Frequency Of Hits Research Articles

Systematic characterization of m6A proteomics across 12 cancer types: a multi-omics integration study.

The modification patterns of N6-methyladenosine (m6A) regulators and interacting genes are deeply involved in tumors. However, the effect of m6A modification patterns on human proteomics remains largely unknown. We evaluated the molecular characteristics and clinical relevance of m6A modification proteomics patterns among 1013 pan-cancer samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). More than half of the m6A proteins were expressed at higher levels in tumor tissues and presented oncogenic characteristics. Furthermore, we performed multi-omics analyses integrating with transcriptomics data of m6A regulators and interactive coding and non-coding RNAs and developed a m6A multi-omics signature to identify potential m6A modification target proteins across global proteomics. It was significantly associated with overall survival in nine cancer types, tumor mutation burden (P = 0.01), and immune checkpoints including PD-L1 (P = 4.9 × 10-8) and PD-1 (P < 0.01). We identified 51 novel proteins associated with the multi-omics signature (PFDR < 0.05). These proteins were functional through pathway enrichment analyses. The protein with the highest hit frequency was CHORDC1, which was significantly up-regulated in tumor tissues in nine cancer types. Its higher abundance was significantly associated with a poorer prognosis in seven cancer types. The identified m6A target proteins might provide infomation for the study of molecular mechanism of cancer.

Impact of Somatic Second Hit and Comutations in Myeloid Neoplasms with Germline DDX41 Mutations

Background: Germline DDX41 mutations are the most common genetic predisposition to myeloid neoplasms (MN) and have been suggested to represent a distinct MN subtype. A second somatic DDX41 mutation (second hit) is known to occur in most patients, with a clear predominance for R525H. However, its impact on disease progression and survival remains elusive. Additionally, comutation patterns are not well defined across all MN subtypes, with limited evidence regarding their prognostic significance. Methods: We performed a retrospective cohort study to evaluate outcomes of DDX41-mutant MN, focusing on the impact of co-occurring mutations, including second hit DDX41 lesions. We included 100 patients with at least 1 DDX41 variant and a MN or precursor condition. DDX41 mutation was identified by an in-house NGS myeloid gene panel. Skin biopsy was the most frequent DNA source for germline testing. When this was not available, we applied a validated model to predict the nature of DDX41 variants based on VAF, public germline databases and known hotspot somatic mutations. Kaplan-Meier analysis and Cox models were used for survival analyses. Observations were censored for transplant. Results: Overall, the median age at diagnosis was 71 years (IQR 65-79) and 66% were male. The underlying diagnosis was MDS in 43% of cases, AML in 47% and other MN in 10% (including chronic myelomonocytic leukemia, myeloproliferative neoplasms and clonal cytopenia of undetermined significance). Most patients had a normal karyotype (77%, 72/93). In the MDS cohort 36% (14/39) had higher-risk (HR) disease (IPSS-R&amp;gt;3.5) and 30% of AML patients (14/46) had adverse risk disease (ELN 2022). Median overall survival (OS) for patients with HR-MDS or AML was 24.6 months (95% CI 7.7-37.4). Out of 169 identified DDX41 variants, 51% were predicted as germline, corresponding to 86% of all patients carrying a germline variant. Twenty-one patients had a DDX41 mutation confirmed in germline DNA, and all would have been predicted by the model. In our cohort, most MN patients carrying a germline DDX41 mutation had a somatic second hit (71%, 61/86) but the presence of a second hit did not impact OS (logrank p=0.72) and its prevalence was not significantly different in patients with lower-risk (LR)-MDS, HR-MDS or AML (p=0.45). This suggests that, albeit the occurrence of a second hit seems related to developing a MN, its presence is not necessarily associated with progression nor worse survival. There was a numerically worse median OS in those harboring the R525H second hit (33 vs 89 months), but the survival distribution was not significantly different (logrank p=0.28). However, an increasing R525H prevalence was noted from LR-MDS to HR-MDS to AML (33%, 67%, 77%; p=0.004). Among patients with germline DDX41 variants, the presence of at least one somatic mutation beyond DDX41 (comutation) was associated with significantly worse OS in univariate analysis (HR 4.26, 95% CI 1.16-15.67, p=0.03) but did not retain significance when diagnosis was added to the model (HR 2.43, 95% CI 0.57-10.36, p=0.23). Yet, the distribution of the proportion of patients with at least one comutation between LR-MDS, HR-MDS and AML was significantly different (p=0.03), with an increase from LR-MDS to the other 2 categories. The same results held true for the presence of 2 or more mutations. The top 5 comutations were TET2 (14%), ASXL1 (13%), SRSF2 (11%), DNMT3A (10%) and CUX1 (10%). Interestingly, there was a significantly lower prevalence of CUX1 in MDS than in AML (2% vs 17%, p=0.02) and a tendency for increased frequency from LR-MDS to HR-MDS to AML (0% vs 7% vs 17%, p=0.07), highlighting a potential role in disease progression. There was no significant difference when comparing the clone sizes of second hit DDX41 mutations and comutations (median VAF 14% vs 14%, p= 0.78). Conclusions: While most patients with germline DDX41 MN harbor a somatic second hit, its presence was not predictive of survival and its frequency was not differently distributed across the MDS-AML continuum. The presence of additional comutations equally lacked survival impact. However, the frequency of patients with any somatic comutation, the frequency of R525H second hit, and the occurrence of CUX1 mutation increased from MDS to AML, placing these as candidate drivers of leukemic progression in germline DDX41 MN. Moreover, similar clone sizes of somatic DDX41 mutations and comutations favors co-occurrence of these events.

MUESTREO SECUENCIAL PARA EL MONITOREO DE RENDIMIENTOS EN GRANJAS DEL GUSANO REY (ZOPHOBAS SPP. [COLEOPTERA: TENEBRIONIDAE]) EN LA AMAZONIA

&lt;p class="rfpMnscText"&gt;&lt;strong&gt;Background&lt;/strong&gt;: Sampling for monitoring commercial production of kingworm (&lt;em&gt;Zophobas&lt;/em&gt; spp.) requires knowledge about optimal sample sizes and methods for projecting yields. &lt;strong&gt;Hypothesis and objective&lt;/strong&gt;: A sequential enumerative sampling (SES) based on larval weight records should present significant levels of productivity prediction under known margins of error and precision. To verify this, it was proposed to evaluate the performance of an SES method in two kingworm’s farms in Tarapoto, Peruvian Amazon. &lt;strong&gt;Methodology&lt;/strong&gt;: Means (m) and respective variances (s&lt;sup&gt;2&lt;/sup&gt;) of larvae number and weight since six sample units (SU) of 500 ml from 35 production units (PU) of 48 l were obtained. Log-transformed data were fitted to Taylor’s Power Law TPL (log s&lt;sup&gt;2&lt;/sup&gt; =log a +b. log m). A Morisita’s index transformation was applied with original larvae number data to obtain an independent measure of intra-sample spatial arrangement. TPL elements constituted the Green's function optimal sample size for three margins of error E. Sequential sampling simulations were carried out, whose means predicted yields comparing two methods of weight relationship between SU and PU (w/W, linear function), with their respective census. &lt;strong&gt;Results&lt;/strong&gt;: Number of larvae (s&lt;sup&gt;2&lt;/sup&gt; =1.06 m&lt;sup&gt;1.61&lt;/sup&gt;) and weights (s&lt;sup&gt;2&lt;/sup&gt; =0.79 m&lt;sup&gt;1.53&lt;/sup&gt;) showed highly significant adjustments in TPL, with aggregation coefficients corresponding crowded spatial arrangement. Larval density and I&lt;sub&gt;p&lt;/sub&gt; index showed close correlation. Although simulations provided a lower hit frequency than expected, the mean precision increased highly significantly while increasing the error margin, with detection levels of 0.25, 2.23 and 12.57 g to E 50, 30 and 20 %, respectively. &lt;strong&gt;Implications&lt;/strong&gt;: Applying SES, kingworm’s breeders should standardize substrate volume contained in each UP and adjust their w/W conversion factor to avoid plus sampling efforts. &lt;strong&gt;Conclusion&lt;/strong&gt;: The SES suits the needs of productivity monitoring, where using of w/W ratio and 50 % margins of error are associated with greater effectiveness and precision with a sample size of n&lt;sub&gt;i&lt;/sub&gt;&amp;lt;3. &lt;/p&gt;

Leveraging American football helmet accelerometer data to estimate associations between cumulative repetitive head impact exposure and chronic traumatic encephalopathy

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We previously showed that duration of American football play is associated with risk and severity of CTE pathology. Helmet accelerometers have been used previously to examine frequency, linear acceleration, and rotational acceleration of hits sustained across youth, high school, and college football. Here we projected this data onto former American football playing brain donors to examine the relationship between cumulative frequency of hits, linear acceleration, and rotational acceleration during players’ athletic careers and CTE pathology.Method656 former American football playing brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank were examined for CTE pathology and severity. Years and position of play at each level (youth, high school, college, professional) were acquired through retrospective clinical interviews with brain donors next‐of‐kin. From a literature search of studies using helmet accelerometers, we calculated the mean frequency of hits, linear acceleration (g‐force), and rotational acceleration (rad/sec2) for one year of play at each level‐position combination. These values were projected onto brain donors’ career exposure to derive cumulative frequency of head impacts (CHII), cumulative linear acceleration (CHII‐G), and cumulative rotational acceleration (CHII‐R). Separate logistic regression models examined the relationship of years of play, CHII, CHII‐G, and CHII‐R on CTE status and severity (low vs. high), adjusting for age at death.ResultThe mean (SD) age at death was 59.7 (20.1) and 451 (68.8%) had CTE pathology. Each cumulative measure was significantly associated with presence of CTE (p’s&lt;.001) and severity of CTE (p’s&lt;.001). Based on ROC analyses, CHII‐R (AUC=0.765, p&lt;.001) and CHII‐G (AUC= 0.758, p&lt;.001) performed significantly better than years of play (AUC=0.716) in classifying CTE pathology, and there was no difference between years of play and CHII (AUC=0.698, p=0.25). Similar relationships were observed for CTE severity. Model fit and cross‐validation statistics were also consistent (Table 2).ConclusionAmong former American football playing brain donors, cumulative linear and rotational acceleration were better predictors of CTE pathology than duration of play or cumulative hits. The findings suggest head impact intensity is an important factor in developing CTE pathology.

Temporal presentations of heparin‐induced thrombocytopenia following cardiac surgery: A single‐center, retrospective cohort study

BackgroundHeparin‐induced thrombocytopenia (HIT) is an important adverse drug reaction that can occur postcardiac surgery. Preoperative exposure to unfractionated heparin (UFH) is common, raising the issue of how frequently cardiac surgery‐associated HIT occurs after immunizing preoperative exposure to heparin. ObjectiveTo determine the frequency and clinical picture of HIT occurring within 4 days of cardiac surgery (early presentation) versus later presentations (typical, delayed). MethodsWe identified patients with laboratory‐confirmed HIT following cardiac surgery over 30 years in a single cardiac surgery center. Three different clinical presentations of HIT were identified: typical (HIT‐related platelet count fall beginning between postoperative days [PODs] 5–10), delayed (patients with falls after POD10 or who presented following hospital discharge), and early (established before POD5, including during cardiac surgery [acute intraoperative HIT]). ResultsOf 129 patients identified with HIT complicating cardiac surgery, 100 had typical and 16 had delayed presentation of HIT; only 13 patients (10.1%) presented with early HIT, all of whom had received exposure to UFH during the 10 days before cardiac surgery. No patient was identified in whom remote preoperative UFH exposure was implicated in explaining early HIT. Notably, five patients appeared to have had acute intraoperative HIT, without immediate adverse consequences. ConclusionsApproximately 90% of patients with HIT after cardiac surgery appear to develop this complication due to immunization triggered by cardiac surgery; however, in approximately 10% of patients, early presentation during the first four PODs (or intraoperatively) can be explained by recent immunizing exposure to heparin.

CrowdLoc: Robust image indoor localization with edge-assisted crowdsensing

Image indoor localization, which is advantageous in infrastructure-less deployment and high positioning accuracy among various indoor localization schemes, is usually deployed in a lightweight end (shooting picture) and heavyweight server (searching image for location in the database) manner. Such a scheme is suffered from two major drawbacks: (1) The uploading and searching of the shooting pictures cause a severe burden to the server. (2) The image map will become defected as time elapse, such as missing features in initialization maps and continuous changes in the scene. To keep the image map up-to-date, a labor-intensive site survey is required with dedicated devices. The frequent updating will further exhaust the limited resources in the server. These two drawbacks have greatly hindered the image-based indoor localization from large-scale deployment. To this end, we study how to use crowdsourcing data to mitigate map defects and optimize location computation and map storage through edge architecture. In this paper, we propose CrowdLoc, an edge-assisted image localization architecture with lightweight multi-view localization on clients and crowdsourcing map-cache on the edge. Our method is mainly innovative in three parts. Firstly, CrowdLoc provides a lightweight multi-view localization on the client-side and the low-confidence localization can be offloaded to the edge server to use the crowdsourcing map for more accurate calculation. Secondly, CrowdLoc uses a map defect perception algorithm to recognize the update of the scene during user localization and update the crowdsourcing map-cache automatically on the edge side. Thirdly, in order to improve cache utilization, we propose a cache elimination strategy that runs periodically on the edge side. It can classify cache data according to the frequency of cache hits on a regular basis, remove invalidation data, and persist long-term updated data to the client map to reduce clients’ computing offload. We evaluate the performance of our method based on the real data in the lobby of an experimental building with a map missing rate of 20% and a map update rate of 40%. The results show that the mean localization error of CrowdLoc is 1.54 meters, which is 59.4% lower than that of multi-view localization without crowdsourcing maps, and only 0.56 meters higher than localization in non-defective maps.

Evaluating the impact of turbidity, precipitation, and land use on nutrient levels and atrazine concentrations in Illinois surface water as determined by citizen scientists

The objective of this study was to evaluate the impact of turbidity, precipitation, land use, and five-week variation on nutrient levels and atrazine concentrations across Illinois state. To acquire the greatest number of samples in a cost and time-sensitive manner, data were collected by citizen scientists. Volunteers collected data regarding five water quality metrics: nitrites, nitrates, phosphates, atrazine, and turbidity once per week from April 19 until May 17, 2017. A subset (24 %) of volunteers also collected turbidity measurements. Data regarding precipitation was obtained from the Community Collaborative Rain, Hail and Snow Network (CoCoRaHS), a long-standing grassroots volunteer network of backyard weather observers. Three ordinal regression analyses were performed: one without a blocking effect, a second with week as a blocking effect, and a third with watershed as a blocking effect. In all cases, turbidity was significantly associated with elevated levels of nitrate (Pseudo R2–0.48 to 0.94) and phosphate (Pseudo R2–0.60 to 0.80), while precipitation was significantly associated with elevated levels of nitrate (Pseudo R2–0.25 to 0.35). While analyzing five-week variation, the nitrite and nitrate levels, but not phosphate or atrazine, tended to increase at each site. Further, nitrite and nitrate levels significantly varied between the four land uses – agricultural, urban, suburban, and park. When data were analyzed by the three most well-sampled watersheds, Kankakee, Des Plaines, and Chicago, it was identified that the nutrient levels in the Kankakee and Chicago watersheds were significantly elevated relative to the Des Plaines watershed. Finally, cluster analysis identified that clusters dominated by agricultural land, and to a lesser extent suburban land use, had the most elevated nutrient concentration and the greatest frequency of atrazine hits. Data collected by citizen scientists can provide insight into the geospatial variability of nutrients and agrichemicals and can do so across large geographies.

Effect of educational video on newborn care for the knowledge of pregnant and postpartum women and their families.

to evaluate the effect of educational video on newborn care to increase the knowledge of pregnant, postpartum, and family members. a quasi-experimental study, with pre-intervention and post-intervention evaluation with a single group. Fifty-eight pregnant, postpartum, and family members treated in basic health units and a hospital in Ceará, Brazil, participated. The study used the McNemar and binomial tests for the analysis. after the intervention, there was an increase in the frequency of hits, from 70.82% to 92.97%. Most of the questions presented a significant increase of hits (p < 0.05) with an emphasis on sleeping position, drying of clothes, free demand for breastfeeding, and things to avoid (such as accessories in the sleeping place and talc in diaper change). the educational video was effective to participants in acquiring knowledge on the care of newborns and can assist in health education activities carried out by nurses.

Optical and mathematical method for studying electrode discharge spots with a liquid electrode

High-speed visualization of the discharge with a liquid cathode, color image processing were performed. The area of cathode spots concentration was identified. Statistical characteristics of the distribution of cathode spots were obtained in order to determine the range in which the intensity code of the green color channel changes, the polygon function of the empirical distribution of the intensity code for the green color channel. The graphical dependence on the frequency of the cathode spot indication hit into the specified interval of the color intensity code was created.

A New Efficient Cache Replacement Strategy for Named Data Networking

The Information-Centric Network (ICN) is a future internet architecture with efficient content retrieval and distribution. Named Data Networking (NDN) is one of the proposed architectures for ICN. NDN’s innetwork caching improves data availability, reduce retrieval delays, network load, alleviate producer load, and limit data traffic. Despite the existence of several caching decision algorithms, the fetching and distribution of contents with minimum resource utilization remains a great challenge. In this paper, we introduce a new cache replacement strategy called Enhanced Time and Frequency Cache Replacement strategy (ETFCR) where both cache hit frequency and cache retrieval time are used to select evicted data chunks. ETFCR adds time cycles between the last two requests to adjust data chunk’s popularity and cache hits. We conducted extensive simulations using the ccnSim simulator to evaluate the performance of ETFCR and compare it to that of some well-known cache replacement strategies. Simulations results show that ETFCR outperforms the other cache replacement strategies in terms of cache hit ratio, and lower content retrieval delay.

Screening and diagnosis of heparin-induced thrombocytopenia in the pediatric population: A tertiary centre experience

IntroductionHeparin-induced thrombocytopenia (HIT) is a life-threatening side effect of heparin necessitating immediate heparin discontinuation. A missed diagnosis of HIT carries significant morbidity and mortality, while overdiagnosis may result in unnecessary and potentially harmful use of alternative anticoagulants in the pediatric population. We aimed to determine the proportion of HIT screening tests at our pediatric tertiary care centre ultimately leading to a diagnosis of HIT by functional assay (either lumi-aggregometry or serotonin-release assay). We hypothesized that the frequency of HIT at our centre would be lower than that reported in the literature. Materials and methodsWe conducted a retrospective review including children aged 0 to 18 years who had HIT testing performed at our centre between 2010 and 2018 (N = 189; 51% female). A screening enzyme immunoassay, if positive, is followed by a functional assay which must be positive to establish the diagnosis of HIT. Data were analyzed to establish trends in demographic and clinical features of patients with a positive HIT screening test. Our primary outcome was the rate of HIT confirmed by functional testing amongst children screened for HIT from 2010 to 2018. Results and conclusionsThere were 233 screening tests performed on 189 distinct patients. Only one patient (0.4%) received a diagnosis of HIT based on functional assay. This patient was a 16-year-old female later found to have a JAK2 mutation. The false positive rate of the enzyme immunoassay was 9.4% (N = 22). There were no positive enzyme immunoassay tests in the neonatal age group (N = 49). These results reinforce that HIT is rare in children.

Metabolic Screening of Cytotoxic T-cell Effector Function Reveals the Role of CRAC Channels in Regulating Lethal Hit Delivery.

Cytotoxic T lymphocytes (CTL) mediate cytotoxicity toward tumor cells by multistep cell-cell interactions. However, the tumor microenvironment can metabolically perturb local CTL effector function. CTL activity is typically studied in two-dimensional (2D) liquid coculture, which is limited in recapitulating the mechanisms and efficacy of the multistep CTL effector response. We here developed a microscopy-based, automated three-dimensional (3D) interface coculture model suitable for medium-throughput screening to delineate the steps and CTL effector mechanisms affected by microenvironmental perturbation. CTL effector function was compromised by deregulated redox homeostasis, deficient mitochondrial respiration, as well as dysfunctional Ca2+ release-activated Ca2+ (CRAC) channels. Perturbation of CRAC channel function dampened calcium influx into CTLs, delayed CTL degranulation, and lowered the frequency of sublethal hits (i.e., additive cytotoxicity) delivered to the target cell. Thus, CRAC channel activity controls both individual contact efficacy and CTL cooperativity required for serial killing of target cells. The multistep analysis of CTL effector responses in 3D coculture will facilitate the identification of immune-suppressive mechanisms and guide the rational design of targeted intervention strategies to restore CTL effector function.

Chemotherapy and Radiation Results in Distinct Patterns of Somatic Mutations in Subsequent Myeloid Disease

Approximately 10% of myeloid neoplasia (MN) may be attributed to extrinsic factors. While environmental exposures are difficult to assess in their impact, iatrogenic causes of MDS, such as previous treatment (tx) with chemotherapy (ctx) or radiation (rtx), are easier to obtain from a patient's history. However, the distinction of a therapy-related MN (tMN) from germline-mediated and spontaneous second MN, e.g ., due to aging, may be problematic. Distinct etiologies may imply specific molecular defects; for instance, tMN types include topoisomerase II inhibitor-induced translocations of 11q23 and 21q22. We hypothesize that tMN is driven by a specific subset of somatic hits.Among 1058 patients (pts) seen at Cleveland Clinic between July 2002 and July 2017 (68% MDS, 24% AML, 8% MDS/MPN); 266 had tMN, with clearly-defined tx history with ctx, rtx, or a combination of ctx and rtx (both) for their primary malignancy (PM) and 109 pts had a history of PM without tx using ctx or rtx (second MN or sMN). Median age at diagnosis (dx) was 64 (9-88), 68 (20-92) and 74 (47-95) years (y) in pMN, tMN and sMN, respectively (p<.0001). Average latency for tMN vs. sMN was 8.6y vs . 10y (p=0.5). Higher-risk MDS/AML was found in 13%, 26% and 22% of pMN, sMN, and tMN, respectively.For tMN and sMN, prostate (20%, 32%), breast (30.5%, 16%), and colorectal cancers (7%, 16%) were the most common PM. Hematologic neoplasia as PM was more common in tMN than sMN (25% vs . 3.7%, p<.0001). Family history of malignancy was enriched in pts with pMN vs. sMN and tMN (OR 1.7, p=0.001, OR 1.6, p=0.057). Del7/7q was most common in tMN vs. pMN (OR 2.8, p<.0001) and sMN (OR 3.6, p=0.0004). Complex karyotype was enriched in tMN vs. sMN and pMN (30%, 13% 16%, p<.0001). NGS for somatic mutations (60-gene panel) was available for 145 tMN, 65 sMN, and the remaining 683 pts with no history of PM prior to MN dx (primary MN or pMN). To determine differences in patterns of somatic driver lesions in each group, we compared frequency of all mutations (MUT) as well as ancestral hits, as assessed by recapitulation of clonal hierarchy using variant allele frequency and zygosity.General somatic patterns of acquisition were similar in frequency and ancestral hits in tMN, pMN and sMN and featured TET2, DNMT3A, and SRSF2MUTS. However, there were significant differences. TP53 (13.1%), EZH2 (7.6%), WT1 (2.8%), and KITMUTS (3.5%) were overrepresented in tMN vs. pMN (OR 2.6, p=0.002 ; OR 1.9, p=0.083 ; OR 3.2; p=0.08 ; OR 6.1, p=0.01) and sMN (OR 2.3, p=0.15; OR 1.3, p= 0.78 ; OR 1.8, p=1 ; OR Infinity, p=0.186). TP53 and EZH2MUTS were also more common ancestral hits in tMN (11%, 4.8%) vs. pMN (3.5%, 2%) (p=0.0004, p=0 .07). TP53MUTpersisted in being associated with tx as an ancestral hit when sMN (3.1%) was used as a control (p=0.06) . In tMN, IDH1, SRSF2, CUX1, and PHF6MUTS (0.7%, 10.3%, 3.5%, 4.1%) were underrepresented relative to sMN (7.7%, 20%, 7.7%, 9.2%) (p=0.011, p=0.077, p=0.29, p=0.19). Indeed, these were more frequent in sMN than pMN (OR 3.07, p=0.042 ; OR 1.99, p=0.044 ; OR 3, p=0.042 ; OR 4.85, p=0.005) and were ancestral events in 4.6%, 12.3%, 1.5%, 1.5% sMN cases.Specific tx modalities have been associated with molecular lesions. We analyzed whether or not rtx and ctx had the same impact on the profile of somatic lesions. TP53MUT correlated primarily with ctx vs rtx (OR 7.2 , p=0.06). However, it was highest when both were used vs. rtx (OR 11.5, p=0.01). Notably, TP53MUT tMN cases were associated with complex karyotype relative to TP53WT tMN cases (OR 20, p<0.0001). ETV6 and EZH2MUTS were found only in pts with rtx or both, never ctx alone (p=0.05, p=0.004, respectively). In addition to increasing mutational frequency, rtx also increased the propensity for EZH2MUT to become the ancestral hit relative to pMN (OR 2.4, p=0.07) and sMN (OR 1.5, p=0.7), albeit less significantly. EZH2MUT had no influence on complex cytogenetics.In conclusion, our study demonstrates that tMN are molecularly diverse with increased frequency of specific hits including TP53, EZH2, WT1, and KITMUT. The tMN entity may be contaminated by cases with sMN with a hereditary component or spontaneous sMN, in whom molecular patterns may be distinct. However, we were unable to establish an entirely distinct molecular signature related to cytotoxic therapy. DisclosuresAdvani:Pfizer: Consultancy; Takeda/ Millenium: Research Funding. Gerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Co-crystallization with diabodies: A case study for the introduction of synthetic symmetry

This work presents a method for introducing synthetic symmetry into protein crystallization samples using an antibody fragment termed a diabody (Dab). These Dabs contain two target binding sites, and engineered disulfide bonds have been included to modulate Dab flexibility. The impacts of Dab engineering have been observed through assessment of thermal stability, small-angle X-ray scattering, and high-resolution crystal structures. Complexes between the engineered Dabs and HIV-1 reverse transcriptase (RT) bound to a high-affinity DNA aptamer were also generated to explore the capacity of engineered Dabs to enable the crystallization of bound target proteins. This strategy increased the crystallization hit frequency obtained for RT-aptamer,and the structure of a Dab-RT-aptamer complex was determined to 3.0-Å resolution. Introduction of synthetic symmetry using a Dab could be a broadly applicable strategy, especially when monoclonal antibodies for a target have previously been identified.

Analysis of Multi-Hit Crystals in Serial Synchrotron Crystallography Experiments Using High-Viscosity Injectors

Serial Synchrotron Crystallography (SSX) is rapidly emerging as a promising technique for collecting data for time-resolved structural studies or for performing room temperature micro-crystallography measurements using micro-focused beamlines. SSX is often performed using high frame rate detectors in combination with continuous sample scanning or high-viscosity or liquid jet injectors. When performed using ultra-bright X-ray Free Electron Laser (XFEL) sources serial crystallography typically involves a process known as ’diffract-and-destroy’ where each crystal is measured just once before it is destroyed by the intense XFEL pulse. In SSX, however, particularly when using high-viscosity injectors (HVIs) such as Lipidico, the crystal can be intercepted multiple times by the X-ray beam prior to exiting the interaction region. This has a number of important consequences for SSX including whether these multiple-hits can be incorporated into the data analysis or whether they need to be excluded due to the potential impact of radiation damage. Here, we investigate the occurrence and characteristics of multiple hits on single crystals using SSX with lipidico. SSX data are collected from crystals as they tumble within a high viscous stream of silicone grease flowing through a micro-focused X-ray beam. We confirmed that, using the Eiger 16M, we are able to collect up to 42 frames of data from the same single crystal prior to it leaving the X-ray interaction region. The frequency and occurrence of multiple hits may be controlled by varying the sample flow rate and X-ray beam size. Calculations of the absorbed dose confirm that these crystals are likely to undergo radiation damage but that nonetheless incorporating multiple hits into damage-free data should lead to a significant reduction in the number of crystals required for structural analysis when compared to just looking at a single diffraction pattern from each crystal.

Inversion formula for Dirichlet series and its application

A contour integration method, used to study the asymptotic of the sums of coefficients of Dirichlet series, is based on the Inversion formula. It allows you to express the sum of the coefficients in terms of the sum of the series. This approach gives effective estimates if the abscissa of absolute convergence 𝜎𝑎 > 1. In some cases, when studying arithmetical functions in generating Dirichlet series, this value is less than 1. As a rule, in this case, the Tauberian Delange theorem, which gives only the main term of asymptotic, is applied. However, generating Dirichlet series have better analytical properties than we need for the Delange theorem application. The contour integration method allows to count on precise results, but it need the inversion formula which is effective for series with 𝜎𝑎 < 1. In this paper the such inversion formula is presented and is proved to be an effective tool on examining the distribution of d(n) function values in the residue classes coprim with a module. W. Narkievicz used Delange theorem to obtain the main term of the asymptotic for frequency of hits of the values of function d(n) in residue classes. Application of the inversion formula allowed us to obtain more precise results.

High-Throughput Screening for the Discovery of Enzyme Inhibitors.

Enzymes are common targets in high-throughput screening and related campaigns. An analysis of papers published between 1990 and 2018 showed that kinases were the most common enzymes investigated, fluorescence-based assays were the most common readout method, and cancer and bacterial infections were the most common therapeutic areas. High-throughput screening and fragment-screening campaigns published between 2017 and 2019 were analyzed in more depth, giving 75 examples of hit to lead development. Kinases, phosphatases, proteases, and peptidases were the most common targets, fluorescent assays were the most commonly used, and a wide variety of structural features were observed within the derived drugs. Hit frequency was largely independent of library size and positively correlated with Z' value for the assay. Binding of metal ions to library compounds and substrates is an underappreciated source of false-positive results and unreproducible behavior.

Influencia de las variables contextuales en la intervención del portero de hockey patines en la falta directa

El objetivo del presente estudio fue analizar el efecto de las variables contextuales del partido en la intervención del portero de hockey patines durante las faltas directas. Se realizó un estudio documental basado en la Ok Liga 2015-16 y fueron analizadas todas las faltas directas (n=637). Los datos fueron recogidos de las actas de juego de la Real Federación Española de Patinaje. Se analizaron las variables contextuales: minuto de partido, estado del marcador, momento de la temporada, importancia de la falta directa y localización del partido. Se realizó un análisis correlacional mediante la prueba chi cuadrado de Pearson para identificar la relación entre las variables del estudio y la eficacia del portero. Los resultados constataron que el minuto de partido presenta una relación significativa con la eficacia del portero (χ2= 17,665; Sig.=,04; p &lt; ,05; w = ,167). un aumento de la frecuencia de faltas directas en los momentos finales, el 43,96% son lanzadas en los últimos 10 minutos de partido, y una mejora de la eficacia del portero en los momentos críticos (77,1%). Estos resultados pueden contribuir a una mejor comprensión de la importancia de los porteros en el resultado final de los partidos de hockey patines. The aim of the present study was to analyze the effect of the match’s contextual variables on the roller hockey goalkeeper intervention during free hits. A documentary study based on the Ok Liga 2015-16 was carried out and all the direct free hit of this season were analyzed (n=637). The data were collected from the playing records of the Real Federación Española de Patinaje. The contextual variables analyzed in direct free hit were: the minute of the match, score status, season time, importance of the direct free hit and match location. A correlational analysis has been performed using the Pearson's chi-squared test to identify the relationship between contextual variables and goalkeeper’s efficiency. The results show that the minute of the match has a significant relationship with the goalkeeper's efficiency (χ2= 17.665, Sig. =.04, p &lt; .05; w = .167), an increase in the frequency of direct free hit in the final moments, 43.96% are thrown in the last 10 minutes of the game, and an improvement in the goalkeeper's efficiency in critical moments (77.1%). These results can contribute to a better understanding of the goalkeepers’ importance in roller hockey matches result. O objetivo do presente estudo foi analisar o efeito das variáveis ​​contextuais do jogo na intervenção do guarda-redes de hóquei em patins nos livres diretos. Um estudo documental baseado na Ok Liga 2015-16 foi realizado e foram analisados todos os livres diretos (n = 637). Os dados foram coletados das minutas do jogo da Real Federación Española de Patinaje. Foram analisadas as variáveis ​​contextuais: minuto de jogo, estado do marcador, momento da época, importância do livre direto e localização do jogo. Foi realizada um análise correlacional pelo teste qui-quadrado de Pearson para identificar a relação entre as variáveis ​​do estudo e a eficácia do guarda-redes. Os resultados mostraram que o minuto de jogo tem relação significativa com a eficácia de guarda-redes (χ2 = 17.665, Sig = .04, p &lt; .05; w = ,167), um aumento na freqüência dos livres diretos nos momentos finais do jogo, 43.96% são marcados nos últimos 10 minutos do jogo, e uma melhora na eficácia do guarda-redes nos momentos críticos (77.1%). Esses resultados podem contribuir para uma melhor compreensão da importância dos guarda-redes no resultado final dos jogos de hóquei em patins.

Distribution of the Number of Square-Free Divisors in Residue Classes

The notion of weekly uniform distribution of arithmetical functions was introduced by W. Narckiewicz. For many functions in various papers, the problem of existence of such distribution was solved, and asymptotic formulas for frequency of hits of function values in residue classes coprime with a module were established. These asymptotic formulas contained, as a rule, only principal part of the asymptotics. A similar problem is solved in the present paper for the function which gives the number of square-free divisors of a natural number, but the asymptotic formula is the asymptotic series.

An NDN Cache Management for MEC

To enhance network performance, the named data networking architecture (NDN) caches data-packets in the network nodes on a downstream network path. Then it uses such cached requested data-packets to respond to new request-packets. Hence, a cache management scheme (CMS) is the essential point of NDN. CMS generally considers two main factors. One is a short response time and the other is storage efficiency. To rapidly respond to requests, CMS generally tries to cache data-packets near users as much as possible. To efficiently manage storage, it uses the popularity of the data. That is, proportionally to the popularity of the data, it increases the number of nodes caching data-packets and manages the lifetime of caches. However, few data objects are as popular as many users globally enjoy in the real world. Hence, if the assumptions about content- usage are practically changed, CMS can waste cache storage and not significantly improve network efficiency. We show that many caches have expired and are not used at all. To improve such inefficiency of CMS, this paper propose to simultaneously apply two cache decision factors, the expected frequency of a cache hit and the popularity of data. That is, it proposes to gradually cache transmitted data in nodes in which their expected cache-usage frequency is relatively high. To show the effectiveness of our proposal, we implement LdC (a limited domain cache policy) and evaluate the performance of LdC. The evaluation result shows that it can enhance the cache-storage efficiency by up to 65% compared with existing CMS without degrading the network efficiency.