Sequence Preference Research Articles

Neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) in patients with clinically node-positive upper tract urothelial cancer (UTUC) who underwent radical nephroureterectomy (RNU).

486 Background: UTUC is less common and associated with poorer stage-for-stage prognosis compared to urothelial bladder cancer. AC is regarded as a standard-of-care in high-risk UTUC based on superior disease-free survival compared to observation in the POUT trial, though fewer than 10% of patients in this trial had lymph node involvement.1 CheckMate 274 revealed lesser magnitude of benefit with adjuvant nivolumab in UTUC compared to bladder cancer on post hoc analysis.2 The preferred sequence of perioperative systemic therapy in node positive UTUC remains unclear. Methods: We queried the National Cancer Database for adult patients with clinically node positive (cTanyN1-3M0) UTUC diagnosed between 2004 and 2018. Patients were divided into two groups based on the perioperative treatment strategy - NAC or AC. Patients who did not undergo RNU were excluded from analyses. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 862 patients were identified - 362 (42%) underwent NAC while 500 (58%) received AC. No significant differences were noted between the groups regarding age, sex, or insurance status. Patients with cT1-2 UTUC more often received NAC (27.9% vs 11.8%, P <0.001) while those with cT3-4 disease more frequently received AC (38.9% vs 57.4%, p<0.001). Rates of NAC vs AC were not significantly different based on clinical N stage (P = 0.35). Overall survival in the NAC group was significantly longer than the AC group (median of 47.1 vs. 20.2 months, log-rank P < 0.001). On multivariable analysis, only the sequence of perioperative chemotherapy was independently predictive of overall survival (Hazard Ratio of 1.38 for AC, with 95% CI 1.14-1.68, P = 0.001). Conclusions: In this large retrospective analysis of outcomes among patients with clinically node positive UTUC who underwent RNU, NAC was associated with significantly longer overall survival compared to AC.

Engineering DNA Crystals toward Studying DNA-Guest Molecule Interactions.

Sequence-selective recognition of DNA duplexes is important for a wide range of applications including regulating gene expression, drug development, and genome editing. Many small molecules can bind DNA duplexes with sequence selectivity. It remains as a challenge how to reliably and conveniently obtain the detailed structural information on DNA-molecule interactions because such information is critically needed for understanding the underlying rules of DNA-molecule interactions. If those rules were understood, we could design molecules to recognize DNA duplexes with a sequence preference and intervene in related biological processes, such as disease treatment. Here, we have demonstrated that DNA crystal engineering is a potential solution. A molecule-binding DNA sequence is engineered to self-assemble into highly ordered DNA crystals. An X-ray crystallographic study of molecule-DNA cocrystals reveals the structural details on how the molecule interacts with the DNA duplex. In this approach, the DNA will serve two functions: (1) being part of the molecule to be studied and (2) forming the crystal lattice. It is conceivable that this method will be a general method for studying drug/peptide-DNA interactions. The resulting DNA crystals may also find use as separation matrices, as hosts for catalysts, and as media for material storage.

Treatment of extranodal NK/T-cell lymphoma: From past to future.

Extranodal NK/T-cell lymphoma (ENKTCL) is the most common subtype of T/NK-cell lymphoma in Asia and Latin America, but very rare in North American and Europe. Patient survival has improved significantly over the past two decades. However, standard treatment has not yet been established, although dozens of prospective trials have been conducted. To help understand how the treatment of ENKTCL has evolved in the past and what trends lie ahead, we have comprehensively reviewed the treatment of this aggressive malignancy, with a particular focus on neglected or unanswered issues, such as the optimal staging method, the best partner of asparaginase (Asp), the individualized administration of Asp, the preferred sequence of CT and RT and so on. Overall, the 5-year overall survival (OS) of patients with Ann Arbor stage I/II disease increased from < 50% in the early 20th century to > 80% in recent years, and the median OS of patients with Ann Arbor stage III/IV disease increased from < 1 year to more than 3 years. The improvement in patient survival is largely attributable to advances in radiation technology and the introduction of Asp and anti-PD-1/PD-L1 immunotherapy into practice. Radiotherapy is essential for patients with early-stage disease, while Asp-based chemotherapy (CT) and PD-1/PD-L1 inhibitors significantly improved the prognosis of patients with advanced-stage disease. ENKTCL management is trending toward simpler regimens, less toxicity, and higher efficacy. Novel drugs, such as manufactured T cells, monoclonal antibodies, and small molecule inhibitors, are being intensively investigated. Based on the fact that ENKTCL is highly resistant to cytotoxic drugs except Asp, and aggressive CT leads to higher toxicity rather than better outcomes, we recommend it is unnecessary to expend additional resources to compare different combinations of Asp with cytotoxic agents. Instead, more efforts should be made to optimize the use of Asp and immunotherapy to maximize efficacy and minimize toxicity, explore ways to overcome resistance to Asp and immunotherapy, identify novel treatment targets, and define subpopulations who may benefit more from specific treatments.

RNA structure directs the targeting specificity of Cas13d.

Type VI CRISPR enzymes exclusively bind and cleave target RNAs, and are widely used for gene regulation, RNA tracking, and diagnostics. However, a systematic understanding of their RNA binding specificity is lacking. Here, we describe RNA-CHAMP, a massively parallel platform that repurposes used next-generation DNA sequencing chips to measures the binding affinity for >10,000 RNA targets containing structural perturbations, mismatches, insertions, and deletions relative to the guide RNA. We profile the RNA binding specificity of Cas13d, a compact and widely used RNA nuclease. Contrary to other type VI CRISPR enzymes, Cas13d does not have a protospacer flanking sequence (PFS) preference. Cas13d tolerates mismatches, insertions, and deletions, but is exquisitely sensitive to secondary structure within the target RNA. Basepairing in the distal region of the target RNA strongly decreases Cas13d binding, whereas structuring the first six nucleotides inhibits nuclease activity without impacting binding. A biophysical model built from these data reveals that target recognition begins at the distal end of unstructured target RNAs and proceeds to the proximal end with limited RNA melting. Using this model, we design a series of partially mismatched guide RNAs that modulate nuclease activity to detect single nucleotide polymorphisms (SNPs) in circulating SARS-CoV-2 variants. This work describes the key determinants of RNA targeting by a type VI CRISPR enzyme to improve RNA targeting and CRISPR diagnostics. More broadly, RNA-CHAMP provides a quantitative platform for systematically measuring protein-RNA interactions.

Optimizing the flatness of 4H-silicon carbide wafers by tuning the sequence of lapping

In this letter, we optimize the flatness of 4H silicon carbide (4H-SiC) wafers by tuning the sequence of single-sided lapping, enlightened by the different mechanical properties of the Si face and C face of 4H-SiC. After wire sawing, the coarse lapping and fine lapping are carried out to rapidly remove the surface damage and optimize the flatness of 4H-SiC wafers. From the point of view of controlling the values of the bow and warp of 4H-SiC wafers, the coarse-lapping sequence of the C-face lapping followed by Si-face lapping is beneficial, while the preferred fine-lapping sequence is Si-face lapping followed by C-face lapping. Nanoindentation tests indicate that the C face has higher hardness and lower fracture toughness than the Si face. This gives rise to thicker surface damage at the C face after the wire sawing. After removing the same amount of wire-sawing induced surface damage, the thickness of residual surface damage of the C face is higher than that of the Si face after the coarse lapping. The fine lapping basically removes all the surface damage and creates the near-perfect C face and Si face. The higher amount of surface damage of the C face after the coarse lapping and the higher fracture toughness of the near-perfect Si face after the fine lapping can tolerate more plastic deformations, which gives rise to the superior flatness of the C-face-followed-by-Si-face coarse lapped and the Si-face-followed-by-C-face fine lapped 4H-SiC wafers, respectively.

INTEGRATED MARKETING COMMUNICATION PREFERENCES COFFEE SHOP IN SURABAYA

In modern era, technological developments affect people's lifestyles, especially in consumption behaviour which switched to be a consumptive one, we can barely see drinking coffee which now becoming a lifestyle. “coffee shop” comes up as a new coffee shop in Surabaya in November 2018. Some innovations in Integrated Marketing Communication activities or known as IMC have been carried out by companies. Ever since the company stood they did IMC activities, covering advertising, public relations, sales promotion, sponsorship, and digital marketing. This research aims to find out the consumer preferences of some of the IMC activities and it’s most effective aspect for the company. This research is a quantitative descriptive study by conducting surveys from 96 people as a sample. The respondents were coffee shop consumers who had bought more than once and were aware of the IMC activities by coffee shop. The survey results were processed by weighting which obtained the coffee shop consumer preference sequence regarding IMC activities that had been carried out. The results of this study indicate consumer preferences in the form of using Instagram as a digital media in first place, sponsorship at the Indie Kopi event in second place, use of the Ladies Day banner as a print advertising medium in third place, Riding activities with the Surabaya motorcycle community in fourth place, and the presence of discounted prices (Ladies Day, Univ Day, Valentine Day) took fifth place.

Structure and Formation of Z-DNA and Z-RNA.

Despite structural differences between the right-handed conformations of A-RNA and B-DNA, both nucleic acids adopt very similar, left-handed Z-conformations. In contrast to their structural similarities and sequence preferences, RNA and DNA exhibit differences in their ability to adopt the Z-conformation regarding their hydration shells, the chemical modifications that promote the Z-conformation, and the structure of junctions connecting them to right-handed segments. In this review, we highlight the structural and chemical properties of both Z-DNA and Z-RNA and delve into the potential factors that contribute to both their similarities and differences. While Z-DNA has been extensively studied, there is a gap of knowledge when it comes to Z-RNA. Where such information is lacking, we try and extend the principles of Z-DNA stability and formation to Z-RNA, considering the inherent differences of the nucleic acids.

Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome.

Spalt-like 4 (SALL4) maintains vertebrate embryonic stem cell identity and is required for the development of multiple organs, including limbs. Mutations in SALL4 are associated with Okihiro syndrome, and SALL4 is also a known target of thalidomide. SALL4 protein has a distinct preference for AT-rich sequences, recognised by a pair of zinc fingers at the C-terminus. However, unlike many characterised zinc finger proteins, SALL4 shows flexible recognition with many different combinations of AT-rich sequences being targeted. SALL4 interacts with the NuRD corepressor complex which potentially mediates repression of AT-rich genes. We present a crystal structure of SALL4 C-terminal zinc fingers with an AT-rich DNA sequence, which shows that SALL4 uses small hydrophobic and polar side chains to provide flexible recognition in the major groove. Missense mutations reported in patients that lie within the C-terminal zinc fingers reduced overall binding to DNA but not the preference for AT-rich sequences. Furthermore, these mutations altered association of SALL4 with AT-rich genomic sites, providing evidence that these mutations are likely pathogenic.

Resource Matching in the Supply Chain Based on Environmental Friendliness under a Smart Contract

This study aims to solve the problem of environmental pollution caused by industry through the upgrading and transformation of the supply chain, supply chain resource allocation, and related aspects. Specifically, environmental friendliness is added to the resource-matching problem of the cloud platform supply chain. Additionally, learning theory and dynamic evaluation systems are introduced when creating a preference sequence. The deferred-acceptance algorithm is used for matching. Finally, the automatic matching of blockchain smart contracts ensures the interests of both matching parties. Through the analysis of the example at the end of the study, we found that (1) the deviation table of demand side 5 and supply side 7 in the example shows that the deviation between demand side 5 as demand side and supply side 7 is only 11.55186, and the deviation between supply side 7 as demand side and demand side 5 is only 6.56778, and both sides form a high-quality pairing when matched with other partners. No excessive waste of its resources occurs. (2) Effectively ensure the openness and transparency of the supply chain production process; (3) The impact of environmental factors on enterprises is fully considered. In the analysis of the calculation cases, it can be found that demand side 10 has extremely high requirements for the environmental friendliness of its partners, and although supplier 2 has a very high preference for demand side 10, it is not successfully matched because the environmental friendliness of its own enterprise is not up to the standard, while supplier 1 has an environmental friendliness of up to 92 and is finally matched with Demand side 10; (4) Through the comparison test in the appendix, it can be found that the improved GS algorithm achieves the distinction between positive and negative partners. After multiple rounds of scoring, positive demand side 1, 3 was matched with positive supply side 2, 4, which can strengthen the enthusiasm of both partners and avoid negative cooperation.

A Faster Prostate MRI: Comparing a Novel Denoised, Single-Average T2 Sequence to the Conventional Multiaverage T2 Sequence Regarding Lesion Detection and PI-RADS Score Assessment.

The T2 w sequence is a standard component of a prostate MRI examination; however, it is time-consuming, requiring multiple signal averages to achieve acceptable image quality. To determine whether a denoised, single-average T2 sequence (T2 -R) is noninferior to the standard multiaverage T2 sequence (T2 -S) in terms of lesion detection and PI-RADS score assessment. Retrospective. A total of 45 males (age range 60-75 years) who underwent clinically indicated prostate MRI examinations, 21 of whom had pathologically proven prostate cancer. A 3 T; T2 w FSE, DWI with ADC maps, and dynamic contrast-enhanced images with color-coded perfusion maps. T2 -R images were created from the raw data utilizing a single "average" with iterative denoising. Nine readers randomly assessed complete exams including T2 -R and T2 -S images in separate sessions. PI-RADS version 2.1 was used. All readers then compared the T2 -R and T2 -S images side by side to evaluate subjective preference. An additional detailed image quality assessment was performed by three senior level readers. Generalized linear mixed effects models for differences in lesion detection, image quality features, and overall preference between T2 -R and T2 -S sequences. Intraclass correlation coefficients (ICC) were used to assess reader agreement for all comparisons. A significance threshold of P= 0.05 was used for all statistical tests. There was no significant difference between sequences regarding identification of lesions with PI-RADS ≥3 (P= 0.10) or PI-RADS score (P= 0.77). Reader agreement was excellent for lesion identification (ICC=0.84). There was no significant overall preference between the two sequences regarding image quality (P= 0.07, 95% CI: [-0.23, 0.01]). Reader agreement was good regarding sequence preference (ICC=0.62). Use of single-average, denoised T2 -weighted images was noninferior in prostate lesion detection or PI-RADS scoring when compared to standard multiaverage T2 -weighted images. 3. Stage 3.

There's something about a pattern: Choice between pattern and random sequences in implicit learning.

Three experiments examined the preference for pattern versus random sequences. In all experiments the elements composing the sequences were visual images presented sequentially on a touchscreen. Reinforcement was randomly programmed on .16 of the element presentations for each type of trial. For pattern sequences the elements occurred in the same order and at the same location on each presentation of the sequence. For random sequences the elements could occur in any order on a given trial. The experiments were conducted in two phases. In the first phase, termed forced-choice, subjects, male Silver Kings, were given either a pattern sequence or a random sequence to work on in a given trial. Subjects received this first phase until performance on each type of sequence was equated. In the second phase, termed free-choice, subjects could choose which of the two sequences to work on in each trial. Results indicated that although performance was equated between the two types of sequences in the forced-choice phase, when given the choice subjects selected the pattern sequence on 70 percent of the trials. This finding held in Experiments 1 and 2 although there were procedural differences between these two experiments. In Experiment 3 the reinforcement probability for random sequences was increased to be 50 percent higher than for pattern sequence. In this arrangement subjects chose random sequences on nearly 83 percent of the free-choice trials, indicating that the preference for pattern sequences was not intractable. Results suggest that the preference for pattern sequences that was observed when reinforcement was equated between the two types of sequences may have been the result of the added information concerning forthcoming element presentations that was available from pattern sequences. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Application of artificial intelligence in the detection and stratification of prostate cancer: Literature review

This review examines the current methodologies employed in utilizing artificial intelligence for the identification and classification of prostate cancer using magnetic resonance imaging data. It outlines the volume of data utilized and highlights the most commonly sought-after sequences employed for training neural networks. The review further presents the accuracy metrics of the neural networks analyzed, accompanied by a succinct explanation of each metric. Furthermore, the review pinpoints the limitations associated with contemporary neural networks devised for the detection and classification of prostate cancer using magnetic resonance imaging data, as well as the challenges encountered during their creation and implementation.In summary, this comprehensive analysis delves into the existing approaches in leveraging artificial intelligence for prostate cancer detection and stratification through magnetic resonance imaging data. It addresses the data scale and preferred magnetic resonance imaging sequences employed for neural network training. The review provides a breakdown of accuracy indicators for the neural networks evaluated, elucidating their respective capabilities. Moreover, the review identifies the drawbacks associated with current neural network models developed for prostate cancer detection and stratification via magnetic resonance imaging data, while also recognizing the complexities involved in their development and practical application.

Accurate prediction of isocitrate dehydrogenase -mutation status of gliomas using SLOW-editing magnetic resonance spectroscopic imaging at 7 T MR.

2-hydroxy-glutarate (2HG) is a metabolite that accumulates in isocitrate dehydrogenase (IDH)-mutated gliomas and can be detected noninvasively using MR spectroscopy. However, due to the low concentration of 2HG, established magnetic resonance spectroscopic imaging (MRSI) techniques at the low field have limitations with respect to signal-to-noise and to the spatial resolution that can be obtained within clinically acceptable measurement times. Recently a tailored editing method for 2HG detection at 7 Tesla (7 T) named SLOW-EPSI was developed. The underlying prospective study aimed to compare SLOW-EPSI to established techniques at 7 T and 3 T for IDH-mutation status determination. The applied sequences were MEGA-SVS and MEGA-CSI at both field strengths and SLOW-EPSI at 7 T only. Measurements were performed on a MAGNETOM-Terra 7 T MR-scanner in clinical mode using a Nova 1Tx32Rx head coil and on a 3 T MAGNETOM-Prisma scanner with a standard 32-channel head coil. Fourteen patients with suspected glioma were enrolled. Histopathological confirmation was available in 12 patients. IDH mutation was confirmed in 9 out of 12 cases and 3 cases were characterized as IDH wildtype. SLOW-EPSI at 7 T showed the highest accuracy for IDH-status prediction (91.7% accuracy, 11 of the 12 predictions correct with 1 false negative case). At 7 T, MEGA-CSI had an accuracy of 58.3% and MEGA-SVS had an accuracy of 75%. At 3 T, MEGA-CSI showed an accuracy of 63.6% and MEGA-SVS of 33.3%. The co-edited cystathionine was detected in 2 out of 3 oligodendroglioma cases with 1p/19q codeletion. Depending on the pulse sequence, spectral editing can be a powerful tool for the noninvasive determination of the IDH status. SLOW-editing EPSI sequence is the preferable pulse sequence when used at 7 T for IDH-status characterization.

Dynamic Preference Learning for Complex Cobotic Tasks

In complex tasks requiring robots to collaborate with multiple human users for successful human-robot interaction, it is essential to capture user preferences in the control design. This work considers both the subjective judgements of a users preferences, to formulate a preference measure that can be used in control design. Novel to the work, is the consideration of the temporal impact that current preferences have on previously provided preferences. We formulate a weighted set-wise preference learning problem that considers the historical preferences of an individual, capturing the impact of memory on human user's preferences. We address the challenge of how to choose the best preference features as the individuals set-wise preference comparisons are sequentially presented by designing a weighted sequential preference estimator. We build upon the concept of an individual's preferences to a group of users’ preferences, modelling group preferences as a normal distribution. We further extend the sequential individual preference estimation approach to multiple users’ preference through the derivation of a stochastic gradient descent group preference estimator. An experimental study with 43 participants is conducted to support the proposed approaches.

ETHNOMATHEMATICS: ARITHMETIC SEQUENCE PATTERNS OF MINANGKABAU CARVING ON SINGOK GONJONG

This study aimed to explore the arithmetic sequence pattern found in Minangkabau carvings mounted on singok gonjong. The method used is a qualitative method with an ethnographic approach. Data was collected by observation, interviews, literature studies, and documentation. The object of this study is Minangkabau carving on singok gonjong. The data obtained in this study came fromdirect observation, results of interviews with Minang carving craftsmen, documentation, and literature studies. The results showed three kinds of arithmetic sequence patterns in Minang carvings in singok gonjong. The first is the arithmetic sequence pattern on the saik galamai carving with formula Un = n. The second is the pattern of odd and even arithmetic sequences on the sikambang manih carving wtih the odd formula U(2n+1) = 3n + 1 and the even formula U(2n) = 3n. The last is the pattern of odd and even arithmetic sequences on the combined engraving of saik galamai and sikambang manih wtih the odd formula U(2n+1) = 4n + 1 and the even formula U(2n) = 4n. The conclusion shows that the presence of patterns on the saik galamai carvings and sikambang manih carvings found on Singok Gonjong can be used as a preference for learning arithmetic sequences at school

A phase III, multicenter, randomized controlled trial of preoperative versus postoperative stereotactic radiosurgery for patients with surgically resectable brain metastases

BackgroundPostoperative stereotactic radiosurgery (SRS) is a standard management option for patients with resected brain metastases. Preoperative SRS may have certain advantages compared to postoperative SRS, including less uncertainty in delineation of the intact tumor compared to the postoperative resection cavity, reduced rate of leptomeningeal dissemination postoperatively, and a lower risk of radiation necrosis. The recently published ASCO-SNO-ASTRO consensus statement provides no recommendation for the preferred sequencing of radiotherapy and surgery for patients receiving both treatments for their brain metastases.MethodsThis multicenter, randomized controlled trial aims to recruit 88 patients with resectable brain metastases over an estimated three-year period. Patients with ten or fewer brain metastases with at least one resectable, fulfilling inclusion criteria will be randomized to postoperative SRS (standard arm) or preoperative SRS (investigational arm) in a 1:1 ratio. Randomization will be stratified by age (< 60 versus ≥60 years), histology (melanoma/renal cell carcinoma/sarcoma versus other), and number of metastases (one versus 2–10). In the standard arm, postoperative SRS will be delivered within 3 weeks of surgery, and all unresected metastases will receive primary SRS. In the investigational arm, enrolled patients will receive SRS of all brain metastases followed by surgery of resectable metastases within one week of SRS. In either arm, single fraction or hypofractionated SRS in three or five fractions is permitted. The primary endpoint is to assess local control at 12 months in both arms. Secondary endpoints include local control at other time points, regional/distant brain recurrence rates, leptomeningeal recurrence rates, overall survival, neurocognitive outcomes, and adverse radiation events including radiation necrosis rates in both arms.DiscussionThis trial addresses the unanswered question of the optimal sequencing of surgery and SRS in the management of patients with resectable brain metastases. No randomized data comparing preoperative and postoperative SRS for patients with brain metastases has been published to date.Trial registrationClinicaltrials.gov, NCT04474925; registered on July 17, 2020. Protocol version 1.0 (January 31, 2020). Sponsor: Alberta Health Services, Edmonton, Canada (Samir Patel, MD).

Multi-objective optimization of heating operation of stratum ventilation under different clothing insulations using Taguchi method, RSM, and SPA-TOPSIS

Stratum ventilation (SV) for heating can provides a comfortable indoor environment, good intake air quality, and energy efficiency when operated correctly. The studies that have been conducted have focused on the operations of SV that occupants’ clothing insulation was set to a fixed value (i.e., clothing insulation of cooling season and heating season is 0.5 clo and 1 clo, respectively), with little attention to different clothing insulations. This study aimed to access the optimal ventilation parameters (i.e., supply air velocity, supply vane angle, and supply air temperature) to satisfy the requirements of thermal comfort for occupants with different clothing insulations, whilst improving indoor air quality and achieving energy savings. Firstly, based on experimentally validated Computational Fluid Dynamics (CFD) simulations, the Taguchi method was used to analyze the effects of operation parameters (i.e., supply vane angle, supply air velocity, supply air temperature, and outdoor air temperature) on the thermal comfort of occupants with different clothing insulations. The results show that the operation parameters affected the thermal comfort of occupants with different clothing insulations inconsistently. Then, taking clothing insulation as one of the important influencing factors in the optimization process, the multi-objective optimization of stratum ventilation for heating conditions was performed by a sequential preference technique based on the set pair analysis method (SPA-TOPSIS) of similarity to the ideal solution. To reduce the costs of computational, response surface models (RSMs) of ventilation performance was formulated and then used to assess the ventilation performance for all operations optimized by SPA-TOPSIS. The results showed that the dynamical optimization of ventilation parameters significantly improves ventilation performance considering different clothing insulations.

Reversions to consensus are positively selected in HIV-1 and bias substitution rate estimates.

Human immunodeficiency virus 1 (HIV-1) is a rapidly evolving virus able to evade host immunity through rapid adaptation during chronic infection. The HIV-1 group M has diversified since its zoonosis into several subtypes at a rate of the order of 10-3 changes per site per year. This rate varies between different parts of the genome, and its inference is sensitive to the timescale and diversity spanned by the sequence data used. Higher rates are estimated on short timescales and particularly for within-host evolution, while rate estimates spanning decades or the entire HIV-1 pandemic tend to be lower. The underlying causes of this difference are not well understood. We investigate here the role of rapid reversions toward a preferred evolutionary sequence state on multiple timescales. We show that within-host reversion mutations are under positive selection and contribute substantially to sequence turnover, especially at conserved sites. We then use the rates of reversions and non-reversions estimated from longitudinal within-host data to parameterize a phylogenetic sequence evolution model. Sequence simulation of this model on HIV-1 phylogenies reproduces diversity and apparent evolutionary rates of HIV-1 in gag and pol, suggesting that a tendency to rapidly revert to a consensus-like state can explain much of the time dependence of evolutionary rate estimates in HIV-1.

The R736H cancer mutation in DNMT3A modulates the properties of the FF-subunit interface

The DNMT3A DNA methyltransferase is an important epigenetic enzyme that is frequently mutated in cancers, particularly in AML. The heterozygous R736H mutation in the FF-interface of the tetrameric enzyme is the second most frequently observed DNMT3A cancer mutation, but its pathogenic mechanism is unclear. We show here that R736H leads to a moderate reduction in catalytic activity of 20–40% depending on the substrate, but no changes in CpG specificity, flanking sequence preferences and subnuclear localization. Strikingly, R736H showed a very strong stimulation by DNMT3L and the R736H/DNMT3L complex was 3-fold more active than WT/DNMT3L. Similarly, formation of mixed R736H/DNMT3A WT FF-interfaces led to an increased activity. R736H/DNMT3L and mixed R736H/DNMT3A WT FF-interfaces were less stable than interfaces not involving R736H, suggesting that an increased flexibility of the mixed interfaces stimulates catalytic activity. Our data suggest that aberrant activity of DNMT3A R736H may lead to DNA hypermethylation in cancer cells which could cause changes in gene expression.

Preference for rural living environment improvement initiatives in China

AbstractThe Chinese government has launched the Rural Living Environment Improvement Initiative (RLEII) to solve the poor living conditions in rural areas. The initiative enhances rural greenery; provides sanitary toilets; and promotes proper disposal of animal manure, sewage, and household waste in rural areas. We collected data using in‐person interviews with 938 rural residents in Xinjiang, China, to elicit their preference, preference intensity, and preference heterogeneity for RLEII. Results indicated that rural residents prefer to see shortcomings of the RLEII addressed. Rural greening construction is identified with the highest preference intensity. We also find significant heterogeneity in rural residents' preferences for each attribute of RLEII. The preference heterogeneity is rooted in the region's economic condition (poor vs. nonpoor region). It is essential to understand rural residents' choice for rural public goods supply and to respect their preference intensity, sequence, and heterogeneity for RLEII to enhance the implementation performance. We discuss the implications of these findings.