Ddx5 Targeted Epigenetic Modification of Pericytes in Pulmonary Hypertension After Intrauterine Growth Restriction.

Newborns with intrauterine growth restriction (IUGR) have a higher likelihood of developing pulmonary arterial hypertension (PAH) in adulthood. Although there is increasing evidence suggesting that pericytes play a role in regulating myofibroblast transdifferentiation and angiogenesis in malignant and cardiovascular diseases, their involvement in the pathogenesis of IUGR-related pulmonary hypertension and the underlying mechanisms remain incompletely understood. To address this issue, a study was conducted using a Sprague-Dawley rat model of IUGR-related pulmonary hypertension. Our investigation revealed increased proliferation and migration of pulmonary microvascular pericytes in IUGR-related pulmonary hypertension, accompanied by weakened endothelial-pericyte interactions. Through whole-transcriptome sequencing, Ddx5 (DEAD-box protein 5) was identified as one of the hub genes in pericytes. DDX5, a member of the RNA helicase family, plays a role in the regulation of ATP-dependent RNA helicase activities and cellular function. MicroRNAs have been implicated in the pathogenesis of PAH, and microRNA-205 (miR-205) regulates cell proliferation, migration, and angiogenesis. The results of dual-luciferase reporter assays confirmed the specific binding of miR-205 to Ddx5. Mechanistically, miR-205 negatively regulates Ddx5, leading to the degradation of ß-catenin by inhibiting the phosphorylation of Gsk3ß at serine 9. In vitro experiments showed the addition of miR-205 effectively ameliorated pericyte dysfunction. Furthermore, in vivo experiments demonstrated that miR-205 agomir could ameliorate pulmonary hypertension. Our findings indicated that the downregulation of miR-205 expression mediates pericyte dysfunction through the activation of Ddx5. Therefore, targeting the miR-205/Ddx5/p-Gsk3ß/ß-catenin axis could be a promising therapeutic approach for IUGR-related pulmonary hypertension.

Unraveling the Mfn2-Warburg effect nexus: a therapeutic strategy to combat pulmonary arterial hypertension arising from catch-up growth after IUGR.

BACKGROUND: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive. METHODS AND RESULTS: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats. CONCLUSIONS: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.

Establishing an animal model for peritoneal catheter malfunction caused by omental wrapping using negative pressure suction: in vitro and in vivo exploration.

BACKGROUND: This study aims to establish a simplified and effective animal model of catheter malfunction caused by omental wrapped using negative pressure suction. METHOD: The peritoneal dialysis catheter outlet was linked to a negative-pressure (0-75mmHg) suction pump to intensify the negative pressure. Different negative pressures were tested for model construction in vitro. In vivo, a model of peritoneal catheter malfunction caused by omental wrapped was constructed in five beagles after catheter placement. Catheter drainage conditions and related complications were monitored before and after the model establishment. RESULTS: In the vitro experiment, the overall success rate of constructed models was 90% (36/40). The total malfunction rate was higher in 62.5 mmHg (10/10) and 75 mmHg (10/10) than in 12.5 mmHg (8/10) and 37.5 mmHg (8/10). The outflow velocity of dialysate at 62.5 mmHg was significantly lower than that at 12.5 mmHg and 37.5 mmHg, without a statistically significant difference compared to 75 mmHg. In the in vivo experiment, catheter outflow velocity increased, and residual fluid volume decreased after omental wrapped (99.6 ± 6.7 ml/min vs. 32.6 ± 4.6 ml/min at initial five minutes, p < 0.0001; 69.2 ± 16.3 ml vs. 581.0 ± 109.4 ml, p < 0.001). And the outflow velocity was finally below 2 ml/min. No severe related complications (such as infection, organ damage, or bleeding) were observed through laparoscopic examination and dialysate tests seven days post-operation. CONCLUSION: Utilizing negative pressure suction to increase negative pressure around catheter tip is a simple, safe, and effective method for establishing an animal model of omental wrapped leading to catheter malfunction.

Development and validation of LightGBM algorithm for optimizing of Helicobacter pylori antibody during the minimum living guarantee crowd based gastric cancer screening program in Taizhou, China.

Gastric cancer continues to be a significant health concern in China, with a high incidence rate. To mitigate its impact, early detection and treatment is key. However, conducting large-scale endoscopic gastric cancer screening is not feasible in China. Instead, a more appropriate approach would be to initially screen high-risk groups and follow up with endoscopic testing as needed. We conducted a study on 25,622 asymptomatic participants aged 45-70 years from a free gastric cancer screening program in the Taizhou city government's Minimum Living Guarantee Crowd (MLGC) initiative. Participants completed questionnaires, blood tests, and underwent gastrin-17 (G-17), pepsinogen I and II (PGI and PGII), and H. pylori IgG antibody (IgG) assessments. Using the light gradient boosting machine (lightGBM) algorithm, we developed a predictive model for gastric cancer risk. In the full model, F1 score was 2.66%, precision was 1.36%, and recall was 58.14%. In the high-risk model, F1 score was 2.51%, precision was 1.27%, and recall was 94.55%. Excluding IgG, the F1 score was 2.73%, precision was 1.40%, and recall was 68.62%. We conclude that H. pylori IgG appears to be able to be excluded from the prediction model without significantly affecting its performance, which is important from a health economic point of view. It suggests that screening indicators can be optimized, and expenditures reduced. These findings can have important implications for policymakers, as we can focus resources on other important aspects of gastric cancer prevention and control.

ARL9 is upregulated and serves as a biomarker for a poor prognosis in colon adenocarcinoma.

BACKGROUND: ARL9 is a newly identified member of the ARF family, and the clinical significance of ARL9 in colon adenocarcinoma is unknown. In this study, we aimed to explore the expression of ARL9 mRNA in colon adenocarcinoma, and its effect on the prognosis of patients with colon adenocarcinoma. METHODS: We investigated the differential expression of ARL9 between colon adenocarcinoma tissue and adjacent tissues through a bioinformatics analysis using The Cancer Genome Atlas (TCGA) database. The correlation between clinical characteristics and the mRNA expression level of ARL9 were analyzed. A survival analysis and a Cox regression analysis were used to determine the prognostic significance of ARL9. Finally, we conducted a gene set enrichment analysis (GSEA) to explore the ARL9 signaling pathways involved in the development of colon adenocarcinoma. The effect of the expression of ARL9 on the proliferation and migration of colon adenocarcinoma was analyzed by the CCK8 method and a cell scratch test, respectively. RESULTS: The mRNA expression of ARL9 in colon adenocarcinoma tissues was higher in comparison to the level in normal adjacent tissues (P < 0.05). The mRNA expression of ARL9 was not related to sex, tumor stage, T stage, N stage, M stage, but to age. The 5-year survival rate of colon adenocarcinoma patients with high ARL9 mRNA expression levels was significantly lower than that of patients with low ARL9 mRNA expression levels (P < 0.05). Age and the high mRNA expression of ARL9 were independent risk factors for a poor prognosis in patients with colon adenocarcinoma. The GSEA suggested that ARL9 may be able to upregulate cell adhesion, extracellular matrix receptor interactions, tumor-associated pathways, and downregulate the citrate cycle and tricarboxylic acid cycle pathway, which are involved in the development of colon adenocarcinoma. After knocking down ARL9, the proliferation and migration abilities of colon adenocarcinoma cells were decreased (P < 0.01). CONCLUSION: The mRNA expression of ARL9 is upregulated in colon adenocarcinoma, and higher mRNA expression levels are associated with a poor prognosis. Knocking down ARL9 can reduce the proliferation and migration of colon adenocarcinoma cells. ARL9 mRNA can be used as a prognostic biomarker in patients with colon adenocarcinoma.

[Substitution mode of rare and endangered Chinese medicinal materials and research strategy of multi-component replacement].

Rare and endangered Chinese medicinal materials are the material basis for innovation and development of Chinese medicinal materials and their curative effects are remarkable. However, the resources are in shortage due to various man-made or natural factors such as rising demand, overexploitation and environmental degradation. Therefore, finding alternatives is a feasible and effective solution. This study systematically sorted out the list of rare and endangered Chinese medicinal materials, and combed relevant policies and regulations. According to existing research, the substitution model of rare and endangered Chinese medicinal materials was constructed from the theoretical level. In view of the slow search for substitutes, the failure to follow the basic theory of traditional Chinese medicine in the process of research and development, the difficulty in breaking through technologies and the incomplete guarantee of the clinical efficacy of substitutes, a multi-component replacement was proposed to replace the originals with more effective components from a wide range of sources. This study was expected to promote the study on the substitutes of rare and endangered Chinese medicinal materials to step into a new stage.

The role of RNA m6A methylation in the regulation of postnatal hypoxia-induced pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a complex pulmonary vascular disease characterized by an imbalance in vasoconstrictor/vasodilator signaling within the pulmonary vasculature. Recent evidence suggests that exposure to hypoxia early in life can cause alterations in the pulmonary vasculature and lead to the development of PH. However, the long-term impact of postnatal hypoxia on lung development and pulmonary function remains unknown. N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of PH remains poorly characterized. Thus, the purpose of this investigation was to test the two-fold hypothesis that (1) postnatal exposure to hypoxia would alter lung development leading to PH in adult rats, and (2) m6A modification would change in rats exposed to hypoxia, suggesting it plays a role in the development of PH. METHODS: Twenty-four male Sprague-Dawley rats were exposed to a hypoxic environment (FiO2: 12%) within 24 h after birth for 2 weeks. PH was defined as an increased right ventricular pressure (RVP) and pathologic changes of pulmonary vasculature measured by α-SMA immunohistochemical staining. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to analyze m6A modification changes in lung tissue in 2- and 9-week-old rats that were exposed to postnatal hypoxia. RESULTS: Mean pulmonary arterial pressure, lung/body weight ratio, and the Fulton index was significantly greater in rats exposed to hypoxia when compared to control and the difference persisted into adulthood. m6A methyltransferase and demethylase proteins were significantly downregulated in postnatal hypoxia-induced PH. Distinct m6A modification peak-related genes differed between the two groups, and these genes were associated with lung development. CONCLUSIONS: Our results indicate postnatal hypoxia can cause PH, which can persist into adulthood. The development and persistence of PH may be because of the continuous low expression of methyltransferase like 3 affecting the m6A level of PH-related genes. Our findings provide new insights into the impact of postnatal hypoxia and the role of m6A in the development of pulmonary vascular pathophysiology.

Follow-up study of airway microbiota in children with persistent wheezing.

BACKGROUND: Increasing evidence revealed that airway microbial dysbiosis was associated with increased risk of asthma, or persistent wheezing (PW). However, the role of lung microbiota in PW or wheezing recurrence remains poorly understood. METHODS: In this prospective observational study, we performed a longitudinal 16S rRNA-based microbiome survey on bronchoalveolar lavage (BAL) samples collected from 35 infants with PW and 28 age-matched infants (control group). A 2-year follow-up study on these PW patients was conducted. The compositions of lower airway microbiota were analyzed at the phylum and genus levels. RESULTS: Our study showed a clear difference in lower airway microbiota between PW children and the control group. Children with PW had a higher abundance of Elizabethkingia and Rothia, and lower abundance of Fusobacterium compared with the control group. At the end of the 2-year follow-up, 20 children with PW (57.1%) experienced at least one episode of wheezing, and 15 (42.9%) did not suffer from wheezing episodes. Furthermore, PW children with recurrence also had increased abundances of Elizabethkingia and Rothia relative to those who had no recurrence. Additionally, wheezing history, different gender, and caesarean section demonstrated a greater impact in airway microbiota compositions. CONCLUSION: This study suggests that the alterations of lower airway microbiota could be strongly associated with the development of wheezing, and early airway microbial changes could also be associated with wheezing recurrence later in life.

Treatment planning of volumetric modulated arc therapy and positioning optimization for hippocampal-avoidance prophylactic cranial irradiation.

BACKGROUND: Hippocampal-avoidance prophylactic cranial irradiation (HA-PCI) offers potential neurocognitive benefits but raises technical challenges to treatment planning. This study aims to improve the conventional planning method using volumetric modulated arc therapy (VMAT) technique and investigate a better patient's head positioning to achieve a high quality of HA-PCI treatment plans. METHODS: The improved planning method set a wide expansion of hippocampus as a special region for dose decline. The whole brain target was divided into two parts according to whether the slice included hippocampus and their optimization objectives were set separately. Four coplanar full arcs with partial field sizes were employed to deliver radiation dose to different parts of the target. The collimator angle for all arcs was 90°. Tilting patient's head was achieved by rotating CT images. The improved planning method and tilted head positioning were verified using datasets from 16 patients previously treated with HA-PCI using helical tomotherapy (HT). RESULTS: For the improved VMAT plans, the max and mean doses to hippocampus were 7.88 Gy and 6.32 Gy, respectively, significantly lower than those for the conventional VMAT plans (P < 0.001). Meanwhile, the improved planning method significantly improved the plan quality. Compared to the HT plans, the improved VMAT plans result in similar mean dose to hippocampus (P > 0.1) but lower max dose (P < 0.02). Besides, the target coverage was the highest for the improved VMAT plans. The tilted head positioning further reduced the max and mean doses to hippocampus (P < 0.05), significantly decreased the max dose to lens (P < 0.001) and resulted in higher plan quality as compared to nontilted head positioning. CONCLUSIONS: The improved planning method enables the VMAT plans to meet the clinical requirements of HA-PCI treatment with high plan quality and convenience. The tilted head positioning provides superior dosimetric advantages over the nontilted head positioning, which is recommended for clinical application.

Integrating ecosystem services and landscape ecological risk into adaptive management: Insights from a western mountain-basin area, China.

There is an increasing interest in introducing ecosystem services (ESs) and landscape ecological risk (LER) into environmental policies and governance. Yet, we know little about how to integrate LER into real decision-making and ESs management. Using the ESs valuation method and the models of InVEST and LER, this study analyzed the spatiotemporal changes of cropland food production, carbon storage, water yield, biodiversity index and LER of Bailongjiang watershed (BLJW), China in 1990, 2002 and 2014, and the relationship between them. We found clear spatial differences in both ESs and LER levels in BLJW during the study period. The cropland food production service kept rising, and the areas of high yield mainly distributed in the loessal regions of BLJW with intensive human population. The carbon storage, water yield and biodiversity index first decreased and then increased. The LER was higher in the areas along the valleys with low elevation and intensive human activities. The regional ecological zoning based on overlay analysis of ESs with LER is effective for providing interactive spatial knowledge for adaptive landscape management. Our results illustrate the integrative approach on linking landscape ecological risk with ecosystem services is a comprehensive and helpful methodology for both regional risk reduction and ecosystem services enhancement at landscape scale.

[Finite element analysis of the effect of local posterior sclera collagen cross-linking on eyeball shape].

China is the country with high incidence of high myopia in the world. High myopia can cause severe vision impairment. So far, there is no effective treatment for high myopia in clinic. Scleral collagen cross-linking surgery has been proven to be effective in preventing animal eye axial elongation in vitro and in vivo. However, the influence of posterior scleral collagen cross-linking on the deformation of the whole eyeball is still unclear. In this study, finite element simulation were used to analyze the changes of eyeball shape and the position of light casting on the retina after posterior sclera cross-linking, and the mathematical algorithm was written to verify their similarity. The results showed that the shape of the whole eyeball was still very similar before and after cross-linking, and the diopter of the eyeball after cross-linking had little change, which had almost no effect on the position of light projection on the retina. Our results indicate that posterior sclera cross-linking wouldn't lead to distortion to the optometry, that is, the increase of elastic modulus in local scleral tissue after cross-linking wouldn't cause new problem of optometry and vision.

A bicyclic pentapeptide-based highly potent and selective pan-SIRT1/2/3 inhibitor harboring Nε-thioacetyl-lysine.

Past few years have seen an active pursuit of the inhibitors for the deacylation catalyzed by the seven human sirtuins (i.e. SIRT1-7) as valuable chemical biological/pharmacological probes of this enzymatic deacylation and lead compounds for developing novel therapeutics for human diseases. In the current study, we prepared eight monocyclic and one bicyclic analogs of a linear pentapeptide-based potent (sub-µM IC50's) pan-SIRT1/2/3 inhibitor Zheng laboratory discovered recently that harbors the catalytic mechanism-based SIRT1/2/3 inhibitory warhead Nε-thioacetyl-lysine at its central position. We found that the bicyclic analog exhibited largely comparable SIRT1/2/3 inhibitory potencies to those of the parent linear pentapeptide, however, the former is proteolytically much more stable than the latter. Moreover, the bicyclic analog displayed very weak inhibition against SIRT5/6/7, was cell permeable, and exhibited an anti-proliferative effect on the human SK-MEL-2 melanoma cells. This bicyclic analog could be a lead for the future development of more potent and still selective pan-SIRT1/2/3 inhibitors whose use in studies on human sirtuin biology, pharmacology, and medicinal chemistry could complement with the use of the potent inhibitors selective for a single human sirtuin.

A longitudinal evaluation of improvements in treatment plan quality for lung cancer with volumetric modulated arc therapy.

PURPOSE: To investigate planning time and number of optimizations in routine clinical lung cancer plans based on the plan quality improvements following each optimization. MATERIALS AND METHOD: We selected 40 patients with lung cancer who were treated with conventional fractionated radiotherapy (CFRT). The 40 plans (divided into two groups with one or two target volumes) were completed by 9 planners using volumetric modulated arc therapy (VMAT). A planning strategy, including technique script for each group and a planning process for data collection, was introduced. The total planning time, number of optimizations, and dose-volume parameters of each plan were recorded and analyzed. A plan quality metric (PQM) was defined according to the clinical constraints. Statistical analysis of parameters of each plan following each optimization was performed for evaluating improvements in plan quality. RESULTS: According to the clinical plans generated by different planners, the median number of optimizations of each group was 4, and the median planning time was approximately 1 h (68.6 min and 62.0 min for plans with one or two target volumes, respectively). The dose deposited in organs at risk (OARs) gradually decreased, and the PQM values gradually improved following each optimization. The improvements were significant only between adjacent optimizations from the first optimization (Opt1) to the third optimization (Opt3). CONCLUSION: Increasing the number of optimizations was associated with significantly improved sparing of OARs with slight effects on the dose coverage and homogeneity of target volume. Generally, based on the designed planning strategy, there was no significant improvement of the plan quality for more than three optimizations.

Postnatal delayed growth impacts cognition but rescues programmed impaired pulmonary vascular development in an IUGR rat model.

BACKGROUND AND AIMS: Intrauterine growth restriction (IUGR) is a state of slower fetal growth usually followed by a catch-up growth. Postnatal catch-up growth in IUGR models increases the incidence of pulmonary arterial hypertension in adulthood. Here, we hypothesize that the adverse pulmonary vascular consequences of IUGR may be improved by slowing down postnatal growth velocity. Meanwhile, cognitive function was also studied. METHODS AND RESULTS: We established an IUGR rat model by restricting maternal food throughout gestation. After birth, pups were fed a regular or restricted diet during lactation by changing litter size. Thus, there were three experimental groups according to the dam/offspring diet: C/C (gold standard), IUGR with catch-up growth (R/C) and IUGR with delayed growth (R/D). In adulthood (14 weeks of age), we assessed pulmonary vascular development by hemodynamic measurement and immunohistochemistry. Our results showed that adult R/C offspring developed an elevated mean pulmonary arterial pressure (mPAP) and pulmonary arteriolar remodeling accompanied with decreased eNOS mRNA and protein expressions compared to C/C or R/D offspring. This suggested that delayed postnatal growth improved pulmonary circulation compared to postnatal catch-up growth. Conversely, adult R/D offspring performed poorly in cognition. Behavior test and electrophysiology results exhibited a reduced synaptic plasticity. Furthermore, decreased mRNA expression levels of the memory-related gene zif268 and transcription factor recruitment factor p300 in the hippocampus region were also observed in R/D group. CONCLUSION: These findings indicate that delayed postnatal growth results in cognitive impairment, but it reverses elevations in mPAP induced by postnatal catch-up growth following IUGR.

A new homogeneity index definition for evaluation of radiotherapy plans.

PURPOSE: The goal of this study was to define a new homogeneity index (HI) to evaluate dose homogeneity within a target volume. MATERIALS AND METHODS: The new HI is based on the area under an ideal dose-volume histogram curve (IA), the area under the achieved dose-volume histogram curve (AA), and the overlapping area between the IA and AA (OA). It is defined as the ratio of the square of OA to the product of the IA and AA. To evaluate the performance of the new HI, 88 cases were selected and two plans were designed for each case. The homogeneity of the two plans was first evaluated by three physicists, with their judgments forming the evaluation standard and then evaluated by the new HI and other HIs of Dmax /Dp , D5 /D95 , (D2  - D98 )/Dp , (D2  - D98 )/D50 and S-index. An evaluation was determined to be accurate if its result was agreed upon by physicists. The percentage accuracy of evaluation was calculated as the ratio of the number of accurate evaluations to the total number of evaluations. Pearson's chi-square test was performed for statistical analysis. RESULTS: The percentage accuracies of the new HI, Dmax /Dp , D5 /D95 , (D2  - D98 )/Dp , (D2  - D98 )/D50 , and S-index were 98.51%, 88.80%, 94.78%, 94.78%, 96.27%, and 97.01%, respectively. The newly defined HI had the highest accuracy of all the HIs, with the difference being statistically significant (P < 0.05). CONCLUSIONS: The newly defined HI was shown to be effective in the evaluation of dose homogeneity, and we recommended it for evaluating the homogeneity of radiotherapy plans.

Cyclic Peptide-Based Sirtuin Substrates.

In the current study, four side chain-to-side chain cyclic peptides (three 5-mers and one 4-mer) harboring Nε-acetyl-lysine or Nε-myristoyl-lysine were found to be in vitro substrates of the human SIRT1/2/3-catalyzed deacylation with good substrate activities, as judged by the kcat/KM ratios.

Simple N(ε)-thioacetyl-lysine-containing cyclic peptides exhibiting highly potent sirtuin inhibition.

Transforming a linear pentapeptidic pan-SIRT1/2/3 inhibitor harboring the catalytic mechanism-based sirtuin inhibitory warhead N(ε)-thioacetyl-lysine into its side chain-to-side chain cyclized derivatives was able to furnish highly potent SIRT1/2/3 inhibition (low nM). This finding attests to the feasibility of developing structurally simple yet highly potent catalytic mechanism-based cyclic peptidic sirtuin inhibitors.

The chemical biology of sirtuins.

The sirtuin family of enzymes are able to catalyze the N(ε)-acyl-lysine deacylation reaction on histone and non-histone protein substrates. Over the past years since the discovery of its founding member (i.e. the yeast silent information regulator 2 (sir2) protein) in 2000, the sirtuin-catalyzed deacylation reaction has been demonstrated to play an important regulatory role in multiple crucial cellular processes such as transcription, DNA damage repair, and metabolism. This reaction has also been regarded as a current therapeutic target for human diseases such as cancer, and metabolic and neurodegenerative diseases. The unique ß-nicotinamide adenine dinucleotide (ß-NAD(+) or NAD(+))-dependent nature of the sirtuin-catalyzed deacylation reaction has also engendered extensive mechanistic studies, resulting in a mechanistic view of the enzyme chemistry supported by several lines of experimental evidence. On the journey toward these knowledge advances, chemical biological means have constituted an important functional arsenal; technically, a variety of chemical probes and modulators (inhibitors and activators) have been developed and some of them have been employed toward an enhanced mechanistic and functional (pharmacological) understanding of the sirtuin-catalyzed deacylation reaction. On the other hand, an enhanced mechanistic understanding has also facilitated the development of a variety of chemical probes and modulators. This article will review the tremendous accomplishments achieved during the past few years in the field of sirtuin chemical biology. It is hoped that this would also help to set a stage for how outstanding mechanistic and functional questions for the sirtuin-catalyzed deacylation reaction could be addressed in the future from the chemical biology perspective.

Novel sirtuin inhibitory warheads derived from the N(ε)-acetyl-lysine analog L-2-amino-7-carboxamidoheptanoic acid.

Built upon the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead L-2-amino-7-carboxamidoheptanoic acid (L-ACAH, a close structural analog of N(ε)-acetyl-lysine) that our laboratory discovered recently, in the current study, its carboxamide NH2-ethylated analog was found to be a ∼2.4-6.6-fold stronger SIRT1/2/3 inhibitory warhead than L-ACAH. Carboxamide NH2-dodecylated and carboxymethylated analogs of L-ACAH were also identified as potent SIRT6 and SIRT5 inhibitory warheads, respectively.

Impact of 1.5†T Magnetic Field on Treatment Plan Quality in MR-Guided Radiotherapy: Typical Phantom Test Cases.

PURPOSE: This study aims to investigate the influence of the magnetic field on treatment plan quality using typical phantom test cases, which encompass a circle target test case, AAPM TG119 test cases (prostate, head-and-neck, C-shape, multi-target test cases), and a lung test case. MATERIALS AND METHODS: For the typical phantom test cases, two plans were formulated. The first plan underwent optimization in the presence of a 1.5 Tesla magnetic field (1.5 T plan). The second plan was re-optimized without a magnetic field (0 T plan), utilizing the same optimization conditions as the first plan. The two plans were compared based on various parameters, including con-formity index (CI), homogeneity index (HI), fit index (FI) and dose coverage of the planning target volume (PTV), dose delivered to organs at risk (OARs) and normal tissue (NT), monitor unit (MU). A plan-quality metric (PQM) scoring procedure was employed. For the 1.5 T plans, dose verifications were performed using an MR-compatible ArcCHECK phantom. RESULTS: A smaller dose influence of the magnetic field was found for the circle target, prostate, head-and-neck, and C-shape test cases, compared with the multi-target and lung test cases. In the multi-target test case, the significant dose influence was on the inferior PTV, followed by the superior PTV. There was a relatively large dose influence on the PTV and OARs for lung test case. No statistically significant differences in PQM and MUs were observed. For the 1.5 T plans, gamma passing rates were all higher than 95% with criteria of 2 mm/3% and 2 mm/2%. CONCLUSION: The presence of a 1.5 T magnetic field had a relatively large impact on dose parameters in the multi-target and lung test cases compared with other test cases. However, there were no significant influences on the plan-quality metric, MU and dose accuracy for all test cases.