Erratum: “Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response” [Biomicrofluidics 15, 021501 (2021)]

It has been drawn to the authors’ attention that our original article1 did not appropriately attribute portions of a figure that we had reused from Ref. 2. The figure caption as it should have appeared follows. FIG. 2. (a) Schematic depicting human lung, (b) respiratory airways including the bronchioles and the alveolus, (c) gas exchange at the alveolar-capillary membrane of the alveolar sac, and (d) the distribution of the predominant cell types of the human lung. The images for (a) and (b) created by using the visuals in the SMART Servier Medical Art (https://smart.servier.com/) program licensed under a Creative Commons Attribution 3.0 Unported License. Images for (c) and (d) are reprinted with permission from P. Bajaj et al., ACS Biomater. Sci. Eng. 2, 473 (2016). Copyright 2016 American Chemical Society

Erratum: “Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response” [Biomicrofluidics 15, 021501 (2021)]

It has been drawn to the authors’ attention that our original article1 did not appropriately attribute portions of a figure that we had reused from Ref. 2. The figure caption as it should have appeared follows. FIG. 2. (a) Schematic depicting human lung, (b) respiratory airways including the bronchioles and the alveolus, (c) gas exchange at the alveolar-capillary membrane of the alveolar sac, and (d) the distribution of the predominant cell types of the human lung. The images for (a) and (b) created by using the visuals in the SMART Servier Medical Art (https://smart.servier.com/) program licensed under a Creative Commons Attribution 3.0 Unported License. Images for (c) and (d) are reprinted with permission from P. Bajaj et al., ACS Biomater. Sci. Eng. 2, 473 (2016). Copyright 2016 American Chemical Society

Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response

Respiratory viral infections are leading causes of death worldwide. A number of human respiratory viruses circulate in all age groups and adapt to person-to-person transmission. It is vital to understand how these viruses infect the host and how the host responds to prevent infection and onset of disease. Although animal models have been widely used to study disease states, incisive arguments related to poor prediction of patient responses have led to the development of microfluidic organ-on-chip models, which aim to recapitulate organ-level physiology. Over the past decade, human lung chips have been shown to mimic many aspects of the lung function and its complex microenvironment. In this review, we address immunological responses to viral infections and elaborate on human lung airway and alveolus chips reported to model respiratory viral infections and therapeutic interventions. Advances in the field will expedite the development of therapeutics and vaccines for human welfare

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Dissecting the role of biliary epithelial cells during non-alcoholic fatty liver disease progression

The liver is the largest solid organ and the only one capable of using regenerative mechanisms to recover its mass fully. Although liver regeneration from acute injuries has been effective and extensively studied, chronic liver damage has adverse effects on hepatic histology, such as fibrosis or cirrhosis, suggesting that regenerative mechanisms have been disrupted. The most common form of chronic liver disorder, non-alcoholic fatty liver disease (NAFLD), is a growing cause of end-stage liver disease worldwide and is estimated to increase 2-3-fold by 2030. Despite the enormous amount of ongoing research on this topic, no treatment is available, leaving liver transplantation as the only current option. One approach to revert this situation focuses on facultative liver stem cells derived from the biliary epithelium. This recent alternative comes from the breakthrough that biliary epithelial cells (BEC) can be assembled into complex three-dimensional organoid structures in vitro from bile duct-derived stem cells. These BEC-organoids can be expanded as stem cells, with a similar phenotype to injury-induced BECs in vivo, and also can be differentiated into functional hepatocyte-like cells with engraftment ability upon transplantation. Considering the potential of BEC-organoids, I focused on dissecting the role and unveiling the potential of BECs in the context of NAFLD. BECs undergo rapid reprogramming and proliferation in chronic liver diseases, including the fibrotic stage of NAFLD, a process known as ductular reaction (DR). Thus, studying DR provides new insights into the BEC expansion mechanisms. For this purpose, I first investigated the effect of hepatic overload on BECs to study the initiation of DR during the early stages of NAFLD. I demonstrated that lipid overload induces the conversion of adult cholangiocytes into proliferating BECs and promotes their expansion via the activation of the E2F transcription factors, which drives cell cycle progression while promoting glycolytic metabolism. These observations, while correlative, reveal unexpected connections between lipid metabolism and stemness, and set the ground for future research in understanding the role and the therapeutic potential of lipid metabolism and E2Fs in controlling BEC activation. On the other hand, DR correlates closely with the severity of fibrosis in NAFLD, even though the function is largely unknown. Thus, I studied the effect of the mechanical properties of the fibrotic environment in BEC-organoid cultures by using the synthetic matrix we developed together with colleagues. The investigation of BECs cultured in a defined mechanical environment mimicking fibrotic stiffness revealed decreased stem cell capacities and increased inflammation, hepatic injury, and matrix metalloproteases. Finally, by using recently published data comparing BEC-organoid cultures from healthy and NASH patients, I revealed that hydrogels with fibrotic stiffness mimic the phenotype of organoids derived from NASH patients. As a result, investigating aberrant stiffness will enable the development of powerful DR models and future therapeutics for enhancing stem cell-mediated liver regeneration. Overall, the results from this thesis should spark future enthusiasm for the potential of BECs in studying DR regenerative mechanisms and developing therapies.UPSCHOONJAN

INVESTIGATION OF GROUNDWATER QUALITY IN AQUIFERS BETWEEN KONYA HIGHWAY AND ÇAYYOLU ROAD (ANKARA)

Bu çalışma, Çayyolu-Konya Yolu arasındaki (Ankara) akiferlerde, yeraltı sularının kalitesinin incelenmesini kapsar. Kuyulardan alınan yeraltı suyu örneklerinin pH, sıcaklık, elektriksel iletkenlik parametreleri yerinde ölçülmüş, laboratuarda ise katyon ve anyon analizleri yapılmıştır. Sonuçlar grafiksel yöntemlerle, standartlar ve yönetmeliklerle karşılaştırılmıştır. İnceleme alanına ait su kimyası verileri Piler, Schoeller, Wilcox ve ABD Tuzluluk Laboratuarı diyagramları çizilerek değerlendirmeleri yapılmış, yeraltı sularındaki baskın hidrokimyasal fasiyesin sodyum ve bikarbonat olduğu tespit edilmiştir. Standart parametrelerin dışında, su örneklerinde bor ve florür analizleri de yapılmış ve yine içme suyu ve sulama suyu standartlarıyla karşılaştırılmıştır. Hidrojeolojik incelemeler kapsamında, bölgedeki hidrojeolojik oluşumlar tanımlanmıştır. Bölgenin jeolojisi ile, suların mineral v doygunlukları karşılaştırılarak; su örneklerinin hangi jeolojiye ait akiferden geldiği yorumlanmıştır. Bu çalışmada yapılan analizler su örneklerinin içme suyu olarak kullanılmasını saptamak için yeterli olmamakla beraber, elde edilen veriler genel anlamda fikir vermesi amacıyla içme suyu kriterleri yönünden de değerlendirilmiştir.This study covers the investigation of groundwater quality in aquifers between Konya Highway and Çayyolu Road (Ankara). The pH, temperature and the electrical conductivity parameters of the groundwater samples collected from wells were calculated on site, and their cation and anion analyses have been carried out in the laboratory. By using graphical methods, the results are interpreted in comparison to standards and regulation. After the water chemistry data from the research area are evulated by drawing Piper, Schoeller, Wilcox and US Salinity Laboratory diagrams, it is determined that the domiant hydrochemical facies in the underground waters are sodium and bicarbonate type. Other than the standard parameters, boron and fluoride analysis are also conducted on water samples, and the results are compare again with drinking and irrigation waters. Within the framework of hydrogeological studies, hydrogeological formation in the region have been determined. Comparative study between the geological characteristics of the region and the mineral saturation of the waters were used to interpret which water conduits the water samples came from and to which geology these water conduits belong. Although the results of this study are not sufficient enough to determine whether the water samples can be used as drinking water or not; the results are also evaluate against drinking water standards to give a general idea

Two Echelon Locatıon Routıng Problem Wıth Sımultaneous Pıck Up And Delıvery And Solutıon Approaches

Son yıllarda şehir lojistiği kavramının önem kazanmasıyla lojistik ağlar çok aşamalı olarak tasarlanmaya başlamıştır. Çevresel sorunlar konusunda farkındalığın artmasıyla da ileri ve geri yöndeki lojistik faaliyetleri birleştirme eğilimi oluşmuştur. Ayrıca, maliyet etkin lojistik ağların tasarlanması için tesis yerleşim yerleri ve dağıtım rotaları kararlarının birlikte ele alınması gerekliliği ortaya çıkmıştır. Bu tezde iki aşamalı, ileri ve geri yönde lojistik faaliyetlerin eş-zamanlı olarak gerçekleştirildiği lojistik ağ tasarımı problemi ele alınmıştır. Literatürde ilk kez bu tezde ele alınan bu problem, İki Aşamalı Yer Seçimi ve Eş-Zamanlı Topla Dağıt Araç Rotalama Problemi (2A/YS-ETDARP) olarak adlandırılmıştır. 2A/YS-ETDARP, ana ve ara depoların yerlerinin ve her iki aşamada topla-dağıt faaliyetlerini eşzamanlı gerçekleştirecek araç rotalarının toplam maliyeti enazlayacak şekilde belirlenmesi olarak tanımlanır. Günlük hayatta bu problem ile depozitolu içecek firmalarının ve market zincirlerinin dağıtım sistemlerinde karşılaşılmaktadır. Bu tezde, 2A/YS-ETDARP’ın çözümü için düğüm tabanlı bir matematiksel model geliştirilmiş ve geçerli eşitsizlikler kullanılarak güçlendirilmiştir. Ayrıca, problemin farklı durumları için matematiksel modelin uyarlamaları yapılmıştır. 2A/YS-ETDARP, NP-zor problemdir. Bu nedenle, küçük ve orta boyutlu problemleri çözmek için Dal-Kesme algoritmasına (DK) dayalı bir kesin çözüm algoritması geliştirilmiştir. Büyük boyutlu problemlere kısa sürelerde iyi kalitede çözüm üretebilmek için de Değişken Komşu Arama ve İteratif Yerel Arama algoritmalarına dayalı karma bir sezgisel algoritma (İYA_DKA) önerilmiştir. Bu sezgisel algoritma, DK’da üst sınırları iyileştirmek amacıyla da kullanılmıştır. Literatürden uyarlanan veri setleri üzerinde yapılan sayısal analizler ile İYA_DKA ve DK algoritması ile makul süreler içerisinde iyi kalitede çözümlere ulaşılabildiği görülmüştürIn recent years, the concept of city logistics has gained importance and logistics networks have been designed in multiple echelons. With the increase in environmental awareness, a tendency has emerged to combine forward and backward logistics activities. Additionally, a necessity of combining facility location and routing decisions has occurred to design cost-effective logistics networks. In this thesis, a two-echelon logistics network design in which forward and reverse logistic activities are performed simultaneously is considered. This problem, studied firstly in this thesis, is called Two Echelon Location Routing and Simultaneous Pickup and Delivery Problem (2E-LRPSPD). The 2E-LRPSPD can be defined as determining the location of main and intermediate depots and designing vehicle routes to be used for simultaneous pickup and delivery activities at both echelons to minimize total cost. A node-based mathematical model is developed to solve the problem and it is strengthened by using valid inequalities. In addition, mathematical model is adapted for three different versions of the 2E-LRPSPD. The 2E-LRPSPD is an NP-Hard problem. Thus, an exact solution algorithm based on branch & cut (BC) is proposed to solve small- and medium-size problems. A heuristic algorithm based on Iterated Local Search (ILS) and Variable Neighborhood Search (VNS) algorithms, ILS_VNS, is also developed to solve large-size problems in a short computation time. Meanwhile, the ILS_VNS is implemented to tighten upper bounds for the BC algorithm. The performances of the BC and ILS_VNS are investigated on test instances derived from literature. Numerical analyses show that good quality solutions are obtained in reasonable times by ILS_VNS and BC algorithms