cells and can be used as novel markers of senescence, such as arylsulfatase ARSA. The abundant secretome of senescent cells, known as SASP, is considered their main pathological mediator; however, little is known about the mechanisms of SASP secretion. Some secretory cells, including melanocytes, use the small GTPase RAB27A to perform lysosomal secretion. We found that this process is exacerbated in the case of senescent melanoma cells, as revealed by the exposure of lysosomal membrane integral proteins LAMP1 and LAMP2 in their plasma membrane. Interestingly, a subset of SASP components, including cytokines CCL2, CCL3, CXCL12, cathepsin CTSD, or the protease inhibitor SERPINE1, are secreted in a RAB27A-dependent manner in senescent melanoma cells. Finally, proteins previously identified as plasma biomarkers of aging are highly enriched in the lysosomes of senescent cells, including CTSD. We conclude that the lysosomal proteome of senescent cells is profoundly reconfigured, and that some senescent cells can be highly active in lysosomal exocytosis.© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd

Loss of Serpina1 in Mice Leads to Altered Gene Expression in Inflammatory and Metabolic Pathways

The SERPINA1 gene encodes alpha1-antitrypsin (AAT), an acute phase glycoprotein and serine protease inhibitor that is mainly (80-90%) produced in the liver. Point mutations in the SERPINA1 gene can lead to the misfolding, intracellular accumulation, and deficiency of circulating AAT protein, increasing the risk of developing chronic liver diseases or chronic obstructive pulmonary disease. Currently, siRNA technology can knock down the SERPINA1 gene and limit defective AAT production. How this latter affects other liver genes is unknown. Livers were taken from age- and sex-matched C57BL/6 wild-type (WT) and Serpina1 knockout mice (KO) aged from 8 to 14 weeks, all lacking the five serpin A1a-e paralogues. Total RNA was isolated and RNA sequencing, and transcriptome analysis was performed. The knockout of the Serpina1 gene in mice changed inflammatory, lipid metabolism, and cholesterol metabolism-related gene expression in the liver. Independent single-cell sequencing data of WT mice verified the involvement of Serpina1 in cholesterol metabolism. Our results from mice livers suggested that designing therapeutic strategies for the knockout of the SERPINA1 gene in humans must account for potential perturbations of key metabolic pathways and consequent mitigation of side effects.RNA sequencing was supported by the grant ISCIII-AESI PI20CIII/00015.S

Target Displacements during Eye Blinks Trigger Automatic Recalibration of Gaze Direction

Eye blinks cause disruptions to visual input and are accompanied by rotations of the eyeball [1]. Like every motor action, these eye movements are subject to noise and introduce instabilities in gaze direction across blinks [2]. Accumulating errors across repeated blinks would be debilitating for visual performance. Here, we show that the oculomotor system constantly recalibrates gaze direction during blinks to counteract gaze instability. Observers were instructed to fixate a visual target while gaze direction was recorded and blinks were detected in real time. With every spontaneous blink-while eyelids were closed-the target was displaced laterally by 0.5° (or 1.0°). Most observers reported being unaware of displacements during blinks. After adapting for ∼35 blinks, gaze positions after blinks showed significant biases toward the new target position. Automatic eye movements accompanied each blink, and an aftereffect persisted for a few blinks after target displacements were eliminated. No adaptive gaze shift occurred when blinks were simulated with shutter glasses at random time points or actively triggered by observers, or when target displacements were masked by a distracting stimulus. Visual signals during blinks are suppressed by inhibitory mechanisms [3-6], so that small changes across blinks are generally not noticed [7, 8]. Additionally, target displacements during blinks can trigger automatic gaze recalibration, similar to the well-known saccadic adaptation effect [9-11]. This novel mechanism might be specific to the maintenance of gaze direction across blinks or might depend on a more general oculomotor recalibration mechanism adapting gaze position during intrinsically generated disruptions to visual input

Functional aplasia of the contralateral A1 segment influences clinical outcome in patients with occlusion of the distal internal carotid artery

Background: The importance of an A1 aplasia remains unclear in stroke patients. In this work, we analyze the impact of an A1 aplasia contralateral to an acute occlusion of the distal internal carotid artery (ICA) on clinical outcomes. Methods: We conducted a retrospective study of consecutive stroke patients treated with mechanical thrombectomy at 12 tertiary care centers between January 2015 and February 2021 due to an occlusion of the distal ICA. Functional A1 aplasia was defined as the absence of A1 or hypoplastic A1 (>50% reduction to the contralateral site). Functional independence was measured by the modified Rankin Scale (mRS ≤ 2). Results: In total, 81 out of 1068 (8%) patients had functional A1 aplasia contralateral to distal ICA occlusion. Patients with functional contralateral A1 aplasia were more severely affected on admission (median NIHSS 18, IQR 15–23 vs. 17, IQR 13–21; aOR: 0.672, 95% CI: 0.448–1.007, p = 0.054) and post-interventional ischemic damage was larger (median ASPECTS 5, IQR 1–7, vs. 6, IQR 3–8; aOR: 1.817, 95% CI: 1.184–2.789, p = 0.006). Infarction occurred more often within the ipsilateral ACA territory (20/76, 26% vs. 110/961, 11%; aOR: 2.482, 95% CI: 1.389–4.437, p = 0.002) and both ACA territories (8/76, 11% vs. 5/961, 1%; aOR: 17.968, 95% CI: 4.979–64.847, p ≤ 0.001). Functional contralateral A1 aplasia was associated with a lower rate of functional independence at discharge (6/81, 8% vs. 194/965, 20%; aOR: 2.579, 95% CI: 1.086–6.122, p = 0.032) and after 90 days (5/55, 9% vs. 170/723, 24%; aOR: 2.664, 95% CI: 1.031–6.883, p = 0.043). Conclusions: A functional A1 aplasia contralateral to a distal ICA occlusion is associated with a poorer clinical outcome

Introduction: Shakespeare's public spheres

Habermas’ sense of a “cultural Public Sphere” is a notoriously complex term and, when applied to Early Modern cultures, needs careful definition. This essay both introduces the variety of methods by which we might approach playtexts with a view to their public – auditory – impact and contributes to a debate about an audience's understanding of Shakespeare's plays. By selecting two words and their spread of use in one play, Twelfth Night, we might appreciate the potential for meaningful ambiguity latent in how we hear the language of live performance. If we search for how certain terms (in this case, the cluster of semes derived from repetitions of “fancy” and “play”), we might find at times incompatible senses, yet we get near to appreciating the range of Early Modern dramatic language