bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thioridazine requires calcium influx to induce MLL-AF6–rearranged AML cell death
Authors: Tregnago Claudia , Da Ros Ambra , Porcù Elena , Benetton Maddalena , Simonato Manuela , Simula Luca , Borella Giulia , Polato Katia , Minuzzo Sonia , Borile Giulia , Cogo Paola , Campello Silvia , Massi Alessandro , Romagnoli Romeo , Buldini Barbara , Locatelli Franco , Pigazzi Martina 
Published: September 2020

Abstract
In pediatric acute myeloid leukemia (AML), intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the cornerstones of treatment in high-risk cases, with severe late effects and a still high risk of disease recurrence as the main drawbacks. The identification of targeted, more effective, safer drugs is thus desirable. We performed a high-throughput drug-screening assay of 1280 compounds and identified thioridazine (TDZ), a drug that was highly selective for the t(6;11)(q27;q23) MLL-AF6 (6;11)AML rearrangement, which mediates a dramatically poor (below 20%) survival rate. TDZ induced cell death and irreversible progress toward the loss of leukemia cell clonogenic capacity in vitro. Thus, we explored its mechanism of action and found a profound cytoskeletal remodeling of blast cells that led to Ca2+ influx, triggering apoptosis through mitochondrial depolarization, confirming that this latter phenomenon occurs selectively in t(6;11)AML, for which AF6 does not work as a cytoskeletal regulator, because it is sequestered into the nucleus by the fusion gene. We confirmed TDZ-mediated t(6;11)AML toxicity in vivo and enhanced the drug’s safety by developing novel TDZ analogues that exerted the same effect on leukemia reduction, but with lowered neuroleptic effects in vivo. Overall, these results refine the MLL-AF6 AML leukemogenic mechanism and suggest that the benefits of targeting it be corroborated in further clinical trials.
A novel approach for predicting protein S-glutathionylation
Authors: Anashkina Anastasia A. , Poluektov Yuri M. , Dmitriev Vladimir A. , Kuznetsov Eugene N. , Mitkevich Vladimir A. , Makarov Alexander A. , Petrushanko Irina Yu. 
Published: September 2020

Abstract
Background
S-glutathionylation is the formation of disulfide bonds between the tripeptide glutathione and cysteine residues of the protein, protecting them from irreversible oxidation and in some cases causing change in their functions. Regulatory glutathionylation of proteins is a controllable and reversible process associated with cell response to the changing redox status. Prediction of cysteine residues that undergo glutathionylation allows us to find new target proteins, which function can be altered in pathologies associated with impaired redox status. We set out to analyze this issue and create new tool for predicting S-glutathionylated cysteine residues.

Results
One hundred forty proteins with experimentally proven S-glutathionylated cysteine residues were found in the literature and the RedoxDB database. These proteins contain 1018 non-S-glutathionylated cysteines and 235 S-glutathionylated ones. Based on 235 S-glutathionylated cysteines, non-redundant positive dataset of 221 heptapeptide sequences of S-glutathionylated cysteines was made. Based on 221 heptapeptide sequences, a position-specific matrix was created by analyzing the protein sequence near the cysteine residue (three amino acid residues before and three after the cysteine). We propose the method for calculating the glutathionylation propensity score, which utilizes the position-specific matrix and a criterion for predicting glutathionylated peptides.

Conclusion
Non-S-glutathionylated sites were enriched by cysteines in − 3 and + 3 positions. The proposed prediction method demonstrates 76.6% of correct predictions of S-glutathionylated cysteines. This method can be used for detecting new glutathionylation sites, especially in proteins with an unknown structure.
Pedigree analysis of pre-breeding efforts in Trifolium spp. germplasm in New Zealand
Authors: Egan L. M. , Hofmann R. W. , Seguin P. , Ghamkhar K. , Hoyos-Villegas V. 
Published: September 2020

AbstractBackgroundPrebreeding in plants is the activity designed to identify useful characteristics from wild germplasm and its integration in breeding programs. Prebreeding aims to introduce new variation into the populations of a species of interest. Pedigree analysis is a valuable tool for evaluation of variation in genebanks where pedigree maps are used to visualize and describe population structure and variation within these populations. Margot Forde Germplasm Centre (MFGC) is New Zealand’s national forage genebank and holds a collection of ~ 75 species of the genusTrifolium, of which only a dozen have been taken through prebreeding programs. The main objective of this study was to construct pedigree maps and analyse patterns of relatedness for seven minorTrifoliumspecies accessions contained at the MFGC. These species areTrifolium ambiguum, Trifolium arvense, Trifolium dubium, Trifolium hybridum, Trifolium medium, Trifolium subterraneumand theTrifolium repensxTrifolium occidentaleinterspecific hybrids. We present a history ofTrifoliumspp. prebreeding in New Zealand and inform breeders of possible alternative forage species to use.ResultsPedigree data from accessions introduced between 1950 and 2016 were used and filtered based on breeding activity. Kinship levels amongTrifoliumspp. remained below 8% and no inbreeding was found. Influential ancestors that contributed largely to populations structure were identified. The Australian cultivar ‘Monaro’ had a strong influence over the whole population of accessions inT. ambiguum.T. subterraneumandT. repensxT. occidentalehad the largest number of generations (3).T. ambiguumandT. mediumhad the highest cumulative kinship across the decades.ConclusionsWe conclude that there are high levels of diversity in the sevenTrifoliumspp. studied. However, collection and prebreeding efforts must be strengthened to maximize utilization and bring useful genetic variation.
Benchmarking hybrid assembly approaches for genomic analyses of bacterial pathogens using Illumina and Oxford Nanopore sequencing
Authors: Chen Zhao , Erickson David L. , Meng Jianghong 
Published: September 2020

Abstract
Background
We benchmarked the hybrid assembly approaches of MaSuRCA, SPAdes, and Unicycler for bacterial pathogens using Illumina and Oxford Nanopore sequencing by determining genome completeness and accuracy, antimicrobial resistance (AMR), virulence potential, multilocus sequence typing (MLST), phylogeny, and pan genome. Ten bacterial species (10 strains) were tested for simulated reads of both mediocre- and low-quality, whereas 11 bacterial species (12 strains) were tested for real reads.

Results
Unicycler performed the best for achieving contiguous genomes, closely followed by MaSuRCA, while all SPAdes assemblies were incomplete. MaSuRCA was less tolerant of low-quality long reads than SPAdes and Unicycler. The hybrid assemblies of five antimicrobial-resistant strains with simulated reads provided consistent AMR genotypes with the reference genomes. The MaSuRCA assembly of Staphylococcus aureus with real reads contained msr(A) and tet(K), while the reference genome and SPAdes and Unicycler assemblies harbored blaZ. The AMR genotypes of the reference genomes and hybrid assemblies were consistent for the other five antimicrobial-resistant strains with real reads. The numbers of virulence genes in all hybrid assemblies were similar to those of the reference genomes, irrespective of simulated or real reads. Only one exception existed that the reference genome and hybrid assemblies of Pseudomonas aeruginosa with mediocre-quality long reads carried 241 virulence genes, whereas 184 virulence genes were identified in the hybrid assemblies of low-quality long reads. The MaSuRCA assemblies of Escherichia coli O157:H7 and Salmonella Typhimurium with mediocre-quality long reads contained 126 and 118 virulence genes, respectively, while 110 and 107 virulence genes were detected in their MaSuRCA assemblies of low-quality long reads, respectively. All approaches performed well in our MLST and phylogenetic analyses. The pan genomes of the hybrid assemblies of S. Typhimurium with mediocre-quality long reads were similar to that of the reference genome, while SPAdes and Unicycler were more tolerant of low-quality long reads than MaSuRCA for the pan-genome analysis. All approaches functioned well in the pan-genome analysis of Campylobacter jejuni with real reads.

Conclusions
Our research demonstrates the hybrid assembly pipeline of Unicycler as a superior approach for genomic analyses of bacterial pathogens using Illumina and Oxford Nanopore sequencing.
Development and clinical application of a novel CRISPR-Cas12a based assay for the detection of African swine fever virus
Authors: Wang Xiaoying , He Sheng , Zhao Na , Liu Xiaohong , Cao Yongchang , Zhang Guihong , Wang Gang , Guo Chunhe 
Published: September 2020

Abstract
Background
As no treatment or effective vaccine for African swine fever virus (ASFV) is currently available, a rapid, highly sensitive diagnostic is urgently needed to curb the spread of ASFV.

Results
Here we designed a novel CRISPR-Cas12a based assay for ASFV detection. To detect different ASFV genotypes, 19 crRNAs were designed to target the conserved p72 gene in ASFV, and several crRNAs with high activity were identified that could be used as alternatives in the event of new ASFV variants. The results showed that the sensitivity of the CRISPR-Cas12a based assay is about ten times higher than either the commercial quantitative PCR (qPCR) kit or the OIE-recommended qPCR. CRISPR-Cas12a based assay could also detect ASFV specifically without cross-reactivity with other important viruses in pigs and various virus genotypes. We also found that longer incubation times increased the detection limits, which could be applied to improve assay outcomes in the detection of weakly positive samples and new ASFV variants. In addition, both the CRISPR-Cas12a based assay and commercial qPCR showed very good consistency.

Conclusions
In summary, the CRISPR-Cas12a based assay offers a feasible approach and a new diagnostic technique for the diagnosis of ASFV, particularly in resource-poor settings.
Dynamic needle tip positioning versus the angle-distance technique for ultrasound-guided radial artery cannulation in adults: a randomized controlled trial
Authors: Bai Bing , Tian Yuan , Zhang Yuelun , Yu Chunhua , Huang Yuguang 
Published: September 2020

Abstract
Background
Ultrasound guidance can increase the success rate and reduce the incidence of complications of arterial cannulation. There are few studies on the utility of the dynamic needle tip positioning (DNTP) technique versus the angle-distance (AD) technique for ultrasound-guided radial arterial cannulation in adult surgical patients. We assessed and compared the success rates and incidences of complications of these two short-axis out-of-plane techniques.

Methods
A total of 131 adult surgical patients were randomized into DNTP and AD groups to undergo ultrasound-guided radial artery cannulation. The primary outcome was first-pass success without posterior wall puncture. The secondary outcomes included the first-pass success rate, 10-min overall success rate, cannulation time, posterior wall puncture, and the number of skin punctures.

Results
The first-pass success rates without posterior wall puncture were 53.8% in the DNTP group and 44.6% in the AD group (RR = 1.22, 95% CI: 0.86–1.72; P = 0.26). The cannulation time was significantly longer (P = 0.01) in the DNTP group [79.65 (54.3–109.4) seconds] than in the AD group [47.6 (24.9–103.8) seconds]. The posterior wall puncture rate was significantly lower (P = 0.002) in the DNTP group (29.2%) than in the AD group (56.1%; RR = 0.56, 95% CI: 0.42–0.82).

Conclusions
There were no significant differences in the first-pass success rate, with or without arterial posterior wall puncture, or in the 10-min overall success rate between the DNTP and AD groups. However, the cannulation time was longer and the posterior wall puncture rate was lower in the DNTP group.

Trial registration
The trial was registered at www.clinicaltrials.gov (No: NCT03656978). Registered 4 September 2018.
Electrocardiographic findings of methanol toxicity: a cross-sectional study of 356 cases in Iran
Authors: Nikoo Mohammad Hossein , Arjangzadeh Alireza , Pakfetrat Maryam , Boogar Shahrokh Sadeghi , Mohammadkarimi Vahid , Ostovan Vahid Reza , Khodamoradi Zohre , Roozbeh Jamshid , Khalili Mohammadreza , Shirazi Farnaz Kamali Haghighi , Kouhi Paryia , Heydari Seyed Taghi 
Published: September 2020

Abstract
Background
Methanol is widely used in industry; however, methanol poisoning is not common. In this regard, a number of outbreaks have been recently reported due to inappropriate processing of alcoholic beverages. Shiraz, a city located in the southern part of Iran, faced one of such outbreaks in 2020 during COVID-19 pandemic. There is no sufficient literature on the electrocardiographic findings in methanol toxicity. This study aimed to address this gap in the literature.

Method
A total of 356 cases with methanol toxicity referred to Shiraz University of Medical Science Tertiary Hospitals (Faghihi and Namazi) in March and April, 2020. The clinical findings of blindness and impaired level of consciousness, lab data such as arterial blood gas, electrolytes, and creatinine, and the most common findings from ECGs were collected.

Results
The most common ECG findings were J point elevation (68.8%), presence of U wave (59.2%), QTc prolongation (53.2% in males and 28.6% in females), and fragmented QRS (33.7%). An outstanding finding in this study was the presence of myocardial infarction in 5.3% of the cases. This finding, to the best of our knowledge, has only been reported in a few case reports. Brugada pattern (8.1%) and Osborn wave (3.7%) were the other interesting findings.
In multivariate analysis, when confounding factors were adjusted, myocardial infarction, atrioventricular conduction disturbances, sinus tachycardia, and the prolonged QTC > 500 msecond were four independent factors correlated with methanol toxicity severity measured with arterial blood PH on arterial blood gas measurements, with odds ratios of 12.82, 4.46, 2.32 and 3.15 (P < 0.05 for all), respectively.

Conclusion
Electrocardiographic variations during methanol intoxication are remarkable and well-correlated with poisoning severity. Myocardial infarction was an egregious and yet a common concerning finding in this sample, which need to be ruled out in methanol toxicity.
How does multimorbidity affect middle-aged adults? A cross-sectional survey in the Singapore primary healthcare setting
Authors: Sim Sai Zhen , Koh Hui Li , Lee Sabrina Poay Sian , Young Doris Yee Ling , Lee Eng Sing 
Published: September 2020

AbstractBackgroundMultimorbidity is of increasing prevalence and importance. It has been associated with poorer health-related quality of life (HrQoL) especially in the elderly population. Despite substantial multimorbidity in the middle-aged population, defined as those aged between 40-64 years old, there is a paucity of research investigating the impact of multimorbidity in this population. This study aimed to investigate the association between multimorbidity and HrQoL in the middle-aged primary care population in Singapore.MethodsA cross-sectional study was conducted at a primary care centre in Singapore. Interviewer-administered questionnaires were used to collect data regarding the participants’ sociodemographic characteristics, chronic conditions, and HrQoL, as measured by the EuroQol five dimensions 3-levels questionnaire (EQ5D). We defined multimorbidity as the presence of three or more conditions, out of a list of 14 chronic conditions. The associations between multimorbidity and the components of the EQ5D were assessed using multivariable regression analyses.ResultsThe study included 297 participants, aged 40–64 years, of which 124 (41.7%) had multimorbidity. After adjusting for sociodemographic factors, participants with multimorbidity had significantly lower EQ5D UI, (β-coefficient − 0.064 (C.I -0.125, − 0.003),p = 0.04), but not significantly lower EQ5D VAS, (β-coefficient − 0.045 (C.I 0.102, 0.012),p = 0.12). Additionally, participants with multimorbidity had higher odds (OR = 2.41,p = 0.01) of reporting problems due to pain/discomfort.ConclusionMultimorbidity was not significantly associated with the overall health state, as measured by the EQ5D VAS, in middle-aged primary care patients. However, it was associated with the EQ5D UI which is a composite measure of five specific domains of HrQoL. Specifically, there was a statistically significant association between multimorbidity and the pain domain. Further studies are required to understand the relationship between multimorbidity and pain to enable physicians to better manage pain and HrQoL in this population.
Epidemiology of gastroesophageal reflux disease in Iran: a systematic review and meta-analysis
Authors: Karimian Mohammad , Nourmohammadi Hassan , Salamati Majid , Hafezi Ahmadi Mohammad Reza , Kazemi Fatemeh , Azami Milad 
Published: September 2020

AbstractBackgroundGastroesophageal reflux disease (GERD), which leads to acid reflux into the esophagus, is a common gastrointestinal disorder. Several studies have shown the prevalence of GERD in Iranian population, but their evidence is contradictory. Therefore, the present study was conducted to investigate the epidemiology of GERD in Iran.MethodsThe entire steps of this systematic review and meta-analysis were based on the MOOSE protocol, and the results were reported accordance with the PRISMA guideline. This review is registered on PROSPERO (registration number: CRD42020142861). To find potentially relevant published articles, comprehensive search was done on international online databases Scopus, Science Direct, EMBASE, PubMed/Medline, CINAHL, EBSCO, Cochrane Library, Web of Science, Iranian online databases and the Google Scholar search engine in June 2019. Cochran test and I2index were used to assess the heterogeneity of the studies. Data were analyzed using Comprehensive Meta-Analysis software ver. 2. The significance level of the test was considered to beP <  0.05.ResultsThe daily, weekly, monthly, and overall prevalence of GERD symptoms in Iranian population was 5.64% (95%CI [confidence interval]: 3.77–8.35%;N = 66,398), 12.50% (95%CI: 9.63–16.08%;N = 110,388), 18.62% (95%CI: 12.90–26.12%;N = 70,749) and 43.07% (95%CI: 35.00–51.53%;N = 73,189), respectively. The daily, weekly, monthly, and overall prevalence of heartburn in Iranian population was 2.46% (95%CI: 0.93–6.39%;N = 18,774), 9.52% (95%CI: 6.16–14.41%;N = 54,125), 8.19% (95%CI: 2.42–24.30%;N = 19,363) and 23.20% (95%CI: 13.56–36.79%;N = 26,543), respectively. The daily, weekly, monthly, and overall prevalence of regurgitation in Iranian population was 4.00% (95%CI: 1.88–8.32%;N = 18,774), 9.79% (95%CI: 5.99–15.60%;N = 41,140), 13.76% (95%CI: 6.18–44.31%;N = 19,363) and 36.53% (95%CI: 19.30–58.08%;N = 21,174), respectively. The sensitivity analysis for prevalence of all types GERD, heartburn and regurgitation symptoms by removing a study showed that the overall estimate is still robust.ConclusionThe present meta-analysis provides comprehensive and useful information on the epidemiology of GERD in Iran for policy-makers and health care providers. This study showed a high prevalence of GERD in Iran. Therefore, effective measures on GERD-related factors such as lifestyle can be among the health policies of Iran.
Clinicopathological study of mixed cryoglobulinemic glomerulonephritis secondary to hepatitis B virus infection
Authors: Li Chao , Li Hang , Su Wei , Wen Yu-bing , Ye Wei , Ye Wen-ling , Cai Jian-fang , Qin Xu-zhen , Li Xue-mei , Li Xue-wang 
Published: September 2020

Abstract
Background
Cryoglobulinemic glomerulonephritis (CryoGn) caused by hepatitis B virus (HBV) infection was rarely reported. Our study aimed to investigate the clinical features, renal pathology findings, and prognosis in patients with HBV related CryoGn.

Methods
This was a retrospective study including seven Chinese patients with HBV related CryoGn in a tertiary referral hospital from April 2016 to March 2019. The clinical and pathological data were collected and analyzed.

Results
Age at renal biopsy was 47 ± 12 years, with female/male ratio 3/4. Urine protein was 5.6 (3.0, 6.6) g/d and five cases presented with nephrotic syndrome. The baseline eGFR was 23.5 (20.2, 46.3) ml/min per 1.73m2. The extrarenal manifestations included purpura (n = 6), arthralgia (n = 1), peripheral neuropathy (n = 1), and cardiomyopathy (n = 1). Six cases had type II cryoglobulinemia with IgMκ, the other one had type III. The median cryocrit was 4.0 (1.0, 15.0) %. Renal pathologic findings on light microscopy: endocapillary proliferative glomerulonephritis (Gn) (n = 3), membranoproliferative Gn (n = 3), and mesangial proliferative Gn (n = 1). On immunofluorescence microscopy, the predominant type of immunoglobulin deposits was IgM (n = 5). HBsAg and HBcAg deposits were found in one case. Ultrastructural studies showed granular subendothelial and mesangial electron-dense deposits in all patients and microtubules in one case. All patients received antiviral medications. They were given corticosteroid alone (n = 2) or combined with cyclophosphamide (n = 4) or mycophenolate mofetil (n = 1). Two patients received plasmapheresis. The median follow-up time was 18 (6, 37) months. Four patients got remission, two patients died of pneumonia, and one progressed to end-stage renal disease (ESRD). At endpoint of follow-up, 24hUP was 2.1 (0.8–5.2) g/d, and eGFR was 55.3 (20.7, 111.8) ml/min per 1.73m2. The median cryocrit decreased to 1.0 (0, 5.75) %.

Conclusions
The etiology of mixed CryoGn should be screened for HBV infection. Endocapillary proliferative Gn and membranoproliferative Gn were the common pathologic patterns. Diagnosis and treatment in early stage benefit patients’ renal outcomes. Immunosuppressive therapy should be considered for severe renal disease, based on efficient antiviral therapy.