Blunting Effect Research Articles

Damage constitutive model and numerical simulation of in-plane tear failure for architectural fabric membranes

Tearing failure is the key factor affecting the safety of tension fabric structures, but there is a lack of material damage models and numerical methods needed to simulate tearing failure. This paper investigates the macroscopic damage model of architectural fabrics and the numerical simulation method for its tearing failure. Firstly, based on the incremental stress update scheme, theoretical descriptions of the material model considering the nonlinear elastic damage behavior are presented. Then, the influence of stiffness softening laws and the mesh schemes are investigated, and the advantages of easy implantation and good precision of the proposed model are validated by comparison with the cohesive element model embedded in ABAQUS. Compared with the experiment results and theoretical model, the predicted results are in good agreement for various crack length cases, and the nonlinear variation mechanism of tearing residual strength is revealed. Also, the effect of the tensile strength and fracture energy are discussed, and it is found that the crack tip blunting effect causes the linear elastic fracture mechanics not applicable.

Influence of reverted austenite on fatigue life of 18 % nickel maraging steel

AbstractMaraging steels containing 18 % nickel are based on a low‐carbon iron‐nickel‐cobalt‐molybdenum system. These steels demonstrate a remarkable combination of high strength and high toughness. To investigate the effect of overaging and resulting austenite reversion on the fatigue behavior of C250 maraging steel, specimens in the solution annealed state were overaged at 510 °C for various intervals, resulting in volume fractions of reverted austenite ranging from 2.6 % to 11.4 %. The staircase method was used to calculate the fatigue limit. S−N curves were generated by testing a minimum of four stress levels and at least three samples at each stress level. Basquin's equation was used to fit the experimental stress‐life data, and the Basquin exponent and fatigue strength coefficient were calculated. The presence of 2.6 % reverted austenite in the microstructure improved the fatigue limit and fatigue ratio, without significantly reducing tensile strength. The results can be interpreted in terms of reverted austenite having a crack blunting effect on the propagating cracks. A small amount of reverted austenite in the range of 2 %–3 % vol has a beneficial effect on the fatigue life.

Glutamate Infusion Reduces Myocardial Dysfunction after Coronary Artery Bypass Grafting According to NT-proBNP: Summary of 2 Randomized Controlled Trials (GLUTAmate for Metabolic Intervention in Coronary Surgery [GLUTAMICS I-II

BackgroundGlutamate is reported to enhance the recovery of oxidative metabolism and contractile function of the heart after ischemia. The effect appears to be blunted in diabetic hearts. Elevated plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) reflects myocardial dysfunction. In the GLUTAmate for Metabolic Intervention in Coronary Surgery (GLUTAMICS) II trial, the proportion of patients with diabetes had nearly doubled to 47% compared with the cohort used for sample size estimation, and a significant effect on the postoperative rise in NT-proBNP was only observed in patients without diabetes. ObjectiveWe aimed to summarize the pooled NT-proBNP results from both GLUTAMICS trials and address the impact of diabetes. MethodsData from 2 prospective, randomized, double-blind multicenter trials with similar inclusion criteria and endpoints were pooled. Patients underwent a coronary artery bypass grafting (CABG) ± valve procedure and had a left-ventricular ejection fraction of ≤0.30 or a European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) of ≥3.0 with at least 1 cardiac risk factor. Intravenous infusion of 0.125 M L-glutamic acid or saline at 1.65 mL/kg/h was started 10–20 min before reperfusion and continued for 150 min. The primary endpoint was the difference between preoperative and day 3 postoperative NT-proBNP levels. ResultsA total of 451 patients, 224 receiving glutamate and 227 controls, fulfilled the inclusion criteria. Glutamate was associated with a reduced primary endpoint (5344 ± 5104 ng/L and 6662 ± 5606 ng/L in glutamate and control groups, respectively; P = 0.01). Postoperative mortality at ≤30 d was 0.9% and 3.5% (P = 0.11), whereas stroke at ≤24 h was 0.4% and 2.6% in glutamate and control groups, respectively (P = 0.12). No adverse events related to glutamate were observed. A significant interaction regarding the primary endpoint was only detected between glutamate and insulin-treated diabetes groups (P = 0.04). Among patients without insulin-treated diabetes, the primary endpoint was 5047 ± 4705 ng/L and 7001 ± 5830 ng/L in the glutamate and control groups, respectively (P = 0.001). ConclusionsInfusion of glutamate reduced the postoperative rise in NT-proBNP after CABG in medium- to high-risk patients. A significantly blunted effect was observed only in insulin-treated patients with diabetes. Clinical trial detailsThis trial was registered at www.clinicaltrials.gov as NCT02592824.

Deep phenotyping of 11,880 highlanders reveals novel adaptive traits in native Tibetans

Tibetans are the ideal population to study genetic adaptation in extreme environments. Here, we performed systematic phenotyping of 11,880 highlanders, covering 133 quantitative traits of 13 organ systems. We provided a comprehensive phenotypic atlas by comparing altitude adaptation and altitude acclimatization. We found the differences between adaptation and acclimatization are quantitative rather than qualitative, with a whole-system "blunted effect" seen in the adapted Tibetans. We characterized twelve different functional changes between adaptation and acclimatization. More importantly, we established a landscape of adaptive phenotypes of indigenous Tibetans, including 45 newly identified Tibetan adaptation-nominated traits, involving specific changes of Tibetans in internal organ state, metabolism, eye morphology, and skin pigmentation. In addition, we observed a sex-biased pattern between altitude acclimatization and adaptation. The generated atlas of phenotypic landscape provides new insights into understanding of human adaptation to high-altitude environments, and it serves as a valuable blueprint for future medical and physiological studies.

The importance of serial sarcomere addition for muscle function and the impact of aging.

During natural aging, skeletal muscle experiences impairments in mechanical performance due, in part, to changes in muscle architecture and size, notably with a loss of muscle cross-sectional area. Another important factor that has received less attention is the shortening of fascicle length, potentially reflective of a decrease in serial sarcomere number (SSN). Interventions that promote the growth of new serial sarcomeres, such as chronic stretching and eccentric-biased resistance training, have been suggested as potential ways to mitigate age-related impairments in muscle function. While current research suggests it is possible to stimulate serial sarcomerogenesis in muscle in old age, the magnitude of sarcomerogenesis may be less than in young muscle. This blunted effect may be partly due to age-related impairments in the pathways regulating mechanotransduction, muscle gene expression, and protein synthesis, as some have been implicated in SSN adaptation. The purpose of this review was to investigate the impact of aging on the ability for serial sarcomerogenesis, and elucidate the molecular pathways that may limit serial sarcomerogenesis in old age. Age-related changes in mTOR, IGF-1, myostatin, and serum response factor signalling, MuRFs, and satellite cells may hinder serial sarcomerogenesis. In addition, our current understanding of SSN in older humans is limited by assumptions based on ultrasound-derived fascicle length. Future research should explore the effects of age-related changes in the identified pathways on the ability to stimulate serial sarcomerogenesis, and better estimate SSN adaptations to gain a deeper understanding of the adaptability of muscle in old age.

Chemical Characterization of Different Extracts from Artemisia annua and Their Antioxidant, Enzyme Inhibitory and Anti-Inflammatory Properties.

Artemisia annua L. (Asteraceae Family) is an important plant in Asia that has been used for treating different diseases, including fever due to malaria, wounds, tubercolisis, scabues, pain, convulsions, diabetes, and inflammation. In this study we aimed to evaluate the effects of different polarity extracts (hexane, dichloromethane, ethyl acetate, ethanol, ethanol/water (70 %) and water) from A. annua against the burden of inflammation and oxidative stress occurring in colon tissue exposed to LPS. In parallel, chemical composition, antiradical, and enzyme inhibition effects against α-amylase, α-glucosidase, tyrosinase, and cholinesterases were evaluated. The water extract contained the highest content of the total phenolic with 34.59 mg gallic acid equivalent (GAE)/g extract, while the hexane had the highest content of the total flavonoid (20.06 mg rutin equivalent (RE)/g extract). In antioxidant assays, the polar extracts (ethanol, ethanol/water and water) exhibited stronger radical scavenging and reducing power abilities when compared to non-polar extracts. The hexane extract showed the best AChE, tyrosinase and glucosidase inhibitory effects. All extracts revealed effective anti-inflammatory agents, as demonstrated by the blunting effects on COX-2 and TNFα gene expression. These effects seemed to be not related to the only phenolic content. However, it is worthy of interest to highlight how the higher potency against LPS-induced gene expression was shown by the water extract ; thus suggesting a potential phytotherapy application in the management of clinical symptoms related to inflammatory colon diseases, although future in vivo studies are needed to confirm such in vitro and ex vivo observations.

An analytical model to predict back face deformation of hybrid soft body armors under ballistic impact

In the design of soft body armors for ballistic protection, the blunt trauma effect has to be taken into account and it is usually evaluated by the back face deformation (BFD). Most of the current research on blunt trauma is based on experiments and simulations, whereas the development of analytical models is still rare. This study develops an analytical model to predict BFD for a hybrid panel composed of modified aramid fabrics and Ultra-high molecular weight polyethylene (UHMWPE) unidirectional sheets, which is based on the two-stage damage evolution: shear plugging and tensile bulge. Firstly, the shear and tensile energy of the hybrid panel as well as the deformation energy of the clay were constructed. Secondly, the characteristic equations were developed according to the law of energy conservation and BFD could be obtained by solving the equations. The results of the analytical model were found to be in good agreement with experiments and FE simulations. With the assistance of the model, the effect of projectile geometry and optimized designs for hybrid panels have been studied.

Direct numerical simulation of slender cones with variable nose bluntness based on graphics processing unit computation

Direct numerical simulation with up to 10×109 scale grid points based on graphics processing unit computation is carried out to investigate the bluntness effect on the hypersonic boundary-layer transition over a slender cone with zero angle of attack at Mach 6. Four cases with the nose radii of 1, 10, 20, and 40 mm are conducted, and the corresponding Reynolds number based on the nose radius varies from 1.0×104 to 4.0×105. Random disturbances with a broad spectrum of frequencies and a wide range of azimuthal wavenumbers were applied to the wall to simulate disturbances caused by wall roughness. The numerical results show that as the nose tip radius increases, the transition position gradually moves downstream with increased transition region. For the case with a nose radius of 1 mm, the flow transition and entropy swallowing occur almost simultaneously, while for other cases, the transition takes place earlier than the entropy swallowing. In consequence, the disturbance amplitude upstream of the transition in the 1 mm case is much larger than that of other cases. To further study the mechanism of the transition, the frequency spectrum analysis is carried out. It is found that all cases exhibit two characteristic frequencies within the transition region, i.e., the high frequency and extremely low frequency. Owing to the influence of the entropy layer, the characteristic high frequency of the 1 mm case is significantly higher than that of other cases. With the increase in the nose radius, the characteristic frequency of the high frequency decreases gradually.

Experimental Investigations on High-Speed Aerodynamic Heating over Inflatable Decelerators

Heat transfer measurements and high-speed schlieren flow visualization were performed over a cylinder with an aft-attached inflatable decelerator configuration at Mach 3.9. Back wall temperature measurements using thermocouples were used to derive the heat flux distribution over the decelerator surface. A strong nonlinear rise in peak heat flux with angle of attack is observed and windward–leeward effects are quantified. Using appropriate flow and geometric symmetries, heat maps are generated over the regions of the decelerator, which are critical for its thermal design. The effect of fore-end bluntness in terms of peak heat fluxes and integrated heat loads is investigated. The results indicate a possibility of flying at a small angle of attack to reduce the integrated heat loads while simultaneously generating some lift. Tests up to an angle of attack of 20 deg show that even though the peak heating rises strongly, the overall integrated heat loads on the surface of the decelerator remain manageable. A local minimum is seen in peak heat flux levels on the surface at angles of attack of 12–16 deg.

Perceived discrimination and stress response profiles among Mexican-origin Adolescents

The hypothalamic-pituitary-adrenal (HPA) axis is one of the major stress response systems in the human body and it is sensitive to social evaluative stress. The functioning of HPA axis is commonly measured with cortisol. Research on cortisol has focused on cortisol reactivity and its diurnal rhythm using salivary cortisol to inform short-term stress responses. Cortisol can also be measured through hair, which tracks individuals’ cumulative stress response. To more comprehensively understand cortisol levels and responses to stress, this study used a person-centered approach to examine stress response profiles based on individuals’ cortisol reactivity, diurnal cortisol rhythms, and hair cortisol concentration. Participants were 290 Mexican-origin adolescents (Mage = 17.38; 52% female). Latent profile analysis was used to characterize stress response profiles identified using three daily salivary samples across four days, seven saliva samples throughout the Trier Social Stress Test, and hair cortisol. The resulting profiles were examined in relation to discrimination and covariates. Analyses identified two stress response profiles. Most of the participants (88%) were in the “lower” profile (blunted diurnal cortisol rhythm and lower pattern of cortisol reactivity) and the remainder were in the “higher” profile (elevated diurnal cortisol rhythm and increased pattern of cortisol reactivity). Adolescents in the “lower” group reported more discrimination than those in the “higher” group. Findings of the study demonstrate the first attempt to integrate different aspects of stress responses in the HPA axis. Results also highlight the blunting effects of discrimination on Mexican-origin adolescents’ basal cortisol and responses to stress.

Study of blunt impact effects of rifle bullet penetrating the SiC/UHMWPE armor covered human torso

To study the behind armor blunt trauma (BABT), a finite element model of a 5.8 mm rifle bullet penetrating the SiC/UHMWPE armor covered human torso was established. The human torso model comprises internal organs (heart, lung, liver, and stomach), skeleton (sternum, ribs, and spine), and muscle. It is assumed that the skeleton and muscle is linear elastic, and all internal organs are viscoelastic and hyperelastic. The impact response of a rifle bullet penetrating a human target with bulletproof armor at a speed of 900m/s is numerically simulated. The deformation data of bullet and body armor were obtained. In addition, the von Mises stresses of muscle, skeleton, and internal organs were analyzed. The numerical model provides an effective method for studying BABT and the improvement of bulletproof armor.

On-line quality control and tool wear evaluation in trimming process by data analytics techniques

Sheet metal is an extremely common form of use in broad engineering sectors and represents the main consumption of steel and aluminum in Europe. All production processes where sheet metal is used require cutting operations. Therefore, it is an extremely relevant procedure, common and of great economic importance in material-intensive sectors such as automotive, construction and engineering. In a competitive environment where the demand for quality increases continuously and using harder to process high-performance materials, online monitoring and quality control become an attractive prospective. In this regard, application of data analytics techniques offers a promising toolset for fast and efficient analysis. This work presents a pilot demonstration of an instrumented sheet metal cutting line that integrates online quality control and predictive maintenance concepts, namely detection of wear in tools as well as problems arising from the raw material and process. Automated sequential cutting was performed using a straight trimming die mounted on a hydraulic press to cut High-Mn TWIP steel strip. Three piezoelectric force sensors were located in the trimming tool, collecting cycle data. Tests performed included studying the effect of blunting on the M2 (1.3343) tool, as well as the influence of correct lubrication. The resulting data were analyzed through the extraction of several parameters from each cycle to correlate die wear-induced force response evolutions with the shear-induced deformation in High-Mn TWIP steel sheets. Extracted parameters were the maximum and minimum force of each cycle and the impulse (integrated force over time) was computed and segmented by plastic deformation and crack contributions. Our analysis show that advanced algorithms can be used to analyze sensor data on an automated installation, revealing OK/NOK conditions and anomalous events.

RENAL SYMPATHETIC DENERVATION AND NEURO-HORMONAL EVALUATION BY SELECTIVE VENOUS CATHETERIZATION: THE RESIDENCY STUDY

Objective: Renal denervation (RD) is effective in reducing blood pressure (BP) in hypertensive patients, but the pathophysiologic mechanisms underlying the variable individual response are unclear and early markers of procedural success are lacking. The aim of the study was to evaluate intra-/peri-operative effects of RD on the renin-angiotensin-aldosterone system (RAAS) either as determinants and markers of efficacy. Design and method: Patients with resistant hypertension and eGFR>45 ml/min underwent radiofrequency-RD (Medtronic Symplicity-Spyral) with simultaneous sampling of the renal veins (RV), left adrenal vein and pre-renal inferior vena cava (IVC). Samples were collected before (t0) and 15’ after RD from each sequentially-approached side. Additional peripheral blood samples collected on the morning before RD and 3h, 24h and 7 days after the procedure were tested for renin, aldosterone and cortisol. During this timeframe, antihypertensive therapy remained unchanged. Results: Ten patients were recruited (61±11yo; 30%F; BP = 149/84 ±11/12 mmHg on 4 (range 3-6) antihypertensive drugs). Peripheral renin concentration showed no significant changes during/immediately after RD and up to 7 days after, in spite of the observed BP reduction (136/78 ±17/15 mmHg; p<0.05). Similarly, RV renin was unaffected by ipsilateral RD compared to the corresponding t0 values (p = 0.899). Aldosterone and cortisol increased in the adrenal vein during RD (p<0.001), but their IVC-corrected ratio and their peripheral plasma concentrations at follow-up did not, likely reflecting a self-limiting stress reaction. Conclusions: These results do not suggest any direct blunting effect of RD on RAAS, and do not support the contention of monitoring acute RAAS changes as proxies for procedural effectiveness.

Comprehensive plasma genotyping of patients with EGFR positive NSCLC as a monitoring tool for therapy response and disease progression.

e20598 Background: Targeted therapy against molecular drivers has revolutionized the NSCLC standard of care. EGFR activating mutations (mEGFR) are most prominent in Asian NSCLC patients and can benefit from tyrosine kinase inhibitor (TKi) therapy. NCCN guidelines recommend screening lung tumors for detecting mEGFR as a standard of care for TKi inhibitor therapy. However, a significant number of patients with mEGFR do not respond well to TKi due to naturally occurring or therapy-induced TKi blunting mutations. Small gene panels may fail to detect concomitant rare mutations, e.g genomic instability. We longitudinally monitored mEGFR dynamics and the presence of cooccurring clinically important mutations using a comprehensive gene panel in NSCLC patients. Methods: We retrospectively analyzed outcomes from the plasma genotyping of 150 samples from 25 mEGFR-positive NSCLC pts on TKi therapy. For NGS, ctDNA was isolated from longitudinally collected plasma samples (at diagnosis, and during Tx including PD). Libraries prepared using a custom-designed comprehensive gene panel OncoIndx to target 600 cancer-relevant exons, including MSI and HRR pathway genes, were target captured and sequenced in pair-end mode on Illumina platform Nextseq2000. Variant calling was performed using an in-house developed bioinformatics pipeline based on GATK environment. Results: ex 19 deletion variant was the most frequent (35 %) mEGFR followed by L858R (20 %) and T790M (10 %). Rest 10 % had other mutations, including TP53, KRAS, TGFBR1 and PTEN and 25 % of the longitudinal samples did not show any mutations. In 40 % of patients increase in mEGFR vaf correlated with the clinical progression. Surprisingly, these patients had either TP53, RB1 or TGFBR1 variants cooccurring with mEGFR. For the remaining patients, we did not observe a clear temporal correlation with mEGFR vaf. This was corroborated well by the absence of any TKi blunting mutations among these patients. T790M variants were detected only at the progression onset and were absent at earlier time points. MGA, TP53, and RB1 variants were detected along high mEGFR vaf in 10 % of patients around the time of clinical progression. At the genomic scale, TMB scores were low and did not vary longitudinally among the pts. HRD and LOH sores were high and correlated well in patients with mEGFR cooccurrence along variants such as KRAS, TP53, PTEN, and BAP1. Conclusions: Comprehensive plasma genotyping identified cooccurring key drivers that correlated with the clinical progression. Their presence may suggest the blunting effect of TKi and early progression. The patient with high genome instability scores may benefit from HRR inhibitor +TKi combination therapy in EGFR-positive pts. A small patient cohort limits the interpretation of this data and warrants further investigation through clinical trials.

0327 The Effects of Wearable Device Data on Sleep Diary-Derived Metrics of Sleep

Abstract Introduction Precision measurement of sleep metrics like sleep onset latency (SOL) and total sleep time (TST) has long been a challenge. Multiple studies have demonstrated significant discrepancies between sleep diaries and wearable device derived sleep metrics especially in patients with subjective-objective sleep discrepancy (SOSD; e.g., some patients with insomnia). Typically SOSD manifests as longer than expected self-reported SOL and shorter than expected TST. Without a method of reconciliation between sleep diaries and wearable devices, the current practice is to rely on sleep diary data which is suboptimal in the context of SOSD, and could contribute to blunted or nonsignificant effects in clinical trials. The current study investigated the effects of providing wearable device data feedback contemporaneously with the completion of the sleep diary, on a daily basis across 288 nights. We expected that by providing wearable device data feedback, participants with SOSD could be identified and potentially self-correct their SOSD. Methods A 3 phase, randomized, crossover design study was used in which 24 undergraduate college students without a diagnosed sleep disorder completed week-long periods of control condition (digital sleep diary without wearable device data feedback), washout, and then test phase (diary with device feedback). Participants were randomized to start with control or test conditions. Results Within and between subjects analyses were performed to understand the effect of the wearable device data feedback on sleep diary responses. Two participants (8.3%) with SOSD were identified and had marked differences in their estimated SOL (~47 min) that were corrected when provided with their wearable device data. Importantly no subjects copied their wearable device data into their sleep diary. Between subjects analyses revealed no differences in the average or variability of sleep metrics. Conclusion These preliminary results suggest that presenting wearable device data during sleep diary completion may impact self-reporting by individuals with SOSD but not by those without SOSD. In the setting of a clinical trial, participants who have significant SOSD may be contributing to non-disease/non-treatment related variability that may be ameliorated by providing wearable device data during sleep diary completion. Support (if any)

Multiscale Mechanics of Thermal Gradient Coupled Graphene Fracture: A Molecular Dynamics Study

The thermo-mechanical coupling mechanism of graphene fracture under thermal gradients possesses rich applications whereas is hard to study due to its coupled non-equilibrium nature. We employ non-equilibrium molecular dynamics to study the fracture of graphene by applying a fixed strain rate under different thermal gradients by employing different potential fields. It is found that for AIREBO and AIREBO-M, the fracture stresses do not strictly follow the positive correlations with the initial crack length. Strain-hardening effects are observed for “REBO-based” potential models of small initial defects, which is interpreted as blunting effect observed for porous graphene. The temperature gradients are observed to not show clear relations with the fracture stresses and crack propagation dynamics. Quantized fracture mechanics verifies our molecular dynamics calculations. We provide a unique perspective that the transverse bond forces share the loading to account for the nonlinear increase of fracture stress with shorter crack length. Anomalous kinetic energy transportation along crack tips is observed for “REBO-based” potential models, which we attribute to the high interatomic attractions in the potential models. The fractures are honored to be more “brittle-liked” carried out using machine learning interatomic potential (MLIP), yet incapable of simulating post fracture dynamical behaviors. The mechanical responses using MLIP are observed to be not related to temperature gradients. The temperature configuration of equilibration simulation employing the dropout uncertainty neural network potential with a dropout rate of 0.1 is reported to be the most accurate compared with the rest. This work is expected to inspire further investigation of non-equilibrium dynamics in graphene with practical applications in various engineering fields.

Leading-edge bluntness effects on the hypersonic flow over the double wedge at multiple aft-wedge angles

The present numerical investigation focuses on the leading-edge bluntness effects on the double wedge with varied aft-wedge angles exposed to low enthalpy hypersonic free stream conditions. The bluntness ratio in this study varies, ranging from R/L1 = 0 (sharp leading edge) to R/L1 = 0.577 (maximum allowable bluntness), along with the aft-wedge angle varying between θ2 = 45° and 60°. Noticeably, even a small bluntness ratio can completely change the shock interaction pattern compared to its sharp geometrical counterpart due to a detached leading-edge shock, enlarged separation bubble, and location of various shock waves concerning it. Critical bluntness ratios exist for the low aft-wedge θ2 = 45° angle, but increasing the aft-wedge angle makes the flow field highly unsteady for some bluntness ratios. Nevertheless, these bluntness ratios for such double-wedge configurations are reported using the mean of separation bubble size. Moreover, this work unravels the cause of such unsteadiness for the unsteady flow fields using the spatial-temporal evolution of the wall pressure distribution and fast Fourier transform of the pressure fluctuation signal at the compression corner and supports the deduced observation with the help of energy-based proper orthogonal decomposition. The increased shock–boundary layer interaction strength moves the separation point upstream beyond the junction of cylindrical bluntness and inclined fore-wedge surface, accompanying sudden change in its direction of motion that perturbs the shear layer that set to a self-sustained, highly unsteady flow field.

Enhancing cancer treatment and understanding through clustering of gene responses to categorical stressors

Cancer cells have a unique metabolic activity in the glycolysis pathway compared to normal cells, which allows them to maintain their growth and proliferation. Therefore, inhibition of glycolytic pathways may be a promising therapeutic approach for cancer treatment. In this novel study, we analyzed the genetic responses of cancer cells to stressors, particularly to drugs that target the glycolysis pathway. Gene expression data for experiments on different cancer cell types were extracted from the Gene Expression Omnibus and the expression fold change was then clustered after dimensionality reduction. We identified four groups of responses: the first and third were most affected by anti-glycolytic drugs, especially those acting on multiple pathways at once, and consisted mainly of squamous and mesenchymal tissues, showing higher mitotic inhibition and apoptosis. The second and fourth groups were relatively unaffected by treatment, comprising mainly gynecologic and hormone-sensitive groups, succumbing least to glycolysis inhibitors. Hexokinase-targeted drugs mainly showed this blunted effect on cancer cells. This study highlights the importance of analyzing the molecular states of cancer cells to identify potential targets for personalized cancer therapies and to improve our understanding of the disease.

Effect of immunization during pregnancy and pre-existing immunity on diphtheria-tetanus-acellular pertussis vaccine responses in infants

ABSTRACT Immunization during pregnancy (IP) against pertussis is recommended in many countries to protect infants. Although maternal antibodies can influence the infants’ antibody responses to primary vaccinations, their effect on the development of functional antibodies and B cells remain poorly studied. We investigated the maternal immune response to IP and the effect of IP and pre-existing antibodies on infants’ primary vaccine responses in an open-label, non-randomized trial. Forty-seven mothers received tetanus-diphtheria-acellular pertussis (Tdap) vaccine during pregnancy, and 22 mothers were included as controls. Sixty-nine infants received primary doses of DTaP at three and five months of age. Geometric mean concentrations of antibodies to pertussis toxin, filamentous haemagglutinin, pertactin, diphtheria, and tetanus toxins, pertussis toxin neutralizing antibodies (PTNAs), and plasma and memory B-cell frequencies were studied at delivery, and at three, five and six months. Levels of antibodies, PTNAs, and frequencies of memory B-cells were significantly increased at delivery and up to six months after in mothers with IP compared to those without IP (all p < 0.05, except for PT-specific memory B-cells). In vaccinated pregnant women, high pre-existing antibody levels were positively correlated with higher antibody responses after IP. IP blunted the infants’ antibody and plasma B-cell responses to all vaccine antigens, except for tetanus toxin. This blunting effect was the strongest in infants with high concentrations of maternal antibodies. In conclusion, IP resulted in significantly higher concentrations of antibodies in infants up to three months of age (all p < 0.05); but was associated with blunting of various infants’ vaccine responses.

Microstructurally driven self-sharpening mechanism in beaver incisor enamel facilitates their capacity to fell trees.

Beavers (Castor) stand out among mammals for their unique capacity to fell trees using their large, ever-growing incisors. This routine consumption of resistant fodder induces prodigious wear in the lower incisors, despite this blunting effect the incisors maintain a remarkably sharp cutting edge. Notably, the enamel edges of their incisors show a highly complex two-part microstructure of which the biomechanical import is unknown. Here, using fracture analysis, nanoindentation, and wear testing on North American beaver (C. canadensis) incisors we test the microstructure's possible contribution to maintaining incisal sharpness. Although comparable in hardness, the inner enamel preferentially fails and readily wears at 2.5 times the rate of the outer enamel. The outer microstructure redirects all fractures in parallel, decreasing fracture coalescence. Conversely, the inner microstructure facilitates crack coalescence increasing the wear rate by isolating layers of enamel prisms that readily fragment. Together these two architectures form a microstructurally driven self-sharpening mechanism contained entirely within the thin enamel shell. Our results demonstrate that enamel microstructures exposed at the occlusal surface can markedly influence both enamel crest shape and surface texture in wearing dentitions. The methods introduced here open the door to exploring the biomechanical functionality and evolution of enamel microstructures throughout Mammalia. STATEMENT OF SIGNIFICANCE: Enamel microstructure varies significantly with the diversity of diets, bite forces, and tooth shapes exhibited by mammals. However, minimal micromechanical exploration of microstructures outside of humans, leaves our understanding of biomechanical functions in a nascent stage. Using biologically informed mechanical testing, we demonstrate that the complex two-part microstructure that comprises the cutting edge of beaver incisors facilitates self-sharpening of the enamel edge. This previously unrecognized mechanism provides critical maintenance to the shape of the incisal edge ensuring continued functionality despite extreme wear incurred during feeding. More broadly, we show how the architecture of prisms and the surrounding interprismatic matrix dictate the propagation of fractures through enamel fabrics and how the pairing of enamel fabrics can result in biologically advantageous functions.