Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.     

Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas

Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future.     

Soluble ST2 as a Potential Biomarker for Abdominal Aortic Aneurysms—A Single-Center Retrospective Cohort Study

The maximal aortic diameter is the only clinically applied predictor of abdominal aortic aneurysm (AAA) progression and indicator for surgical repair. Circulating biomarkers resulting from AAA pathogenesis are attractive candidates for the diagnosis and prognosis of aneurysmal disease. Due to the reported role of interleukin 33 in AAA development, we investigated the corresponding circulating receptor molecules of soluble suppression of tumorigenesis 2 (sST2) in AAA patients regarding their marker potential in diagnosis and prognosis. We conducted a single-center retrospective cohort study in a diagnostic setting, measuring the circulating serum sST2 protein levels of 47 AAA patients under surveillance, matched with 25 peripheral artery disease (PAD) patients and 25 healthy controls. In a prognostic setting, we analyzed the longitudinal monitoring data of 50 monitored AAA patients. Slow versus fast AAA progression was defined as a <2 or ≥2 mm increase in AAA diameter over 6 months and a <4 or ≥4 mm increase over 12 months. Additionally, the association of circulating serum sST2 and AAA growth was investigated using a specifically tailored log-linear mixed model. Serum sST2 concentrations were significantly increased in AAA patients compared with healthy individuals: the median of AAA patient cohort was 112.72 ng/mL (p = 0.025) and that of AAA patient cohort 2 was 14.32 ng/mL (p = 0.039) versus healthy controls (8.82 ng/mL). Likewise, PAD patients showed significantly elevated sST2 protein levels compared with healthy controls (the median was 12.10 ng/mL; p = 0.048) but similar concentrations to AAA patients. Additionally, sST2 protein levels were found to be unsuited to identifying fast AAA progression over short-term periods of 6 or 12 months, which was confirmed by a log-linear mixed model. In conclusion, the significantly elevated protein levels of sST2 detected in patients with vascular disease may be useful in the early diagnosis of AAA but cannot distinguish between AAA and PAD or predict AAA progression.     

Long-term deterioration of lubricant-infused nanoporous anodic aluminium oxide surface immersed in NaCl solution

This study investigated the deterioration of a lubricant-infused anodic aluminium oxide surface in a 1M NaCl solution for~200 days.Direct observation by cryo-SEM and quantitative analyses by UV spectroscopy and EIS revealed that the long-term deterioration of the lubricant-infused surface was divided into two stages:the surface-adhered lubricant layer gradually dissolved at a constant rate until the substrate was exposed;afterwards the lubricant infused in the nanochannels began to diffuse and was depleted after~200 days.The EIS results also revealed that the defects reduced the corrosion resistance of the lubricant-infused surface considerably.     

交叉层积木数值模拟研究以及连接损伤分析

木建筑由于结构冗余性以及钉接节点超强的吸能耗能能力在抗震中表现良好.交叉层积木是一种新型的建筑材料.本文以交叉层积木3种柔性连接试验为基础,采用Open Sees中Pinching4自定义模型模拟连接滞回曲线的高度非线性、强度退化、刚度退化和捏拢现象.基于主次半循环累积能量的损伤模型,对交叉层积木连接进行损伤分析,并提出该连接的5种性能水平的损伤指数.Pinching4模型与连接试验结果吻合较好,进一步证明该模型模拟木节点连接性能的可行性和有效性.损伤因子对应的损伤程度基本符合试验规律,其平均值在合理范围内,计算结果离散性较低.     

Reducing understaffing and shift work with Temporal Profile Optimization (TPO)

The ergonomic quality of shift schedules can be improved by reducing time periods with understaffing (resulting in work-pressure, poor quality, etc.) and evening, night and/or weekend work.Improving the quality of forecasts regarding future workforce requirements as well as the optimization of work processes by moving as much work as possible to more suitable time zones are two approaches to this.We introduce and propose Temporal Profile Optimization (TPO) as a systematic approach to question the demand as well as its translation to workforce planning. Temporal profiles describe the number of employees needed over time (e.g. for different days of the week, times of day, for different calendar days) as well as the shift-times and staffing levels planned to meet this workforce demand.With Temporal Profile Forecasts we introduce a forecasting method that is based on time-stamped historical data and methodologically supplements traditional time series models like SARIMA in many ways. With Temporal Profile Reengineering we use systematic and often participatory methods from business process reengineering to identify moveable work and streamline the load lines by (re-)distributing movable work such that shifts and schedules are improved.The approach is illustrated along two business cases. Using TP-Forecasts for air traffic controllers increased forecasting accuracy whereby a different shift design was possible resulting in 3–4% less shift work. In a warehouse of an Austrian freight carrier a TP-Forecast together with TP-Reengineering helped to rearrange work processes such that the resulting workforce requirements curve had a more even form. This allowed for shorter shifts than before (thereby decreasing overtime).Experiences made so far stress the potential of Temporal Profile Optimization.     

Norepinephrine Inhibits Lipopolysaccharide-Stimulated TNF-α but Not Oxylipin Induction in n-3/n-6 PUFA-Enriched Cultures of Circumventricular Organs

Sensory circumventricular organs (sCVOs) are pivotal brain structures involved in immune-to-brain communication with a leaky blood–brain barrier that detect circulating mediators such as lipopolysaccharide (LPS). Here, we aimed to investigate the potential of sCVOs to produce n-3 and n-6 oxylipins after LPS-stimulation. Moreover, we investigated if norepinephrine (NE) co-treatment can alter cytokine- and oxylipin-release. Thus, we stimulated rat primary neuroglial sCVO cultures under n-3- or n-6-enriched conditions with LPS or saline combined with NE or vehicle. Supernatants were assessed for cytokines by bioassays and oxylipins by HPLC-MS/MS. Expression of signaling pathways and enzymes were analyzed by RT-PCR. Tumor necrosis factor (TNF)α bioactivity and signaling, IL-10 expression, and cyclooxygenase (COX)2 were increased, epoxide hydroxylase (Ephx)2 was reduced, and lipoxygenase 15-(LOX) was not changed by LPS stimulation. Moreover, LPS induced increased levels of several n-6-derived oxylipins, including the COX-2 metabolite 15d-prostaglandin-J2 or the Ephx2 metabolite 14,15-DHET. For n-3-derived oxylipins, some were down- and some were upregulated, including 15-LOX-derived neuroprotectin D1 and 18-HEPE, known for their anti-inflammatory potential. While the LPS-induced increase in TNFα levels was significantly reduced by NE, oxylipins were not significantly altered by NE or changes in TNFα levels. In conclusion, LPS-induced oxylipins may play an important functional role in sCVOs for immune-to-brain communication.     

Kraftbestimmung in Schrägseilen durch dynamische Messung

Force Determination in Stay Cables by Means of Vibration Measurements The knowledge of the actual tensile forces in the cables in the ropes or cables of cable‐stayed bridges or in external tendons is required for the examination and assessment of these elements. The determination of these forces by lift‐off tests with hydraulic jacks is connected with considerable expenditures as well as the danger of damages. But also the accuracies achieved by vibration measurements were, however, not satisfying. For high cable forces and short cables in some cases errors of up to ± 10% of the actual cable force could be determined. Therefore fast and non‐destructive methods for the determination of the forces are required. In this paper, a practicable technology to determine the cable force by means of vibration measurements is illustrated at the Viennese cable stayed bridge crossing the Vienna Donaukanal.     

Die Geschichte der San Francisco–Oakland Bay Bridge

The history of the San Francisco–Oakland Bay Bridge. The San Francisco‐Oakland Bay Bridge is an eminent example of american bridge engineering. It consists of a twin suspension bridge and a cantilever truss bridge which are connected by a tunnel through Yerba Buena Island. This article describes the way from the feasibility studies to the present time. In addition, it details some specific design and construction features, for example the steel construction work and the foundation of the central anchorage which connects the two suspension bridges. Recent reinforcement measures, and the plans for the replacement of the East Bay Crossing by a self‐anchored single tower suspension bridge to improve earthquake safety, are also discussed.