bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms
Authors: Taylor Justin , Mi Xiaoli , North Khrystyna , Binder Moritz , Penson Alexander , Lasho Terra , Knorr Katherine , Haddadin Michael , Liu Bo , Pangallo Joseph , Benbarche Salima , Wiseman Daniel , Tefferi Ayalew , Halene Stephanie , Liang Yang , Patnaik Mrinal M. , Bradley Robert K. , Abdel-Wahab Omar 
Published: July 2020

Abstract
Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q &lt; .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, ∼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.
Expression of Nras
Q61R and MYC transgene in germinal center B cells induces a highly malignant multiple myeloma in mice
Authors: Wen Zhi , Rajagopalan Adhithi , Flietner Evan D. , Yun Grant , Chesi Marta , Furumo Quinlan , Burns Robert T. , Papadas Athanasios , Ranheim Erik A. , Pagenkopf Adam C. , Morrow Zachary T. , Finn Remington , Zhou Yun , Li Shuyi , You Xiaona , Jensen Jeffrey , Yu Mei , Cicala Alexander , Menting James , Mitsiades Constantine S. , Callander Natalie S. , Bergsagel P. Leif , Wang Demin , Asimakopoulos Fotis , Zhang Jing 
Published: July 2020

Abstract
NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and an MYC transgene in germinal center (GC) B cells (VQ mice). VQ mice developed a highly malignant MM characterized by a high proliferation index, hyperactivation of extracellular signal-regulated kinase and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved programmed cell death protein 1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain immune-checkpoint pathways, and expression of human high-risk MM gene signatures. VQ MM mice recapitulate most of the biological and clinical features of human advanced/high-risk MM. These MM phenotypes are serially transplantable in syngeneic recipients. Two MM cell lines were also derived to facilitate future genetic manipulations. Combination therapies based on MEK inhibition significantly prolonged the survival of VQ mice with advanced-stage MM. Our study provides a strong rationale to develop MEK inhibition–based therapies for treating advanced/relapsed MM.
Investigating the effects of rehabilitation and the use of curved-integrated members on the behavior of chairs
Authors: Hosseini-Tabatabaei Mahmoud-Reza , Bayatkashkoli Ali , Mollaeinia Mahmoud Reza , Kool Farhad , Rahmani Ardakani Mohsen , Madahi Narjes Khaton 
Published: July 2020

AbstractExpanding the service life length of wooden made furniture, and consequently decreasing the demand for raw wood could help the economy of the world society and environmental safety. In this research, an experimental inquiry was conducted to determine the effects of curved members, the frame integrity, chair scheme, and rehabilitation of even the failed chairs on the behavior of chairs. The flexural properties of the curved specimens were firstly determined using the ASTM D143-94 test. Then, three layouts of chairs (A, B, and C) made from poplar wood were examined under the DIN EN-1729-1&2 standard. Finally, the failed chairs were rehabilitated using the sheets of glass fiber-reinforcing polymers (GFRP) and re-tested. The results showed that the rehabilitation of the curved samples causes rebounding of their mechanical properties. Besides, the rehabilitated samples are more flexible than primary ones. Furthermore, the results demonstrate that the capability of the proposed normalized modulus of rupture (NMOR) criterion, in contrast to the current modulus of rupture (MOR) one, for predicting the failure modes and regions of the wooden and composite structures. The experiments on the chairs showed that all rehabilitated patterns are more robust than primary schemes. That means, the discarded (or discarding) chairs (due to failure of joints, legs, or, in general, a part of the chairs) return to their service life, and massively reduce the demand for wood, which is strongly favored by environmental aspects. Moreover, rehabilitated layout B (RB), which has two continuous-main-curved members is at least 2.4 times stronger than other rehabilitated patterns, and rehabilitated layout C (RC) having three continuous-main-curved members is about 40% stronger than a rehabilitated custom chair (RA), that illustrates more integrity and strength. Besides that, the strength of RB is 2.22 and 2.04 times that of the corresponding primary chairs, depending on front-to-back and up-to-down loading, respectively. Finally, univariate analyses of variance and least significant difference (LSD) showed the high precision of the results. Consequently, the research provides a facility not only to save original material resources, but also to eliminate furniture waste going in the landfill.
Neuropeptide FF receptor 2 inhibits capsaicin-induced CGRP Upregulation in mouse trigeminal ganglion
Authors: Lin Ya-Tin , Yu Zachary , Tsai Sze-Chi , Hsu Po-Hung , Chen Jin-Chung 
Published: July 2020

Abstract
Background
Stimulation of trigeminovascular pathway is widely used to establish the headache animal model. Headache is a common neurological disorder, in which symptomatic attacks are mediated by calcitonin-gene-related peptide (CGRP). CGRP is synthesized and released from the trigeminal ganglion to transmit pain signals under stimulation. On the other hand, Neuropeptide FF (NPFF) is a candidate transmitter/modulator for migraine, and stimulation of its receptor, NPFFR2, increases the expression and release of CGRP in mice sensory neurons. Here, we investigate the impact of NPFFR2 on trigeminal CGRP level in a capsaicin-induced headache mouse model.

Methods
Mice were intracisternally injected with capsaicin into the cisterna magna to activate the trigeminovascular pathway and induce headache symptoms. Mice pretreated with Npffr2-shRNA or NPFFR2 knockouts were adopted to test the impact of NPFFR2 on capsaicin-induced CGRP upregulation in trigeminal ganglion. The gene silencing effect of Npffr2-shRNA in trigeminal ganglion was confirmed by real-time PCR. Trigeminal CGRP level was determined by immunofluorescence staining, and the percentage of CGRP-positive cell was calculated after setting the signal intensity threshold by Image J software. Amount of trigeminal CGRP in NPFFR2 overexpressed mice was also measured by CGRP ELISA.

Findings
Infusion of capsaicin into the cisterna magna upregulated the CGRP in trigeminal ganglion and induced spontaneous pain behaviors including the reduction of locomotor activity and the increase of freezing behavior. Intracisternal injection of Npffr2-shRNA reduced the mRNA of Npffr2 in trigeminal ganglion. Mice pretreatment with Npffr2-shRNA prevented capsaicin-induced CGRP upregulation in trigeminal ganglion. Similarly, CGRP upregulation was also reduced in NPFFR2 knockout mice. On the contrary, trigeminal CGRP was increased in NPFFR2 overexpressed mice.

Conclusions
Reducing the level of NPFFR2 leads to the downregulation of capsaicin-induced CGRP in trigeminal ganglion, which would consequently attenuate the activation of trigeminovascular pathway. Thus, NPFFR2 could serve as a potential target for neuromodulation of cephalic pain.
Degradation of key photosynthetic genes in the critically endangered semi-aquatic flowering plant Saniculiphyllum guangxiense (Saxifragaceae)
Authors: Folk Ryan A. , Sewnath Neeka , Xiang Chun-Lei , Sinn Brandon T. , Guralnick Robert P. 
Published: July 2020

Abstract
Background
Plastid gene loss and pseudogenization has been widely documented in parasitic and mycoheterotrophic plants, which have relaxed selective constraints on photosynthetic function. More enigmatic are sporadic reports of pseudogenization and loss of important photosynthesis genes in lineages thought to be fully photosynthetic. Here we report the complete plastid genome of Saniculiphyllum guangxiense, a critically endangered and phylogenetically isolated plant lineage, along with genomic evidence of reduced chloroplast function. We also report 22 additional plastid genomes representing the diversity of its containing clade Saxifragales, characterizing gene content and placing variation in a broader phylogenetic context.

Results
We find that the plastid genome of Saniculiphyllum has experienced pseudogenization of five genes of the ndh complex (ndhA, ndhB, ndhD, ndhF, and ndhK), previously reported in flowering plants with an aquatic habit, as well as the surprising pseudogenization of two genes more central to photosynthesis (ccsA and cemA), contrasting with strong phylogenetic conservatism of plastid gene content in all other sampled Saxifragales. These genes participate in photooxidative protection, cytochrome synthesis, and carbon uptake. Nuclear paralogs exist for all seven plastid pseudogenes, yet these are also unlikely to be functional.

Conclusions
Saniculiphyllum appears to represent the greatest degree of plastid gene loss observed to date in any fully photosynthetic lineage, perhaps related to its extreme habitat specialization, yet plastid genome length, structure, and substitution rate are within the variation previously reported for photosynthetic plants. These results highlight the increasingly appreciated dynamism of plastid genomes, otherwise highly conserved across a billion years of green plant evolution, in plants with highly specialized life history traits.
Multivariate network meta-analysis incorporating class effects
Authors: Owen Rhiannon K. , Bujkiewicz Sylwia , Tincello Douglas G. , Abrams Keith R. 
Published: July 2020

Abstract
Background
Network meta-analysis synthesises data from a number of clinical trials in order to assess the comparative efficacy of multiple healthcare interventions in similar patient populations. In situations where clinical trial data are heterogeneously reported i.e. data are missing for one or more outcomes of interest, synthesising such data can lead to disconnected networks of evidence, increased uncertainty, and potentially biased estimates which can have severe implications for decision-making. To overcome this issue, strength can be borrowed between outcomes of interest in multivariate network meta-analyses. Furthermore, in situations where there are relatively few trials informing each treatment comparison, there is a potential issue with the sparsity of data in the treatment networks, which can lead to substantial parameter uncertainty. A multivariate network meta-analysis approach can be further extended to borrow strength between interventions of the same class using hierarchical models.

Methods
We extend the trivariate network meta-analysis model to incorporate the exchangeability between treatment effects belonging to the same class of intervention to increase precision in treatment effect estimates. We further incorporate a missing data framework to estimate uncertainty in trials that did not report measures of variability in order to maximise the use of all available information for healthcare decision-making. The methods are applied to a motivating dataset in overactive bladder syndrome. The outcomes of interest were mean change from baseline in incontinence, voiding and urgency episodes. All models were fitted using Bayesian Markov Chain Monte Carlo (MCMC) methods in WinBUGS.

Results
All models (univariate, multivariate, and multivariate models incorporating class effects) produced similar point estimates for all treatment effects. Incorporating class effects in multivariate models often increased precision in treatment effect estimates.

Conclusions
Multivariate network meta-analysis incorporating class effects allowed for the comparison of all interventions across all outcome measures to ameliorate the potential impact of outcome reporting bias, and further borrowed strength between interventions belonging to the same class of treatment to increase the precision in treatment effect estimates for healthcare policy and decision-making.
Multiple imputation with missing indicators as proxies for unmeasured variables: simulation study
Authors: Sperrin Matthew , Martin Glen P. 
Published: July 2020

Abstract
Background
Within routinely collected health data, missing data for an individual might provide useful information in itself. This occurs, for example, in the case of electronic health records, where the presence or absence of data is informative. While the naive use of missing indicators to try to exploit such information can introduce bias, its use in conjunction with multiple imputation may unlock the potential value of missingness to reduce bias in causal effect estimation, particularly in missing not at random scenarios and where missingness might be associated with unmeasured confounders.

Methods
We conducted a simulation study to determine when the use of a missing indicator, combined with multiple imputation, would reduce bias for causal effect estimation, under a range of scenarios including unmeasured variables, missing not at random, and missing at random mechanisms. We use directed acyclic graphs and structural models to elucidate a variety of causal structures of interest. We handled missing data using complete case analysis, and multiple imputation with and without missing indicator terms.

Results
We find that multiple imputation combined with a missing indicator gives minimal bias for causal effect estimation in most scenarios. In particular the approach: 1) does not introduce bias in missing (completely) at random scenarios; 2) reduces bias in missing not at random scenarios where the missing mechanism depends on the missing variable itself; and 3) may reduce or increase bias when unmeasured confounding is present.

Conclusion
In the presence of missing data, careful use of missing indicators, combined with multiple imputation, can improve causal effect estimation when missingness is informative, and is not detrimental when missingness is at random.
Optimisation of medications used in residential aged care facilities: a systematic review and meta-analysis of randomised controlled trials
Authors: Almutairi Hend , Stafford Andrew , Etherton-Beer Christopher , Flicker Leon 
Published: July 2020

Abstract
Background
Frail older adults living in residential aged care facilities (RACFs) usually experience comorbidities and are frequently prescribed multiple medications. This increases the potential risk of inappropriate prescribing and its negative consequences. Thus, optimising prescribed medications in RACFs is a challenge for healthcare providers.

Objective
Our aim was to systematically review interventions that increase the appropriateness of medications used in RACFs and the outcomes of these interventions.

Methods
Systematic review and meta-analysis of randomised control trials (RCTs) and cluster randomised control trials (cRCTs) were performed by searching specified databases (MEDLINE, PubMed, Google scholar, PsycINFO) for publications from inception to May 2019 based on defined inclusion criteria. Data were extracted, study quality was assessed and statistically analysed using RevMan v5.3. Medication appropriateness, hospital admissions, mortality, falls, quality of life (QoL), Behavioural and Psychological Symptoms of Dementia (BPSD), adverse drug events (ADEs) and cognitive function could be meta-analysed.

Results
A total of 25 RCTs and cRCTs comprising 19,576 participants met the inclusion criteria. The studies tested various interventions including medication review (n = 13), staff education (n = 9), multi-disciplinary case conferencing (n = 4) and computerised clinical decision support systems (n = 2). There was an effect of interventions on medication appropriateness (RR 0.71; 95% confidence interval (CI): 0.60,0.84) (10 studies), and on medication appropriateness scales (standardised mean difference = − 0.67; 95% CI: − 0.97, − 0.36) (2 studies). There were no apparent effects on hospital admission (RR 1.00; 95% CI: 0.93, 1.06), mortality (RR 0.98; 95% CI: 0.86, 1.11), falls (RR 1.06; 95% CI: 0.89,1.26), ADEs (RR 1.04; 95% CI: 0.96,1.13), QoL (standardised mean difference = 0.16; 95% CI:-0.13, 0.45), cognitive function (weighted mean difference = 0.69; 95% CI: − 1.25, 2.64) and BPSD (RR 0.68; 95% CI: 0.44,1.06) (2 studies).

Conclusion
Modest improvements in medication appropriateness were observed in the studies included in this systematic review. However, the effect on clinical measures was limited to drive strong conclusions.
Tolerability and safety of urotainer® polihexanide 0.02% in catheterized patients: a prospective cohort study
Authors: Pannek Jürgen , Everaert Karel , Möhr Sandra , Vance Will , Van der Aa Frank , Kesselring Jürg 
Published: July 2020

Abstract
Background
In patients with indwelling bladder catheters for > 2 weeks, bacterial colonization is inevitable, leading to urinary tract infections or encrustations with subsequent catheter blockage. Currently, bladder irrigations are the most frequently used prophylactic means, but the best solution remains yet to be determined. In vitro studies demonstrate that polihexanide is a promising option for catheter irrigation, but no data about safety and tolerability exist.

Methods
In a prospective observational study in patients with indwelling bladder catheter for > 2 weeks, a 0.02% polihexanide solution was used to rinse the catheter on five consecutive days. Adverse events, tolerability and vital signs were assessed before, during, after and at the end of the treatment period.

Results
There was no serious adverse event in the study. A total of 28 adverse events (AEs) in 15 (46.88%) participants were experienced. Absolute changes in pain scores were not clinically relevant. No incidences of either flushing or sweating were found during instillation. Bladder spasms during instillation were reported in two cases during a single instillation. Mean pulse rates did not change by more than 3 beats per minute. Mean changes in body temperature did not exceed 0.12 °C. Clinically relevant changes in blood pressure were recorded for 3 patients.

Conclusions
This is the first study to demonstrate that a 0.02% polihexanide solution can safely be used for catheter irrigation.

Trial registration
ClinicalTrials.gov (NCT02157415), June 6th, 2014.
Community-based rehabilitation service in Chengdu, Southwest China: a cross-sectional general survey
Authors: Chen Siliang , Lei Yi , Dai Hua , Wu Jia , Yang Ziyu , Liao Xiaoyang 
Published: July 2020

Abstract
Background
World Health Organization initiated community-based rehabilitation (CBR) in 1978, and by now, it has been an essential process of medical services worldwide. China had strengthened primary health care on building more than 35,000 community health centers (CHCs) in cities, and more than 34,000 township health centers (THCs) in the rural area. Nevertheless, it remains unclear that if these primary health centers could provide optional rehabilitation services for disabilities. And this study aims at evaluating the supply capacity of rehabilitation service in primary health centers of Chengdu, a regional center city of southwest China.

Method
We conducted a general investigation of primary health centers in Chengdu, a city located in southwest China with more than 15 million population. Our investigation covered all of Chengdu’s 390 primary health centers from October to November 2016. We researched these primary health centers on basic rehabilitation services, diseases, and rehabilitation equipment quantity and quality, and traditional Chinese medicine (TCM) physiotherapy.

Result
Rehabilitation therapy is available in 88.9% (337 of 379) of all primary health centers. Meanwhile, CHCs slightly surpass THCs with an available rate of 92.2% (106 of 115) and 87.5% (231 of 264), respectively. Traditional Chinese Medicine (TCM) physiotherapy is available in 97.1% (368 of 379) of all primary health centers, 97.3% (112 of 115) of CHCs and 97.0% (256 of 264) of THCs. Quantitative analysis showed that substantial factors which could make an impact on the number of patients per year contain: categories of rehabilitation disease (P < 0.001, 95% confidence interval (CI) [− 1.571, − 0.702]),number of rehabilitation bed (P < 0.001, 95%CI [− 1.249, − 0.290]).

Conclusion
CBR and TCM physiotherapy has become accessible for disabilities in most basic health centers of Chengdu City, whereas, available rate of CBR in THCs is lesser than in CHCs, which suggests an imbalance in primary health service development between rural and urban area. Categories of rehabilitation diseases, and the number of rehabilitation beds constitute co-factors that make an impact on the CBR capacity of basic health centers.
Genome-wide identification of methylated CpG sites in nongenital cutaneous warts
Authors: AL-Eitan Laith N. , Alghamdi Mansour A. , Tarkhan Amneh H. , Al-Qarqaz Firas A. 
Published: July 2020

AbstractBackgroundLow-risk HPV infection has not been the subject of epigenetic investigation. The present study was carried out in order to investigate the methylation status of CpG sites in non-genital cutaneous warts.MethodsGenomic DNA was extracted from 24 paired epidermal samples of warts and normal skin. DNA samples were bisulfite converted and underwent genome-wide methylation profiling using the Infinium MethylationEPIC BeadChip Kit.ResultsFrom a total of 844,234 CpG sites, 56,960 and 43,040 CpG sites were found to be hypo- and hypermethylated, respectively, in non-genital cutaneous warts. The most differentially methylated CpG sites in warts were located within theC10orf26,FAM83H-AS1,ZNF644,LINC00702,GSAP,STAT5A,HDAC4,NCALD, andEXOC4genes.ConclusionNon-genital cutaneous warts exhibit a unique CpG methylation signature.