Unraveling the role of the FHL family in cardiac diseases: Mechanisms, implications, and future directions.

Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.

Penguin-Driven Dissemination and High Enrichment of Antibiotic Resistance Genes in Lake Sediments across Antarctica.

Numerous penguins can propagate pathogens with antibiotic resistance genes (ARGs) into Antarctica. However, the effects of penguin dissemination on the lake ARGs still have received little attention via guano deposition. Here, we have profiled ARGs in ornithogenic sediments subject to penguin guano (OLS) and nonornithogenic sediments (NOLS) from 16 lakes across Antarctica. A total of 191 ARGs were detected in all sediment samples, with a much higher abundance and diversity in OLS than in NOLS. Surprisingly, highly diverse and abundant ARGs were found in the OLS with a detection frequency of >40% and an absolute abundance of (2.34 × 109)-(4.98 × 109) copies g-1, comparable to those in coastal estuarine sediments and pig farms. The strong correlations of identified resistance genes with penguin guano input amount, environmental factors, mobile genetic elements, and bacterial community, in conjunction with network and redundancy analyses, all indicated that penguins were responsible for the dissemination and high enrichment of ARGs in lake sediments via the guano deposition, which might greatly outweigh local human-activity effects. Our results revealed that ARGs could be carried into lakes across the Antarctica through penguin migration, food chains, and guano deposition, which were closely connected with the widespread pollution of ARGs at the global scale.

The role of a novel mineralocorticoid receptor antagonist, finerenone, in chronic kidney disease: mechanisms and clinical advances.

BACKGROUND: Chronic kidney disease (CKD) poses a significant health risk in contemporary society. Current CKD treatments primarily involve renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, albeit associated with hyperkalemia risks. A novel selective mineralocorticoid receptor antagonist, finerenone, offers a promising, safer alternative for CKD therapy. This review comprehensively assesses the role and efficacy of finerenone in CKD treatment by analyzing clinical and animal studies. Emerging evidence consistently supports finerenone's ability to effectively slow the progression of CKD. By targeting the mineralocorticoid receptor, finerenone not only mitigates renal damage but also exhibits a favorable safety profile, minimizing hyperkalemia concerns. CONCLUSION: Finerenone emerges as a valuable addition to CKD therapy, demonstrating potential benefits in delaying CKD progression while minimizing side effects. Nevertheless, further clinical trials are necessary to provide a comprehensive understanding of its safety and efficacy.

Secreted frizzled-related protein 5: A promising therapeutic target for metabolic diseases via regulation of Wnt signaling.

Metabolic diseases pose a significant global health challenge, characterized by an imbalance in metabolism and resulting in various complications. Secreted frizzled-related protein 5 (SFRP5), an adipokine known for its anti-inflammatory properties, has gained attention as a promising therapeutic target for metabolic diseases. SFRP5 acts as a key regulator in the Wnt signaling pathway, exerting its influence on critical cellular functions including proliferation, differentiation, and migration. Its significance extends to the realm of adipose tissue biology, where it plays a central role in regulating inflammation, insulin resistance, adipogenesis, lipid metabolism, glucose homeostasis, and energy balance. By inhibiting Wnt signaling, SFRP5 facilitates adipocyte growth, promotes lipid accumulation, and contributes to a decrease in oxidative metabolism. Lifestyle interventions and pharmacological treatments have shown promise in increasing SFRP5 levels and protecting against metabolic abnormalities. SFRP5 is a pivotal player in metabolic diseases and presents itself as a promising therapeutic target. An overview of SFRP5 and its involvement in metabolic disorders and metabolism is provided in this comprehensive review. By elucidating these aspects, valuable insights can be gained to foster the development of effective strategies in combating metabolic diseases.

Daphnetin inhibits RANKL-induced osteoclastogenesis in vitro.

Osteoporosis is a common orthopedic disease which is associated with hyper-activated osteoclastogenesis. Daphnetin is a natural coumarin derivative isolated from Genus Daphne, which possesses antiarthritis effect. However, the role of daphnetin in osteoclastogenesis has not been illustrated. This study aimed to investigate the effects of daphnetin on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in vitro. Our results showed that the osteoclast formation was significantly suppressed by daphnetin treatment in bone marrow-derived macrophages (BMMs), which was illustrated by reduced number of tartrate-resistant acid phosphatase positive multinucleated osteoclasts and decreased expression levels of tumor necrosis factor receptor-associated factors (TRAF6), c-Fos, nuclear factor of activated T cells c1, and cathepsin K. RANKL caused significant induction effects in reactive oxygen species (ROS) generation and nicotinamide adenine dinucleotide phosphate oxidase activity, whereas the induction was dramatically reduced after pretreatment with daphnetin. In addition, daphnetin prevented the RANKL-induced activation of NF-κB and Akt/GSK-3ß pathways in BMMs. These findings indicated that daphnetin exhibited an inhibitory effect on RANKL-induced osteoclastogenesis in vitro. The effect of daphnetin might be mediated by inhibiting ROS signal transduction, as well as preventing the activation of NF-κB and Akt/GSK-3ß signaling pathways. These findings indicated that daphnetin might be considered as a new therapeutic approach for the osteoporosis treatment.

Development of a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in Fusarium fujikuroi.

Iterative metabolic engineering of Fusarium fujikuroi has traditionally been hampered by its low homologous recombination efficiency and scarcity of genetic markers. Thus, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas9) system has emerged as a promising tool for precise genome editing in this organism. Some integrated CRISPR/Cas9 strategies have been used to engineer F. fujikuroi to improve GA3 production capabilities, but low editing efficiency and possible genomic instability became the major obstacle. Herein, we developed a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in F. fujikuroi. This system, based on an autonomously replicating sequence, demonstrated the capability of a single plasmid harboring all editing components to achieve 100%, 75%, and 37.5% editing efficiency for single, double, and triple gene targets, respectively. Remarkably, even with a reduction in homologous arms to 50 bp, we achieved a 12.5% gene editing efficiency. By employing this system, we successfully achieved multicopy integration of the truncated 3-hydroxy-3-methyl glutaryl coenzyme A reductase gene (tHMGR), leading to enhanced GA3 production. A key advantage of our plasmid-based gene editing approach was the ability to recycle selective markers through a simplified protoplast preparation and recovery process, which eliminated the need for additional genetic markers. These findings demonstrated that the single-plasmid CRISPR/Cas9 system enables rapid and precise multiple gene deletions/integrations, laying a solid foundation for future metabolic engineering efforts aimed at industrial GA3 production.

Metabolic diseases and healthy aging: identifying environmental and behavioral risk factors and promoting public health.

Aging is a progressive and irreversible pathophysiological process that manifests as the decline in tissue and cellular functions, along with a significant increase in the risk of various aging-related diseases, including metabolic diseases. While advances in modern medicine have significantly promoted human health and extended human lifespan, metabolic diseases such as obesity and type 2 diabetes among the older adults pose a major challenge to global public health as societies age. Therefore, understanding the complex interaction between risk factors and metabolic diseases is crucial for promoting well-being and healthy aging. This review article explores the environmental and behavioral risk factors associated with metabolic diseases and their impact on healthy aging. The environment, including an obesogenic environment and exposure to environmental toxins, is strongly correlated with the rising prevalence of obesity and its comorbidities. Behavioral factors, such as diet, physical activity, smoking, alcohol consumption, and sleep patterns, significantly influence the risk of metabolic diseases throughout aging. Public health interventions targeting modifiable risk factors can effectively promote healthier lifestyles and prevent metabolic diseases. Collaboration between government agencies, healthcare providers and community organizations is essential for implementing these interventions and creating supportive environments that foster healthy aging.

Flow-through charge detection mass spectrometry to categorize micron-sized particles.

This paper outlines the use of charge detection mass spectrometry to simultaneously measure the charge and mass of micron-sized particles. In a flow-through instrument, the detection of charge was achieved through charge induction onto cylindrical electrodes that connect to a differential amplifier. Mass was determined by particle acceleration under the influence of an electric field. Particles ranging from 30 to 400 fg (3 to 7 µm diameter) were tested. The detector design can measure particle mass within 10% accuracy for particles up to 620 fg with total charge ranging from 500e- to 56 ke-. This charge and mass range are expected to be relevant for dust on Mars.

BAM15 as a mitochondrial uncoupler: a promising therapeutic agent for diverse diseases.

Subcellular organelles dysfunction is implicated in various diseases, including metabolic diseases, neurodegenerative diseases, cancer, and cardiovascular diseases. BAM15, a selective mitochondrial uncoupler, has emerged as a promising therapeutic agent due to its ability to enhance mitochondrial respiration and metabolic flexibility. By disrupting the coupling between electron transport and ATP synthesis, BAM15 dissipates the proton gradient, leading to increased mitochondrial respiration and energy expenditure. This review provides a comprehensive overview of BAM15, including its mechanism of action and potential therapeutic applications in diverse disease contexts. BAM15 has shown promise in obesity by increasing energy expenditure and reducing fat accumulation. In diabetes, it improves glycemic control and reverses insulin resistance. Additionally, BAM15 has potential in non-alcoholic fatty liver disease, sepsis, and cardiovascular diseases by mitigating oxidative stress, modulating inflammatory responses, and promoting cardioprotection. The safety profile of BAM15 is encouraging, with minimal adverse effects and remarkable tolerability. However, challenges such as its high lipophilicity and the need for alternative delivery methods need to be addressed. Further research is necessary to fully understand the therapeutic potential of BAM15 and optimize its application in clinical settings.

The combined effect of fire and nitrogen addition on biodiversity and herbaceous aboveground productivity in a coastal shrubland.

Introduction: Fire and nitrogen (N) deposition each impact biodiversity and ecosystem productivity. However, the effect of N deposition on ecosystem recovery after fire is still far from understood, especially in coastal wetlands. Methods: We selected a typical coastal shrubland to simulate three N deposition levels (0, 10, and 20 g N m-2 year-1) under two different burned conditions (unburned and burned) in the Yellow River Delta of North China. Soil properties, soil microbial biodiversity, shrub growth parameters, herbaceous biodiversity, and aboveground productivity were determined after experimental treatments for 1 year. Results: We found that fire had a stronger influence on the ecosystem than N addition. One year after the fire, shrub growth had significantly decreased, while soil pH, soil electrical conductivity, herbaceous biodiversity, soil microbial biodiversity, and herbaceous aboveground productivity significantly increased. Conversely, a single year of N addition only slightly increased herbaceous aboveground productivity. The combined effect of fire and N addition was only significant for fungus biodiversity and otherwise had minimal influence. Interestingly, we found that herbaceous aboveground productivity was positively associated with fungal community diversity under unburned conditions but not in burned shrublands. Fire showed a great impact on soil parameters and biodiversity in the coastal wetland ecosystem even after a full year of recovery. Discussion: Fire may also diminish the influence of several belowground factors on herbaceous aboveground productivity, which ultimately reduces recovery and stability. Appropriate N addition may be an effective way to improve the ecosystem productivity in a wetland dominated by shrub species.

Secreted frizzled-related proteins: A promising therapeutic target for cancer therapy through Wnt signaling inhibition.

The Wnt signaling system is a critical pathway that regulates embryonic development and adult homeostasis. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signaling that act by binding directly to Wnt ligands or Frizzled receptors. SFRPs can act as anti-Wnt agents and suppress cancer growth by blocking the action of Wnt ligands. However, SFRPs are often silenced by promoter methylation in cancer cells, resulting in hyperactivation of the Wnt pathway. Epigenetic modifiers can reverse this silencing and restore SFRPs expression. Despite the potential of SFRPs as a therapeutic target, the effects of SFRPs on tumor development remain unclear. Therefore, a review of the expression of various members of the SFRPs family in different cancers and their potential as therapeutic targets is warranted. This review aims to summarize the current knowledge of SFRPs in cancer, focusing on their expression patterns and their potential as novel therapeutic targets.

Circularly polarized luminescence of pinene-modified tetradentate platinum(II) enantiomers containing fused 5/6/6 metallocycles.

In this study, a couple of tetradentate Pt(II) enantiomers ((-)-1 and (+)-1) and a couple of tetradentate Pt(IV) enantiomers ((-)-2 and (+)-2) containing fused 5/6/6 metallocycles have been synthesized by controlling reaction conditions. Two valence forms could transform into each other through mild chemical oxidants and reductants. Single-crystal X-ray diffraction confirms the structures of (-)-1 and (-)-2. The coordination sphere of the Pt(II) cation in (-)-1 displays a distorted square-planar geometry and a platinum centroid helix chirality. In contrast, the structure of (-)-2 reveals a distorted octahedral geometry. The solution and the solid of (-)-1 are highly luminescent. Complex (-)-1 shows a prominent aggregation-induced emission enhancement (AIEE) behavior in DMSO/water solution with emission quantum yield (Φ em) up to 73.2%. Furthermore, highly phosphorescent Pt(II) enantiomers exhibit significant circularly polarized luminescence (CPL) with a dissymmetry factor (g lum) of order 10-3 in CH2Cl2 solutions at room temperature. Symmetrically appreciable CPL signals are observed for the enantiomers (-)-1 and (+)-1.

Study on the desulfurization performance of iron/ethanolamine/deep eutectic solvent system.

Deep eutectic solvent (DES) was applied as the solvent of iron/alcohol amine system, and the prepared iron/ethanolamine/DES system was found to be a good desulfurizer for H2S removal. The absorbents were characterized by Fourier transform infrared spectroscopy. The iron/ethanolamine/DES system showed a significantly enhanced desulfurization performance compared with DES solution of iron or alcohol amine separately. Besides, the absorbents showed relatively stable desulfurization performance, which could keep a high H2S removal efficiency in a wide temperature range from 30-90°C. The iron/ethanolamine/DES system could be recycled for at least three times. The desulfurization product was analyzed by energy dispersive spectrum and X-ray diffraction, and the desulfurization product was identified as sulfur element.

Simulation and measurement of image charge detection with printed-circuit-board detector and differential amplifier.

We present a novel and thorough simulation technique to understand image charge generated from charged particles on a printed-circuit-board detector. We also describe a custom differential amplifier to exploit the near-differential input to improve the signal-to-noise-ratio of the measured image charge. The simulation technique analyzes how different parameters such as the position, velocity, and charge magnitude of a particle affect the image charge and the amplifier output. It also enables the designer to directly import signals into circuit simulation software to analyze the full signal conversion process from the image charge to the amplifier output. A novel measurement setup using a Venturi vacuum system injects single charged particles (with diameters in the 100 s of microns range) through a PCB detector containing patterned electrodes to verify our simulation technique and amplifier performance. The measured differential amplifier presented here exhibits a gain of 7.96 µV/e- and a single-pass noise floor of 1030 e-, which is about 13× lower than that of the referenced commercial amplifier. The amplifier also has the capability to reach a single-pass noise floor lower than 140 e-, which has been shown in Cadence simulation.

Evaluation of MLC leaf transmission on IMRT treatment plan quality of patients with advanced lung cancer.

The purpose of this paper was to evaluate the impact of leaf treatment of multileaf collimator (MLC) in plan quality of intensity-modulated radiotherapy (IMRT) of patients with advanced lung cancer. Five MLCs with different leaf transmissions (0.01%, 0.5%, 1.2%, 1.8%, and 3%) were configured for an accelerator in a treatment planning system. Correspondingly, 5 treatment plans with the same optimization setting were created and evaluated quantitatively for each patient (11 patients total) who was diagnosed with advanced lung cancer. All of the 5 plans for each patient met the dose requirement for the planning treatment volumes (PTVs) and had similar target dose homogeneity and conformity. On average, the doses to selected organs were as follows: (1) V5, V20, and the mean dose of total lung; (2) the maximum and mean dose to spinal cord planning organ-at-risk volume (PRV); and (3) V30 and V40 of heart, decreased slightly when MLC transmission was decreased, but with no statistical differences. There is a clear grouping of plans having total quality score (SD) value, which is used to evaluate plan quality: (1) more than 1 (patient nos. 1 to 3, 5, and 8), and more than 2.5 (patient no. 6); (2) less than 1 (patient nos. 7 and 10); (3) around 1 (patient nos. 4, 9, and 11). As MLC transmission increased, overall SD values increased as well and plan dose requirement was harder to meet. The clinical requirements were violated increasingly as MLC transmission became large. Total SD with and without normal tissue (NT) showed similar results, with no statistically significant differences. Therefore, decrease of MLC transmission did have minimum impact on plan, and it improved target coverage and reduced normal tissue radiation slightly, with no statistical significance. Plan quality could not be significantly improved by MLC transmission reduction. However, lower MLC transmission may have advantages on lung sparing to low- and intermediate-dose exposure. Besides conventional fraction, hyperfraction, or stereotactic body radiotherapy (SBRT), the reduction on lung sparing is still essential because it is highly relevant to radiation pneumonitis (RP). It has potential to diminish incidence of RP and improve patient's quality of life after irradiation with lowered MLC transmission.

[Candida species distribution in the patients with high risk of deep fungal infections and relevant risk factors: a prospective cohort study].

OBJECTIVE: To study the distribution of Candida spp. in the patients with high-risk of fungal infection and the risk factors of deep candidiasis. METHODS: A prospective cohort study was performed among 440 consecutive hospitalized patients admitted to the hematology wards, geriatric wards, and ICUs from May 2004 to April 2005. Stool, urine, and saliva were cultured during the period 72 - 96 h after hospitalization for the first time and then once a week till the patient was discharged or by the end of the sixth week. If deep fungal infection was suspected culture of blood, sputum, bacterium-free body fluid, and/or biopsy specimens were cultured. Medical records were reviewed to analyze the possible risk factors. RESULTS: 426 strains of Candida spp. were isolated from 152 patients, with Candida albicans accounting for 67.4% and other Candida spp for 32.6%. 61 patients were discovered to express Candida colonization. The major species isolated from patients with Candida colonization was Candida albicans. The risk factors identified included two or more broad-spectrum antibiotic administration (odds ratio 16.204; 95% confidence interval, 2.005 to 130.980), Candida colonization (10.636; 3.743 to 30.222), and urinary canal administration (4.285; 1.399 to 13.127). CONCLUSION: Candida albicans is still the major organism isolated from the high risk fungal infection patients. Two or more broad-spectrum antibiotic administration, Candida colonization, and urinary canal administration are proved to be the risk factors, with the broad-spectrum antibiotic administration exhibiting more influence than Candida colonization and urinary canal administration.

N-terminal-pro-B-type natriuretic peptide (NT-proBNP): reference range for Chinese apparently healthy people and clinical performance in Chinese elderly patients with heart failure.

BACKGROUND: N-terminal-pro-B-type natriuretic peptide (NT-proBNP) has been found to be a useful marker for the diagnosis of heart failure (HF) and left ventricular systolic dysfunction. We established a reference range for Chinese apparently healthy people based on age and gender and evaluated the clinical performance of NT-proBNP in the diagnosis of asymptomatic and symptomatic HF. METHODS: A group of 442 apparently healthy subjects were enrolled for reference range study. For the clinical performance study, serum NT-proBNP and clinical data were analyzed in 111 elderly patients with HF and 60 normal elderly controls. Serum NT-proBNP was measured by the Roche Elecsys 2010 immunoassay analyzer. RESULTS: NT-proBNP reference range in Chinese people based on age and gender was <83.72 ng/l for men and <131.6 ng/l for women aged 60 years, which were lower than those for western countries. NT-proBNP had a close correlation with New York Heart Association (NYHA) classification (r=0.818) and LVEF (r=-0.636). The ROC curve analysis revealed an AUC of 0.921 for the diagnosis of HF, 0.840 for asymptomatic HF (NYHA I) and 0.951 for symptomatic HF (NYHA II-IV). The optimal cutoff values for detecting HF, asymptomatic HF and symptomatic HF were 102.2, 102.2, and 204.8 ng/l, respectively. NT-proBNP had high positive predictive value (PPV) for the diagnosis of HF (96.8%), asymptomatic HF (90.3%) and symptomatic HF (90.9%), but low negative predictive value (NPV) for diagnosing HF and asymptomatic HF (74.0% and 78.1%, respectively) except symptomatic HF (93.3%). CONCLUSIONS: Chinese people have lower reference range of serum NT-proBNP. NT-proBNP assay has a good clinical performance for the diagnosis of symptomatic HF but is not suitable as a screening test for HF.

[Efficiency of APACHE II and III scoring system in the prognostication of patients older than 75 years].

OBJECTIVE: To observe the efficiency of both the APACHE II/III scoring systems in predicting the prognosis of patients older than 75 years. METHODS: We calculated both the APACHE II and III scores in patients older than 75 years who were admitted to the geriatric intensive care unit (GICU) of our hospital in a duration of 6 months. The scores and predicting death rates were compared with the actual death rates. RESULTS: There was definite correlation between the APACHE II/III scores and the actual death rates. Sensitivity of the APACHE II/III systems are 66.7% and 41.7% respectively. Specificity of the APACHE II/III systems are 90.9% and 100% respectively. CONCLUSIONS: Both the APACHE II/III systems can do well in predicting the prognosis of ICU patients older than 75 years, but APACHE III tends to underestimate the hospital death rate of elderly patients.

A three-source model for the calculation of head scatter factors.

Accurate determination of the head scatter factor Sc is an important issue, especially for intensity modulated radiation therapy, where the segmented fields are often very irregular and much less than the collimator jaw settings. In this work, we report an Sc calculation algorithm for symmetric, asymmetric, and irregular open fields shaped by the tertiary collimator (a multileaf collimator or blocks) at different source-to-chamber distance. The algorithm was based on a three-source model, in which the photon radiation to the point of calculation was treated as if it originated from three effective sources: one source for the primary photons from the target and two extra-focal photon sources for the scattered photons from the primary collimator and the flattening filter, respectively. The field mapping method proposed by Kim et al. [Phys. Med. Biol. 43, 1593-1604 (1998)] was extended to two extra-focal source planes and the scatter contributions were integrated over the projected areas (determined by the detector's eye view) in the three source planes considering the source intensity distributions. The algorithm was implemented using Microsoft Visual C/C++ in the MS Windows environment. The only input data required were head scatter factors for symmetric square fields, which are normally acquired during machine commissioning. A large number of different fields were used to evaluate the algorithm and the results were compared with measurements. We found that most of the calculated Sc's agreed with the measured values to within 0.4%. The algorithm can also be easily applied to deal with irregular fields shaped by a multileaf collimator that replaces the upper or lower collimator jaws.

Delivery time comparison for intensity-modulated radiation therapy with/without flattening filter: a planning study.

The treatment delivery time of intensity-modulated radiation therapy (IMRT) with a multileaf collimator (MLC) is generally longer than that of conventional radiotherapy. In theory, removing the flattening filter from the treatment head may reduce the beam-on time by enhancing the output dose rate, and then reduce the treatment delivery time. And in practice, there is a possibility of delivering the required fluence distribution by modulating the unflattened non-uniform fluence distribution. However, the reduction of beam-on time may be discounted by the increase of leaf-travel time and (or) verification-and-recording (V&R) time. Here we investigate the overall effect of flattening filter on the treatment delivery time of IMRT with MLCs implemented in the step and shoot method, as well as with compensators on six hybrid machines. We compared the treatment delivery time with/without flattening filter for ten nasopharynx cases and ten prostate cases by observing the variations of the ratio of the beam-on time, segment number, leaf-travel time and the treatment delivery time with dose rate, leaf speed and V&R time. The results show that, without the flattening filter, the beam-on time reduces for both static MLC and compensator-based techniques: the number of segments and the leaf-travel time increase slightly for the static MLC technique; the relative IMRT treatment delivery time decreases more with lower dose rate, higher leaf speed and shorter V&R overhead time. The absolute treatment delivery time reduction depends on the fraction dose. It is not clinically significant at a fraction dose of 2 Gy for the technique of removing the flattening filter, but becomes significant when the fraction dose is as high as that for radiosurgery.