Frizzled2 receives WntA signaling during butterfly wing pattern formation.

Butterfly color patterns provide visible and biodiverse phenotypic readouts of the patterning processes. Although the secreted ligand WntA has been shown to instruct the color pattern formation in butterflies, its mode of reception remains elusive. Butterfly genomes encode four homologs of the Frizzled-family of Wnt receptors. Here, we show that CRISPR mosaic knockouts of frizzled2 (fz2) phenocopy the color pattern effects of WntA loss of function in multiple nymphalids. Whereas WntA mosaic clones result in intermediate patterns of reduced size, fz2 clones are cell-autonomous, consistent with a morphogen function. Shifts in expression of WntA and fz2 in WntA crispant pupae show that they are under positive and negative feedback, respectively. Fz1 is required for Wnt-independent planar cell polarity in the wing epithelium. Fz3 and Fz4 show phenotypes consistent with Wnt competitive-antagonist functions in vein formation (Fz3 and Fz4), wing margin specification (Fz3), and color patterning in the Discalis and Marginal Band Systems (Fz4). Overall, these data show that the WntA/Frizzled2 morphogen-receptor pair forms a signaling axis that instructs butterfly color patterning and shed light on the functional diversity of insect Frizzled receptors.

A genetic switch for male UV iridescence in an incipient species pair of sulphur butterflies.

Mating cues evolve rapidly and can contribute to species formation and maintenance. However, little is known about how sexual signals diverge and how this variation integrates with other barrier loci to shape the genomic landscape of reproductive isolation. Here, we elucidate the genetic basis of ultraviolet (UV) iridescence, a courtship signal that differentiates the males of Colias eurytheme butterflies from a sister species, allowing females to avoid costly heterospecific matings. Anthropogenic range expansion of the two incipient species established a large zone of secondary contact across the eastern United States with strong signatures of genomic admixtures spanning all autosomes. In contrast, Z chromosomes are highly differentiated between the two species, supporting a disproportionate role of sex chromosomes in speciation known as the large-X (or large-Z) effect. Within this chromosome-wide reproductive barrier, linkage mapping indicates that cis-regulatory variation of bric a brac (bab) underlies the male UV-iridescence polymorphism between the two species. Bab is expressed in all non-UV scales, and butterflies of either species or sex acquire widespread ectopic iridescence following its CRISPR knockout, demonstrating that Bab functions as a suppressor of UV-scale differentiation that potentiates mating cue divergence. These results highlight how a genetic switch can regulate a premating signal and integrate with other reproductive barriers during intermediate phases of speciation.

[Analysis of risk factors of short-term prognosis in patients with severe Budd-Chiari syndrome].

Objective: To explore the risk factors of short-term prognosis of severe Budd-Chiari syndrome (BCS) patients,established and verified the nomogram prediction model for these BCS patients and evaluated its clinical application value. Methods: This study is a retrospective cohort study. The clinical data of 171 patients with severe BCS diagnosed were retrospectively analyzed in the Department of Hepatopancreatobiliary Surgery First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023. There were 105 males and 66 females, aged (52.1±12.8) years (range: 18 to 79 years). The patients were divided into two groups based on whether they died within 28 days: the death group (n=38) and the survival group (n=133). The risk factors for short-term death of patients were analyzed,and independent risk factors were screened by univariate and multivariate analysis. Furthermore,these factors were used to establish the nomogram prediction model. The area under the curve(AUC),the Bootstrap Resampling,the Hosmer-Lemeshow test and the Decision Curve Analysis(DCA) were used to verify the model's differentiation,internal verification,calibration degree and clinical effectiveness,respectively. Results: Univariate and multivariate Logistics regression analysis showed that the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time were independent risk factors (P<0.05). The above factors were used to successfully establish the prediction model with 0.908 of AUC and 0.895 of the internal verification of AUC,indicating that the predictive model was valuable. The 0.663 P-values in the Hosmer-Lemeshow test indicated the high calibration degree of the model. The clinical effectiveness of the model was proved by the 18% clinical benefit population using the DCA curve with the 17% probability threshold. Conclusions: The independent risk factors are the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time. An adequate basis was acquired by establishing a nomogram prediction model of the short-term prognosis of severe BCS,which was helpful for early clinical screening and identification of high-risk patients with severe BCS who could die in the short term and timely providing timely intervention measures for improving the prognosis.

[Study the involvement of Langerin in mediating epicutaneous sensitization of atopic dermatitis-like mouse model].

Objective: To explore the role of Langerin in mediating epicutaneous sensitization of atopic dermatitis (AD) in mouse model. Methods: Mice were topically treated with calcipotriol (MC903) plus ovalbumin (OVA) on the ears to establish AD mouse models, and mice were divided into wild-type control group, wild-type AD group, Langerin knockout control group, and Langerin knockout AD group. Changes of lesion were daily observed. Infiltration of inflammatory cells, mRNA expression of Tslp, Il4, Il13, Il17a, and Il22, levels of serum total IgE, OVA-specific IgE (sIgE), OVA sIgG1 and OVA sIgG2a, proportion of regulatory T (Treg) cells in cervical draining lymph nodes were evaluated at the end of model preparation. Results: Skin tumidness and thickness, dermal inflammatory cells infiltration, the mRNA expression levels of Tslp, Il4, Il13, Il17a and Il22 in wild-type AD groups were higher than those in wild-type control groups, with (1.80±0.66, 1.64±0.25, 1.71±0.54, 2.41±0.23, 2.49±0.32) and (0.53±0.45, 0.85±0.29, 0.73±0.50, 0.72±0.25, 0.56±0.29), respectively (all P<0.05). In addition, the levels of serum total IgE, OVA sIgE and OVA sIgG1 in wild-type AD groups were higher than those in wild-type control groups, with [(1 216.00±572.70) ng/ml, (597.00±538.30) ng/ml, 1.59±0.09] and [(24.22±35.04) ng/ml, (20.01±41.71) ng/ml, 1.16±0.03], respectively (all P<0.05). In Langerin knockout mice, compared to wild-type mice, skin erythema, skin tumidness, epidermal thickening, inflammatory cell infiltration were more obvious; the mRNA expression levels of Tslp, Il4, Il13, Il17a and Il22 were upregulated with (8.19±6.44, 2.53±0.69, 2.82±0.73, 3.94±1.32, 3.80±1.43) (all P<0.05); the levels of serum total IgE, OVA sIgE and OVA sIgG1 were significantly increased with (2 508.00±657.10) ng/ml, (1 808.00±470.70) ng/ml, (1.73±0.09) (all P<0.05); the number of CD4+CD25+CD127-Treg cells were decreased significantly with (13.25±0.96)% and (15.31±1.47)%, respectively (P<0.05). Conclusion: Langerin is involved in mediating epicutaneous sensitization of the AD mouse model and plays a negative immunoregulatory role.

[C2 pedicle screw insertion assisted by mobilization of the vertebral artery in cases with high-riding vertebral artery].

Objective: To examine the feasibility, safety, and efficacy of mobilization of the vertebral artery for C2 pedicle screws in cases with high-riding vertebral artery (HRVA). Methods: The clinical data of 12 patients with basilar invagination and atlantoaxial dislocation underwent atlantoaxial reduction and fixation in the Department of Neurosurgery, the First Affiliated Hospital of University of Science and Technology of China between January 2020 and November 2021 were retrospectively analyzed. All patients had high-riding vertebral artery on at least one side that prohibited the insertion of C2 pedicle screws. There were 2 males and 10 females aged (48.0±12.8) years (range: 17 to 67 years). After correction of vertical dislocation during the operation, the C2 pedicle screw insertion and occipitocervical fixation and fusion were performed using the vertebral artery mobilization technique. Neurological function was assessed using the Japanese Orthopedic Association (JOA) scale. The preoperative and postoperative JOA score and the main radiological measurements, including the anterior atlantodental interval (ADI), the distance of the odontoid tip above the Chamberlain line, the clivus-canal angle, were collected and compared by paired t-test. Results: Mobilization of the high-riding vertebral artery was successfully completed, and C2 pedicle screws were then fulfilled after the vertebral artery was protected. There was no injury to the vertebral artery during the operation. Meanwhile, no severe surgical complications such as cerebral infarction or aggravated neurological dysfunction occurred during the perioperative period. Satisfactory C2 pedicle screw placement and reduction were achieved in all 12 patients. All patients achieved bone fusion 6 months after surgery. No looseness and shift in internal fixation or reduction loss was observed during the follow-up period. Compared to the preoperative, the postoperative ADI decreased from (6.1±1.9) mm to (2.0±1.2) mm (t=6.73, P<0.01), the distance of the odontoid tip above the Chamberlain line decreased from (10.4±2.5) mm to (5.5±2.3) mm (t=7.12, P<0.01), the clivus-canal angle increased from (123.4±11.1) ° to (134.7±9.6) ° (t=2.50, P=0.032), the JOA score increased from 13.3±2.1 to 15.6±1.2 (t=6.99, P<0.01). Conclusion: The C2 pedicle screw insertion assisted by mobilization of the vertebral artery is safe and considerably effective, providing a choice for internal fixation in cases with high-riding vertebral arteries.

Warming signals in temperate reef communities following more than a decade of ecological stability.

Ecosystem structure and function are increasingly threatened by changing climate, with profound effects observed globally in recent decades. Based on standardized visual censuses of reef biodiversity, we describe 27 years of community-level change for fishes, mobile macroinvertebrates and macroalgae in the Tasmanian ocean-warming hotspot. Significant ecological change was observed across 94 reef sites (5-10 m depth range) spanning four coastal regions between three periods (1992-95, 2006-07, 2017-19), which occurred against a background of pronounced sea temperature rise (+0.80°C on average). Overall, fish biomass increased, macroinvertebrate species richness and abundance decreased and macroalgal cover decreased, particularly during the most recent decade. While reef communities were relatively stable and warming was slight between the 1990s and mid-2000s (+0.12°C mean temperature rise), increased abundances of warm affinity fishes and invertebrates accompanied warming during the most recent decade (+0.68°C rise). However, significant rises in the community temperature index (CTI) were only found for fishes, invertebrates and macroalgae in some regions. Coastal warming was associated with increased fish biomass of non-targeted species in fished zones but had little effect on reef communities within marine reserves. Higher abundances of larger fishes and lobsters inside reserves appeared to negate impacts of 'thermophilization'.

Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Homing behaviour by destructive crown-of-thorns starfish is triggered by local availability of coral prey.

Corallivorous crown-of-thorns starfishes (Acanthaster spp.) can decimate coral assemblages on Indo-Pacific coral reefs during population outbreaks. While initial drivers of population irruptions leading to outbreaks remain largely unknown, subsequent dispersal of outbreaks appears coincident with depletion of coral prey. Here, we used in situ time-lapse photography to characterize movement of the Pacific crown-of-thorns starfish (Acanthaster cf. solaris) in the northern and southern Great Barrier Reef in 2015, during the fourth recorded population outbreak of the starfish, but prior to widespread coral bleaching. Daily tracking of 58 individuals over a total of 1117 h revealed all starfish to move a minimum of 0.52 m, with around half of all tracked starfish showing negligible daily displacement (less than 1 m day-1), ranging up to a maximum of 19 m day-1. Movement was primarily nocturnal and daily displacement varied spatially with variation in local availability of Acropora spp., which is the preferred coral prey. Two distinct behavioural modes emerged: (i) homing movement, whereby tracked paths (as tested against a random-walk-model) involved short displacement distances following distinct 'outward' movement to Acropora prey (typically displaying 'feeding scars') and 'homebound' movement to nearby shelter; versus (ii) roaming movement, whereby individuals showed directional movement beyond initial tracking positions without return. Logistic modelling revealed more than half of all tracked starfish demonstrated homing when local abundance (percentage cover) of preferred Acropora coral prey was greater than 33%. Our results reveal facultative homing by Acanthaster with the prey-dependent behavioural switch to roaming forays providing a mechanism explaining localized aggregations and diffusion of these population irruptions as prey is locally depleted.

Production of mobile invertebrate communities on shallow reefs from temperate to tropical seas.

Primary productivity of marine ecosystems is largely driven by broad gradients in environmental and ecological properties. By contrast, secondary productivity tends to be more variable, influenced by bottom-up (resource-driven) and top-down (predatory) processes, other environmental drivers, and mediation by the physical structure of habitats. Here, we use a continental-scale dataset on small mobile invertebrates (epifauna), common on surfaces in all marine ecosystems, to test influences of potential drivers of temperature-standardized secondary production across a large biogeographic range. We found epifaunal production to be remarkably consistent along a temperate to tropical Australian latitudinal gradient of 28.6°, spanning kelp forests to coral reefs (approx. 3500 km). Using a model selection procedure, epifaunal production was primarily related to biogenic habitat group, which explained up to 45% of total variability. Production was otherwise invariant to predictors capturing primary productivity, the local biomass of fishes (proxy for predation pressure), and environmental, geographical, and human impacts. Highly predictable levels of epifaunal productivity associated with distinct habitat groups across continental scales should allow accurate modelling of the contributions of these ubiquitous invertebrates to coastal food webs, thus improving understanding of likely changes to food web structure with ocean warming and other anthropogenic impacts on marine ecosystems.

Diabetes in adults with intellectual disability: prevalence and associated demographic, lifestyle, independence and health factors.

BACKGROUND: As people with intellectual disabilities (ID) are now living longer, they are more at risk of developing non-communicable diseases, including type 2 diabetes mellitus. However, understanding of factors associated with diabetes for targeted management and prevention strategies is limited. This study aimed to investigate prevalence of diabetes in adults (aged ≥18 years) with ID and its relationship with demographic, lifestyle, independence and health factors. METHOD: This was a cross-sectional analysis of interview data from 1091 adults with ID from the Leicestershire Learning Disability Register from 1 January 2010 to 31 December 2016. Logistic regression models were used to identify factors associated with diabetes in the study population. RESULTS: The study population did not have healthy lifestyles: just under half reported having lower physical activity levels than people without ID of a similar age; one-quarter consumed fizzy drinks daily; and 20% consumed five or more fruit and/or vegetables per day. Prevalence of carer/self-reported diabetes was 7.3% (95% confidence interval 5.9-9.0). After adjustment, diabetes was positively associated with South Asian ethnicity (P = 0.03) and older age groups (P < 0.001). Diabetes was less common in people living with family members (P = 0.02). We did not find a relationship between any of the lifestyle, independence and health factors investigated. CONCLUSIONS: A significant proportion of people with ID are living with diabetes. Diabetes management and prevention strategies should be tailored to individuals' complex needs and include consideration of lifestyle choices. Such strategies may want to focus on adults of South Asian ethnicity and people living in residential homes where prevalence appears to be higher.

[Development and application of a fundus image quality assessment system based on computer vision technology].

Objective: To develop a fundus image quality assessment system based on computer vision technology and to verify its accuracy by comparing the results of artificial discrimination and using this system. Methods: The process of image evaluation was divided into four modules: fundus image preprocessing, fundus image quality evaluation, fundus image content detection and evaluation result output. The system was designed to automatically evaluate the image quality of each fundus image, identify the optic disc and macula, and judge whether the image was qualified or not according to the image quality discrimination rules. A total of 2 397 fundus images of 787 type 2 diabetes patients were selected as the test data set. The average age of the patients, including 384 males and 403 females, was (69.65±19.09) years old. The images were taken by the staff of community health service centers in Shanghai with a fundus camera. The fundus image quality assessment system was used to conduct quality control and classification of the data set. At the same time, 12 professional fundus picture readers were employed to conduct manual quality control and classification of this data set. The system quality control results and artificial quality discrimination results were compared and analyzed. Results: The fundus image quality assessment system automatically recognized left and right eyes and eye positions on the input fundus images. The quality control interface included four indicator lights, which respectively corresponded to the images with the optic disc or macula as the center of the left or right eye. Evaluation of each fundus image was completed within 1 second, and the results were automatically displayed on the user interface. The 2 397 fundus photos were identified manually as 1 846 qualified photos and 551 unqualified photos. Among the unqualified images, 62 (11.27%) were too dark, 51 (9.27%) were too bright, 59 (10.73%) were not clear in the macular area, 36 (6.54%) showed no macula or optic disc, 125 (22.73%) could not present the fundus structure, 175 (31.82%) were blurred, and 42 (7.64%) were blocked. The results of the system and manual assessment were consistent in 1 788 qualified images (96.86%) and 550 unqualified images (99.82%), with an overall consistency rate of 97.54%. Conclusion: The fundus image quality assessment system can achieve highly consistent results with the professional judgment of ophthalmologists and has the characteristics of objectivity. (Chin J Ophthalmol, 2020, 56:920-927).

Density-dependent feedbacks, hysteresis, and demography of overgrazing sea urchins.

Sea urchin grazing can result in regime shift from productive kelp beds to sea urchin barren grounds that represent an alternative and stable reef state. Here we examine the stability of urchin barrens by defining the demographics of the Australian urchin Heliocidaris erythrogramma during regime shift to, and maintenance of, barrens. Inverse-logistic modeling of calibrated in situ annual growth increments for five urchin populations, two from kelp beds and three from barrens, demonstrate slowing of urchin growth as availability and consumption of standing and/or drift kelp declines. Population age structures were predicted from observed sizes over four years (2012-2015, n = 5,864 individuals), which indicated stable age distributions for populations both maintaining barrens and actively grazing among kelp beds. Younger age distributions occurred on barrens whereas more mature populations existed within kelp beds, indicating that high recruitment facilitates maintenance of barrens while overgrazing appeared more reliant on adult urchins grazing from the edges of kelp beds, as opposed to juvenile recruitment among kelp. Leslie-matrix projections indicated potential for unchecked population growth for all study populations, but which varied depending on whether local or regional recruitment rates were modeled. Ultimately, strong density dependence was observed to check population growth; with high-recruitment/high-density populations offset by reduced growth rates and decreased longevity. Increasing disease rates among older urchins in high-density populations were consistent with observed density-dependent mortality, while tethering of healthy urchins revealed highest predation on small urchins within kelp beds, suggesting some remnant resilience of declining kelp habitat. Results demonstrate that the greatest opportunity for urchin population control is when reefs exist in the kelp bed state, at which point urchin populations are prone to negative feedback. Conversely, control of urchins on barrens is demonstrably difficult given positive density-dependent feedbacks that act to stabilize population size and which evidently underpin the hysteresis effect governing the persistence of this alternative stable state.

Drift-kelp suppresses foraging movement of overgrazing sea urchins.

Sea urchins have the capacity to destructively overgraze kelp beds and cause a wholesale shift to an alternative and stable 'urchin barren' reef state. However, destructive grazing appears labile and contingent on behavioural shift. Changes in supply of allochthonous 'drift-kelp' food are hypothesised as a trigger of change in urchin grazing behaviour, yet field tests are lacking. Here we conduct a suite of in situ behavioural surveys and manipulative experiments within kelp beds and on urchin barrens to examine foraging movements and evidence for a behavioural switch to an 'overgrazing mode' by the Australian urchin Heliocidaris erythrogramma (Echinometridae). Tracking urchins using time-lapse photography revealed urchin foraging to conform to a random walk model within kelp beds and on barrens. However, many individuals tended towards local movement within proximal crevices and movement was reduced in kelp beds compared to barrens. Directional movement of urchins toward newly available kelp was experimentally inducible, consistent with locally observed 'mobile-feeding-fronts' that develop at barrens-kelp interfaces. Habitat-specific feeding modes were also evidenced by herbivory assays which revealed urchin grazing rates to be high on both drift-kelp and standing kelp on barren grounds, while drift-kelp but not standing kelp was consumed at high rates within kelp beds. Time-lapse tracking of urchin foraging before/after addition of drift-kelp revealed a reduction in foraging across the reef surface after drift-kelp capture. Collectively, results indicate that the availability of drift-kelp is a pivotal trigger in determining urchin feeding modes which thus mediates the shift between alternative stable states for rocky reef ecosystems.

Genetics of immune-mediated inflammatory diseases.

Immune-mediated inflammatory diseases (IMIDs) are characterized by dysregulation of the normal immune response, which leads to inflammation. Together, they account for a high disease burden in the population, given that they are usually chronic conditions with associated co-morbidities. Examples include systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease and type 1 diabetes. Since the advent of genome-wide association studies, evidence of considerable genetic overlap in the loci predisposing to a wide range of IMIDs has emerged. Understanding the genetic risk and extent of genetic overlap between IMIDs may help to determine which genes control which aspects of the different diseases; it may identify potential novel therapeutic targets for a number of these conditions, and/or it may facilitate repurposing existing therapies developed originally for different conditions. The findings show that autoantibody-mediated autoimmune diseases cluster more closely with each other than autoantibody-negative diseases such as psoriasis, psoriatic arthritis, Crohn's disease and ankylosing spondylitis which, instead, form a seronegative genetic cluster. The genetic clustering largely mirrors the known response to existing biological therapies, but apparent anomalies in treatment response are discussed.

Reduced resistance to sediment-trapping turfs with decline of native kelp and establishment of an exotic kelp.

Understanding the strength and type of interactions among species is vital to anticipate how ecosystems will respond to ongoing anthropogenic stressors. Here, we examine the ecological function of native (Ecklonia radiata) and invasive (Undaria pinnatifida) kelps in resisting shifts to sediment-trapping turf on reefs within the highly urbanized temperate Port Phillip Bay (PPB), Australia. Short-term (30 days) and long-term (232 days) manipulations demonstrated that kelp laminae can clear and maintain the substratum free of turfs, while conversely, removal of kelp leads to a proliferation of turfs. Analyses looking at the relationship between total length of E. radiata and U. pinnatifida and the area cleared of turf algae showed that the clearing effect of E. radiata over a year was greater than that of U. pinnatifida due to the annual die-back of the invasive. A natural experiment (608 days) identified that ongoing sea urchin (Heliocidaris erythrogramma) grazing led to native kelp bed decline, facilitating turf dominance. Even though U. pinnatifida establishes once native beds are disturbed, its ecological function in clearing turf is weaker than E. radiata, given its annual habit. In PPB, turfs represent the more persistent and problematic algal group and are likely changing the structure, function, and energy flows of shallow temperate reefs in this urbanised embayment.

KrasG12D-LOH promotes malignant biological behavior and energy metabolism of pancreatic ductal adenocarcinoma cells through the mTOR signaling pathway.

Oncogenic Kras with loss of heterozygosity (LOH) is frequently detected in various tumours. However, the exact function and mechanism by which KrasG12D-LOH operates remain unclear. Therefore, the current study investigated the effect of KrasG12D-LOH on the malignant phenotype of pancreatic ductal adenocarcinoma (PDAC) cells. Our investigation revealed that KrasG12D-LOH is associated with increased proliferation, invasion and reduced apoptosis in PDAC cells. The results also exhibited enhanced glycolytic phenotype of KrasG12D-LOH PDAC cells. Hyperactive mTOR plays a significant role in the initiation and maintenance of tumors. To investigate the correlation between KrasG12D-LOH and mTOR, the mTOR signaling pathway was detected by western blot analysis. We found that KrasG12D-LOH up-regulated Akt, AMPK, REDD1 and mTOR in PDAC cells. In summary, our results demonstrated that KrasG12D-LOH promotes oncogenic Kras-induced PDAC by regulating energy metabolism and mTOR signaling pathway. These data may provide novel therapeutic perspectives for PDAC.

Dunye Guanxinning Improves Acute Myocardial Ischemia-Reperfusion Injury by Inhibiting Neutrophil Infiltration and Caspase-1 Activity.

Acute myocardial infarction is the most serious manifestation of cardiovascular disease, and it is a life-threatening condition. Dunye Guanxinning (DG) is a protective traditional Chinese patent herbal medicine with high clinical efficacy and suitable for the treatment of myocardial infarction. However, the mechanism through which it is beneficial is unclear. In this study, we hypothesized that DG improves acute myocardial ischemia-reperfusion injury by inhibiting neutrophil infiltration and caspase-1 activity. We found that DG administration decreased infarct size and cardiomyocyte apoptosis and improved left ventricular ejection fraction, fractional shortening, end-systolic volume index, end-systolic diameter, and carotid arterial blood flow output in rats. DG administration also improved hemorheological parameters, myocardial damage biomarkers, and oxidative stress indexes. The findings showed that DG administration inhibited neutrophil infiltration and reduced the serum interleukin-1 beta (IL-1ß) level and myocardial IL-1ß maturation. Moreover, DG administration inhibited caspase-1 activity and activated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in rat hearts. These results suggested that DG administration inhibits inflammasome activity and IL-1ß release through the AMPK pathway. Our findings support the clinical efficacy of DG and partially reveal its mechanism, which is beneficial for understanding the therapeutic effects of this protective traditional Chinese patent drug.

3D-QSAR pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation toward identifying lead compounds for NS2B-NS3 protease inhibitors.

NS2B-NS3 protease has been identified to serve as lead drug design target due to its significant role in West Nile viral (WNV) and dengue virus (DENV) reproduction and replication. There are currently no approved chemotherapeutic drugs and effective vaccines to inhibit DENV and WNV infections. In this work, 3D-QSAR pharmacophore model has been developed to discover potential inhibitory candidates. Validation through Fischer's model and decoy test indicate that the developed 3D pharmacophore model is highly predictive for DENV inhibitors, which was then employed to screen ZINC chemical library to obtain reasonable hits. Following ADMET filtering, 15 hits were subjected to further filter through molecular docking and CoMFA modeling. Finally, top three hits were identified as lead compounds or potential inhibitory candidates with IC50 values of ∼0.4637 µM and fitness of ∼57.73. It is implied from CoMFA modeling that substituents at the side site of benzotriazole such as a p-nitro group (e.g. biphenyl head) and a carbonyl (e.g. carboxylate function) at the side site of furan or amino group may improve bioactivity of ZINC85645245, respectively. Molecular dynamics simulations (MDS) were performed to discover new interactions and reinforce the binding modes from docking for the hits also. The QSAR and MDS results obtained from this work should be useful in determining structural requirements for inhibitor development as well as in designing more potential inhibitors for NS2B-NS3 protease.