Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Deep vein thrombosis after open hepatectomy or other major upper abdominal surgery in Taiwan: A prospective and cross-sectional study relevant to the issue of pharmacological thromboprophylaxis.

BACKGROUD/PURPOSE: Venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is an important complication in patients who underwent open hepatic surgery as well as other major upper abdominal surgery. This study aims to investigate the occurrence of postoperative DVT without pharmacological thromboprophylaxis in such cohorts in Taiwan. METHODS: This is a prospective, cross-sectional cohort study conducted from March 2010 to December 2011. Patients who underwent major upper abdominal surgery, including open hepatectomy, were enrolled. Color duplex compression ultrasonography (CUS) was used to detect DVT. Symptomatic PE was excluded if there were no suggestive respiratory symptoms or sudden death. Relevant clinicopathological and surgical information of each patient was collected and analyzed. RESULTS: 195 patients (118 male and 77 female) were enrolled, with a median age of 63.6 years. The majority (169/195, 88.7%) were treated for active malignancy. Totally 147 patients received open hepatectomy. Only one asymptomatic and distal postoperative DVT event was identified by CUS, which occurred on a 73-year-old female patient who received a left lateral segmental hepatectomy for removing the advanced hepatocellular carcinoma (pathologic stage, T3aN0M0). No cases of symptomatic PE or sudden death were observed. No correlation between DVT and precipitating factor was demonstrated in our cohort. CONCLUSION: Without pharmacological thromboprophylaxis, a low rate of postoperative DVT among patients undergoing open hepatectomy (0.7%, 1/147) or major upper abdominal surgery (0.5%, 1/195) in Taiwan was reported. A distinctively regional role of pharmacological thromboprophylaxis for hepatic surgery was also suggested by our data.

Adversarial Patch Attacks on Deep-Learning-Based Face Recognition Systems Using Generative Adversarial Networks.

Deep learning technology has developed rapidly in recent years and has been successfully applied in many fields, including face recognition. Face recognition is used in many scenarios nowadays, including security control systems, access control management, health and safety management, employee attendance monitoring, automatic border control, and face scan payment. However, deep learning models are vulnerable to adversarial attacks conducted by perturbing probe images to generate adversarial examples, or using adversarial patches to generate well-designed perturbations in specific regions of the image. Most previous studies on adversarial attacks assume that the attacker hacks into the system and knows the architecture and parameters behind the deep learning model. In other words, the attacked model is a white box. However, this scenario is unrepresentative of most real-world adversarial attacks. Consequently, the present study assumes the face recognition system to be a black box, over which the attacker has no control. A Generative Adversarial Network method is proposed for generating adversarial patches to carry out dodging and impersonation attacks on the targeted face recognition system. The experimental results show that the proposed method yields a higher attack success rate than previous works.

An interference model for visual working memory: Applications to the change detection task.

Most studies of visual-working memory employ one of two experimental paradigms: change-detection or continuous-stimulus reproduction. In this study, we extended the Interference Model (IM; Oberauer & Lin, 2017), which was designed for continuous reproduction, to the single-probe change-detection task. In continuous reproduction, participants occasionally report the non-target items instead of the target. The presence of non-target response is predicted by the Interference Model, which relies in part on the interference of non-target items to explain the set-size effect. By presenting a probe matching a non-target item, we can investigate the amount of interference from non-target items in change detection. As predicted by the Interference Model, we observed poorer performance in rejecting a probe matching a non-target item compared to a new probe (i.e., a cost due to intrusions from non-targets). We fitted the IM along with the Variable Precision, the Slot-Averaging, and the Neural-Population model to the data from two change-detection experiments. The models were equipped with a Bayesian decision rule based on the one used in Keshvari, van den Berg, and Ma (2013). The Interference Model and the Neural-Population model successfully predicted the set-size effect and the non-target intrusion cost, whereas the Variable Precision (VP) and Slot-Averaging (SA) models failed to predict the intrusion cost at all. Even with additional assumptions enabling VP and SA to produce intrusion costs, the IM still performed better than the competing models quantitatively.

Deep vein thrombosis after major orthopedic surgery in Taiwan: A prospective cross-sectional study and literature review.

BACKGROUND/PURPOSE: Postoperative venous thromboembolism is an important complication in Taiwan. We prospectively investigated the occurrence of deep vein thrombosis (DVT) after major orthopedic surgery without pharmacologic thromboprophylaxis in a cohort of 120 patients (46 males, 74 females, median age 71 years) at our institute. METHODS: Color duplex compression ultrasonography (CUS) was used to detect DVT before and after the operation, while contrast venography was performed postoperatively for comparison and validation. RESULTS: Total knee arthroplasty (TKA, 57 cases) and total hip arthroplasty (23 cases) were the most commonly performed operations. The rate of postoperative DVT was 7.5% (9/120), including five with proximal DVT and four with distal DVT. All were detected in the limbs on the operated side. Four of them were symptomatic DVT cases. Venography was performed in 19 patients and confirmed most findings of CUS, indicating the effectiveness of CUS for detecting DVT. The type of surgery (TKA) was significantly correlated with postoperative DVT. No clinically symptomatic pulmonary embolism or sudden death events were noted. CONCLUSION: Nine out of 120 (7.5%) orthopedic patients without pharmacologic thromboprophylaxis developed postoperative sonographic DVT in our study. The DVT rate is consistent with other reports from various Asian countries and evidence from meta-analyses.

Discovery of 2',6-Bis(4-hydroxybenzyl)-2-acetylcyclohexanone, a Novel FtsZ Inhibitor.

Multi-drug resistance is increasing in the pathogenic bacterium S. pneumoniae, which is mainly responsible for meningitis and community-acquired pneumonia (CAP), highlighting the need for new anti-pneumococcal agents. We have identified a potential anti-pneumococcal agent, enol 3, which acts by hindering the cell division process by perturbing Z-ring dynamics inside the cell. Enol 3 was also shown to inhibit FtsZ polymerization and induce its aggregation in vitro but does not affect the activity of tubulin and alkaline phosphatase. Docking studies show that 3 binds near the T7 loop, which is the catalytic site of FtsZ. Similar effects on Z-ring and FtsZ assembly were observed in B. subtilis, indicating that 3 could be a broad-spectrum anti-bacterial agent useful in targeting Gram-positive bacteria. In conclusion, compound 3 shows strong anti-pneumococcal activity, prompting further pre-clinical studies to explore its potential.

Phase I first-in-human study of HLX07, a novel and improved recombinant anti-EGFR humanized monoclonal antibody, in patients with advanced solid cancers.

Purpose This study aimed to evaluate the safety and pharmacokinetic (PK) profiles of HLX07, a novel, recombinant, humanized anti-epidermal growth factor receptor (EGFR) antibody, in patients with advanced solid cancers who had failed standard therapy or for whom no standard therapy was available. Methods In this prospective, open-label, Phase I dose escalation study, patients aged ≥18 years (≥20 years for patients in Taiwan) with histologically-confirmed metastatic or recurrent epithelial carcinoma that had no K-RAS or B-RAF mutations were enrolled in a '3 + 3' escalation design. HLX07 was administered weekly by 2-h intravenous infusion at doses ranging from 50 to 800 mg. The primary endpoint was summary listing of participants reporting treatment-emergent adverse events (TEAEs). Secondary endpoints included PK analysis, serum anti-HLX07 antibody assessments and efficacy. Results In total, 19 patients were enrolled between 1 October 2016 and 16 July 2019 to receive HLX07 at doses of 50 (n = 3), 100 (n = 3), 200 (n = 3), 400 (n = 3), 600 (n = 3) and 800 (n = 4) mg per week. All patients experienced at least one TEAE, most commonly fatigue (68.4%), nausea (47.4%), paronychia (31.6%) and vomiting (31.6%). Serious TEAEs were reported in 11 patients but only one serious TEAE (dyspnea in 600 mg cohort) was regarded as possibly related to study treatment. No dose limiting toxicity (DLT) was reported. Systemic exposure to HLX07 increased proportionally with dose. Anti-HLX07 antibodies were not detected in any patients. Conclusion HLX07 was well tolerated (at dose levels up to 800 mg/week) and promising in patients with advanced solid cancers.Clinical Trial Registration: The study was registered at ClinicalTrials.gov : NCT02648490 (Jan 7, 2016).

Review article inferior vena cava thrombosis: a case series of patients observed in Taiwan and literature review.

Inferior vena cava thrombosis (IVCT) is rare and can be under-recognized. However, the associated complications and mortality may be severe. We report the first case series of IVCT observed in Taiwan with a brief literature review. Eight Taiwanese patients with IVCT between May 2012 and December 2019 were enrolled in this study. Deep venous thrombosis (DVT, 8/8) and pulmonary embolism (5/8) were reported. Various risk factors were identified, including an unretrieved inferior vena cava (IVC) filter, pregnancy, surgery, presence of lupus of anticoagulants, essential thrombocythemia, antithrombin deficiency, and hemoglobin H disease. Of note, four of our patients experienced complete IVC thrombosis with bilateral lower extremity swelling (due to DVT) and abdominal wall superficial venous dilatation, while four other patients presented with partial IVCT and unilateral DVT. The etiology, clinical characteristics, presentations, diagnosis, and treatment of IVCT were reviewed.

Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry.

BACKGROUND/PURPOSE: Multiple myeloma (MM) is a monoclonal plasma cell malignancy. The primary choice of treatment for MM is induction therapy followed by autologous stem cell transplantation (ASCT). This study aimed to analyze the treatment efficacy of ASCT in a Taiwanese cohort and evaluate possible prognostic factors. METHODS: From the database of the Taiwan Blood and Marrow Transplantation registry, data on 396 patients with MM who underwent ASCT were reviewed. RESULTS: The average age of participants was 54.8 years, and there were more men than women (57.6% vs. 42.4%). Most patients were diagnosed with IgG-type myeloma (52.4%), followed by IgA-type (23.2%) and light-chain type (21.4%). Patients with Durie Salmon Staging System (DSS) III disease accounted for 61.9% of the study cohort, while 23.7% had stage II and 14.4% had stage I disease. The median progression-free survival (PFS) and overall survival (OS) after ASCT were 46.5 months and 70.4 months, respectively. DSS III was a poor prognostic factor affecting both PFS and OS with a duration of 35.9 months and 69.0 months, respectively, compared with the other two stages (p = 0.006 and p = 0.03, respectively). In addition, patients with better treatment response before ASCT had better PFS and OS compared with those who did not show a response (both p < 0.0001). The overall incidence of organ toxicities associated with transplantation was low. CONCLUSION: In conclusion, our cohort showed that myeloma patients with early DSS and better treatment response before ASCT had better long-term survival outcomes.

Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma.

This phase 4, single-arm, non-randomized, open-label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m2 , twice weekly for 2 weeks, followed by a 10-day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre-specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) Cmax (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non-Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half-life (t1/2 ), area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ), volume of distribution (Vz ), and systemic clearance were not assessable. All patients experienced treatment-emergent adverse events (TEAEs); 78% were drug-related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUClast [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non-Asian population (AUClast [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.

Valence- and element-dependent water oxidation behaviors: in situ X-ray diffraction, absorption and electrochemical impedance spectroscopies.

Metal oxides of the spinel family have shown great potential towards the oxygen evolution reaction (OER), but the fundamental OER mechanism of spinel oxides is still far from being completely understood, especially for the role of the metal ions. Owing to various coordinated sites of divalent/trivalent metals ions and surface conditions (morphology and defects), it is a great challenge to have a fair assessment of the electrocatalytic performance of spinel systems. Herein, we demonstrated a series of MFe2O4 (M = Fe, Co, Ni, Zn) with a well-controlled morphology to achieve a comprehensive study of electrocatalytic activity toward OER. By utilizing several in situ analyses, we could conclude a universal rule that the activities for OER in the metal oxide systems were determined by the occurrence of a phase transformation, and this structural transformation could work well in both crystallographic sites (Td and Oh sites). Additionally, the divalent metal ion significantly dominated the formation of oxyhydroxide through an epitaxial relationship, which depended on the atomic arrangement at the interface of spinel and metal oxyhydroxide, while trivalent metal ions remained unchanged as a host lattice. The metal oxyhydroxide was formed during a redox reaction rather than being formed during OER. The occurrence of the redox reaction seems to accompany a remarkable increase in resistance and capacitance might result from the structural transformation from spinel to metal oxyhydroxide. We believe that the approaching strategies and information obtained in the present study can offer a guide to designing a promising electrocatalytic system towards the oxygen evolution reaction and other fields.

Hierarchical Bayesian measurement models for continuous reproduction of visual features from working memory.

The article presents Bayesian hierarchical modeling frameworks for two measurement models for visual working memory. The models can be applied to the distributions of responses on a circular feature dimension, as obtained with the continuous reproduction (a.k.a. delayed estimation) task. The first measurement model is a mixture model that describes the response distributions as a mixture of one (Zhang & Luck, 2008) or several (Bays, Catalao, & Husain, 2009) von-Mises distribution(s) and a uniform distribution. The second model is a novel, interference-based measurement model. We present parameter recovery simulations for both models, demonstrating that the hierarchical framework enables precise parameter estimates when a small number of trials are compensated by a large number of subjects. Simulations with the mixture model show that the Bayesian hierarchical framework minimizes the previously observed estimation bias for memory precision in conditions of low performance. Unbiased and reasonably precise parameter estimates can also be obtained from the interference measurement model, though some parameters of this model demand a relatively large amount of data for precise measurement. Both models are applied to two experimental data sets. Experiment 1 measures the effect of memory set size on the model parameters. Experiment 2 provides evidence for the assumption in the interference model that the target feature tends to be confused with features of those nontargets that are close to the target on the dimension used as retrieval cue.

A noninterventional observational registry of patients with multiple myeloma treated with lenalidomide in Taiwan.

BACKGROUND/PURPOSE: The incidence of multiple myeloma in Asia has risen in the past 30 years. Lenalidomide, an IMiD immunomodulatory agent, has improved the overall survival in patients with relapsed/refractory multiple myeloma (RRMM) when used with dexamethasone versus dexamethasone alone. This observational registry (T-CC-MM-009; NCT01752075) assessed the safety and efficacy of lenalidomide plus dexamethasone in a large Chinese population of patients with RRMM. METHODS: This registry followed the first 100 patients treated with lenalidomide plus dexamethasone in Taiwan. Patients were ≥18 years old and had ≥1 prior treatment. The recommended starting dose for the first four 28-day cycles was 25 mg lenalidomide on days 1-21 and 40 mg dexamethasone on days 1-4, 9-12, and 17-20. Thereafter, dexamethasone was given on days 1-4 only. The primary objective was safety; secondary objectives were efficacy, lenalidomide dosage, and reasons for discontinuation. RESULTS: The median duration of treatment was 34.6 weeks, and 75.5% completed ≥3 cycles. Most patients (82.7%) experienced ≥1 treatment-related adverse event; the most commonly reported were neutropenia (23.5%), thrombocytopenia (19.4%), anemia (16.3%), fatigue (16.3%), and hypoesthesia (15.3%). Bleeding events (25.5% of patients) were mostly grade 1/2 (80%). Three patients (3%) had venous thromboembolic events. Two invasive second primary malignancies were reported; however, time to onset was <1 year, suggesting they may not be related to lenalidomide. The overall response rate was 34.7%; median time to disease progression was 20.5 months. CONCLUSION: These data confirm the safety and efficacy of lenalidomide plus dexamethasone for patients with RRMM in Taiwan.

Identification of dual PPARα/γ agonists and their effects on lipid metabolism.

The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50µM and 100µM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid ß-oxidation in HuH7 hepatocytes.

The evolution of the coding exome of the Arabidopsis species--the influences of DNA methylation, relative exon position, and exon length.

BACKGROUND: The evolution of the coding exome is a major driving force of functional divergence both between species and between protein isoforms. Exons at different positions in the transcript or in different transcript isoforms may (1) mutate at different rates due to variations in DNA methylation level; and (2) serve distinct biological roles, and thus be differentially targeted by natural selection. Furthermore, intrinsic exonic features, such as exon length, may also affect the evolution of individual exons. Importantly, the evolutionary effects of these intrinsic/extrinsic features may differ significantly between animals and plants. Such inter-lineage differences, however, have not been systematically examined. RESULTS: Here we examine how DNA methylation at CpG dinucleotides (CpG methylation), in the context of intrinsic exonic features (exon length and relative exon position in the transcript), influences the evolution of coding exons of Arabidopsis thaliana. We observed fairly different evolutionary patterns in A. thaliana as compared with those reported for animals. Firstly, the mutagenic effect of CpG methylation is the strongest for internal exons and the weakest for first exons despite the stringent selective constraints on the former group. Secondly, the mutagenic effect of CpG methylation increases significantly with length in first exons but not in the other two exon groups. Thirdly, CpG methylation level is correlated with evolutionary rates (dS, dN, and the dN/dS ratio) with markedly different patterns among the three exon groups. The correlations are generally positive, negative, and mixed for first, last, and internal exons, respectively. Fourthly, exon length is a CpG methylation-independent indicator of evolutionary rates, particularly for dN and the dN/dS ratio in last and internal exons. Finally, the evolutionary patterns of coding exons with regard to CpG methylation differ significantly between Arabidopsis species and mammals. CONCLUSIONS: Our results suggest that intrinsic features, including relative exonic position in the transcript and exon length, play an important role in the evolution of A. thaliana coding exons. Furthermore, CpG methylation is correlated with exonic evolutionary rates differentially between A. thaliana and animals, and may have served different biological roles in the two lineages.

Safety, Tolerability, and Preliminary Efficacy of Serplulimab, a Novel Anti-PD-1 Antibody, in Patients with Metastatic or Recurrent Solid Tumors: A Phase I Study.

BACKGROUND: Serplulimab is a novel, recombinant, humanized, monoclonal, anti-programmed death 1 antibody with a similar or better affinity and pre-clinical antitumor activity than pembrolizumab and nivolumab. OBJECTIVE: This phase I, open-label, dose-escalation study evaluated serplulimab in patients with advanced solid tumors. The second interim analysis of the dose-finding phase is reported here. METHODS: Adult patients with histologically confirmed metastatic/recurrent solid tumors who had progressed on, or were intolerant to/clinically unsuitable for standard treatment, were enrolled. Four intravenous serplulimab dose levels were evaluated: 0.3, 1.0, 3.0, and 10.0 mg/kg every 2 weeks in 28-day cycles for up to 2 years. Primary endpoints were the incidence of treatment-emergent adverse events and the maximum tolerated dose. RESULTS: By 27 July, 2020 (data cut-off), 29 patients with stage IV disease (34.5% with lung cancer) received one or more doses of serplulimab. One (3.4%) patient had completed treatment and 26 (89.7%) had discontinued from the study. The maximum tolerated dose was not reached. Twenty-two (75.9%) patients experienced treatment-emergent adverse events related to serplulimab, most frequently nausea (24.1%), with no notable differences in incidence between dose cohorts; of these, grade ≥ 3 events occurred in four (13.8%) patients. Pharmacokinetic data demonstrated minimal accumulation of serplulimab after repeated administration. Functional programmed death 1 blockade was observed across dose levels. Objective response and disease control rates were 8.0 and 60.0%, respectively. CONCLUSIONS: Serplulimab was well tolerated and demonstrated antitumor activity. These data support further study of serplulimab in larger patient populations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03468751 (19 March, 2018).

Independent effects of alternative splicing and structural constraint on the evolution of mammalian coding exons.

Alternative splicing (AS) is known to significantly affect exon-level protein evolutionary rates in mammals. Particularly, alternatively spliced exons (ASEs) have a higher nonsynonymous-to-synonymous substitution rate (dN/dS) ratio than constitutively spliced exons (CSEs), possibly because the former are required only occasionally for normal biological functions. Meanwhile, intrinsically disordered regions (IDRs), the protein regions lacking fixed 3D structures, are also reported to have an increased evolutionary rate due to lack of structural constraint. Interestingly, IDRs tend to be located in alternative protein regions. Yet which of these two factors is the major determinant of the increased dN/dS in mammalian ASEs remains unclear. By comparing human-macaque and human-mouse one-to-one orthologous genes, we demonstrate that AS and protein structural disorder have independent effects on mammalian exon evolution. We performed analyses of covariance to demonstrate that the slopes of the (dN/dS-percentage of IDR) regression lines differ significantly between CSEs and ASEs. In other words, the dN/dS ratios of both ASEs and CSEs increase with the proportion of IDR (PIDR), whereas ASEs have higher dN/dS ratios than CSEs when they have similar PIDRs. Since ASEs and IDRs may less frequently overlap with protein domains (which also affect dN/dS), we also examined the correlations between dN/dS ratio and exon type/PIDR by controlling for the density of protein domain. We found that the effects of exon type and PIDR on dN/dS are both independent of domain density. Our results imply that nature can select for different biological features with regard to ASEs and IDRs, even though the two biological features tend to be localized in the same protein regions.

Assessing determinants of exonic evolutionary rates in mammals.

From studies investigating the differences in evolutionary rates between genes, gene compactness and gene expression level have been identified as important determinants of gene-level protein evolutionary rate, as represented by nonsynonymous to synonymous substitution rate (d(N)/d(S)) ratio. However, the causes of exon-level variances in d(N)/d(S) are less understood. Here, we use principal component regression to examine to what extent 13 exon features explain the variance in d(N), d(S), and the d(N)/d(S) ratio of human-rhesus macaque or human-mouse orthologous exons. The exon features were grouped into six functional categories: expression features, mRNA splicing features, structural-functional features, compactness features, exon duplicability, and other features, including G + C content and exon length. Although expression features are important for determining d(N) and d(N)/d(S) between exons of different genes, structural-functional features and splicing features explained more of the variance for exons of the same genes. Furthermore, we show that compactness features can explain only a relatively small percentage of variance in exon-level d(N) or d(N)/d(S) in either between-gene or within-gene comparison. By contrast, d(S) yielded inconsistent results in the human-mouse comparison and the human-rhesus macaque comparison. This inconsistency may suggest rapid evolutionary changes of the mutation landscape in mammals. Our results suggest that between-gene and within-gene variation in d(N)/d(S) (and d(N)) are driven by different evolutionary forces and that the role of mRNA splicing in causing the variation in evolutionary rates of coding sequences may be underappreciated.