bluuebunny/crossref_metadata_2025_split huggingface dataset:
An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML
Authors: Lin Shan , Larrue Clément , Scheidegger Nastassja K. , Seong Bo Kyung A. , Dharia Neekesh V. , Kuljanin Miljan , Wechsler Caroline S. , Kugener Guillaume , Robichaud Amanda L. , Conway Amy Saur , Mashaka Thelma , Mouche Sarah , Adane Biniam , Ryan Jeremy A. , Mancias Joseph D. , Younger Scott T. , Piccioni Federica , Lee Lynn H. , Wunderlich Mark , Letai Anthony , Tamburini Jérôme , Stegmaier Kimberly 
Published: September 2021

Abstract

CRISPR–Cas9-based genetic screens have successfully identified cell type–dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets.

Significance:
There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.
This article is highlighted in the In This Issue feature, p. 275
The developmental variations of the sagitta otolith in the young and mature male of a hermaphrodite polynemidae fish, Eleutheronema tetradactylum (Shaw, 1804)
Authors: Roy Soumen , Bardhan Itika 
Published: September 2021

The Eleutheronema tetradactylum is a protandrous, hermaphrodite, marine perciformes fish. The body length of this fish acts as an important diagnostic marker for male and female discrimination. The present study describes for the first time the ultrastructural characteristics on the medial surface of the sagitta otolith in different body size groups of males of E. tetradactylum (Polynemidae: Perciformes) using scanning electron microscopy. The sagitta is a spindle-shaped structure that includes a well-developed rostrum and a poorly developed antirostrum. The sulcus is ostio-pseudocaudal type, almost straight and devoid of the collum. The ostium is a well-developed, vase-shaped structure. The cauda includes the colliculum and a well-developed caudal bulb with several distinct growth stripes. The length of the caudal bulb is significantly correlated to the growth of the body size of the fish. The excisura major is indistinct and the excisura minor is absent. The cristae are distinct on both sides of the sulcus. The one-way ANOVA test revealed that the development of several sagitta features shows significant differences in various body size groups of E. tetradactylum. The growth of the sagitta length is more closely related to the fork length than the sagitta width. Therefore, the sagitta length and the caudal bulb length can be used as important predictors to evaluate the fish size. The cauda region of the sagitta in E. tetradactylum is unique as well as more decorative than those of another Polynemidae fish and other hermaphrodite, marine perciformes fishes. The sagitta characteristics of E. tetradactylum might be advantageous in the identification of the sex and the taxonomy of the hermaphrodite fish species.
Efficient Correction of a Hypertrophic Cardiomyopathy Mutation by ABEmax-NG
Authors: Ma Shuhong , Jiang Wenjian , Liu Xujie , Lu Wen-Jing , Qi Tao , Wei Jingjing , Wu Fujian , Chang Yun , Zhang Siyao , Song Yabing , Bai Rui , Wang Jianbing , Lee Andrew S. , Zhang Hongjia , Wang Yongming , Lan Feng 
Published: September 2021

Rationale:
Genetic editing has shown great potential for the treatment of human hereditary disorders via the elimination of mutations in embryos. However, the efficiency and safety of germline gene editing are not well understood.

Objective:
We aimed to examine the preclinical efficacy/safety of embryonic base editing in a mouse model of hypertrophic cardiomyopathy (HCM) using a novel adenine base editor (ABE) platform.

Methods and Results:

Here, we described the use of an ABEmax-NG to directly correct the pathogenic R404Q/+ mutation (
Myh6
c.1211C>T) in embryos for a mouse model of HCM, increasing the number of wild-type embryos for in vitro fertilization. Delivery of the ABEmax-NG mRNA to embryos from R404Q/+ HCM mice resulted in 62.5% to 70.8% correction of the
Myh6
c.1211C>T, reducing the level of mutant RNA and eliminating HCM in the postnatal mice as well as their offspring. In addition, the same single guide RNA was also used to target an intronic locus (chr2: +36,585,842) with an overall editing rate of 86.7%, thus confirming that ABEmax-NG can efficiently edit target loci with different protospacer adjacent motifs (PAM) and genomic distribution in vivo. Compared with CRISPR/single-stranded oligodeoxynucleotides–mediated correction, ABEmax-NG displayed a much higher correction rate without introducing indels. DNA and RNA off-target analysis did not detect off-target editing in treated embryos and founder mice. In utero injection of adeno-associated virus 9 encoding the ABEmax-NG also resulted in around 25.3% correction of the pathogenic mutation and reduced of mutant RNA, thereby indicating ABEmax-NG has the potential to correct the HCM mutation in vivo.

Conclusions:

We developed an ABEmax-NG system, which efficiently corrected a pathogenic
Myh6
HCM mutation in mouse embryos without off-target lesions, thus safely eliminating HCM in derived mice and their progeny.
Reporting of Results by Sex in Randomized Controlled Trials of Acute Stroke Therapies (2010–2020)
Authors: Pudar Julia , Strong Brent , Howard Virginia J. , Reeves Mathew J. 
Published: September 2021

Background and Purpose:
When reporting primary results from randomized controlled trials, recommendations include reporting results by sex. We reviewed the reporting of results by sex in contemporary acute stroke randomized controlled trials.

Methods:
We searched MEDLINE for articles reporting the primary results of phase 2 or 3 stroke randomized controlled trials published between 2010 and June 2020 in one of nine major clinical journals. Eligible trials were restricted to those with a therapeutic intervention initiated within one month of stroke onset. Of primary interest was the reporting of results by sex for the primary outcome. We performed bivariate analyses using Fisher exact tests to identify study-level factors associated with reporting by sex and investigated temporal trends using an exact test for trend.

Results:

Of the 115 studies identified, primary results were reported by sex in 37% (n=42). Reporting varied significantly by journal, with the
New England Journal of Medicine
(61%) and
Lancet
journals (40%) having the highest rates (
P
=0.03). Reporting also differed significantly by geographic region (21% Europe versus 48% Americas,
P
=0.03), trial phase (13% phase 2 versus 40% phase 3,
P
=0.05), and sample size (24% <250 participants versus 61% >750 participants,
P
<0.01). Although not statistically significant (
P
=0.11), there was a temporal trend in favor of greater reporting among later publications (25% 2010–2012 versus 48% 2019–2020).

Conclusions:
Although reporting of primary trial results by sex improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to encourage journals and authors to comply with current reporting recommendations.
Sources of Learning: Zhu Xi’s Theory of Moral Development
Authors: Song Jaeyoon 
Published: September 2021

Abstract
As moral philosopher Zhu Xi (1130–1200) sought to nurture the autonomous moral self. In his pedagogical scheme, one ought to cultivate the innate goodness of the heart, investigate principles in things, and embody ethical standards in daily life. In Zhu Xi’s view, the ability to exercise moral autonomy is obtained through a long period of moral and ethical training under the close surveillance of one’s immediate surroundings since early childhood. For this reason, Zhu Xi emphasized the practice of social norms as well as the performance of mundane rituals as the preconditions for the development of the autonomous moral self. By combining the Lesser Learning (xiaoxue 小學) with the Great Learning (daxue 大學), Zhu Xi articulated an integrated vision of moral development from the heteronomous performing of ethical duties to the autonomous embodiment of moral principles.
The standard deviation structure as a new approach to growth analysis in the farmed Pacific white shrimp, Penaeus vannamei (Decapoda, Penaeidae)
Authors: Castillo-Vargasmachuca Sergio G. , Aragón-Noriega E. Alberto , Ponce-Palafox Jesús T. , Rodríguez-Domínguez Guillermo , De los Santos Raúl Claro 
Published: September 2021

Abstract
In the present study, weight-at-age data of reared Pacific white shrimp, Penaeus vannamei Boone, 1931, were analysed under four different assumptions of variance (observed, constant, depensatory, and compensatory variance) in order to analyse the robustness for selecting the right standard deviation structure to parametrize the Von Bertalanffy, Logistic and Gompertz models. Selection of the best model and variance criteria were obtained based on the Bayesian information criterion (BIC). According to the results of the BIC, the observed variance in the present study proved to constitute the best way to parametrize the three above-listed growth models, and the Von Bertalanffy model appeared to be the best to represent the growth curve found. This is an asymptotic sigmoid curve with an inflection point. Based on these results, using the observed error structure to calculate the growth parameters in multi-model inference analyses is recommended.
Two new species of the problematic harpacticoid genus Itunella (Copepoda, Canthocamptidae)
Authors: Karanovic Tomislav 
Published: September 2021

Abstract
The genus Itunella Brady, 1896 has a troubled taxonomic past, partly because of paucity of its members, but mostly because of inadequate research. A lack of detail in species descriptions and redescriptions, absence of alternative methods for testing species hypotheses, combined with a notion that most marine and estuarine animals have wide distributions and enormous intraspecific variability, all resulted in blurring of some interspecific boundaries, synonymizing without examination of the type material, and founding species diagnoses on dubious characters. Itunella yeondeokensis sp. nov. is described here in great detail from a small sandy beach on the east coast of Korea. It differs from all reported and illustrated congeners by an extremely long inner apical seta on the third exopodal segment of second to fourth swimming legs. This is the second member of this genus from Korea, the first one being described from three estuaries also on the east coast. All other congeners are European species. An overview of all published species and records of this genus is provided, as well as a dichotomous key to valid species to aid in their identification. Itunella kieferi sp. nov. is a new name for a single female from Germany, previously reported as a member of a widely distributed and polymorphic species.
Admissibility of Evidence Obtained by Torture and Inhuman or Degrading Treatment. Does the European Court of Human Rights Offer a Coherent and Convincing Approach?
Authors: Jasiński Wojciech 
Published: September 2021

Abstract
The paper presents and assesses the approach of the ECtHR to admissibility of evidence obtained through torture and inhuman or degrading treatment in the criminal process. The author examines the content of the standard, its justifications and the consistency of the ECtHR's reasoning. The paper refers both to the admissibility of statements and real evidence as well as to primary and derivate evidence obtained in violation of Article 3 echr. The admissibility of evidence obtained by oppressive conduct of private individuals is also analysed. The assessment of the Strasbourg Court’s case law indicates that its approach is quite nuanced and, unfortunately, inconsistent and incoherent. Its main shortcoming is the lack of an in-depth analysis of the rationale for the inadmissibility of evidence obtained by maltreatment and the piecemeal treatment of individual categories of such evidence devoid of attempt to comprehensively address its admissibility in criminal proceedings.
Christians, Jews, and Muslims in the Syriac Story of the Mystery Hidden in the Eucharistic Offering
Authors: Minov Sergey 
Published: September 2021

Abstract
This article contains the unpublished Syriac text of the Story of the Mystery Hidden in the Eucharistic Offering, an anonymous hagiographical composition that tells the story of the conversion of a Muslim king. The text of the Story, published on the basis of two manuscripts (Birmingham, Cadbury Research Library, Mingana Syr. 71, and Manchester, John Rylands Library, Syr. 59), is accompanied by an English translation and discussion of its message.
Development of poly (vinylidene fluoride)/silver nanoparticle electrospun nanofibre mats for energy harvesting
Authors: Thotadara Shivalingappa Roopa , Narasimha Murthy Hebbale Narayana Rao , Purushothaman Pradeep , Badiger Prasanna , Savarn Swapnil , Majumdar Utsav , Angadi Gangadhar 
Published: September 2021

Energy harvesting using piezoelectric materials finds attention of researchers due to miniaturisation. Polyvinylidene fluoride (PVDF) is one such polymeric material with high piezoelectric and pyroelectric properties and hence is used for sensors, actuators, energy harvesting and biomedical devices. This study reports electrospinning of PVDF/Ag nanoparticles (AgNP) nanofibre mats for energy harvesting. Nanofibre mats were prepared by adopting voltage (20 kV), flow rate (1.5 mL/hour) and tip to collector distance (19 cm). The fibre mats were characterised using Fourier-Transformed Infrared Spectroscopy (FTIR), X-Ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). FTIR and XRD results showed 11.84% and 36.36% increase in β-phase and crystallinity, respectively, due to the addition of 1.5 wt. % AgNP to PVDF. SEM micrographs showed decrease in bead formation and increase in fibre diameter from 40 nm to 355 nm due to the addition of AgNP. Sensitivity and voltage output were studied. The fibre mats were used for development of a miniature burglar alarm system, and its response to the applied pressure was tested.
Integrating Palliative Care Into a Neurosurgical Intensive Care Unit (NS-ICU): A Quality Improvement (QI) Project
Authors: Poi Choo Hwee , Koh Mervyn Yong Hwang , Koh Tessa Li-Yen , Wong Yu-Lin , Mei Ong Wendy Yu , Gu Chunguang , Yow Fionna Chunru , Tan Hui Ling 
Published: September 2021

Objectives: We conducted a pilot quality improvement (QI) project with the aim of improving accessibility of palliative care to critically ill neurosurgical patients. Methods: The QI project was conducted in the neurosurgical intensive care unit (NS-ICU). Prior to the QI project, referral rates to palliative care were low. The ICU-Palliative Care collaborative comprising of the palliative and intensive care team led the QI project from 2013 to 2015. The interventions included engaging key stake-holders, establishing formal screening and referral criteria, standardizing workflows and having combined meetings with interdisciplinary teams in ICU to discuss patients’ care plans. The Palliative care team would review patients for symptom optimization, attend joint family conferences with the ICU team and support patients and families post-ICU care. We also collected data in the post-QI period from 2016 to 2018 to review the sustainability of the interventions. Results: Interventions from our QI project and the ICU-Palliative Care collaborative resulted in a significant increase in the number of referrals from 9 in 2012 to 44 in 2014 and 47 the year later. The collaboration was beneficial in facilitating transfers out of ICU with more deaths outside ICU on comfort-directed care (96%) than patients not referred (75.7%, p < 0.05). Significantly more patients had a Do-Not-Resuscitation (DNR) order upon transfer out of ICU (89.7%) compared to patients not referred (74.2.%, p < 0.001), and had fewer investigations in the last 48 hours of life (p < 0.001). Per-day ICU cost was decreased for referred patients (p < 0.05). Conclusions: Multi-faceted QI interventions increased referral rates to palliative care. Referred patients had fewer investigations at the end-of-life and per-day ICU costs.
Extreme immunotherapy: emergency immunology to defeat pandemics
Authors: Nixon Douglas F. , Marín-Hernández Daniela , Hupert Nathaniel 
Published: September 2021

AbstractThe ongoing global COVID-19 pandemic has thrown into sharp relief the gap between modern biology’s ability to investigate and respond to a novel pathogen and modern medicine’s ability to marshal effective front-line interventions to limit its immediate health impact. While we have witnessed the rapid development of innovative vaccines against SARS-CoV-2 using novel molecular platforms, these have yet to alter the pandemic’s long-term trajectory in all but a handful of high-income countries. Health workers at the clinical front lines have little more in their clinical armamentarium than was available a century ago—chiefly oxygen and steroids—and yet advances in modern immunology and immunotherapeutics suggest an underuse of extant and effective, if unorthodox, therapies, which we now call “Extreme Immunotherapies for Pandemics (EIPs).”
Identification of key miRNAs and mRNAs related to coronary artery disease by meta-analysis
Authors: Liu Long , Zhang Jingze , Wu Mei , Xu Haiming 
Published: September 2021

Abstract
Background
To illustrate the mechanism of miRNA and mRNA in coronary artery diseasen (CAD), differentially expressed microRNAs (DEmiRNAs) and genes (DEGs) were analyzed.

Methods
The mRNA transcription profiles of GSE20680 (including 87 blood samples of CAD and 52 blood samples of control), GSE20681 (including 99 blood samples of CAD and 99 blood samples of control) and GSE12288 (including 110 blood samples of CAD and 112 blood samples of control) and the miRNA transcription profiles of GSE59421 (including 33 blood samples of CAD and 37 blood samples of control), GSE49823 (including 12 blood samples of CAD and 12 blood samples of control) and GSE28858 (including 13 blood samples of CAD and 13 blood samples of control) were downloaded from Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/). Then, the homogenous expressed mRNAs and miRNAs across the three mRNA transcription profiles and three miRNA transcription profiles were screened using the Fishers exact test in MetaDE. ES package. The weighted gene co-expression network analysis (WGCNA) was used to analyze gene modules. Additionally, the integrated miRNAs–targets regulatory network using the DEmiRNA and their targets was constructed using Cytoscape.

Results
A total of 1201 homogenously statistically significant DEGs were identified including 879 up-regulated and 322 down-regulated DEGs, while a total of 47 homogenously statistically significant DEmiRNAs including 37 up-regulated and 10 down-regulated DEmiRNAs in CAD compared with the controls across the three mRNA transcription profiles and the three miRNA transcription profiles. A total of 5067 genes were clustered into 9 modules in the training dataset, among which, 8 modules were validated. In the miRNAs-targets network, there existed 267 interaction relationships among 5 miRNAs (hsa-miR-361-5p, hsa-miR-139-5p, hsa-miR-146b-5p, hsa-miR-502-5p and hsa-miR-501-5p) and 213 targets. CAV1 could be the target of hsa-miR-361-5 while HSF2 was the target of both hsa-miR-361-5p and hsa-miR-146b-5p. CAV1 was significantly enriched in the GO term of regulation of cell proliferation.

Conclusion
hsa-miR-361-5p, has-miR-146b-5p, CAV1 and HSF2 could play an important role in CAD.
The impact of antihypertensive treatment initiation on health-related quality of life and cardiovascular risk factor levels: a prospective, interventional study
Authors: Tahkola Aapo , Korhonen Päivi , Kautiainen Hannu , Niiranen Teemu , Mäntyselkä Pekka 
Published: September 2021

AbstractBackgroundEffective prevention and treatment of hypertension is one of the most potential interventions in terms of preventing cardiovascular deaths and disabilities. However, the treatment control is often poor. This may be partly explained by the impact of hypertension diagnoses and treatment on health-related quality of life. Quality of life is also an important outcome for a hypertensive patient. Most of the previous studies on health-related quality of life in hypertension have concentrated on patients with treated hypertension and less is known about the initiation of medication and the first treatment year.MethodsIn this interventional study, we followed 111 primary care patients with newly diagnosed hypertension in real world primary care setting in Finland for 12 months.ResultsWe found significant decrease in both systolic and diastolic blood pressure levels, as well as modest decrease in cholesterol levels and alcohol consumption. However, the health-related quality of life also slightly deteriorated during the first treatment year.ConclusionsOur study shows that the initiation of hypertension treatment results in cardiovascular risk decrease among newly diagnosed Finnish hypertensive patients, but it is accompanied by small negative impact on health-related quality of life. However, the deterioration in health-related quality of life is of small magnitude and earlier research demonstrates several measures to enhance treatment and avoid impairment in health-related quality of life.Trial registrationClinicalTrials NCT02377960 (Date of registration: 04/03/2015).