An Improved Coupled Level Set and Continuous Moment-of-Fluid Method for Simulating Multiphase Flows with Phase Change

An improved algorithm for computing multiphase flows is presented in which the multimaterial Moment-of-Fluid(MOF)algorithm for multiphase flows,initially described by Li et al.(2015),is enhanced addressing existing MOF difficulties in computing solutions to problems in which surface tension forces are crucial for understanding salient flow mechanisms.The Continuous MOF(CMOF)method is motivated in this article.The CMOF reconstruction method inherently removes the"checkerboard instability"that persists when using the MOF method on surface tension driven multiphase(multimaterial)flows.The CMOF reconstruction algorithm is accelerated by coupling the CMOF method to the level set method and coupling the CMOF method to a decision tree machine learning(ML)algorithm.Multiphase flow examples are shown in the two-dimensional(2D),three-dimensional(3D)axisymmetric"RZ",and 3D coordinate systems.Examples include two material and three material multiphase flows:bubble formation,the impingement of a liquid jet on a gas bubble in a cryogenic fuel tank,freezing,and liquid lens dynamics.

Comment on: Effect of intubation in patients with functional epiphora after endoscopic dacryocystorhinostomy

Dear Editor,We read with interest the article by Han et al[1]in which they retrospectively assessed the effect of bicanalicular intubation for functional epiphora after a failed endoscopic dacryocystorhinostomy(DCR).They confirmed the post-DCR“functional obstruction”based on fluorescein dye disappearance(FDDT)and irrigation test[1].

Diabetic cardiomyopathy:Importance of direct evidence to support the roles of NOD-like receptor protein 3 inflammasome and pyroptosis

Recently,the roles of pyroptosis,a form of cell death induced by activated NODlike receptor protein 3(NLRP3)inflammasome,in the pathogenesis of diabetic cardiomyopathy(DCM)have been extensively investigated.However,most studies have focused mainly on whether diabetes increases the NLRP3 inflammasome and associated pyroptosis in the heart of type 1 or type 2 diabetic rodent models,and whether various medications and natural products prevent the development of DCM,associated with decreased levels of cardiac NLRP3 inflammasome and pyroptosis.The direct link of NLRP3 inflammasome and associated pyroptosis to the pathogenesis of DCM remains unclear based on the limited evidence derived from the available studies,with the approaches of NLRP3 gene silencing or pharmaceutical application of NLRP3 specific inhibitors.We thus emphasize the requirement for more systematic studies that are designed to provide direct evidence to support the link,given that several studies have provided both direct and indirect evidence under specific conditions.This editorial emphasizes that the current investigation should be circumspect in its conclusion,i.e.,not overemphasizing its role in the pathogenesis of DCM with the fact of only significantly increased expression or activation of NLRP3 inflammasome and pyroptosis in the heart of diabetic rodent models.Only clear-cut evidence-based causative roles of NLRP3 inflammasome and pyroptosis in the pathogenesis of DCM can help to develop effective and safe medications for the clinical management of DCM,targeting these biomarkers.

Glucagon-like-peptide-1 receptor agonists and the management of type 2 diabetes-backwards and forwards

This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor agonists(GLP-1RAs)in the management of type 2 diabetes and this editorial provides complementary information.We initially give a brief historical perspective of the development of GLP-1RAs stimulated by recognition of the‘incretin effect’,the substantially greater insulin increase to enteral when compared to euglycaemic intravenous glucose,and the identification of the incretin hormones,GIP and GLP-1.In addition to stimulating insulin,GLP-1 reduces postprandial glucose levels by slowing gastric emptying.GLP-1RAs were developed because native GLP-1 has a very short plasma half-life.The majority of current GLP-1RAs are administered by subcutaneous injection once a week.They are potent in glucose lowering without leading to hypoglycaemia,stimulate weight loss in obese individuals and lead to cardiovascular and renal protection.The landscape in relation to GLP-1RAs is broadening rapidly,with different formulations and their combination with other peptides to facilitate both glucose lowering and weight loss.There is a need for more information relating to the effects of GLP-1RAs to induce gastrointestinal symptoms and slow gastric emptying which is likely to allow their use to become more effective and personalised.

Surgical or medical treatment of obesity-associated type 2 diabetesan increasing clinical conundrum

In this editorial,we comment on the article by He et al,specifically in relation to the efficacy of bariatric surgery vs glucagon-like peptide-1 receptor agonist(GLP-1RA)therapy in the management of type 2 diabetes(T2D)associated with obesity.Bariatric surgery has now also been shown to be safe and effective in pre-teens and teenagers with obesity and T2D,but information on newer GLP-1RAs in these groups is predictably limited.In older individuals(age>65 years),both bariatric surgery and GLP-1RA therapy improve cardiovascular outcomes.Baria-tric surgery is not infrequently associated with post-operative postprandial hypoglycemia,which is not the case with GLP-1RAs and,paradoxically,there is evidence that GLP-1RAs may reduce both the frequency and severity of postprandial hypoglycemia.Comparative trials of the long-term efficacy of bariatric surgery and GLP-1RAs are indicated.

Implications of genetic testing and informed consent before and after genetic testing in individuals with cancer

Recent advancements in next generation sequencing have allowed for genetic information become more readily available in the clinical setting for those affected by cancer and by treating clinicians.Given the lack of access to geneticists,medical oncologists and other treating physicians have begun ordering and interpreting genetic tests for individuals with cancer through the process of"mainstreaming".While this process has allowed for quicker access to genetic tests,the process of"mainstreaming"has also brought several challenges including the dissemination of variants of unknown significance results,ordering of appropriate tests,and accurate interpretation of genetic results with appropriate followup testing and interventions.In this editorial,we seek to explore the process of informed consent of individuals before obtaining genetic testing and offer potential solutions to optimize the informed consent process including categorization of results as well as a layered consent model.

Apoptosis and the target genes of microRNA-21

MicroRNA-21(miR-21) is frequently up-regulated in cancer and the majority of its reported targets are tumor suppressors.Through functional suppression,miR-21 is implicated in practically every walk of oncogenic life:the promotion of cell proliferation,invasion and metastasis,genome instability and mutation,inflammation,replicative immortalization,abnormal metabolism,angiogenesis,and evading apoptosis,immune destruction,and growth suppressors.In particular,miR-21 is strongly involved in apoptosis.In this article,we reviewed the experimentally validated targets of miR-21 and found that two thirds are linked to intrinsic and/or extrinsic pathways of cellular apoptosis.This suggests that miR-21 is an oncogene which plays a key role in resisting programmed cell death in cancer cells and that targeting apoptosis is a viable therapeutic option against cancers expressing miR-21.

Cyclooxygenase-2 and epithelial growth factor receptor up-regulation during progression of Barrett's esophagus to adenocarcinoma

AIM： To investigate the expression of cyclooxygenase-2 （COX-2） and epithelial growth factor receptor （EGFR） throughout the progression of Barrett＇s esophagus （BE）. METHODS： COX-2 and EGFR protein expressions were detected by using immunohistochemical method. A detailed cytomorphological changes were determined. Areas of COX-2 and EGFR expression were quantified by using computer Imaging System. RESULTS： The expressions of both COX-2 and EGFR increased along with the progression from BE to esophagus adenocarcinoma （EAC）. A positive correlation was found between COX-2 expression and EGFR expression. CONCLUSION： COX-2 and EGFR may be cooperative in the stepwise progression from BE to EAC, thereby leading to carcinogenesis.

Homocysteine mediates transcriptional changes of the inflammatory pathway signature genes in human retinal pigment epithelial cells

AIM：To test whether homocysteine（Hcy） can influence the transcriptional profile, we hypothesized that Hcy can lead to the induction of proinflammatory molecules in the retinal cells of aging people.METHODS：An unbiased in vitro inflammatory pathway focused study was designed employing retinal pigment epithelial（RPE） cell line, ARPE-19. Cells were cultured in the presence or absence of Hcy to capture target genes＇ expression profile. Three different concentrations of Hcy were added in the culture medium of confluent monolayers. c RNAs were made from the isolated total RNAs and the labeled c RNA probes were hybridized to microarrays specific for human disease pathway inflammatory cytokines, chemokines and their receptor gene micro-array panels as per manufacture＇s recommendations. Two Hcy up-regulated molecules：IL6 and CEBPB were further validated via Western blot analysis. Hcy＇s effect on ARPE-19 cellular morphology and genomic DNA integrity were also evaluated.RESULTS：Gene microarray analyses of RPE cells in response to Hcy treatment revealed alterations in the expressions of several inflammatory gene transcripts such as CCL5, CEBPB, IL13RA2, IL15 RA, IL6, IL8 and CXCL3 that were up-regulated. The transcripts for C3, CCL2, IL11 RA and IL18 genes exhibited down-regulation. The IL6 and CEBPB expressions were subsequently validated at the protein levels. Treatment of the retinal cells with increasing Hcy concentration influenced their density in culture however their morphology and DNA integrity remained unaffected. CONCLUSION：These findings suggest that Hcy can potentially mediate the expression of chemokines,cytokines and interleukins receptors in the retinal cells without having any debilitating effects on their morphology and the genomic DNA integrity.

Exploitation of the nicotinic anti-inflammatory pathway for the treatment of epithelial inflammatory diseases

Discoveries in the first few years of the 21st century have led to an understanding of important interactions between the nervous system and the inflammatory response at the molecular level, most notably the acetylcholine （ACh）- triggered,α7-nicotinic acetylcholine receptor （α7nAChR）- dependent nicotinic antinflammatory pathway. Studies using the α7nAChR agonist, nicotine, for the treatment of mucosal inflammation have been undertaken but the efficacy of nicotine as a treatment for inflammatory bowel diseases remains debatable. Further understanding of the nicotinic anti-inflammatory pathway and other endogenous anti-inflammatory mechanisms is required in order to develop refined and specific therapeutic strategies for the treatment of a number of inflammatory diseases and conditions, including periodontitis, psoriasis, sarcoidosis, and ulcerative colitis.

Chemoprotective effects of curcumin in esophageal epithelial cells exposed to bile acids

AIM:To investigate the ability of curcumin to counteract the impact of bile acids on gene expression of esophageal epithelial cells.METHODS:An esophageal epithelial cell line(HET1A)was treated with curcumin in the presence of deoxycholic acid.Cell proliferation and viability assays were used to establish an appropriate dose range for curcumin.The combined and individual effects of curcumin and bile acid on cyclooxygenase-2(COX-2)and superoxide dismutase(SOD-1 and SOD-2)gene expression were also assessed.RESULTS:Curcumin in a dose range of 10-100μmol/L displayed minimal inhibition of HET-1A cell viability.Deoxycholic acid at a concentration of 200μmol/L caused a 2.4-fold increase in COX-2 gene expression compared to vehicle control.The increased expression of COX-2 induced by deoxycholic acid was partially reversed by the addition of curcumin,and curcumin reduced COX-2 expression 3.3-to 1.3-fold.HET-1A cells exposed to bile acid yielded reduced expression of SOD-1 and SOD-2 genes with the exception that high dose deoxycholic acid at 200μmol/L led to a 3-fold increase in SOD-2 expression.The addition of curcumin treatment partially reversed the bile acid-induced reduction in SOD-1 expression at all concentrations of curcumin tested.CONCLUSION:Curcumin reverses bile acid suppression of gene expression of SOD-1.Curcumin is also able to inhibit bile acid induction of COX-2 gene expression.

Vulnerability of Large City and Its Implication in Urban Planning: A Perspective of Intra-urban Structure

Vulnerability is a new field and analytical tool in the study of urban safety. Analysis and assessment of vulnerability provide a new basis for urban planning. This study constructed a quantitative index system for assessing vulnerability, based on the city′s sensitivity and emergency response capacity. City size, density, and spatial form influence a city′s sensitivity to crises and risks, to which vulnerability is positively related. Levels of socio-economic development, infrastructures, and emergency management contribute to a city′s emergency response capacity, with which vulnerability is inversely associated. Vulnerability of 19 large Chinese cities was assessed. Harbin and Shenzhen demonstrated the highest and lowest vulnerability among 19 cities, while Beijing, Shanghai and Guangzhou ranked the 5th, the 9th and the 12th. Spatially, northern cities tended to be more vulnerable than southern cities. And the differences in vulnerability among cities were explored based on cities′ physical geography conditions, level of socioeconomic development, infrastructures, regional status, history of disaster, history of urban planning and development, government policies, etc.

The effect of phase angle and wing spacing on tandem flapping wings

In a tandem wing configuration, the hindwing of- ten operates in the wake of the forewing and, hence, its per- formance is affected by the vortices shed by the forewing. Changes in the phase angle between the flapping motions of the fore and the hind wings, as well as the spacing between them, can affect the resulting vortex/wing and vortex/vortex interactions. This study uses 2D numerical simulations to in- vestigate how these changes affect the leading dege vortexes （LEV） generated by the hindwing and the resulting effect on the lift and thrust coefficients as well as the efficiencies. The tandem wing configuration was simulated using an incom- pressible Navier-Stokes solver at a chord-based Reynolds number of 5 000. A harmonic single frequency sinusoidal oscillation consisting of a combined pitch and plunge motion was used for the flapping wing kinematics at a Strouhal num- ber of 0.3. Four different spacings ranging from 0.1 chords to 1 chord were tested at three different phase angles, 0°, 90° and 180°. It was found that changes in the spacing and phase angle affected the timing of the interaction between the vor- tex shed from the forewing and the hindwing. Such an inter- action affects the LEV formation on the hindwing and results in changes in aerodynamic force production and efficiencies of the hindwing. It is also observed that changing the phase angle has a similar effect as changing the spacing. The re- suits further show that at different spacings the peak force generation occurs at different phase angles, as do the peak efficiencies.

Management of lumbar zygapophysial (facet) joint pain

AIM: To investigate the diagnostic validity and therapeutic value of lumbar facet joint interventions in managing chronic low back pain.METHODS: The review process applied systematic evidence-based assessment methodology of controlled trials of diagnostic validity and randomized controlled trials of therapeutic efficacy. Inclusion criteria encompassed all facet joint interventions performed in a controlled fashion. The pain relief of greater than 50% was the outcome measure for diagnostic accuracy assessment of the controlled studies with ability to perform previously painful movements, whereas, for randomized controlled therapeutic efficacy studies, the primary outcome was significant pain relief and the secondary outcome was a positive change in functional status. For the inclusion of the diagnostic controlled studies, all studies must have utilized either placebo controlled facet joint blocks or comparative local anesthetic blocks. In assessing therapeutic interventions, short-term and long-term reliefs were defined as either up to 6 mo or greater than 6 mo of relief. The literature search was extensive utilizing various types of electronic search media including Pub Med from 1966 onwards, Cochrane library, National Guideline Clearinghouse, clinicaltrials.gov, along with other sources includingprevious systematic reviews, non-indexed journals, and abstracts until March 2015. Each manuscript included in the assessment was assessed for methodologic quality or risk of bias assessment utilizing the Quality Appraisal of Reliability Studies checklist for diagnostic interventions, and Cochrane review criteria and the Interventional Pain Management Techniques- Quality Appraisal of Reliability and Risk of Bias Assessment tool for therapeutic interventions. Evidence based on the review of the systematic assessment of controlled studies was graded utilizing a modified schema of qualitative evidence with best evidence synthesis, variable from level Ⅰ to level Ⅴ.RESULTS: Across all databases, 16 high quality diagnostic accuracy studies were identified. In addition, multiple studies assessed the influence of multiple factors on diagnostic validity. In contrast to diagnostic validity studies, therapeutic efficacy trials were limited to a total of 14 randomized controlled trials, assessing the efficacy of intraarticular injections, facet or zygapophysial joint nerve blocks, and radiofrequency neurotomy of the innervation of the facet joints. The evidence for the diagnostic validity of lumbar facet joint nerve blocks with at least 75% pain relief with ability to perform previously painful movements was level Ⅰ, based on a range of level Ⅰ to Ⅴ derived from a best evidence synthesis. For therapeutic interventions, the evidence was variable from level Ⅱ to Ⅲ, with level Ⅱ evidence for lumbar facet joint nerve blocks and radiofrequency neurotomy for long-term improvement(greater than 6 mo), and level Ⅲ evidence for lumbosacral zygapophysial joint injections for short-term improvement only.CONCLUSION: This review provides significant evidence for the diagnostic validity of facet joint nerve blocks, and moderate evidence for therapeutic radiofrequency neurotomy and therapeutic facet joint nerve blocks in managing chronic low back pain.

Adipose stem cell-based regenerative medicine for reversal of diabetic hyperglycemia

Diabetes mellitus(diabetes) is a devastating disease that affects millions of people globally and causes a myriad of complications that lead to both patient morbidity and mortality. Currently available therapies, including insulin injection and beta cell replacement through either pancreas or pancreatic islet transplantation, are limited by the availability of organs. Stem cells provide an alternative treatment option for beta cell replacement through selective differentiation of stem cells into cells that recognize glucose and produce and secrete insulin. Embryonic stem cells, albeit pluripotent, face a number of challenges, including ethical and political concerns and potential teratoma formation. Adipose tissue represents an alternative source of multipotent mesenchymal stem cells, which can be obtained using a relatively simple, non-invasive, and inexpensive method. Similarly to other adult mesenchymal stem cells, adipose-derived stem cells(ADSCs) are capable of differentiating into insulin-producing cells. They are also capable of vasculogenesis and angiogenesis, which facilitate engraftment of donor pancreatic islets when co-transplanted. Additionally, anti-inflammatory and immunomodulatory effects of ADSCs can protect donorislets during the early phase of transplantation and subsequently improve engraftment of donor islets into the recipient organ. Although ADSC-therapy is still in its infancy, the potential benefits of ADSCs are far reaching.

A New Symmetrodont Mammal with Fur Impressions from the Mesozoic of China

Western Liaoning of northeastern China is world-renowned for the MesozoicJehol biota, especially for yielding many feathered dinosaurs, primitive birds, mammals and fossilangiosperm. This paper describes a complete specimen of a symmetrodont mammal with well-preservedhairs and soft tissue from the basal part of the Yixian Formation in the Sihetun area, Beipiao,western Liaoning. It is significant for understanding the morphology, osteology, phylogeny and lifehabits of Mesozoic symmetrodont mammals.

A high methionine,low folate and vitamin B_6/B_(12) containing diet can be associated with memory loss by epigenetic silencing of netrin-1

Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study.We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore,silencing the netrin-1 gene,which encodes the glycoprotein involved in neurogenesis,axonal guidance and maintenance of the synaptic plasticity.Wild type(C57 BL/6 J) mice were fed with a diet containing excess methionine(1.2%),low-folate(0.08 mg/kg),vitamin B_6(0.01 mg/kg),and B_(12)(10.4 mg/kg) for 6 weeks.Mice were examined weekly for the long-term memory function,using a passive avoidance test,which determined loss of fear-motivated long-term memory starting from the fourth week of diet.Similarly,an increase in brain %5-methyl cytosine was observed starting from the 4 th week of diet in mice.Mice fed with a high methionine,low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation,as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis.The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis.Furthermore,the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory.Taken together,these results suggest that a diet rich in methionine and lacking in folate and vitamin B_6/B_(12) can induce defects in learning and memory.Furthermore,the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss.The animal procedures were approved by the Institutional Animal Care and Use Committee,University of Louisville,USA(No.A3586-01) on February 2,2018.

Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells

Methionine adenosyltransferase Ⅱ（MAT Ⅱ） is a key enzyme in cellular metabolism and catalyzes the formation of S-adenosylmethionine （SAMe） from L-methionine and ATE Normal resting T lymphocytes have minimal MAT Ⅱ activity, whereas activated proliferating T lymphocytes and transformed T leukemic cells show significantly enhanced MAT Ⅱ activity. This work was carried out to examine the role of MAT Ⅱ activity and SAMe biosynthesis in the survival of leukemic T cells. Inhibition of MAT Ⅱ and the resultant decrease in SAMe levels enhanced expression of FasL mRNA and protein, and induced DISC （Death Inducing Signaling Complex） formation with FADD （Fasassociated Death Domain） and procaspase-8 recruitment, as well as concomitant increase in caspase-8 activation and decrease in c-FLIPs levels. Fas-initiated signaling induced by MAT Ⅱ inhibition was observed to link to the mitochondrial pathway via Bid cleavage and to ultimately lead to increased caspase-3 activation and DNA fragmentation in these cells. Furthermore, blocking MAT 2A mRNA expression, which encodes the catalytic subunits of MAT Ⅱ, using a small-interfering RNA approach enhanced FasL expression and cell death, validating the essential nature of MAT Ⅱ activity in the survival of T leukemic cells.

Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental autoimmune uveitis

AIM：To test the therapeutic effects of delayed treatment of mesenchymal stem cells（MSCs） in recurrent experimental autoimmune uveitis（r EAU）.METHODS： The efficacy of different regimens of MSC administration in r EAU were tested by evaluation of clinical and pathological intraocular inflammation,as well as retinal structural and functional integrity using optical coherence tomography（OCT） and electroretinogram（ERG）.The retinal sections were also immunostained with antibodies to glial fibrillary acidic protein（GFAP）and rhodopsin（RHO）. RESULTS： Delayed treatment of MSCs effectively alleviated the severity of intraocular inflammation with relative intact of outer retinal structure and function.Moreover,double therapies with longer interval led to an even better clinical evaluation,as well as a trend of decrease in relapse and amelioration of retinal function.MSC therapies also effectively reduced GFAP expression and increased RHO expression in the retina.CONCLUSION： MSC administration can effectively treat developed diseases of rEAU,and multiple therapies can provide additional therapeutic benefits.

Influence of biological sex and exercise on murine cardiac metabolism

Although the structural and functional effects of exercise on the heart are well established,the metabolic changes that occur in the heart during and after exercise remain unclear.In this study,we used metabolomics to assess time-dependent changes in the murine cardiac metabolome following 1 session of treadmill exercise.After the exercise bout,we also recorded blood lactate,glucose,and ketone body levels and measured cardiac mitochondrial respiration.In both male and female mice,moderate-and high-intensity exercise acutely increased blood lactate levels.In both sexes,low-and moderate-intensity exercise augmented circulating 3-hydroxybutryrate levels immediately after the exercise bout;however,only in female mice did high-intensity exercise increase 3-hydroxybutyrate levels,with significant increases occurring 1 h after the exercise session.Untargeted metabolomics analyses of sedentary female and male hearts suggest considerable sex-dependent differences in basal cardiac metabolite levels,with female hearts characterized by higher levels of pantothenate,pyridoxamine,homoarginine,tryptophan,and several glycerophospholipid and sphingomyelin species and lower levels of numerous metabolites,including acetyl coenzyme A,glucuronate,gulonate,hydroxyproline,prolyl-hydroxyproline,carnosine,anserine,and carnitinylated and glycinated species,as compared with male hearts.Immediately after a bout of treadmill exercise,both male and female hearts had higher levels of corticosterone;however,female mice showed more extensive exercise-induced changes in the cardiac metabolome,characterized by significant,time-dependent changes in amino acids(e.g.,serine,alanine,tyrosine,tryptophan,branched-chain amino acids)and the ketone body 3-hydroxybutyrate.Results from experiments using isolated cardiac mitochondria suggest that high-intensity treadmill exercise does not acutely affect respiration or mitochondrial coupling;however,female cardiac mitochondria demonstrate generally higher adenosine diphosphate sensitivity compared with male cardiac mitochondria.Collectively,these findings in mice reveal key sex-dependent differences in cardiac metabolism and suggest that the metabolic network in the female heart is more responsive to physiological stress caused by exercise.