De novo and salvage purine synthesis pathways across tissues and tumors.

Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.

A male-derived nonribosomal peptide pheromone controls female schistosome development.

Schistosomes cause morbidity and death throughout the developing world due to the massive numbers of eggs female worms deposit into the blood of their host. Studies dating back to the 1920s show that female schistosomes rely on constant physical contact with a male worm both to become and remain sexually mature; however, the molecular details governing this process remain elusive. Here, we uncover a nonribosomal peptide synthetase that is induced in male worms upon pairing with a female and find that it is essential for the ability of male worms to stimulate female development. We demonstrate that this enzyme generates ß-alanyl-tryptamine that is released by paired male worms. Furthermore, synthetic ß-alanyl-tryptamine can replace male worms to stimulate female sexual development and egg laying. These data reveal that peptide-based pheromone signaling controls female schistosome sexual maturation, suggesting avenues for therapeutic intervention and uncovering a role for nonribosomal peptides as metazoan signaling molecules.

Mitochondrial complex I promotes kidney cancer metastasis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate Pathway, Contributes to AMPK Activation through Inhibition of PP2A.

The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.

Cortical bone plate properties assessment using inversion of axially transmitted low frequency ultrasonic guided waves.

Over the past few decades, early osteoporosis detection using ultrasonic bone quality evaluation has gained prominence. Specifically, various studies focused on axial transmission using ultrasonic guided waves and have highlighted this technique's sensitivity to intrinsic properties of long cortical bones. This work aims to demonstrate the potential of low-frequency ultrasonic guided waves to infer the properties of the bone inside which they are propagating. A proprietary ultrasonic transducer, tailored to transmit ultrasonic guided waves under 500 kHz, was used for the data collection. The gathered data underwent two-dimensional fast Fourier transform processing to extract experimental dispersion curves. The proposed inversion scheme compares experimental dispersion curves with simulated dispersion curves calculated through the semi-analytical iso-geometric analysis (SAIGA) method. The numerical model integrates a bone phantom plate coupled with a soft tissue layer on its top surface, mimicking the experimental bone phantom plates. Subsequently, the mechanical properties of the bone phantom plates were estimated by reducing the misfit between the experimental and simulated dispersion curves. This inversion leaned heavily on the dispersive trajectories and amplitudes of ultrasonic guided wave modes. Results indicate a marginal discrepancy under 5% between the mechanical properties ascertained using the SAIGA-based inversion and those measured using bulk wave pulse-echo measurements.

Ultrasonic Evaluation of the Bone-Implant Interface.

While implant surgical interventions are now routinely performed, failures still occur and may have dramatic consequences. The clinical outcome depends on the evolution of the biomechanical properties of the bone-implant interface (BII). This chapter reviews studies investigating the use of quantitative ultrasound (QUS) techniques for the characterization of the BII.First, studies on controlled configurations evidenced the influence of healing processes and of the loading conditions on the ultrasonic response of the BII. The gap of acoustical properties at the BII increases (i) during healing and (ii) when stress at the BII increases, therefore inducing a decrease of the reflection coefficient at the BII.Second, an acoustical model of the BII is proposed to better understand the parameters influencing the interaction between ultrasound and the BII. The reflection coefficient is shown to decrease when (i) the BII is better osseointegrated, (ii) the implant roughness decreases, (iii) the frequency of QUS decreases and (iv) the bone mass density increases.Finally, a 10 MHz device aiming at assessing dental implant stability was validated in vitro, in silico and in vivo. A comparison between QUS and resonance frequency analysis (RFA) techniques showed a better sensitivity of QUS to changes of the parameters related to the implant stability.

Metabolic impact of pathogenic variants in the mitochondrial glutamyl-tRNA synthetase EARS2.

Glutamyl-tRNA synthetase 2 (encoded by EARS2) is a mitochondrial aminoacyl-tRNA synthetase required to translate the 13 subunits of the electron transport chain encoded by the mitochondrial DNA. Pathogenic EARS2 variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability, and other features of mitochondrial compromise. Patients with EARS2 deficiency present with variable phenotypes ranging from neonatal lethality to a mitigated disease with clinical improvement in early childhood. Here, we report a neonate homozygous for a rare pathogenic variant in EARS2 (c.949G>T; p.G317C). Metabolomics in primary fibroblasts from this patient revealed expected abnormalities in TCA cycle metabolites, as well as numerous changes in purine, pyrimidine, and fatty acid metabolism. To examine genotype-phenotype correlations in COXPD12, we compared the metabolic impact of reconstituting these fibroblasts with wild-type EARS2 versus four additional EARS2 variants from COXPD12 patients with varying clinical severity. Metabolomics identified a group of signature metabolites, mostly from the TCA cycle and amino acid metabolism, that discriminate between EARS2 variants causing relatively mild and severe COXPD12. Taken together, these findings indicate that metabolomics in patient-derived fibroblasts may help establish genotype-phenotype correlations in EARS2 deficiency and likely other mitochondrial disorders.

Ultrasonic assessment of osseointegration phenomena at the bone-implant interface using convolutional neural network.

Although endosseous implants are widely used in the clinic, failures still occur and their clinical performance depends on the quality of osseointegration phenomena at the bone-implant interface (BII), which are given by bone ingrowth around the BII. The difficulties in ensuring clinical reliability come from the complex nature of this interphase related to the implant surface roughness and the presence of a soft tissue layer (non-mineralized bone tissue) at the BII. The aim of the present study is to develop a method to assess the soft tissue thickness at the BII based on the analysis of its ultrasonic response using a simulation based-convolution neural network (CNN). A large-annotated dataset was constructed using a two-dimensional finite element model in the frequency domain considering a sinusoidal description of the BII. The proposed network was trained by the synthesized ultrasound responses and was validated by a separate dataset from the training process. The linear correlation between actual and estimated soft tissue thickness shows excellent R2 values equal to 99.52% and 99.65% and a narrow limit of agreement corresponding to [ -2.56, 4.32 µm] and [ -15.75, 30.35 µm] of microscopic and macroscopic roughness, respectively, supporting the reliability of the proposed assessment of osseointegration phenomena.

The effects of green growth, environmental-related tax, and eco-innovation towards carbon neutrality target in the US economy.

This study aims to examine the nexus between green growth and carbon neutrality targets in the context of the USA while observing the role of ecological innovation, environmental taxes, and green energy. For this purpose, data were collected from 1970 to 2015 for all the variables of interest. This research utilized the quantile autoregressive distributed lag (QARDL) method due to its various benefits, such as depicting the causality patterns based on different quantiles for different variables like green growth, ecological innovation, environmental taxes, and renewable energy. The findings through the QARDL method showed that the error correction coefficient was significant and negative with the expected negative sign for the different quantiles. The findings showed a significant and negative impact of green growth, square of green growth, ecological innovation, and environmental taxes in determining the carbon dioxide (CO2) emissions for the USA's economy under the long-run estimation. Meanwhile, the outcome for the short-term estimation confirmed that the past and lagged values of CO2 emission were significantly and negatively linked with the current and lagged values of CO2 emission. On the other hand, it was found that green growth and square of green growth, ecological innovation, environmental taxes, and renewable energy played their vital role in reducing haze pollution like PM2.5. Besides, this research also covers the limitations and policy implications.

Reflection of an ultrasonic wave on the bone-implant interface: Comparison of two-dimensional and three-dimensional numerical models.

Quantitative ultrasound is used to characterize osseointegration at the bone-implant interface (BII). However, the interaction between an ultrasonic wave and the implant remains poorly understood. Hériveaux, Nguyen, and Haiat [(2018). J. Acoust. Soc. Am. 144, 488-499] recently employed a two-dimensional (2D) model of a rough BII to investigate the sensitivity of the ultrasonic response to osseointegration. The present letter aimed at assessing the validity of the 2D assumption. The values of the reflection coefficient of the BII obtained with two and three-dimensional models were found not to be significantly different for implant roughness lower than 20 µm. 2D modeling is sufficient to describe the interaction between ultrasound and the BII.

Micromechanical modeling of the contact stiffness of an osseointegrated bone-implant interface.

BACKGROUND: The surgical success of cementless implants is determined by the evolution of the biomechanical properties of the bone-implant interface (BII). One difficulty to model the biomechanical behavior of the BII comes from the implant surface roughness and from the partial contact between bone tissue and the implant. The determination of the constitutive law of the BII would be of interest in the context of implant finite element (FE) modeling to take into account the imperfect characteristics of the BII. The aim of the present study is to determine an effective contact stiffness [Formula: see text] of an osseointegrated BII accounting for its micromechanical features such as surface roughness, bone-implant contact ratio (BIC) and periprosthetic bone properties. To do so, a 2D FE model of the BII under normal contact conditions was developed and was used to determine the behavior of [Formula: see text]. RESULTS: The model is validated by comparison with three analytical schemes based on micromechanical homogenization including two Lekesiz's models (considering interacting and non-interacting micro-cracks) and a Kachanov's model. [Formula: see text] is found to be comprised between 1013 and 1015 N/m3 according to the properties of the BII. [Formula: see text] is shown to increase nonlinearly as a function of the BIC and to decrease as a function of the roughness amplitude for high BIC values (above around 20%). Moreover, [Formula: see text] decreases as a function of the roughness wavelength and increases linearly as a function of the Young's modulus of periprosthetic bone tissue. CONCLUSIONS: These results open new paths in implant biomechanical modeling since this model may be used in future macroscopic finite element models modeling the bone-implant system to replace perfectly rigid BII conditions.

Reflection of an ultrasonic wave on the bone-implant interface: Effect of the roughness parameters.

Quantitative ultrasound can be used to characterize the evolution of the bone-implant interface (BII), which is a complex system due to the implant surface roughness and to partial contact between bone and the implant. The aim of this study is to derive the main determinants of the ultrasonic response of the BII during osseointegration phenomena. The influence of (i) the surface roughness parameters and (ii) the thickness W of a soft tissue layer on the reflection coefficient r of the BII was investigated using a two-dimensional finite element model. When W increases from 0 to 150 µm, r increases from values in the range [0.45; 0.55] to values in the range [0.75; 0.88] according to the roughness parameters. An optimization method was developed to determine the sinusoidal roughness profile leading to the most similar ultrasonic response for all values of W compared to the original profile. The results show that the difference between the ultrasonic responses of the optimal sinusoidal profile and of the original profile was lower to typical experimental errors. This approach provides a better understanding of the ultrasonic response of the BII, which may be used in future numerical simulation realized at the scale of an implant.

Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply.

The mTORC1-signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation, and this has been linked to increased p53 translation and activation of apoptosis. Herein, we show that mTORC1 inhibition during glucose deprivation prevented not only the execution of death, but also induction of energetic stress. mTORC1 inhibition during glucose deprivation decreased AMPK activation and allowed ATP to remain high, which was both necessary and sufficient for protection. This effect was not due to increased catabolic activities such as autophagy, but rather exclusively due to decreased anabolic processes, reducing energy consumption. Specifically, TSC1/2-/- cells become highly dependent on glutamate dehydrogenase-dependent glutamine metabolism via the TCA cycle for survival. Therefore, mTORC1 inhibition during energetic stress is primarily to balance metabolic demand with supply.

Reflection of an ultrasonic wave on the bone-implant interface: A numerical study of the effect of the multiscale roughness.

Quantitative ultrasound is used to characterize and stimulate osseointegration processes at the bone-implant interface (BII). However, the interaction between an ultrasonic wave and the implant remains poorly understood. This study aims at investigating the sensitivity of the ultrasonic response to the microscopic and macroscopic properties of the BII and to osseointegration processes. The reflection coefficient R of the BII was modeled for different frequencies using a two-dimensional finite element model. The implant surface roughness was modeled by a sinusoidal function with varying amplitude h and spatial frequency L. A soft tissue layer of thickness W was considered between bone tissue and the implant in order to model non-mineralized fibrous tissue. For microscopic roughness, R is shown to increase from around 0.55 until 0.9 when kW increases from 0 to 1 and to be constant for kW > 1, where k is the wavenumber in the implant. These results allow us to show that R depends on the properties of bone tissue located at a distance comprised between 1 and 25 µm from the implant surface. For macroscopic roughness, R is highly dependent on h and this dependence may be explained by phase cancellation and multiple scattering effects for high roughness parameters.

Comparison of Resonance Frequency Analysis and of Quantitative Ultrasound to Assess Dental Implant Osseointegration.

Dental implants are widely used in the clinic. However, there remain risks of failure, which depend on the implant stability. The aim of this paper is to compare two methods based on resonance frequency analysis (RFA) and on quantitative ultrasound (QUS) and that aim at assessing implant stability. Eighty-one identical dental implants were inserted in the iliac crests of 11 sheep. The QUS and RFA measurements were realized after different healing times (0, 5, 7, and 15 weeks). The results obtained with the QUS (respectively RFA) method were significantly different when comparing two consecutive healing time for 97% (respectively, 18%) of the implants. The error made on the estimation of the healing time when analyzing the results obtained with the QUS technique was around 10 times lower than that made when using the RFA technique. The results corresponding to the dependence of the ISQ versus healing time were significantly different when comparing two directions of RFA measurement. The results show that the QUS method allows a more accurate determination of the evolution of dental implant stability when compared to the RFA method. This study paves the way towards the development of a medical device, thus providing a decision support system to dental surgeons.

Bacterial bloodstream infections in a tertiary infectious diseases hospital in Northern Vietnam: aetiology, drug resistance, and treatment outcome.

BACKGROUND: Bloodstream infections (BSIs) are associated with high morbidity and mortality worldwide. However their aetiology, antimicrobial susceptibilities and associated outcomes differ between developed and developing countries. Systematic data from Vietnam are scarce. Here we present aetiologic data on BSI in adults admitted to a large tertiary referral hospital for infectious diseases in Hanoi, Vietnam. METHODS: A retrospective study was conducted at the National Hospital for Tropical Diseases between January 2011 and December 2013. Cases of BSI were determined from records in the microbiology department. Case records were obtained where possible and clinical findings, treatment and outcome were recorded. BSI were classified as community acquired if the blood sample was drawn ≤48 h after hospitalization or hospital acquired if >48 h. RESULTS: A total of 738 patients with BSI were included for microbiological analysis. The predominant pathogens were: Klebsiella pneumoniae (17.5%), Escherichia coli (17.3%), Staphylococcus aureus (14.9%), Stenotrophomonas maltophilia (9.6%) and Streptococcus suis (7.6%). The overall proportion of extended spectrum beta-lactamase (ESBL) production among Enterobacteriaceae was 25.1% (67/267 isolates) and of methicillin-resistance in S. aureus (MRSA) 37% (40/108). Clinical data was retrieved for 477 (64.6%) patients; median age was 48 years (IQR 36-60) with 27.7% female. The overall case fatality rate was 28.9% and the highest case fatality was associated with Enterobacteriaceae BSI (34.7%) which accounted for 61.6% of all BSI fatalities. CONCLUSIONS: Enterobacteriaceae (predominantly K. pneumoniae and E. coli) are the most common cause of both community and hospital acquired bloodstream infections in a tertiary referral clinic in northern Vietnam.

Three-dimensional Simulation of Quantitative Ultrasound in Cancellous Bone Using the Echographic Response of a Metallic Pin.

Degenerative discopathy is a common pathology that may require spine surgery. A metallic cylindrical pin is inserted into the vertebral body to maintain soft tissues and may be used as a reflector of ultrasonic wave to estimate bone density. The first aim of this paper is to validate a three-dimensional (3-D) model to simulate the ultrasonic propagation in a trabecular bone sample in which a metallic pin has been inserted. We also aim at determining the effect of changes of bone volume fraction (BV/TV) and of positioning errors on the quantitative ultrasound (QUS) parameters in this specific configuration. The approach consists in coupling finite-difference time-domain simulation with X-ray microcomputed tomography. The correlation coefficient between experimental and simulated speed of sound (SOS)-respectively, broadband ultrasonic attenuation (BUA)-was equal to 0.90 (respectively, 0.55). The results show a significant correlation of SOS with BV/TV ( R = 0.82), while BUA values exhibit a nonlinear behavior versus BV/TV. The orientation of the pin should be controlled with an accuracy of around 1° to obtain accurate results. The results indicate that using the ultrasonic wave reflected by a pin has a potential to estimate the bone density. SOS is more reliable than BUA due to its lower sensitivity to the tilt angle.

Assessment of the biomechanical stability of a dental implant with quantitative ultrasound: A three-dimensional finite element study.

Dental implant stability is an important determinant of the surgical success. Quantitative ultrasound (QUS) techniques can be used to assess such properties using the implant acting as a waveguide. However, the interaction between an ultrasonic wave and the implant remains poorly understood. The aim of this study is to investigate the sensitivity of the ultrasonic response to the quality and quantity of bone tissue in contact with the implant surface. The 10 MHz ultrasonic response of an implant used in clinical practice was simulated using an axisymmetric three-dimensional finite element model, which was validated experimentally. The amplitude of the echographic response of the implant increases when the depth of a liquid layer located at the implant interface increases. The results show the sensitivity of the QUS technique to the amount of bone in contact with the implant. The quality of bone tissue around the implant is varied by modifying the bone biomechanical properties by 20%. The amplitude of the implant echographic response decreases when bone quality increases, which corresponds to bone healing. In all cases, the amplitude of the implant response decreased when the dental implant stability increased, which is consistent with the experimental results.

Lipid changes after leaf wounding in Arabidopsis thaliana: expanded lipidomic data form the basis for lipid co-occurrence analysis.

A direct-infusion electrospray ionization triple-quadrupole mass spectrometry method with multiple reaction monitoring (MRM) was employed to measure 264 lipid analytes extracted from leaves of Arabidopsis thaliana subjected to mechanical wounding. The method provided precise measurements with an average coefficient of variation of 6.1%. Lipid classes analyzed comprised galactolipids and phospholipids (including monoacyl molecular species, molecular species with oxidized acyl chains, phosphatidic acids (PAs)), tri- and tetra-galactosyldiacylglycerols (TrGDGs and TeGDGs), head-group-acylated galactolipids, and head-group-acylated phosphatidylglycerol (acPG), sulfoquinovosyldiacylglycerols (SQDGs), sphingolipids, di- and tri-acylglycerols (DAGs and TAGs), and sterol derivatives. Of the 264 lipid analytes, 254 changed significantly in response to wounding. In general, levels of structural lipids decreased, whereas monoacyl molecular species, galactolipids and phosphatidylglycerols (PGs) with oxidized fatty acyl chains, PAs, TrGDGs, TeGDGs, TAGs, head-group-acylated galactolipids, acPG, and some sterol derivatives increased, many transiently. The observed changes are consistent with activation of lipid oxidizing, hydrolyzing, glycosylating, and acylating activities in the wounding response. Correlation analysis of the levels of lipid analytes across individual control and treated plants was used to construct a lipid dendrogram and to define clusters and sub-clusters of lipid analytes, each composed of a group of lipids which occurred in a coordinated manner. Current knowledge of metabolism supports the notion that observed sub-clusters comprise lipids generated by a common enzyme and/or metabolically downstream of a common enzyme. This work demonstrates that co-occurrence analysis, based on correlation of lipid levels among plants, is a powerful approach to defining lipids generated in vivo by a common enzymatic pathway.