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Background Transcatheter renal denervation (RDN) has had inconsistent efficacy and concerns for durability of denervation. We aimed to investigate long‐term safety and efficacy of transcatheter microwave RDN in vivo in normotensive sheep in comparison to conventional radiofrequency ablation. Methods and Results Sheep underwent bilateral RDN, receiving 1 to 2 microwave ablations (maximum power of 80–120 W for 240 s–480 s) and 12 to 16 radiofrequency ablations (180 s–240 s) in the main renal artery in a paired fashion, alternating the side of treatment, euthanized at 2 weeks (acute N=15) or 5.5 months (chronic N=15), and compared with undenervated controls (N=4). Microwave RDN produced substantial circumferential perivascular injury compared with radiofrequency at both 2 weeks [area 239.8 (interquartile range [IQR] 152.0–343.4) mm2 versus 50.1 (IQR, 32.0–74.6) mm2, P

Many manufacturing firms face considerable difficulties in building export capacity and selling their products in international markets. These firms often struggle with unpredictable cost changes, logistical problems along the supply chain, and rising labor expenses that could threaten the competitive edge of manufacturing operations. As there is also a clear absence of practical export models tailored to the unique needs of industrial firms, our study aims to offer a more holistic approach to assessing the impact of cost components on enhancing export-oriented production capacity (EOPC), a perspective not comprehensively provided by the comparative advantage theory, the Heckscher–Ohlin model, or the resource-based theory. While offering a comprehensive analysis of cost components in production, we argue that adjusting the resources, managing the costs, and enhancing production efficiency can significantly improve the EOPC of the manufacturing firms. Using primary data collected from 200 manufacturing firms in Oman during the period 2012–2016, multiple regression analysis followed by descriptive statistical analysis together with a correlation matrix indicates strong positive relationships between the EOPC and factors such as the raw material cost (RMC), labor wages (LW), labor force (LF), and R&D costs (RND). Multicollinearity assessment shows VIF values below the threshold, suggesting reliable estimates. Interaction terms and market conditions were integrated into the model, enhancing its predictive accuracy. Preliminary multiple regression analysis confirms the significant impact of the RMC, LW, LF, and R&D on the EOPC, while highlighting the importance of market conditions in moderating these effects. The model’s adjusted R2 value indicates a strong fit, showing that the independent variables account for a substantial proportion of the variance in the EOPC. Each variable’s importance is reflected in its coefficient, while p-values assess the statistical significance, highlighting which factors are crucial for enhancing export capabilities. Specifically, low p-values for cost components, labor force size, and wages confirm their significant influence, and varying market conditions further modulate these effects, demonstrating the accurate interplay between internal and external factors. Adjustments in cost components under varying market scenarios were analyzed, indicating optimal strategies for increasing the EOPC. Of the five scenarios proposed to distribute the cost either among some variables while keeping others constant or among all the factors, the best-case scenario adjusted all variables together, resulting in a 20% increment in exports. We conclude with some practical and policy implications for governments to support industries in accessing cheap resources through tax reductions on imported raw materials and efficient supply chains, while promoting innovation, technology adoption, and R&D investment at the firm level.

The depletion of fossil fuels, economic concerns over the sharp fluctuations in oil prices, and environmental concerns including global warming have renewed interest in alternative green energy solutions in the form of renewable energy technologies. Solar energy is one of the most promising and environmentally friendly forms of renewable energy for power generation. However, energy transition towards renewables has been slow in developing countries, particularly in the oil-rich Arab Gulf countries. To assess the perspective of Omani consumers in terms of solar energy use, barriers, and readiness to use solar energy for sustainable development, this study aims to determine the proportion of the Omani population who use solar energy, the barriers to solar energy consumption in Oman, people’s perceptions towards solar energy barriers, policies aimed at promoting solar energy programs, and the likelihood and willingness to use solar energy in the future. This analysis is based on quantitative data collected through a questionnaire survey distributed in Oman between 20 June 2023 to 12 August 2023. We used 113 samples for analysis using Principal Component Analysis and Krushkal–Wallis H-tests. Our results revealed that 95% of the residents and commercial units surveyed are willing to use solar PV in the future. The main barriers identified include high installation costs, high maintenance costs, and lack of awareness. The potential for growth in solar energy consumption and use depends on the capacity of the government to provide substantial incentives, financial support, improved quality, implement public-private partnership programs, as well as introduce a clear solar energy policy. While evaluating consumers’ awareness and intentions to use solar energy in the future, this study offers practical implications for policymakers to forecast the potential growth, identify effective policy instruments for promoting renewable energy, and determine the readiness of the country for transition to cleaner energy consumption.

Purpose – The border closure and lockdowns due to Covid-19 pandemic resulted in partial closure of many industrial and commercial complexes, halted the performance of key strategic sectors such as logistics and supply chains, and thus disrupted the global value chains and the economy. The authors argue, however, that the pursuit of survival has driven companies to innovate and use digitization to overcome the negative consequences of the pandemic. More specifically, in this paper the authors aim to assess the success and challenges faced by companies in digitization policy design, adoption and implementation and their effects on firms’ operation, outputs and customer base during Covid-19. Design/methodology/approach – Sixty-one samples of the companies surveyed between 10 January and 30 April 2021 were analyzed, using the Krushkal–Wallis test and Independent-Samples Mann–Whitney U test to identify the relationships between variables including operation, overall output, customer base, digitization policy, technology use and implementation costs of new technologies. Findings – Results revealed a positive impact of digitization on the operation and overall outputs, while no effect was observed on the customer base. Analysis also showed that only 1.8% of companies were able to fully implement digitization, and that the cost of technology prevented most companies from using emerging technology or implementing their digitization policy. Research limitations/implications – While the research has practical implications, it is not without flaws. For instance, the outcome of technology varies as per geographic area and people. The study was conducted in the Sultanate of Oman, a developing country in the Middle East region; therefore, it is difficult to generalize the outcomes suited to developed countries. The developed countries usually have a population quite used to the advanced technologies so some of the issues raised in the study might not work in the logistics and supply chain sectors of the developed countries. Such countries need separate studies. Practical implications – The findings will have implications for both supply chain companies as well as the technology providers. The supply chain companies will invest in technology infrastructure and add technology as an important component in their business models. The technology providers will consider the costs of implementation and adoption issues of technology in the supply chain companies. Originality/value – To the best of authors' knowledge, no work has been produced on logistics and supply chain companies considering the technological sustainability during the time of Covid-19. The study will improve understanding of the digitization policy design, adoption and implementation and their effects on logistics and supply chain companies’ performance.

Abstract Globally, operational capabilities of small and medium enterprises (SMEs) have been immensely affected by the COVID-19 pandemic, forcing many companies to use technology and innovation rather than the more traditional methods of operations. As the extent to which SMEs’ adoption of technological tools is still unknown, this study assesses the technological transformations and the challenges facing SMEs during the pandemic. It also evaluates the levels of customers satisfaction and future technological innovation plans in SMEs. Using quantitative and qualitative primary date, we empirically examine how COVID-19 lockdowns accelerated technology use in Omani SMEs and test eight hypotheses applying paired t test and Pearson’s correlation. Although the impact of the COVID-19 pandemic has been globally felt, this study focuses on the effect of the pandemic on SMEs operating in the logistics and supply chain sector in the Sultanate of Oman. The primary data used was collected through the survey questionnaire and interviews with business owners and company executives covering the period 2020–2021. The results show strong correlations between technology use before and during COVID-19; technology use during COVID-19 and in future; and technology use before COVID-19 and in future. They also reveal that technology adoption has been a successful persistence strategy during the pandemic and that highly digitized SMEs are more likely to adopt industry 4.0 technology. The findings are expected to have practical implications for policy making by investing and developing digital infrastructure to accelerate digital transformation, while company executives appreciating the requirements and benefits of adopting innovation and technology solutions to remain competitive. We acknowledge the limitation of our study to only SMEs in the Sultanate of Oman and within a short period of time during the COVID-19 pandemic. This makes it hard to generalize our findings; hence, we recommend further research in other business sectors and countries in the post-pandemic to corroborate our findings and compare outcomes. To the best of the authors' knowledge, no research has been done on SMEs that consider technological transformation during COVID-19. The study will advance knowledge of the development and adoption of technology in SMEs, as well as their impacts on productivity and efficiency.

This paper underlines the significance of free trade agreements in attracting foreign direct investment and their impact on the operational capacities of local firms in host countries. It argues that free trade agreements do not only eliminate barriers to trade, but they also increase the size of the regional market and improve the business environment, making it more attractive to foreign direct investment, along with all the attributes and spillover effects associated with it. While determining the type of spillover effects of foreign direct investment associated with Oman’s trade agreements, this paper uses the Kruskal–Wallis H-test and 438 samples from companies surveyed between 1 August and 31 October 2023 to assess the impact of spillovers on the performance of the surveyed companies. The results reveal that technology transfer, knowledge transfer, labour productivity, product efficiency, capital investments, and job creation have positive effects on the firms’ operational capacities, with technology transfer having the highest impact (27%), followed by labour productivity and job creation (18%). The spillover effects are almost the same for company size and percentage of ownership. They also identified manufacturing and tourism as priority sectors and the availability of a skilled workforce as a major challenge. These findings make original contribution to the field as this is probably the first study to produce a firm-level analysis of spillover effects of foreign direct investment and trade agreements in the context of Oman and the wider Gulf region. The paper concludes with practical implications for policy makers when negotiating trade agreements and designing investment policies to optimize spillover effects on the performance of their domestic firms.

The current research deals with an experimental and numerical inspection of the shell and helically coiled tube heat exchanger (SHCTHE) under various circular, elliptic, and square tube cross-sections. The research study strives to ameliorate the thermal-hydraulic performance with single nanofluids of Al2O3/H2O, MgO/H2O, and TiO2/H2O. Various factors were inspected to consider the heat exchanger performance under parameters, SHCTHE inclination angle, HCT diameter ratio, flow direction, the cross-section geometry shape, nanomaterials type, and nanomaterials concentration. The modeling engaging a numerical code tool of ANSYS-FLUENT 19 was accomplished with a 3D (RNG)/k–ϵ model. The mass flow rate and working fluid temperatures through the coil and shell sides were (0.05:0.2 kg/s at 80 °C and 0.05–0.2 kg/s at 10 °C, respectively. One of the most important results was that the SHCTHE with a circular tube cross-section gave the highest Nusselt number with an approximate percentage of 62.5%. The SHCTHE effectiveness and the number of transfer units were enhanced by around 19.35% and 30.78%, respectively, by the greater HCT diameter ratio and Al2O3 nanomaterials. Nusselt number, friction factor, and SHCTHE effectiveness were correlated through equations (52:55) with dimensionless factors and their limitations.

Economic integration, which in today’s global trade is the fundamental component of linking economic ties between countries, is another important factor in the acceleration of economic growth. The provision of trade logistics services is essential to a nation’s economic success in international trade activities. It is essential for enterprises engaged in active international trade to achieve competitive advantages. The international trade and localised commercial activity, to a large extent, is dependent on the logistics and supply chain infrastructure and operational capacity. However, the area received little attention from the perspective of applied economics. The in-depth empirical studies on the impacts of logistics on trade efficiency are few and limited. The study aims to investigate the role of logistics and supply chains in international and national trade in a developing country. It uses secondary data for the analysis. The model and software used in the study are the gravity model and GTAP10a. The time horizon used spans 2014–2030. The results show that in order to enhance trading and commercial activities, a developing country should develop logistics and supply chain infrastructure, train people, and design a flexible logistics policy.

Abstract Background Intravenous iron is often used to treat iron deficiency anaemia in non-dialysis chronic kidney disease (ND-CKD), but the optimal dosing regimen remains unclear. We evaluated the impact of high- versus low-dose intravenous iron isomaltoside on the probability of retreatment with intravenous iron in iron-deficient ND-CKD patients. Methods This real-world, prospective, observational study collected data from 256 ND-CKD patients treated for anaemia in the UK. Following an initial course of iron isomaltoside, patients were followed for ≥12 months. Iron dose and the need for retreatment were determined at the investigators’ discretion. The primary study outcome was the need for retreatment at 52 weeks compared between patients who received >1000 mg of iron during Course 1 and those who received ≤1000 mg. Safety was evaluated through adverse drug reactions. Results The probability of retreatment at Week 52 was significantly lower in the >1000 mg iron group (n = 58) versus the ≤1000 mg group (n = 198); hazard ratio (95% confidence interval [CI]): 0.46 (0.20, 0.91); p = 0.012. Mean (95% CI) haemoglobin increased by 6.58 (4.94, 8.21) g/L in the ≤1000 mg group and by 10.59 (7.52, 13.66) g/L in the >1000 mg group (p = 0.024). Changes in other blood and iron parameters were not significantly different between the two groups. Administering >1000 mg of iron isomaltoside saved 8.6 appointments per 100 patients compared to ≤1000 mg. No serious adverse drug reactions were reported. Of the patients who received ≤1000 mg of iron in this study, 82.3% were eligible for a dose >1000 mg. Conclusions The >1000 mg iron isomaltoside regimen reduced the probability of retreatment, achieved a greater haemoglobin response irrespective of erythropoiesis-stimulating agent treatment, and reduced the total number of appointments required, compared to the ≤1000 mg regimen. Many of the patients who received ≤1000 mg of iron were eligible for >1000 mg, indicating that there was considerable underdosing in this study. Trial registration ClinicalTrials.gov NCT02546154 , 10 September 2015.

Background and Aims: Optimal pain control can be a challenge in cirrhotic patients. The aim was to compare the analgesic efficacy and side effects of intravenous fentanyl patient-controlled analgesia (PCA) with and without bupivacaine boluses in transversus abdominis plane (TAP) and rectus sheath space (RSB) in cirrhotics undergoing liver surgery. Material and Methods: A double-blinded randomized controlled trial (n = 55, child's A) was conducted. Catheters were inserted surgically in TAP and rectal sheath space during surgical closure. Fentanyl PCA + TAP + RSB group (gp) (n = 30): (0.2 ml/kg of 0.25% bupivacaine, 8 hourly) was compared with fentanyl PCA gp (n = 25): [0.2 ml/kg of saline (placebo) injected in catheters 8 hourly] for 48 h postoperatively. Plasma bupivacaine was measured with an enzyme-linked immunosorbent assay at 10 min, 30 min, 1 h, 2 h, and 4 h after each injection and 30 min before next injection. Results: Fentanyl consumption was reduced in (PCA + TAP + RSB) gp compared to PCA gp (Day 1: 325.4 ± 169.1 vs. 1034 ± 231.7, Day 2: 204.44 ± 62.9 vs. 481.6 ± 158.3 μg, P < 0.05). Both groups demonstrated effective pain control at rest [Visual Analog Scales (VAS)

Abstract Anaemia is a commonly diagnosed complication among patients suffering with chronic kidney disease. If left untreated, it may affect patient quality of life. There are several causes for anaemia in this patient population. As the kidney function deteriorates, together with medications and dietary restrictions, patients may develop iron deficiency, resulting in reduction of iron supply to the bone marrow (which is the body organ responsible for the production of different blood elements). Chronic kidney disease patients may not be able to utilise their own body’s iron stores effectively and hence, many patients, particularly those receiving haemodialysis, may require additional iron treatment, usually provided by infusion. With further weakening of kidney function, patients with chronic kidney disease may need additional treatment with a substance called erythropoietin which drives the bone marrow to produce its own blood. This substance, which is naturally produced by the kidneys, becomes relatively deficient in patients with chronic kidney disease. Any patients will eventually require treatment with erythropoietin or similar products that are given by injection. Over the last few years, several iron and erythropoietin products have been licensed for treating anaemia in chronic kidney disease patients. In addition, several publications discussed the benefits of each treatment and possible risks associated with long term treatment. The current guidelines provide advice to health care professionals on how to screen chronic kidney disease patients for anaemia, which patients to investigate for other causes of anaemia, when and how to treat patients with different medications, how to ensure safe prescribing of treatment and how to diagnose and manage complications associated with anaemia and the drugs used for its treatment.

Following recent theories and studies on management, organizational spirit has gained a growing significance and has been a central and fundamental topic in management. Anthropologists, sociologists and recently psychologists and even economists, have paid due attention to these new topics and have made lots of research and hypotheses in order to comprehend them and have used their findings in solving management issues. The study aims at perceiving the relation between organizational spirit and aspects of qualitative comprehensive management. The data was celestial through two questioners, the team work spirit question are specially prepared for the staff, consisted of two main sections, the first part included personal credentials asking for the person's age, education, sex, work experience, employment status, and the second part consisted of 28 questions, administered based on the objectives of the study and the question are to the aspects of comprehensive qualitative management consisting of 49 questions filled out by people in change of different department statistic analysis was carried out using Spearman and freedman’s correlation tests and SPSS software, the findings showed there was a relation between organizational spirit and aspects of qualitative comprehensive management.

Identification of risk factors of acute hepatitis C virus (HCV) infection in Egypt is crucial for developing appropriate prevention strategies. There are few community-based studies on the epidemiology and risk factors of hepatitis C infection in Egypt, which could not provide enough information. Clear identification of past and current risk factors for infection is of utmost importance so that intervention programs can be appropriately focused. This study aims to provide up-to-date information about changes in the incidence of individual risk factors for HCV infection transmission in Egypt.A total of 396 chronic HCV patients on follow-up treatment at liver center in El-Qabbary General Hospital in Alexandria were evaluated retrospectively regarding the potential iatrogenic, community acquired and behavioral HCV risk factors. Risk factors for HCV transmission were found in all study populations.At least three identifiable risk factors were reported by each participant. Some behavioral and community-acquired exposures that entail several risky behaviors particularly, unsafe sexual practices were exclusively established among males. We report a significant decline in prevalence of HCV transmission through blood transfusion, parenteral treatment, hospitalization, surgery, non medicalized circumcision, Hijiama done by informal practitioner, tattooing, folk body piercing and threading, sharing hygiene and sharp items, and the use of communal barber or manicure sets among younger age cluster.The pattern of risk differed among older patients compared to younger age group suggesting improved medical care and infection control measures and raised public health awareness regarding the different modes of viral transmission.

Background: Sex differences exist in the prevalence and progression of major glomerular diseases. Podocytes are the essential cell-type in the kidney which maintain the physiological blood-urine barrier, and pathological changes in podocyte homeostasis are critical accelerators of impairment of kidney function. However, sex-specific molecular signatures of podocytes under physiological and stress conditions remain unknown. This work aimed at identifying sexual dimorphic molecular signatures of podocytes under physiological condition and pharmacologically challenged homeostasis with mechanistic target of rapamycin (mTOR) inhibition. mTOR is a crucial regulator involved in a variety of physiological and pathological stress responses in the kidney and inhibition of this pathway may therefore serve as a general stress challenger to get fundamental insights into sex differences in podocytes., Methods: The genomic ROSAmT/mG-NPHS2 Cre mouse model was used which allows obtaining highly pure podocyte fractions for cell-specific molecular analyses, and vehicle or pharmacologic treatment with the mTOR inhibitor rapamycin was performed for 3 weeks. Subsequently, deep RNA sequencing and proteomics were performed of the isolated podocytes to identify intrinsic sex differences. Studies were supplemented with metabolomics from kidney cortex tissues., Results: Although kidney function and morphology remained normal in all experimental groups, RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways. Interestingly, rapamycin abolished prominent sex-specific clustering of podocyte gene expression and induced major changes only in male transcriptome. Several sex-biased transcription factors could be identified as possible upstream regulators of these sexually dimorphic responses. Concordant to transcriptomics, metabolomic changes were more prominent in males. Remarkably, high number of previously reported kidney disease genes showed intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition., Conclusions: Our results highlight remarkable intrinsic sex-differences and sex-specific response patterns towards pharmacological challenged podocyte homeostasis which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. This work provides rationale and an in-depth database for novel targets to be tested in specific kidney disease models to advance with sex-specific treatment strategies., (© 2024. The Author(s).)

Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APCs), particularly dendritic cells (DCs), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DCs (cDCs) and APCs on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation. By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. Notably, the skin component exhibited heightened immunogenicity when compared to the entire VCA, evidenced by increased frequencies of pan (CD11b - CD11c + ), mature (CD11b - CD11c + MHCII + ) and active (CD11b - CD11c + CD40 + ) DCs and cDC2 subset (CD11b + CD11c + MHCII + ) in the lymphoid tissues and the blood of skin transplant recipients. While donor depletion of cDC and APC reduced frequencies, maturation and activation of DCs in all analyzed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4 + IL-17 + ) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APCs and cDCs mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ashraf, Mengwasser, Reutzel-Selke, Polenz, Führer, Lippert, Tang, Michaelis, Catar, Pratschke, Witzel, Sauer, Tullius and Kern.)

Introduction: Uterus transplantation has revolutionized reproductive medicine for women with absolute uterine factor infertility, resulting in more than 40 reported successful live births worldwide to date. Small animal models are pivotal to refine this surgical and immunological challenging procedure aiming to enhance safety for both the mother and the child., Material and Methods: We established a syngeneic bicornuate uterus transplantation model in young female Lewis rats. All surgical procedures were conducted by an experienced and skilled microsurgeon who organized the learning process into multiple structured steps. Animals underwent meticulous preoperative preparation and postoperative care. Transplant success was monitored by sequential biopsies, monitoring graft viability and documenting histological changes long-term., Results: Bicornuate uterus transplantation were successfully established achieving an over 70% graft survival rate with the passage of time. The bicornuate model demonstrated safety and feasibility, yielding outcomes comparable to the unicornuate model in terms of ischemia times and complications. Longitudinal biopsies were well-tolerated, enabling comprehensive monitoring throughout the study., Conclusions: Our novel bicornuate rat uterus transplantation model provides a distinctive opportunity for sequential biopsies at various intervals after transplantation and, therefore, comprehensive monitoring of graft health, viability, and identification of potential signs of rejection. Furthermore, this model allows for different interventions in each horn for comparative studies without interobserver differences contrary to the established unicornuate model. By closely replicating the clinical setting, this model stands as a valuable tool for ongoing research in the field of uterus transplantation, promoting further innovation and deeper insights into the intricacies of the uterus transplant procedure., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Endothelin-1 is a key regulator of vascular tone and blood pressure in health and disease. We have recently found that ET-1 production in human microvascular endothelial cells (HMECs) can be promoted by angiotensin II (Ang II) through a novel mechanism involving octamer-binding transcription factor-1 (Oct-1), NADPH oxidase-2 (NOX2), and superoxide anions. As the formation of bioactive ET-1 also depends on endothelin-converting enzyme-1 (ECE-1), we investigated the transcriptional regulation of the ECE1 gene. We found that exposure of HMECs to Ang II resulted in a concentration- and time-dependent increase in ECE1 mRNA expression. Pharmacological inhibition of ECE-1 reduced Ang II-stimulated ET-1 release to baseline values. The effect of Ang II on ECE1 mRNA expression was associated with Oct-1 binding to the ECE1 promoter, resulting in its increased activity. Consequently, the Ang II-stimulated increase in ECE1 mRNA expression could be prevented by siRNA-mediated Oct-1 inhibition. It could also be abolished by silencing the NOX2 gene and neutralizing superoxide anions with superoxide dismutase. In mice fed a high-fat diet, cardiac expression of Ece1 mRNA increased in wild-type mice but not in Nox2 -deficient animals. It can be concluded that Ang II engages Oct-1, NOX2, and superoxide anions to stimulate ECE1 expression in the endothelium.

Zinc (Zn) is essential for plants and animals as it plays significant roles in several physiological and biological processes. Its deficiency in soil results in low Zn content food and is one of the major reasons for Zn malnutrition in humans. Biofortification of crops with zinc (Zn) is a viable approach to combat malnutrition, especially in developing countries. A hydroponic study was executed to study response and Zn partitioning in various lentil genotypes. Eight preselected lentil genotypes (Line-11504, Mansehra-89, Masoor-2006, Masoor-85, Line-10502, Markaz-09, Masoor-2004, and Shiraz-96) were grown in solution culture with two Zn levels (control and adequate Zn). Plants were sown in polythene lined iron trays with a two inch layer of prewashed riverbed sand. After 10 days of germination, seedlings were transplanted to a 25L capacity container with nutrient solution for 15 days, and afterward, these plants were divided into two groups, receiving either 2.0 mM Zn or no Zn levels. Three plants of each genotype were harvested at the vegetative growth stage (60 DAT) and the remaining three at physiological maturity (117 DAT). Plants were partitioned into roots, shoots, and grains at harvest. Significant variations in root and shoot dry matter production, grain output, partitioning of Zn in plant parts (root, shoot, and grain), grain phytate reduction, and Zn bioavailability were observed among genotypes. Lentil root accumulated more Zn (54 mg kg-1) with respect to shoot Zn (51 mg kg-1) under Zn supply. The Zn efficient genotypes (Line-11504 and Mansehra-89) produced more root and shoot dry weights at both harvests. There was a positive correlation between the relative growth rate of root and grain phytate concentration (r = 0.55) and [phytate]:[Zn] ratio (r = 0.67). Zn-efficient genotype Mansehra-89 had a maximum root shoot ratio (0.57) and higher grain Zn (60 mg kg-1) with a respectively reduced grain phytate (17 µg g-1) and thus, had more Zn bioavailability (3.01 mg d-1). The genotypic ability for Zn uptake and accumulation within different plant tissues may be incorporated into future crop breeding to improve the nutrition of undernourished consumers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rasheed, Maqsood, Aziz, Ashraf, Saleem, Ehsan, Nawaz, Bilal and Xu.)

Objectives: In the last decade, nanobiotechnology is emerging as a keen prudence area owing to its widespread applications in the medical field. In this context, zero-valent iron nanoparticles (nZVI) have garnered tremendous attention attributed to their cheap, non-toxic, excellent paramagnetic nature, extremely reactive surface, and dual oxidation state that makes them excellent antioxidants and free-radical scavengers. Facile biogenic synthesis, in which a biological source is used as a template for the synthesis of NPs, is presumably dominant among other physical and chemical synthetic procedures. The purpose of this review is to elucidate plant-mediated synthesis of nZVI, although they have been successfully fabricated by microbes and other biological entities (such as starch, chitosan, alginate, cashew nut shell, etc.) as well., Methods: The methodology of the study involved keyword searches of electronic databases, including ScienceDirect, NCBI, and Google Scholar (2008-2023). Search terms of the review included 'biogenic synthesis of nZVI', 'plant-mediated synthesis of nZVI', 'medical applications of nZVI', and 'Recent advancements and future prospects of nZVI'., Results: Various articles were identified and reviewed for biogenic fabrication of stable nZVI with the vast majority of studies reporting positive findings. The resultant nanomaterial found great interest for biomedical purposes such as their use as biocompatible anticancer, antimicrobial, antioxidant, and albumin binding agents that have not been adequately accessed in previous studies., Conclusion: This review shows that there are potential cost savings applications to be made when using biogenic nZVI for medical purposes. However, the encountering challenges concluded later, along with the prospects for sustainable future development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-α) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-α secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-α synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-α gene transcription and TNF-α-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses., Competing Interests: Author HH was employed by CellTrend GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Moll, Luecht, Gyamfi, da Fonseca, Wang, Zhao, Gong, Chen, Ashraf, Heidecke, Hackel, Dragun, Budde, Penack, Riemekasten, Cabral-Marques, Witowski and Catar.)

Aims: Expanded hemodialysis (HDx) therapy with improved molecular cut-off dialyzers exerts beneficial effects on lowering uremia-associated chronic systemic microinflammation, a driver of endothelial dysfunction and cardiovascular disease (CVD) in hemodialysis (HD) patients with end-stage renal disease (ESRD). However, studies on the underlying molecular mechanisms are still at an early stage. Here, we identify the (endothelial) transcription factor Krüppel-like factor 2 (KLF2) and its associated molecular signalling pathways as key targets and regulators of uremia-induced endothelial micro-inflammation in the HD/ESRD setting, which is crucial for vascular homeostasis and controlling detrimental vascular inflammation., Methods and Results: First, we found that human microvascular endothelial cells (HMECs) and other typical endothelial and kidney model cell lines (e.g. HUVECs, HREC, and HEK) exposed to uremic serum from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation II (PERCI-II) crossover clinical trial - comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes - exhibited strongly reduced expression of vasculoprotective KLF2 with HF dialyzers, while dialysis with MCO dialyzers led to the maintenance and restoration of physiological KLF2 levels in HMECs. Mechanistic follow-up revealed that the strong downmodulation of KLF2 in HMECs exposed to uremic serum was mediated by a dominant engagement of detrimental ERK instead of beneficial AKT signalling, with subsequent AP1-/c-FOS binding in the KLF2 promoter region, followed by the detrimental triggering of pleiotropic inflammatory mediators, while the introduction of a KLF2 overexpression plasmid could restore physiological KLF2 levels and downmodulate the detrimental vascular inflammation in a mechanistic rescue approach., Conclusion: Uremia downmodulates vasculoprotective KLF2 in endothelium, leading to detrimental vascular inflammation, while MCO dialysis with the novel improved HDx therapy approach can maintain physiological levels of vasculoprotective KLF2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Wu, Gyamfi, Wang, Luecht, Pfefferkorn, Ashraf, Kamhieh-Milz, Witowski, Dragun, Budde, Schindler, Zickler, Moll and Catar.)

Background: The mouse hind limb model represents a powerful research tool in vascularized composite tissue allotransplantation, but its applicability is limited due to poor graft survival (62%-83%). Vascular thrombosis and massive hemorrhage are the major causes for these drop-outs. We hypothesize that because of better anticoagulation effect and lower risk of thrombocytopenia, application of low molecular weight heparin (LMWH) will minimize vascular complications and enhance graft and animal survival., Methods: Fifty allogeneic hind limb transplantations were performed (C57BL/6 to DBA/2 mice) using five different anticoagulation protocols. Bleeding and thromboembolic events were recorded macroscopically by postoperative hemorrhage and livid discoloration of the graft, respectively. Graft perfusion and survival were monitored daily by capillary-refill-time of graft toes within 2-3 seconds. Vascular congestion and tissue necrosis were examined by histological evaluation of hematoxylin-eosin-stained tissue sections., Results: All transplantations were technically successful. Increase in thromboembolic events and a concomitant decrease in bleeding events were observed with the decreasing concentration of heparin in the perfusion solution. Although treatment of donor and recipient with low dose of LMWH could not reduce thromboembolic events, moderate dose effectively reduced these events. Compared with the poor outcome of graft perfusion with heparin alone, additional treatment of donor and recipient with low dose of LMWH improved graft and animal survival by 18%. Interestingly, animals treated with moderate dose of LMWH demonstrated 100% graft and animal survival., Conclusions: Treatment of donor and recipient mice with a moderate dose of LMWH prevents vascular complications and improves the outcome of murine hind limb transplants., Competing Interests: Barbara Kern is participant in the BIH – Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. Stefan Tullius is an Einstein BIH Visiting Fellow. This study was funded by Stiftung Charité in cooperation with Einstein Foundation Berlin. All the other authors have no financial interest to declare in relation to the content of this article. Disclosure statements are at the end of this article, following the correspondence information., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Increasing evidence suggests that superoxide ions produced by NOX (nicotinamide adenine dinucleotide phosphate oxidases) mediate vascular effects of Ang II (angiotensin II) evoked by atherogenic diets. Here, we analyzed the mechanism by which NOX2 contributes to Ang II-induced ET-1 (endothelin 1) production in human microvascular endothelial cells., Methods: The effects of high-fat diet were compared between WT (wild type) and Nox2 ( mouse NOX2 gene )-deficient mice. ET-1 production and NOX2 expression by human microvascular endothelial cells in vitro were analyzed by ELISA, reverse transcription quantitative polymerase chain reaction, electrophoretic mobility shift assay, promoter deletions, RNA interference, and pharmacological inhibition. Production of superoxide anions was visualized by fluorescent cell labeling., Results: Feeding mice high-fat diet for 10 weeks increased cardiac expression and plasma levels of Ang II and ET-1 in WT but not in Nox2 -deficient animals. Exposure of human microvascular endothelial cells to Ang II resulted in increased ET-1 production, which could be blocked by silencing NOX2 ( human NOX2 gene ). Ang II promoted NOX2 expression through induction of the Oct-1 (human/mouse octamer binding transcription factor 1 protein) and activation of the NOX2 promoter region containing Oct-1-binding sites. Stimulation of NOX2 expression by Ang II was associated with increased production of superoxide anions. Inhibition of Oct-1 by small interfering RNA reduced Ang II-induced NOX2 expression and superoxide anion production, and neutralization of superoxide by SOD (superoxide dismutase) abolished Ang II-stimulated ET1 ( human ET-1 gene ) promoter activity, ET1 mRNA expression, and ET-1 release., Conclusions: Ang II may promote ET-1 production in the endothelium in response to atherogenic diets through a mechanism that involves the transcription factor Oct-1 and the increased formation of superoxide anions by NOX2., Competing Interests: Disclosures None.

The polyamines spermidine and spermine and their common precursor molecule putrescine are involved in tissue injury and repair. Here, we test the hypothesis that impaired polyamine homeostasis contributes to various kidney pathologies in mice during experimental models of ischemia-reperfusion, transplantation, rhabdomyolysis, cyclosporine treatment, arterial hypertension, diabetes, unilateral ureteral obstruction, high oxalate feeding, and adenine-induced injuries. We found a remarkably similar pattern in most kidney pathologies with reduced expression of enzymes involved in polyamine synthesis together with increased expression of polyamine degrading enzymes. Transcript levels of amine oxidase copper-containing 1 (Aoc1), an enzyme which catalyzes the breakdown of putrescine, were barely detectable by in situ mRNA hybridization in healthy kidneys. Aoc1 was highly expressed upon various experimental kidney injuries resulting in a significant reduction of kidney putrescine content. Kidney levels of spermine were also significantly reduced, whereas spermidine was increased in response to ischemia-reperfusion injury. Increased Aoc1 expression in injured kidneys was mainly accounted for by an Aoc1 isoform that harbors 22 additional amino acids at its N-terminus and shows increased secretion. Mice with germline deletion of Aoc1 and injured kidneys showed no decrease of kidney putrescine content; although they displayed no overt phenotype, they had fewer tubular casts upon ischemia-reperfusion injury. Hyperosmotic stress stimulated AOC1 expression at the transcriptional and post-transcription levels in metanephric explants and kidney cell lines. AOC1 expression was also significantly enhanced after kidney transplantation in humans. These data demonstrate that the kidneys respond to various forms of injury with down-regulation of polyamine synthesis and activation of the polyamine breakdown pathway. Thus, an imbalance in kidney polyamines may contribute to various etiologies of kidney injury., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Donor age is a major risk factor for allograft outcome in kidney transplantation. The underlying cellular mechanisms and the recipient's immune response within an aged allograft have yet not been analyzed. A comprehensive immunophenotyping of naïve and transplanted young versus aged kidneys revealed that naïve aged murine kidneys harbor significantly higher frequencies of effector/memory T cells, whereas regulatory T cells were reduced. Aged kidney-derived CD8 + T cells produced more IFNγ than their young counterparts. Senescent renal CD8 + T and NK cells upregulated the cytotoxicity receptor NKG2D and the enrichment of memory-like CD49a + CXCR6 + NK cells was documented in aged naïve kidneys. In the C57BL/6 to BALB/c kidney transplantation model, recipient-derived T cells infiltrating an aged graft produced significantly more IFNγ, granzyme B and perforin on day 7 post-transplantation, indicating an enhanced inflammatory, cytotoxic response towards the graft. Pre-treatment of aged kidney donors with the senolytic drug ABT-263 changed the recipient-derived effector molecule profile to significantly reduced levels of IFNγ and IL-10 compared to controls. Graft function after ABT-263 pre-treatment was significantly improved 28 days post kidney transplantation. In conclusion, renal senescence also occurs at the immunological level (inflamm-aging) and aged organs provoke an altered recipient-dominated immune response in the graft., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Papaya (Carica papaya L.) is grown widely in tropical and sub-tropical regions (Ahmed et al. 2008). In Pakistan, papaya production and consumption are increasing due to its medicinal, nutritional, pharmacological properties and a rich source of antioxidant, vitamin B, potassium, and magnesium. In November 2021, 26 to 35% incidence of fruit rot was observed in 15 fields of Lahore, a district of Punjab, Pakistan. Affected fruit developed circular, gray-to-brown lesions (8 to 10 mm in diameter) with white mycelia forming on the surface of lesions. In advanced stages of the disease, the lesions enlarged in size and led to the rot of entire fruit. To isolate the causal agent, small tissue segments (1 to 2 cm) were excised from 15 symptomatic fruit, surface disinfected with 1% NaClO for 30 s, rinsed with sterile distilled water three times, air dried in laminar flow hood, aseptically transferred onto petri dishes containing potato dextrose agar (PDA) and incubated at 25℃ for 5 days with a 12-h photoperiod. Eleven isolates were obtained that produced white mycelia on PDA. Flask-shaped, dark-pigmented pycnidia formed on PDA after 18 days of incubation at 25°C, which produced α-conidia measuring 4.1 to 7.2 × 1.5 to 3.0 μm and β-conidia measuring 16.4 to 25.5 × 1.0 to 1.6 μm (n = 40). α-conidia were hyaline, fusiform, and single-celled, whereas β-conidia were one-celled, hyaline, and filiform. The morphological characteristics of the fungus were compatible with a Diaporthe species (Gomes et al. 2013). The internal transcribed spacer region (ITS) (OM865414 and OM865415), translation elongation factor 1-alpha (tef1) (OM831226 and OM831229), and histone H3 (HIS) (OM831227 and OM831228) of two representative isolates (UO02 and UO03) were amplified and sequenced using primers ITS1/ITS4 (White et al. 1990), EF1-728F/EF1-986R (Carbone and Kohn 1999), and CYLH3F/H3-1b (Chaisiri et al. 2021), respectively. Blast searches showed 99 to 100% nucleotide identity with reference sequences of several Diaporthe amygdali deposited in NCBI GenBank, including the ex-type strain CBS 126679. A pathogenicity test was also performed on harvested fruit of papaya cv. Bombay using isolates UO02 and UO03. Ten mature and healthy papaya fruit were surface disinfected with 1% NaClO solution for 1 min, rinsed with sterile water and dried. Each fruit was wounded twice with a sterile scalpel (4 to 5 mm incision on the peel) and a 5-mm agar disc with mycelia of each isolate was separately placed in each wound. The wounds were wrapped with Parafilm following inoculation. Sterile PDA plugs were used in separate inoculated controls. All wounds were sealed with parafilm. All fruit were maintained in plastic boxes at 25°C with 80% relative humidity. After 6 days of incubation, rot symptoms similar to those appearing on naturally-infected fruit were observed on inoculated fruits while controls remained asymptomatic. The experiment was repeated twice with similar findings. Diaporthe amygdali was re-isolated (100%) from inoculated fruit and the pathogen identification was confirmed by morphological and molecular analysis, thus fulfilling Koch's postulates. Previously, the pathogen has been reported as a causal agent of canker and shoot blight disease in other countries (Ko and Sun, 2003; Beluzan et al. 2021). To our knowledge, this is the first report of D. amygdali on papaya in Punjab Province of Pakistan. Papaya is an emerging fruit crop in Punjab Province and it is important to further investigate the presence of this pathogen in other papaya orchards of the province since D. amygdali may cause rapid disease outbreaks resulting in severe losses.

Potential role of triacontanol applied as a foliar treatment to ameliorate the adverse effects of salinity on hot pepper plants was evaluated. In this pot experiment, hot pepper plants under 75 mM NaCl stress environment were subjected to foliar application of 25, 50, and 75 µM triacontanol treatments; whereas, untreated plants were taken as control. Salt stress had a significant impact on morphological characteristics, photosynthetic pigments, gas exchange attributes, MDA content, antioxidants activities, electrolytes leakage, vitamin C, soluble protein, and proline contents. All triacontanol treatments significantly mitigated the adversative effects of salinity on hot pepper plants; however, foliar application triacontanol at 75 µM had considerably improved the growth of hot pepper plants in terms of plant height, shoot length, leaf area, plant fresh/dry biomasses by modulating above mentioned physio-biochemical traits. While, improvement in gas exchange properties, chlorophyll, carotenoid contents, increased proline contents coupled with higher SOD and CAT activities were observed in response to 75 µM triacontanol followed by 50 µM triacontanol treatment. MDA and H 2 O 2  contents were decreased significantly in hot pepper plants sprayed with 75 µM triacontanol followed by 50 µM triacontanol foliar treatment. Meanwhile, root and shoot lengths were maximum in 50 µM triacontanol sprayed hot pepper plants along with enhanced APX activity on exposure to salt stress. In crux, exogenous application triacontanol treatments improved hot pepper performance under salinity, however,75 µM triacontanol treatment evidently was more effective in mitigating the lethal impact of saline stress via controlling the ROS generation and increment in antioxidant enzyme activities., (© 2022. The Author(s).)

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is a diagnostic marker of intrinsic kidney injury produced by damaged renal cells and by neutrophils. ANCA-associated vasculitis features necrotizing crescentic GN (NCGN), and ANCA-activated neutrophils contribute to NCGN. Whether NGAL plays a mechanistic role in ANCA-associated vasculitis is unknown., Methods: We measured NGAL in patients with ANCA-associated vasculitis and mice with anti-myeloperoxidase (anti-MPO) antibody-induced NCGN. We compared kidney histology, neutrophil functions, T cell proliferation and polarization, renal infiltrating cells, and cytokines in wild-type and NGAL-deficient chimeric mice with anti-MPO antibody-induced NCGN. To assess the role of T H 17 immunity, we transplanted irradiated MPO-immunized MPO-deficient mice with bone marrow from either wild-type or NGAL-deficient mice; we also transplanted irradiated MPO-immunized MPO/IL-17A double-deficient mice with bone marrow from either IL-17A-deficient or NGAL/IL-17A double-deficient mice., Results: Mice and patients with active ANCA-associated vasculitis demonstrated strongly increased serum and urinary NGAL levels. ANCA-stimulated neutrophils released NGAL. Mice with NGAL-deficient bone marrow developed worsened MPO-ANCA-induced NCGN. Intrinsic neutrophil functions were similar in NGAL-deficient and wild-type neutrophils, whereas T cell immunity was increased in chimeric mice with NGAL-deficient neutrophils with more renal infiltrating T H 17 cells. NGAL-expressing neutrophils and CD3 + T cells were in close proximity in kidney and spleen. CD4 + T cells showed no intrinsic difference in proliferation and polarization in vitro , whereas iron siderophore-loaded NGAL suppressed T H 17 polarization. We found significantly attenuated NCGN in IL-17A-deficient chimeras compared with MPO-deficient mice receiving wild-type bone marrow, as well as in NGAL/IL-17A-deficient chimeras compared with NGAL-deficient chimeras., Conclusions: Our findings support that bone marrow-derived, presumably neutrophil, NGAL protects from ANCA-induced NCGN by downregulating T H 17 immunity., (Copyright © 2020 by the American Society of Nephrology.)

Background The purpose of this study is to analyze potential predisposing factors for a higher risk of recurrence in our esophageal cancer patients managed with neoadjuvant chemotherapy, radiation therapy, and surgery, and to determine their impact on disease-free survival (DFS) and time to recurrence. Methods A total of 154 of 232 patients staged T1b to T4a managed electively at our institute from July 2005 through July 2015 with a tri-modality approach were retrospectively evaluated. Basic demographic, clinical, radiological, operative, and pathological disease-related parameters, along with waiting time for surgery and type of neoadjuvant modality used, were assessed as potential risk factors. The primary endpoint was the impact of these on the risk of recurrence. The secondary endpoint was to study their relation on DFS and time to recurrence. Results The recurrence rate in this particular study was 33.1% over a median follow-up of 35 months (interquartile range = 19-50.3). The median time to recurrence was 12 months, and 94% of recurrences occurred within two years. The median DFS was 33 months, and the one- and three-year DFS was 90% and 72%, respectively. On univariate and multivariate analysis, a complete pathological response (hazard ratio [HR]: 3.8, 95% confidence interval [CI]: 1.41-10.11), negative resection margins (HR: 5.9, 95% CI: 1.69-20.45), and a low nodal index (HR: 6.3, 95% CI: 1.37-28.67 for an index of 0.1-0.2; and HR: 15.2, 95% CI: 0.96-241.73 for an index of >0.2) were found as statistically significant (P = < 0.05) for risk to recurrence. In addition to these three, a low comorbidity index (P = 0.03; HR: 3.5; 95% CI: 1.16-10.52) was an individual positive predictor of DFS. Conclusions A complete pathological response, low nodal index, and margin-negative resection were the identified predictors of freedom from recurrence, with a better DFS and a low comorbidity index as additional indicators of prolonged DFS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Khan et al.)

Forests are important carbon pools as they provide pathway to mitigate climate change. Quantification of forest carbon has gained momentum after Paris Agreement in 2015. This information is a prerequisite for REDD+ implementation and carbon trading. Temperate and subtropical mountain systems of Khyber Pakhtunkhwa province host about one third of Pakistan's 4.51 million ha forests. Present study estimated forest carbon stocks in the Khyber Pakhtunkhwa province of Pakistan. The data was collected from 449 sites in different forests across the province using a stratified cluster sampling technique. Total carbon stock in the forests of the province was estimated at 144.71 million tons with an average of 127.66 ± 9.32 t/ha. Aboveground carbon stock was 68.15 million tons accounting for 48% of the total forest carbon stock of the province. Further, belowground biomass and litter accounted for 10% and 1% respectively. The mean aboveground carbon stock was 59.98 ± 4.26 t/ha. The highest aboveground carbon stock was found in dry temperate forests (99.41 t/ha) followed by moist temperate (85.04 t/ha). Overall, temperate forests have aboveground carbon stock of 90.52 t/ha. Temperate and subtropical forests of Pakistan with high carbon densities have ample potential for reducing forest sector emissions. Therefore, forests of Khyber Pakhtunkhwa province having substantial carbon stocks must be conserved for climate change mitigation. Present study provides a framework for carbon stock assessments in other temperate and subtropical regions of the world.

Industry is going through a transformation phase, enabling automation and data exchange in manufacturing technologies and processes, and this transformation is called Industry 4.0. Industrial Internet-of-Things (IIoT) applications require real-time processing, near-by storage, ultra-low latency, reliability and high data rate, all of which can be satisfied by fog computing architecture. With smart devices expected to grow exponentially, the need for an optimized fog computing architecture and protocols is crucial. Therein, efficient, intelligent and decentralized solutions are required to ensure real-time connectivity, reliability and green communication. In this paper, we provide a comprehensive review of methods and techniques in fog computing. Our focus is on fog infrastructure and protocols in the context of IIoT applications. This article has two main research areas: In the first half, we discuss the history of industrial revolution, application areas of IIoT followed by key enabling technologies that act as building blocks for industrial transformation. In the second half, we focus on fog computing, providing solutions to critical challenges and as an enabler for IIoT application domains. Finally, open research challenges are discussed to enlighten fog computing aspects in different fields and technologies.

Background Pancreatic cancer patients undergoing curative resection need staging laparoscopy for detecting metastatic disease not picked up on standard radiological scans. Identifying these patients can help to prevent unnecessary laparotomies and early induction of palliative therapies. The aim of our study was to determine the effect of staging laparoscopy on resectable pancreatic or periampullary tumors at our hospital. Methods Patients recommended pancreaticoduodenectomy between September 2014 and June 2018 were included in this study. Any significant finding and its impact on management was recorded. Results A total of 120 patients underwent staging laparoscopy. Fifteen patients had suspicious lesions and one patient had cirrhotic liver on staging laparoscopy. Out of these 15 patients nine patients had liver lesions, three patients with peritoneal nodules and three patients having both liver and peritoneal lesions. Among patients with liver lesions, four patients were found to have metastatic deposits. All of the remaining lesions were benign. Plan of curative resection was changed in five patients. Three patients who were planned for pancreaticoduodenectomy cancelled because of hepatic metastasis. One patient with hepatic metastasis showing neuroendocrine tumor considered for resection. One patient with resectable disease had cirrhotic liver on laparoscopy, so not medically fit for this major surgery. Conclusion In patients planned for pancreaticoduodenectomy, staging laparoscopy is an important step to detect metastatic disease involving peritoneum or viscera. It is very helpful in determining the stage of disease and further management plan., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Ashraf et al.)

Natural Killer (NK) cells have recently been recognized as key players in antibody-mediated chronic allograft failure, thus requiring a comprehensive understanding whether NK cells can escape conventional immunosuppressive regimens. Influence of cyclosporine A (CyA) on NK cell function was studied in a mouse model of allogeneic kidney transplantation (KTX, BALB/c to C57BL/6). Recipients were treated daily with CyA (10 mg/kg) for seven or 14 days for long term survival (day 56). Administration of CyA in recipients resulted in significantly reduced frequencies of intragraft and splenic CD8 + T cells, whereas the latter illustrated reduced IFNγ production. In contrast, intragraft and splenic NK cell frequencies remained unaffected in CyA recipients and IFNγ production and degranulation of NK cells were not reduced as compared with controls. Depletion of NK cells in combination with CyA resulted in an improvement in kidney function until day 7 and prolonged graft survival until day 56 as compared to untreated controls. Surviving animals demonstrated higher intragraft frequencies of proliferating CD4 + FoxP3 + Ki67 + regulatory T (T REG ) cells as well as higher frequencies of CD8 + CD122 + T REG . We here demonstrate that NK cell depletion combined with CyA synergistically improves graft function and prolongs graft survival, suggesting that NK cell targeting constitutes a novel approach for improving KTX outcomes., (Copyright © 2019 Ashraf, Sarwar, Kühl, Hunger, Sattler, Aigner, Regele, Sauter, Klingel, Schneeberger, Resch and Kotsch.)

Catheter-associated urinary tract infections (CAUTI) is an alarming hospital based disease with the increase of multidrug resistance (MDR) strains of Proteus mirabilis . Cases of long term hospitalized patients with multiple episodes of antibiotic treatments along with urinary tract obstruction and/or undergoing catheterization have been reported to be associated with CAUTI. The cases are complicated due to the opportunist approach of the pathogen having robust swimming and swarming capability. The latter giving rise to biofilms and probably inducible through autoinducers make the scenario quite complex. High prevalence of long-term hospital based CAUTI for patients along with moderate percentage of morbidity, cropping from ignorance about drug usage and failure to cure due to MDR, necessitates an immediate intervention strategy effective enough to combat the deadly disease. Several reports and reviews focus on revealing the important genes and proteins, essential to tackle CAUTI caused by P. mirabilis . Despite longitudinal countrywide studies and methodical strategies to circumvent the issues, effective means of unearthing the most indispensable proteins to target for therapeutic uses have been meager. Here, we report a strategic approach for identifying the most indispensable proteins from the genome of P. mirabilis strain HI4320, besides comparing the interactomes comprising the autoinducer-2 (AI-2) biosynthetic pathway along with other proteins involved in biofilm formation and responsible for virulence. Essentially, we have adopted a theoretical network model based approach to construct a set of small protein interaction networks (SPINs) along with the whole genome (GPIN) to computationally identify the crucial proteins involved in the phenomenon of quorum sensing (QS) and biofilm formation and thus, could be therapeutically targeted to fight out the MDR threats to antibiotics of P. mirabilis . Our approach utilizes the functional modularity coupled with k-core analysis and centrality scores of eigenvector as a measure to address the pressing issues.

Immunofluorescence (IF) staining of paraffin-embedded tissues is a frequently used method to answer research questions or even detect the abundance of a certain protein for diagnostic use. However, the signal originating from specific antibody-staining might be distorted by autofluorescence (AF) of the assessed tissue. Although the AF phenomenon is well known, its presence is often neglected by insufficient staining controls. In this study, we describe the existence of cellular AF in paraffin-embedded healthy and inflamed human and murine colonic tissues and present ways to reduce AF. The AF signal is detectable at emission spectra from 425 nm-738 nm, upon excitation from 403.6-638.7 nm and appears more pronounced in inflamed tissues. Most signals are located subepithelially in the tissue and in blood vessels. Previous studies have shown that the AF signals are caused by lipofuscin, which accumulates in lamina propria immune cells. In murine small intestine AF signals are present in granules in the Paneth cell zone. For alleviation of the AF signal, sudan black b (SBB) or copper sulfate was used. Incubation of the tissue slices with either one of the substances reduced AF. In conclusion, AF appears as an intrinsic biomarker for colonic inflammation. The dominant existence of AF in immune cells of IBD tissue elucidates the importance of negative controls and the limitation of IF staining for potential diagnostic purposes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

Small trees and saplings are important for forest management, carbon stock estimation, ecological modeling, and fire management planning. Turkish pine (Pinus brutia Ten.) is a common coniferous species and comprises 25.1% of total forest area of Turkey. Turkish pine is also important due to its flammable fuel characteristics. In this study, compatible above-ground biomass equations were developed to predict needle, branch, stem wood, and above-ground total biomass, and carbon stock assessment was also described for Turkish pine which is smaller than 8 cm diameter at breast height or shorter than breast height. Compatible biomass equations are useful for biomass prediction of small diameter individuals of Turkish pine. These equations will also be helpful in determining fire behavior characteristics and calculating their carbon stock. Overall, present study will be useful for developing ecological models, forest management plans, silvicultural plans, and fire management plans.

Language, which allows complex ideas to be communicated through symbolic sequences, is a characteristic feature of our species and manifested in a multitude of forms. Using large written corpora for many different languages and scripts, we show that the occurrence probability distributions of signs at the left and right ends of words have a distinct heterogeneous nature. Characterizing this asymmetry using quantitative inequality measures, viz. information entropy and the Gini index, we show that the beginning of a word is less restrictive in sign usage than the end. This property is not simply attributable to the use of common affixes as it is seen even when only word roots are considered. We use the existence of this asymmetry to infer the direction of writing in undeciphered inscriptions that agrees with the archaeological evidence. Unlike traditional investigations of phonotactic constraints which focus on language-specific patterns, our study reveals a property valid across languages and writing systems. As both language and writing are unique aspects of our species, this universal signature may reflect an innate feature of the human cognitive phenomenon.

Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as an early marker protein for kidney dysfunction in various clinical settings. In this prospective study we evaluated serial changes of serum and urinary NGAL within the first 7 days after kidney transplantation in 170 consecutive recipients. The main focus of this study was to assess the performance of serum and urinary NGAL in the prediction of delayed graft function (DGF) and two-year graft and patient survival. Serum and urine samples of 170 patients undergoing primary kidney transplantation from October 2010 to December 2012 were prospectively collected from day 0 to 7. NGAL was analyzed by ELISA. Multivariate regression models, receiver-operating characteristics (ROC), and areas under ROC curves (AUC) were used to identify predictors of DGF. DGF occurred in 52 patients (30.6%). Serum (AUC = 0.869) and urinary NGAL (AUC = 0.872) on postoperative day (POD) 2 could accurately predict DGF compared to serum creatinine (AUC = 0.619). Multivariate analyses revealed donor age, serum and urinary NGAL significantly associated with DGF (p<0.001). Recipient age was the only significant factor in a cox regression model influencing two-year graft and patient survival. In conclusion, serum and urinary NGAL are early predictors of DGF after kidney transplantation.

Objective: To analyze overall survival patterns of our pancreatic cancer patient population managed with a curative or palliative intent., Study Design: Analytical study., Place and Duration of Study: Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from January 2000 till February 2015., Methodology: Aretrospective review of the data of all of our pancreatic cancer patients was performed, using the hospital information system. Patients with tumor other than adenocarcinoma or a histopathologic diagnosis not made at our hospital are excluded from the study, along with patients having an incomplete medical record for all included variables. The main outcome measure was overall survival in months from the date of diagnosis. All results were segregated and analyzed according to the intervention modality used, i.e. group A: surgery with curative intent, group B: Palliative chemotherapy, and group C: Supportive care. Results were controlled for the confounding variables including age, gender, significant comorbid conditions, stage of disease at initial presentation, tumor location, and histological grade., Results: Among the 197 patients fulfilling the inclusion criteria, 21 (10.7%) were excluded as they were lost to follow-up. Overall Kaplan-Meier survival analysis gave a 56% one-year survival, 22% at 3- and 16% at 5-year. The subset analysis on Cox-regression survival plot showed inferior survival with advancing stage of the disease and a treatment less than definitive surgical resection and adjuvant chemotherapy. On Cox-proportional regression analysis, stage of the disease and treatment modality were only independent predictive factors for overall survival (p < 0.01)., Conclusion: Stage for stage, surgery with curative intent (group A) or palliative chemotherapy (group B) showed a trend towards improved survival as compared to supportive management (group C) alone. The results were more significant for surgical resection arm.

Background: Clinical data suggest that iron disturbances deleteriously affect graft survival after heart transplantation (HTx), but immunological mechanisms underlying this phenomenon have not yet been elucidated., Methods: To identify the mechanistic influence of iron in a murine model of HTx, fully allogeneic BALB/c donor organs were transplanted into iron-overloaded or iron-deficient C57BL/6 mice, and recipients were analyzed for functional and immunological parameters., Results: After HTx, iron overload accelerated acute rejection as observed by shortened graft survival (HTx vs HTx + iron; p = 0.01), elevated rejection score (p < 0.01), and induction of troponin T (p < 0.01). Compared with controls, allografts and recipient spleens derived from iron-overloaded recipients were characterized by a pronounced graft infiltration of CD4 + T cells (p < 0.01), CD3 - NKp46 + natural killer cells (p < 0.05), and reduced frequencies of regulatory T cells (p < 0.01). This was accompanied by lower mRNA expression levels of anti-inflammatory cytokines, including interleukin-10, transforming graft factor-β, and Foxp3. Cardiac allograft survival was further tested under co-stimulation blockade (CTLA4-Ig) showing that naïve grafts transplanted into iron-overloaded recipients illustrated restricted graft outcome compared with wild types (p = 0.0051), which was rescued after treatment with the iron chelator deferoxamine. Iron deficiency (ID) also resulted in enhanced intragraft infiltration of inflammatory cells and accelerated rejection in the acute setting (HTx vs HTx + ID; p = 0.02) and after co-stimulation blockade (p = 0.0059)., Conclusions: We provide novel insights into the understanding of disturbances in iron homeostasis and their consequences after HTX, allowing novel insights regarding improvements in personalized immunosuppression to prolong allograft survival., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: There has been an increasing inclination towards minimally invasive esophagectomies (MIEs) at our institute recently for resectable oesophageal cancer., Objectives: The purpose of the present study is to report peri-operative and long-term procedure specific outcomes of the two groups and analyse their changing pattern at our institute., Methods: All adult patients with a diagnosis of oesophageal cancer managed at our institute from 2005 to 2015 were included in this retrospective study. Patients' demographic and clinical characteristics were recorded through our hospital information system. The cohort of esophagectomies was allocated into two groups, conventional open esophagectomy (OE) or total laparoscopic MIE; hybrid esophagectomies were taken as a separate group. The short-term outcome measures are an operative time in minutes, length of hospital and Intensive Care Unit (ICU) stay in days, post-operative complications and 30 days in-hospital mortality. Complications are graded according to the Clavien-Dindo classification system. Long-term outcomes are long-term procedure related complications over a minimum follow-up of 1 year. Trends were analysed by visually inspecting the graphic plots for mean number of events in each group each year., Results: Our results showed no difference in mortality, length of hospital and ICU stays and incidence of major complications between three groups on uni- and multi-variate analysis (P > 0.05). The operative time was significantly longer in MIE group (odds ratio [OR]: 1.66, confidence interval [CI]: 2.4-11.5). The incidence of long-term complication was low for MIE (OR: 1.0, CI: 133-1.017). However, all post-operative surgical outcomes trended to improve in both groups over the course of this study and stayed better for MIE group except for the operative time., Conclusion: MIE has overall comparable surgical outcomes to its conventional counterpart. Furthermore, the peri-operative outcomes tend to improve in our centre with the maturation of program and experience.

Minimally invasive esophagectomy is becoming the routine procedure for resectable esophageal cancer. The aim of this retrospective study is to analyze the oncologic adequacy of these two procedures at our Centre. Out of 1252 registered esophageal cancer patients at our institute from 2006 to 2015, 206 patients who underwent a surgical resection with curative intent and a complete medical record were retrospectively evaluated thru hospital medical record system (HIS). Patients were allocated into the conventional open OE, and minimally invasive MIE and Hybrid esophagectomy groups. Primary outcomes are tumor recurrence and disease-free survival over a minimum follow-up of 1 year along with assessment of adequacy of pathological specimen in terms of lymph nodes harvested and clear longitudinal <1 cm and circumferential (≥1 mm) resection margins for patients with post-neo-adjuvant residual disease. Secondary endpoint is to look for trends in the adequacy of oncologic clearance in each group over the study period. Overall, there was no statistically significant difference (p > 0.05) between groups (OE vs. MIE vs. Hybrid) for median number of lymph nodes retrieved (13 vs.14 vs.15), resection margin positive disease (55.8 vs. 35.7 vs. 44 % of patients with any residual disease N = 103,50 %), or tumor recurrence (45.2 vs. 37.3 vs. 25 %). Disease-free survival over a mean follow-up of 2.3 years was higher in the conventional group (13.8 months vs. 9.7MIE and 11.8hybrid) without any statistical significance. Learning curve for MIE to achieve a comparable mean lymph nodes harvest to OE was 1 year, while pathological complete resection stayed persistently better with minimally invasive approach. Minimally invasive esophagectomy is found to be oncologically adequate and gives results matching their conventional analogue with an increasing experience.

Objective: The aim of study was to investigate whether cell-penetrating peptides could amplify cellular uptake of plasmid DNA (pDNA) loaded self-nanoemulsifying drug delivery systems (SNEDDS) by mucosal epithelial cells, thereby enhancing transfection efficiency., Methods: HIV-1 Tat peptide-oleoyl conjugate (TAT-OL) was synthesized through amide bond formation between HIV-1 Tat-protein 49-57 (TAT) and oleoyl-chloride (OL). SNEDDS formulation contained 29.7% each of Cremophor EL, Capmul MCM and Crodamol, 9.9% propylene glycol and 1% TAT-OL. SNEDDS with OL instead of TAT-OL served as control., Results: Fluorescent-microscopy demonstrated 0.5% (m/v) nanoemulsions were suitable for subsequent studies. Mucus diffusion of nanoemulsion loaded with fluorescein diacetate (FDA) was 1.5-fold increased by incorporation of TAT-OL. Confocal microscopy confirmed that droplets of nanoemulsions were successfully internalized. Furthermore, quantitative analysis showed that addition of TAT-OL increases uptake of nanoemulsions by 2.3- and 2.6-folds after 2 and 4 hours of incubation, respectively. Cellular internalization pathways were found with substantial decrease in uptake in presence of indomethacin and chlorpromazine. Transfection efficiency investigated on HEK-293-cells was found to be 1.7- and 1.8-fold higher for SNEDDS loaded with TAT-OL compared to Lipofectin and control, respectively., Conclusion: In comparison to prevailing lipid and polymer-based delivery systems, these novel cell-penetrating SNEDDS likely represent most effective, simplistic and expedite dosage form for mucosal gene delivery.

Germ Cell Tumours (GCTs) are rare tumours. Generally 80% are benign and 20% malignant with a bimodal age distribution. The retrospective study was conducted at Shaukat Khanum Cancer Hospital, Lahore, Pakistan, and comprised all paediatric patients below 18 years of age who received treatment for histology-proven GCT from 2006 to 2014. Of the 207 patients, 98(42.3%) were males and 109(52.7%) were females. The most common GCT was yolk sac tumour in 90(43.5%) children followed by mixed GCT in 40(19.3%) and dysgerminoma in 34(16.4%). Gonads were most commonly involved in 165(79.7%) patients with metastasis in 24(11.6%) at presentation and recurrence in 26(12.5%) patients. Overall, 133(64.3%) patients are well and followed up at regular intervals and 55(26.5%) have been lost to follow-up with an expected overall 5-year median survival of 45%. Despite the distinct clinical profile of paediatric GCT, survival can be improved by early diagnosis, regimented treatment according to set guidelines, protocols and by improving follow-up.

A comparative analysis of inflammation between solid organs following donor brain death (BD) is still lacking and the detailed influence of BD accelerating ischaemia-reperfusion injury (IRI) post-transplantation remains to be addressed. Applying a murine model of BD, we demonstrated that 4 h after BD organs were characterized by distinct inflammatory expression patterns. For instance, lipocalin 2 (LCN2), a marker of acute kidney injury, was selectively induced in BD livers but not in kidneys. BD further resulted in significantly reduced frequencies of CD3(+) CD4(+) , CD3(+) CD8(+) T cells and NKp46(+) NK cells in the liver, whereas BD kidneys and hearts were characterized by significantly lower frequencies of conventional dendritic cells (cDCs). Syngeneic models of kidney (KTx) and heart transplantation (HTx) illustrated stronger gene expression in engrafted BD hearts only, but 20 h post-transplantation both organs displayed comparable intragraft lymphocyte frequencies, except for NK cells and graft function. Moreover, the complement factor C3d deposit detected in small vessels and capillaries in cardiac syngrafts did not significantly differ between BD and sham-transplanted groups. Finally, no further influence of donor BD on graft survival was detected in an allogeneic heart transplantation setting (C57BL/6 grafts into BALB/c recipients). We show for the first time that BD organs are characterized by a varying inflammatory profile; however, BD does not accelerate IRI in syngeneic KTx and HTx., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Objectives: Previously, different nonsteroidal anti-inflammatory drugs (NSAIDs) have been evaluated for their potential immunomodulatory activities. Mefenamic acid is a well-known NSAID and is used in the treatment of musculoskeletal disorders, inflammation, fever, and pain. To the best of our knowledge, promising data regarding the immunomodulatory activity of mefenamic acid is scarce. Current study investigates the immunomodulatory activity of mefenamic acid in different models of cell-mediated and humoral immunity., Materials and Methods: Immunomodulatory effects on cell-mediated immunity were evaluated using dinitrochlorobenzene-induced delayed type hypersensitivity (DTH) and cyclophosphamide-induce myelosuppression assays. While effects on humoral immunity were evaluated using hemagglutination assay and mice lethality test., Results: Hematological analysis showed that mefenamic acid significantly reduced white blood cell count, red blood cell (RBC) count, hemoglobin content, lymphocytes levels, and neutrophils levels in healthy mice as compared with control, suggesting the immunosuppressive activity of mefenamic acid. Treatment with mefenamic acid also significantly reduced all the hematological parameters in cyclophosphamide-induced neutropenic mice, as compared with positive control group. We found that treatment with mefenamic acid significantly suppressed DTH after 24 h, 48 h, and 72 h, as compared with positive control group. Mefenamic acid treated groups showed a significant reduction in antibody titer against sheep RBCs as compared to control group, similar to the effect of cyclophosphamide. We also found increased mice lethality rate in mefenamic acid treated groups, as compared with positive control group., Conclusions: The results provided basic information of immunosuppression of mefenamic acid on both cell-mediated and humoral immunity.

Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor-recipient combinations (C57Bl/6 wild-type and Lcn2(-/-) , Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

p66Shc-dependent ROS production contributes to many pathologies including ischemia/reperfusion injury (IRI) during solid organ transplantation. Inhibiting p66Shc activation may provide a novel therapeutic approach to prevent damage, which is poorly managed by antioxidants in vivo. Previous work suggested that pro-oxidant and a pro-apoptotic function of p66Shc required mitochondrial import, which depended on serine 36 phosphorylation. PKCß has been proposed as S36 kinase but cJun N-terminal kinases (JNKs) may also phosphorylate this residue. To simulate the early stages of ischemia/reperfusion (IR) we either used H2O2 treatment or hypoxia/reoxygenation (HR). As during reperfusion in vivo, we observed increased JNK and p38 activity in mouse embryonic fibroblasts (MEFs) and HL-1 cardiomyocytes along with significantly increased p66ShcS36 phosphorylation, ROS production and cell damage. Application of specific inhibitors caused a pronounced decrease in p66ShcS36 phosphorylation only in the case of JNK1/2. Moreover, S36 phosphorylation of recombinant p66Shc by JNK1 but not PKCß was demonstrated. We further confirmed JNK1/2-dependent regulation of p66ShcS36 phosphorylation, ROS production and cell death using JNK1/2 deficient MEFs. Finally, the low ROS phenotype of JNK1/2 knockout MEFs was reversed by the phosphomimetic p66ShcS36E mutant. Inhibiting JNK1/2-regulated p66Shc activation may thus provide a therapeutic approach for the prevention of oxidative damage.