Engineering is traditionally considered a male domain with lower female participation despite various affirmative actions taken in recent decades. There is evidence of greater gender equality as a result of the COVID-19 pandemic and precautionary lockdown measures. With this in mind, this paper investigates whether women engineers in India were more adversely affected than their male counterparts by the COVID-19 pandemic. Such an impact may be explained by ‘intersectional stigma’, expanded upon in the literature on discrimination. The impact of such stigma varies in different countries based on socio-cultural factors. Through the use of ethnographic and statistical research methods on secondary and primary data from a sample of 384 engineers, this paper shows that the impact of COVID-19 is not significantly different between genders in engineering education and employment. This may be due to the high demand for digital engineering skills, and strong family support in Indian society. Engineering branch may play a relatively more important role than gender in terms of impact. This finding has repercussions for continuing engineering education (CEE) programs and regulatory bodies in India in terms of enhancing course content and the results may be used in developing affirmative programs in other regions. Full article

(1) Background: Perioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Based on studies in patients with metastatic gastric cancer, oxaliplatin has replaced cisplatin in the curative setting as well. However, evidence to prefer oxaliplatin over cisplatin in the curative setting is limited. (2) Methods: We compared patient-related and tumor-related outcomes for cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with perioperative chemotherapy in the CRITICS trial. (3) Results: Preoperatively, 632 patients received cisplatin and 149 patients received oxaliplatin. Preoperative severe toxicity was encountered in 422 (67%) patients who received cisplatin versus 89 (60%) patients who received oxaliplatin (p = 0.105). Severe neuropathy was observed in 5 (1%) versus 6 (4%; p = 0.009) patients, respectively. Postoperative severe toxicity occurred in 109 (60%) versus 26 (51%) (p = 0.266) patients; severe neuropathy in 2 (1%) versus 2 (4%; p = 0.209) for patients who received cisplatin or oxaliplatin, respectively. Diarrhea impacted the quality of life more frequently in patients who received oxaliplatin compared to cisplatin. Complete or near-complete pathological response was achieved in 94 (21%) versus 16 (15%; p = 0.126) patients who received cisplatin or oxaliplatin, respectively. Overall survival was not significantly different in both groups (p = 0.300). (4) Conclusions: Both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer. Full article

Background: Tumor dormancy is a crucial mechanism responsible for the late recurrence of breast cancer. Thus, we investigated the clinical relevance of the expression of NR2F1, a known dormancy biomarker. Methods: A total of 6758 transcriptomes of bulk tumors from multiple breast cancer patient cohorts and two single-cell sequence cohorts were analyzed. Results: Breast cancer (BC) with high NR2F1 expression enriched TGFβ signaling, multiple metastases, and stem cell-related pathways. Cell proliferation-related gene sets were suppressed, and MKi67 expression was lower in high NR2F1 BC. In tumors with high Nottingham grade, NR2F1 expression was found to be lower. There was no consistent relationship between NR2F1 expression and metastasis or survival. Cancer mutation rates, immune responses, and immune cell infiltrations were lower in high NR2F1 tumors, whereas the infiltration of stromal cells including cancer-associated fibroblasts (CAFs) was higher. NR2F1 was predominantly expressed in CAFs, particularly inflammatory CAFs, rather than in cancer cells, consistently in the two single-cell sequence cohorts. Conclusions: NR2F1 expression in breast cancer is associated with tumor dormancy traits, and it is predominantly expressed in CAFs in the tumor microenvironment. Full article

Previous studies suggest that nitric oxide is involved in the regulation of the intraocular pressure (IOP) and in the pathophysiology of open-angle glaucoma (OAG). However, prospective studies investigating the association between dietary nitrate intake, a source of nitric oxide, and incident (i)OAG risk are limited. We aimed to determine the association between dietary nitrate intake and iOAG, and to evaluate the association between dietary nitrate intake and IOP. From 1991 onwards, participants were followed each five years for iOAG in the Rotterdam Study. A total of 173 participants developed iOAG during follow-up. Cases and controls were matched on age (mean ± standard deviation: 65.7 ± 6.9) and sex (%female: 53.2) in a case:control ratio of 1:5. After adjustment for potential confounders, total dietary nitrate intake was associated with a lower iOAG risk (odds ratio (OR) with corresponding 95% confidence interval (95% CI): 0.95 (0.91–0.98) for each 10 mg/day higher intake). Both nitrate intake from vegetables (OR (95% CI): 0.95 (0.91–0.98) for each 10 mg/day higher intake) and nitrate intake from non-vegetable food sources (OR (95% CI): 0.63 (0.41–0.96) for each 10 mg/day higher intake) were associated with a lower iOAG risk. Dietary nitrate intake was not associated with IOP. In conclusion, dietary nitrate intake was associated with a reduced risk of iOAG. IOP-independent mechanisms may underlie the association with OAG. Full article

Many heterologous proteins can be secreted by bacterial ATP-binding cassette (ABC) transporters, provided that they are fused with the C-terminal signal sequence, but some proteins are not secretable even though they carry the right signal sequence. The invention of a method to secrete these non-secretable proteins would be valuable both for understanding the secretory physiology of ABC transporters and for industrial applications. Herein, we postulate that cationic “supercharged” regions within the target substrate protein block the secretion by ABC transporters. We also suggest that the secretion of such substrate proteins can be rescued by neutralizing those cationic supercharged regions via structure-preserving point mutageneses. Surface-protruding, non-structural cationic amino acids within the cationic supercharged regions were replaced by anionic or neutral hydrophilic amino acids, reducing the cationic charge density. The examples of rescued secretions we provide include the spike protein of SARS-CoV-2, glutathione-S-transferase, streptavidin, lipase, tyrosinase, cutinase, growth factors, etc. In summary, our study provides a method to predict the secretability and a tool to rescue the secretion by correcting the secretion-blocking regions, making a significant step in understanding the physiological properties of ABC transporter-dependent protein secretion and laying the foundation for the development of a secretion-based protein-producing platform. Full article

Fingolimod is a sphingosine 1-phosphate-receptor modulator approved for the oral treatment of relapsing–remitting multiple sclerosis (RRMS), a form of MS characterized by a pattern of exacerbation of neurological symptoms followed by recovery. Here, we validated a simple and rapid liquid chromatography–tandem mass spectrometry method for the measurement of the concentrations of Fingolimod and its active metabolite Fingolimod-Phosphate (Fingolimod-P) in human plasma. The lower limits of quantification were set at 0.3 and 1.5 ng/mL for Fingolimod and Fingolimod-P, respectively, and the linearity was in the range 0.3–150 ng Fingolimod/mL and 1.5–150 ng Fingolimod-P/mL. After protein precipitation, the extraction recoveries of both analytes were always above 60% with minimal matrix effect. The method was accurate and precise, satisfying the criteria set in the European Medicine Agency guidelines for bioanalytical method validation. The method was then applied to measure Fingolimod and Fingolimod-P concentrations in the plasma of 15 RRMS patients under chronic treatment with Fingolimod, administered daily at the dose of 0.5 mg for up to 24 months. No significant differences were observed between samples collected at 6, 12 and 24 months for both analytes, indicating that the drug’s bioavailability was unaffected by multiple daily doses up to 24 months. The levels of Fingolimod-P were about two-fold higher than the levels of the parent compound. The availability of this analytical method can allow the monitoring of the impact of plasma levels of the drug and its metabolite on inter-individual variability in clinical responses. Full article

Among biometrics, iris and ocular recognition systems are the methods that recognize eye features in an image. Such iris and ocular regions must have a certain image resolution to achieve a high recognition performance; otherwise, the risk of performance degradation arises. This is even more critical in the case of iris recognition where detailed patterns are used. In cases where such low-resolution images are acquired and the acquisition apparatus and environment cannot be improved, recognition performance can be enhanced by obtaining high-resolution images with methods such as super-resolution reconstruction. However, previous survey papers have mainly summarized studies on high-resolution iris and ocular recognition, but do not provide detailed summaries of studies on low-resolution iris and ocular recognition. Therefore, we investigated high-resolution iris and ocular recognition methods and introduced in detail the low-resolution iris and ocular recognition methods and methods of solving the low-resolution problem. Furthermore, since existing survey papers have focused on and summarized studies on traditional handcrafted feature-based iris and ocular recognition, this survey paper also introduced the latest deep learning-based methods in detail. Full article

The objective of the present paper was to discuss the design of farrowing pens and present the first production results of the “SowComfort farrowing pen” (SOWCOMF). The biggest difference between this pen and the traditional pen (TRAD) presented in the study, is that SOWCOMF contains a nest area equipped with a rubber mattress, floor heating, a rack for straw and no separate creep area. It was predicted that SOWCOMF would result in lower piglet mortality compared to TRAD due to a more stimulating and comfortable environment, and that the use of rubber mats in SOWCOMF would reduce the incidence of carpal joint lesions of the piglets. Results from both farms showed that percent mortality of live born piglets was lower in SOWCOMF than TRAD (p = 0.004), especially due to starvation (p < 0.0001) and other causes (p < 0.0001). In contrast, percentage of overlying was higher in SOWCOMF (p < 0.0001). The lower incidence of starved piglets in SOWCOMF than TRAD can possibly be explained by more sow-initiated communication with the piglets (p < 0.001). Most causes of mortality declined over consecutive batches. Percentage of piglets per litter without carpal lesions were significantly higher in the SOWCOMF than in TRAD (p < 0.0001), showing that rubber mats provide more protection of carpal joints. Full article

Diverticular disease is a common clinical problem, particularly in industrialized countries. In most cases, colonic diverticula remain asymptomatic throughout life and sometimes are found incidentally during colonic imaging in colorectal cancer screening programs in otherwise healthy subjects. Nonetheless, roughly 25% of patients bearing colonic diverticula develop clinical manifestations. Abdominal symptoms associated with diverticula in the absence of inflammation or complications are termed symptomatic uncomplicated diverticular disease (SUDD). The pathophysiology of diverticular disease as well as the mechanisms involved in the shift from an asymptomatic condition to a symptomatic one is still poorly understood. It is accepted that both genetic factors and environment, as well as intestinal microenvironment alterations, have a role in diverticula development and in the different phenotypic expressions of diverticular disease. In the present review, we will summarize the up-to-date knowledge on the pathophysiology of diverticula and their different clinical setting, including diverticulosis and SUDD. Full article

In this study, we consider general Markov chains (MC) defined by a transition probability (kernel) that is finitely additive. These Markov chains were constructed by S. Ramakrishnan within the concepts and symbolism of game theory. Here, we study these MCs by using the operator approach. In our work, the state space (phase space) of the MC has any cardinality and the sigma-algebra is discrete. The construction of a phase space allows us to decompose the Markov kernel (and the Markov operators that it generates) into the sum of two components: countably additive and purely finitely additive kernels. We show that the countably additive kernel is atomic. Some properties of Markov operators with a purely finitely additive kernel and their invariant measures are also studied. A class of combined finitely additive MC and two of its subclasses are introduced, and the properties of their invariant measures are proven. Some asymptotic regularities of such MCs were revealed. Full article

The current train model of the train control system is unable to accurately reflect the influence of nonlinear running resistance, line conditions, the mutative train mass value, and external environment changes on the model in train dynamics, resulting in a defect of poor train model performance. The train basic model and additional resistances are discussed in this paper, a novel neural network online learning method of the time-varying dynamic train model is proposed, combined with the characteristics of rail transit lines, and a neural network learning algorithm is designed by categories and steps. This method can identify the train mass value that changes continuously with passengers during running. The energy savings resulting from using the actual varying train mass in the train control system are calculated. The results show that, when compared to the traditional model’s invariant approximate empirical parameters, the time-varying parameter model can follow changes in the train and line environment and obtain quantitative expressions of curve resistance and tunnel resistance with speed. The time-varying train model was used to conduct engineering tests on the Beijing Capital Airport Line; the online learning deviation of train mass was controlled within a margin of 3.08%, and at the same time, energy consumption decreased by 6.13%. Full article

Chinese overcapacity in the steel and coal industry has been on the rise since 2013, which leads to the misallocation of resources and decreases in production efficiency. In 2015, the Chinese central government adopted a series of de-capacity policies to resolve excess capacity and improve corporate profitability. However, there is scant evidence on the impacts of de-capacity policies on the firm profitability. Based on the data from Chinese listed companies in the steel and coal industry, this study constructs the difference-in-difference (DID) method to investigate the effects of the de-capacity policy on the profitability of listed companies in the steel and coal industry empirically. The results show that the de-capacity policy significantly increases the return on equity (ROE) of the experimental group, which is higher than that of the control group by 12.4%. That is partially because of the improvement in gross profit margin, management efficiency, and return on manpower due to the de-capacity policy. This study offers new evidence on the efficiency of China’s de-capacity policy toward the steel and coal industries through data at the enterprise level. Full article

During the boreal spring (March–May), the precipitation that occurs from March over the southeastern Tibetan Plateau (TP) can account for 20–40% of the total annual amount. The origin of this phenomenon has not been clearly understood from a climatological perspective. In this study, the role of topographical and thermal forcing on the precipitation over the southeastern TP in early spring (March) was investigated through sensitivity numerical simulations based on general circulation model. The simulated results show the favorable circulation and static stability to early spring precipitation over the southeastern TP when the model is simultaneously forced by realistic topography, zonal symmetric radiative equilibrium temperature, and diabatic heating over the TP and its surrounding areas. The quasi-stationary wave pattern over the Eurasian continent forced by realistic and TP topographical forcing leads to prolonged low pressure and intensified zonal winds over the southeastern TP due to quasi-steady wave activities. Thermal forcing experiments reveals that sensible heating over the southeastern TP not only strengthens the cyclonic circulation, ascending motion and statically unstable over the southeastern TP through thermal adaptation and the Sverdrup balance, but also triggers an anticyclone at upper tropospheric level extending from north of the Bay of Bengal to the eastern TP, which further favors precipitation over the southeastern TP. This work will provide useful background information for spring climate prediction over the TP. Full article

Gyrotrons are used as high-power sources of coherent radiation operating in pulsed and CW regimes in many scientific and technological fields. In this paper, we discuss two of their numerous applications. The first one is in gyrotron-powered electromagnetic wigglers and undulators. The second one is for driving high-gradient accelerating structures in compact particle accelerators. The comparison, between the requirements imposed by these two concepts on the radiation sources on one hand and the output parameters of the currently available high-performance gyrotrons on the other hand, show that they match each other to a high degree. We consider this as a manifestation of the feasibility and potential of these concepts. It is believed that after the first successful proof-of-principle experiments they will find more wide usage in the advanced FEL and particle accelerators. Full article

Objective: Thyroid cancer encasing the recurrent nerve is rare, and the decision to resect or preserve the nerve is multifactorial. The objective of this study was to histopathologically analyze resected encased nerves to assess the rate of nerve invasion and risk factors. Materials and Methods: A retrospective study was carried out on consecutive patients with resection of the recurrent nerve for primary or recurrent follicular cell-derived or medullary thyroid carcinoma from 2005 to 2020. Demographics, pathology, locoregional invasion, metastases, recurrences and survival were analyzed. Slides were reviewed blindly by two specialized pathologists (AAG, RC) for diagnosis of invasion deep to the epineurium. Results: Fifty-two patients were included: 25 females; average age, 55 (range 8–87). In total, 87% percent (45/52) were follicular cell-derived with 17/45 (37.8%) aggressive variants; 13% (7/52) were medullary carcinoma. Preoperative vocal fold (VF) paralysis was present in 16/52 (30.7%). Pathologically, the nerve was invaded in 44/52 cases (85%): 82% of follicular cell-derived tumors (37/45), 88% of pediatric cases, and 100% of medullary carcinomas (7/7). Nerve invasion was observed in 11/16 (69%) with preoperative VF paralysis and 33/36 (92%) with normal VF function. Only aggressive histology was correlated with nerve invasion in follicular cell-derived tumors (p = 0.019). Conclusions: The encased nerves were pathologically invaded in 82% of follicular cell-derived tumors and in 100% of medullary carcinomas. Nerve invasion was statistically correlated with aggressive histopathological subtypes and was observed in the absence of VF paralysis in 92% of cases. Full article

(1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may improve NASH by modulating lipid and glucose metabolism. We compared effects of single drug to combination treatment as therapeutic strategies against NASH. (2) Methods: We analyzed serum samples and liver biopsies from 85 nonalcoholic fatty liver disease (NAFLD) patients. A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (3) Results: In NAFLD patients, chemokine CCL2 and FGF21 serum levels correlated with inflammatory serum markers, only CCL2 was significantly associated with advanced liver fibrosis. In rodent NASH, CCR2/5 inhibition significantly reduced circulating Ly6C+ monocytes and hepatic monocyte-derived macrophages, alongside reduced hepatic inflammation and fibrosis. FGF21 agonism decreased body weight, liver triglycerides and histological NASH activity. Combination treatment reflected aspects of both compounds upon short- and long-term application, thereby amplifying beneficial effects on all aspects of steatohepatitis and fibrosis. (4) Conclusions: CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients. Full article

Carbon capture on-board ships represents a powerful technological measure in order for the shipping industry to meet the very stringent GHG emission reduction requirements. Operation within the ship environment introduces a number of constraints associated mainly with space, energy supply, and safety which have to be addressed using compact yet efficient solutions. To this end, solvent-based membrane CO₂ capture offers several advantages and has the necessary technological maturity for on-board installation. Solvent choice remains a critical issue both for reasons associated with process efficiency as well as on-board safety. In this paper, we present an up-to-date comprehensive review of the different solvents that can be used for post-combustion CO₂ capture. Furthermore, we investigated the solvents’ performance as determined by their inherent characteristics, properties, and behavior for a range of operating conditions against the strict shipping requirements. A preliminary qualitative comparative assessment was carried out based on appropriately selected key performance indicators (KPIs) pertinent to the requirements of the shipping industry. The identified solvent classes were compared using the most critical KPIs for system integration with the ship. It was concluded that at present, no solvent category can efficiently address all the requirements of the ship. However, widely used solvents such as secondary amines showed relatively good compatibility with the majority of the introduced KPIs. On the other hand, more recently developed molecules, such as phase change solvents and ionic liquids, can easily prevail over the vast majority of the identified solvents as long as they are brought to the same level of technological maturity with benchmark solvents. Such a conclusion points toward the need for accelerating research on more tailor-made and performance-targeted solvents. Full article

Candidiasis (oral, vulvovaginal, or systemic bloodstream infections) are important human fungal infections associated with a high global prevalence in otherwise healthy adults but are also opportunistic infections in immunocompromised patients. With the recent discovery of the multidrug resistant—and often difficult to treat—Candida auris, as well as the rising costs associated with hospitalisations and the treatment of infections caused by Candida species, there is an urgent need to develop effective therapeutics against these pathogenic yeasts. Essential oils have been documented for many years as treatments for different ailments and are widely known and utilised in alternative and complementary therapies, including treating microbial infections. This review highlights knowledge from research on the effects of medicinal plants, and in particular, essential oils, as potential treatments against different Candida species. Studies have been evaluated that describe the experimental approaches used in investigating the anticandidal effects of essential oils (in vivo and in vitro), the established mode of action of the different compounds against different Candida species, the effect of a combination of essential oils with other compounds as potential therapies, and the evidence from clinical trial studies. Full article

Relatively important node mining has always been an essential research topic in complex networks. Existing relatively important node mining algorithms suffer from high time complexity and poor accuracy. Therefore, this paper proposes an algorithm for mining relatively important nodes based on the edge importance greedy strategy (EG). This method considers the importance of the edge to represent the degree of association between two connected nodes. Therefore, the greater the value of the connection between a node and a known important node, the more likely it is to be an important node. If the importance of the edges in an undirected network is measured, a greedy strategy can find important nodes. Compared with other relatively important node mining methods on real network data sets, such as SARS and 9/11, the experimental results show that the EG algorithm excels in both accuracy and applicability, which makes it a competitive algorithm in the mining of important nodes in a network. Full article

Academic citation and social attention measure different dimensions of the impact of research results. Both measures do not correlate with each other, and they are influenced by many factors. Among these factors are the field of research, the type of access, and co-authorship. In this study, the increase in the impact due to co-authorship in scientific articles disaggregated by field of research and access type, was quantified. For this, the citations and social attention accumulated until the year 2021 by a total of 244,880 research articles published in the year 2018, were analyzed. The data source was Dimensions.ai, and the units of study were research articles in Economics, History and Archaeology, and Mathematics. As the main results, a small proportion of the articles received a large part of the citations and most of the social attention. Both citations and social attention increased, in general, with the number of co-authors. Thus, the greater the number of co-authors, the greater the probability of being cited in academic articles and mentioned on social media. The advantage in citation and social attention due to collaboration is independent of the access type for the publication. Furthermore, although collaboration with an additional co-author is in general positive in terms of citation and social attention, these positive effects reduce as the number of co-authors increases. Full article

The aim of traffic flow design in commercial building space planning is to create a comfortable, easily accessible, and identifiable spatial structure in a complex and changeable business environment. However, modern commercial building spaces often appear to be inconsistent with the usage requirements after they are put into use. To understand the real experience evaluation of users, this study selects the commercial project “Guangzhou Nanpu Times Commercial Building Space” as its subject. Based on post-occupancy evaluation (POE), this study uses the analytic hierarchy process (AHP) to construct an evaluation index system of commercial building space traffic flow. The weights and satisfaction scores of the indexes are calculated through expert interviews and questionnaires to analyze the evaluation and reasons for the commercial building space traffic flow design after using the facilities. We thereby obtain the design points of commercial building space traffic flow to provide a scientific, reasonable, and practical basis for the subsequent design of the same type of traffic flow to drive the prosperity and development of commerce. Full article

In this study, precipitation in Tropical South America in the 1931–2016 period is investigated by means of Principal Component Analysis and composite analysis of circulation fields. The associated dynamics are analyzed using the 20th century ERA-20C reanalysis. It is found that the main climatic processes related to precipitation anomalies in Tropical South America are: (1) the intensity and position of the South Atlantic Convergence Zone (SACZ); (2) El Niño Southern Oscillation (ENSO); (3) the meridional position of the Intertropical Convergence Zone (ITCZ), which is found to be related to Atlantic Sea Surface Temperature (SST) anomalies; and (4) anomalies in the strength of the South American Monsoon System, especially the South American Low-Level Jet (SALLJ). Interestingly, all of the analyzed anomalies are related to processes that operate from the Atlantic Ocean, except for ENSO. Results from the present study are in agreement with the state of the art literature about precipitation anomalies in the region. However, the added strength of the longer dataset and the larger study area improves the knowledge and gives new insights into how climate variability and the resulting dynamics are related to precipitation in Tropical South America. Full article

The range of applications of RPAs in various industries indicates that their increased usage could reduce operational costs and time. Remotely piloted aircraft systems (RPASs) can be deployed quickly and effectively in numerous distribution systems and even during a crisis by eliminating existing problems in ground transport due to their structure and flexibility. Moreover, they can also be useful in data collection in damaged areas by correctly defining the condition of flight trajectories. Hence, defining a framework and model for better regulation and management of RPAS-based systems appears necessary; a model that could accurately predict what will happen in practice through the real simulation of the circumstances of distribution systems. Therefore, this study attempts to propose a multi-objective location-routing optimization model by specifying time window constraints, simultaneous pick-up and delivery demands, and the possibility of recharging the used batteries to reduce, firstly, transport costs, secondly, delivery times, and thirdly, estimated risks. Furthermore, the delivery time of the model has been optimized to increase its accuracy based on the uncertain conditions of possible traffic scenarios. It is also imperative to note that the assessment of risk indicators was conducted based on the Specific Operations Risk Assessment (SORA) standard to define the third objective function, which was conducted in a few previous studies. Finally, it shows how the developed NSGA-II algorithm in this study performed successfully and reduced the objective function by 31%. Comparing the obtained results using an NSGA-II meta-heuristic approach, through the rigorous method GAMS, indicates that the results are valid and reliable. Full article

Loss of heterozygosity (LOH) for KRAS, in which a wild-type KRAS allele is progressively lost, promotes invasive and migratory abilities of pancreatic ductal adenocarcinoma (PDAC) cells and tissues. Moreover, the occurrence of Kras^G12D-LOH activates nonclassical glutamine metabolism, which is related to the malignant behavior of PDAC cells. Herein, we aim to demonstrate the regulatory link between hypoxia-inducible factor-2α (HIF-2α) and glutamine metabolism that mediates malignant phenotypes in Kras^G12D-LOH PDAC cells. HIF-2α-shRNA knockdown lentivirus transfection and metabolite analysis were performed in Kras^G12D-LOH and Kras^G12D cell lines, respectively. Cell proliferation, migration, and invasion were examined using Cell Counting Kit-8, colony formation, and Transwell assays. Cell cycle phase and apoptosis were determined using flow cytometry. Western blotting and real-time quantitative PCR were also performed. Additionally, a subcutaneous xenograft mouse model was established. LOH stimulated HIF-2α activity and transactivated c-Myc, which has a central regulatory effect on glutamine metabolism independent of hypoxia. Meanwhile, HIF-2α silencing repressed Kras^G12D-LOH PDAC cell proliferation, invasion, and migration. HIF-2α knockdown inhibited glutamine uptake and GOT1 expression via a c-Myc-dependent pathway. Collectively, Kras^G12D-LOH can activate HIF-2α to regulate c-Myc-mediated glutamine metabolism and promote malignant phenotypes. Moreover, targeting HIF-2α-c-Myc regulated nonclassical glutamine metabolism, providing a new therapeutic perspective for Kras^G12D-LOH PDAC. Full article