bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single transcript unit CRISPR 2.0 systems for robust Cas9 and Cas12a mediated plant genome editing
Authors: Tang Xu , Ren Qiurong , Yang Lijia , Bao Yu , Zhong Zhaohui , He Yao , Liu Shishi , Qi Caiyan , Liu Binglin , Wang Yan , Sretenovic Simon , Zhang Yingxiao , Zheng Xuelian , Zhang Tao , Qi Yiping , Zhang Yong 
Published: December 2018

SummaryCRISPR‐Cas9 and Cas12a are two powerful genome editing systems. Expression of CRISPR in plants is typically achieved with a mixed dual promoter system, in which Cas protein is expressed by a Pol II promoter and a guide RNA is expressed by a species‐specific Pol III promoter such as U6 or U3. To achieve coordinated expression and compact vector packaging, it is desirable to express both CRISPR components under a single Pol II promoter. Previously, we demonstrated a first‐generation single transcript unit (STU)‐Cas9 system, STU‐Cas9‐RZ, which is based on hammerhead ribozyme for processing single guide RNAs (sgRNAs). In this study, we developed two new STU‐Cas9 systems and one STU‐Cas12a system for applications in plants, collectively called the STU CRISPR 2.0 systems. We demonstrated these systems for genome editing in rice with both transient expression and stable transgenesis. The two STU‐Cas9 2.0 systems process the sgRNAs with Csy4 ribonuclease and endogenous tRNA processing system respectively. Both STU‐Cas9‐Csy4 and STU‐Cas9‐tRNA systems showed more robust genome editing efficiencies than our first‐generation STU‐Cas9‐RZ system and the conventional mixed dual promoter system. We further applied the STU‐Cas9‐tRNA system to compare two C to T base editing systems based on rAPOBEC1 and PmCDA1 cytidine deaminases. The results suggest STU‐based PmCDA1 base editor system is highly efficient in rice. The STU‐Cas12a system, based on Cas12a’ self‐processing of a CRISPR RNA (crRNA) array, was also developed and demonstrated for expression of a single crRNA and four crRNAs. Altogether, our STU CRISPR 2.0 systems further expanded the CRISPR toolbox for plant genome editing and other applications.
A New Competing Risks Decomposition: Application to the Effect Of Cutting Unemployment Benefit on Unemployment Durations
Authors: O’Neill Donal 
Published: December 2018

SummaryI propose a competing risks decomposition of the difference in the restricted mean lifetimes of two groups, which distinguishes between the incidence and duration effects of exit states. I use the decomposition to evaluate the effect of a cut in unemployment benefits on unemployment durations in Ireland. Whereas the aggregate effect of the benefit cut is similar for men and women, the decomposition reveals that the channels through which the cut affects unemployment durations differ substantially.
Quantitative tests reveal that microtubules tune the healthy heart but underlie arrhythmias in pathology
Authors: Joca Humberto C. , Coleman Andrew K. , Ward Chris W. , Williams George S. B. 
Published: December 2018

Key points
Our group previously discovered and characterized the microtubule mechanotransduction pathway linking diastolic stretch to NADPH oxidase 2‐derived reactive oxygen species signals that regulate calcium sparks and calcium influx pathways.
Here we used focused experimental tests to constrain and expand our existing computational models of calcium signalling in heart.
Mechanistic and quantitative modelling revealed new insights in disease including: changes in microtubule network density and properties, elevated NOX2 expression, altered calcium release dynamics, how NADPH oxidase 2 is activated by and responds to stretch, and finally the degree to which normalizing mechano‐activated reactive oxygen species signals can prevent calcium‐dependent arrhythmias.
AbstractMicrotubule (MT) mechanotransduction links diastolic stretch to generation of NADPH oxidase 2 (NOX2)‐dependent reactive oxygen species (ROS), signals we term X‐ROS. While stretch‐elicited X‐ROS primes intracellular calcium (Ca2+) channels for synchronized activation in the healthy heart, the dysregulated excess in this pathway underscores asynchronous Ca2+ release and arrhythmia. Here, we expanded our existing computational models of Ca2+ signalling in heart to include MT‐dependent mechanotransduction through X‐ROS. Informed by new focused experimental tests to properly constrain our model, we quantify the role of X‐ROS on excitation–contraction coupling in healthy and pathological conditions. This approach allowed for a mechanistic investigation that revealed new insights into X‐ROS signalling in disease including changes in MT network density and post‐translational modifications (PTMs), elevated NOX2 expression, altered Ca2+ release dynamics (i.e. Ca2+ sparks and Ca2+ waves), how NOX2 is activated by and responds to stretch, and finally the degree to which normalizing X‐ROS can prevent Ca2+‐dependent arrhythmias.
A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma
Authors: Chen Shi-Lu , Zhang Chris Zhiyi , Liu Li-Li , Lu Shi-Xun , Pan Ying-Hua , Wang Chun-Hua , He Yang-Fan , Lin Cen-Shan , Yang Xia , Xie Dan , Yun Jing-Ping 
Published: December 2018

Abstract

Hepatocellular carcinogenesis is attributed to the reprogramming of cellular metabolism as a consequence of the alteration in metabolite-related gene regulation. Identifying the mechanism of aberrant metabolism is of great potential to provide novel targets for the treatment of hepatocellular carcinoma (HCC). Here, we demonstrated that glycogen synthase 2 (GYS2) restricted tumor growth in hepatitis B virus–related HCC via a negative feedback loop with p53. Expression of GYS2 was significantly downregulated in HCC and correlated with decreased glycogen content and unfavorable patient outcomes. GYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 expression. GYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation. Furthermore, GYS2 enhanced the p300-induced acetylation of p53 at K373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex. In summary, our findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC.

Significance:
We elucidated the clinical significance, biological function, and regulation of the HBx/GYS2/p53 axis, which supplement the understanding of tumor glycogen metabolism and provide potential prognostic and therapeutic targets for HCC treatment.
Comparative Effectiveness of Aspirin and Clopidogrel Versus Aspirin in Acute Minor Stroke or Transient Ischemic Attack
Authors: Kim Joon-Tae , Park Man-Seok , Choi Kang-Ho , Cho Ki-Hyun , Kim Beom Joon , Park Jong-Moo , Kang Kyusik , Lee Soo Joo , Kim Jae Guk , Cha Jae-Kwan , Kim Dae-Hyun , Nah Hyun-Wook , Park Tai Hwan , Park Sang-Soon , Lee Kyung Bok , Lee Jun , Hong Keun-Sik , Cho Yong-Jin , Park Hong-Kyun , Lee Byung-Chul , Yu Kyung-Ho , Oh Mi Sun , Kim Dong-Eog , Ryu Wi-Sun , Choi Jay Chol , Kwon Jee-Hyun , Kim Wook-Joo , Shin Dong-Ick , Yeo Min-Ju , Sohn Sung Il , Hong Jeong-Ho , Lee Ji Sung , Lee Juneyoung , Saver Jeffrey L. , Johnston S. Claiborne , Bae Hee-Joon 
Published: December 2018

Background and Purpose—
This study aimed to compare the effectiveness of dual antiplatelet therapy with clopidogrel-aspirin to that of aspirin monotherapy in patients with acute minor cerebral ischemia using a prospective, nationwide, multicenter, stroke registry database in South Korea.

Methods—
CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events)-like patients who met eligibility criteria modeled on the CHANCE trial eligibility criteria, including (1) acute minor ischemic stroke defined as National Institutes of Health Stroke Scale score ≤3 or lesion positive transient ischemic attack within 24 hours of onset and (2) noncardioembolic stroke mechanism. Propensity scores using the inverse probability of treatment weighting was used to adjust for baseline imbalances. The primary outcome was the composite of all stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death by 3 months.

Results—

Among 5590 patients meeting the eligibility criteria, age was 64±13 year and 62.6% were male. Aspirin and combination of clopidogrel-aspirin were administered in 66.1% and 33.9% of patients, respectively. In unadjusted analysis, rates of the 3-month primary vascular event outcome were lower with clopidogrel-aspirin versus aspirin, 9.9% versus 12.2% (hazard ratio, 0.79 [0.67–0.95]). In propensity-weighted Cox proportional hazards regression with robust estimation, clopidogrel-aspirin was associated with a lower risk of the primary vascular event outcome (hazard ratio, 0.76 [0.63–0.92]) and all stroke events (hazard ratio, 0.74 [0.61–0.90]). Among 6 predefined subgroup analyses, 3 showed potential modification of treatment effect, with lesser benefit associated with the absence of prior antiplatelet use (
P
interaction
=0.01) and younger age (<75 years,
P
interaction
=0.07), and absence of benefit associated with small vessel occlusion subtype (
P
interaction
=0.08).

Conclusions—
Dual antiplatelet therapy with aspirin and clopidogrel was associated with reduced stroke, myocardial infarction, and vascular death in the 3 months following a presenting minor, noncardioembolic ischemic stroke. Benefits may be particularly magnified in patients with a history of prior antiplatelet therapy, older age, and nonsmall vessel disease stroke mechanism.
Functional Magnetic Resonance Imaging of Inhibitory Control Reveals Decreased Blood Oxygen Level Dependent Effect in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Gavazzi Gioele , Orsolini Stefano , Salvadori Emilia , Bianchi Andrea , Rossi Arianna , Donnini Ida , Rinnoci Valentina , Pescini Francesca , Diciotti Stefano , Viggiano Maria Pia , Mascalchi Mario , Pantoni Leonardo 
Published: December 2018

Background and Purpose—
Small-vessel damage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is associated with impaired vascular constriction and dilation. We used a functional magnetic resonance imaging task with an event-related design of stimulus to explore the anticipated abnormally decreased blood oxygen level dependent effect in CADASIL.

Methods—
Twenty-one CADASIL patients and 16 healthy controls performed a Go/No-go task exploring reactive and proactive phases of inhibition control in a 3-T magnet.

Results—
Error number and reaction times were not different between patients and controls. Analysis of the reactive inhibition (No-go/baseline contrast) did not show clusters of lower or higher blood oxygen level dependent effect in patients or controls. Analysis of the proactive inhibition (alertness contrast) in CADASIL patients revealed a lower blood oxygen level dependent effect in the alerting network (anterior cingulate cortex and insula, thalamus), lower brain stem and left cerebellar hemisphere (crus I) that is involved in executive functions.

Conclusions—
In CADASIL patients, an event-related Go/No-go task reveals a lower blood oxygen level dependent effect in the alerting network and areas involved in executive functions possibly reflecting the altered hemodynamic response secondary to small-vessel changes. Our observation extends the role of MR in demonstrating one of the fundamental pathophysiological changes of CADASIL.
Mobile Technology for Primary Stroke Prevention
Authors: Krishnamurthi Rita , Hale Leigh , Barker-Collo Suzanne , Theadom Alice , Bhattacharjee Rohit , George Ann , Arroll Bruce , Ranta Annamarie , Waters Debra , Wilson Denise , Sandiford Peter , Gall Seana , Parmar Priyakumari , Bennett Derrick , Feigin Valery 
Published: December 2018

Background and Purpose—
Feasibility of utilizing the Stroke Riskometer App (App) to improve stroke awareness and modify stroke risk behaviors was assessed to inform a full randomized controlled trial.

Methods—
A parallel, open-label, 2-arm prospective, proof-of-concept pilot randomized controlled trial. Participants were randomized to usual care/control or App intervention group and assessed at baseline, 3, and 6 months. The App measures stroke risk and provides information on management of risk factors. Participants were aged >19 years with at least 2 modifiable stroke risk factors identified, no prior stroke, and owned a smartphone.

Results—

Fifty participants (24 control, 26 App) were recruited from 148 eligible participants. Retention in the trial was 87%. Mean cardiovascular health (Life’s Simple 7) improved by 0.36 (95% CI, −2.10 to 1.38) in the App group compared with 0.01 (95% CI, −1.34 to 1.32) in controls (
P
=0.6733).

Conclusions—
These findings support a full randomized controlled trial to test the effectiveness of the Stroke Riskometer for primary stroke prevention.

Clinical Trial Registration—

URL:
www.anzctr.org.au
. Unique Identifier: ACTRN12616000376448.
Impact of Childhood Arterial Ischemic Stroke Standardized Classification and Diagnostic Evaluation Classification on Further Course of Arteriopathy and Recurrence of Childhood Stroke
Authors: Böhmer Maik , Niederstadt Thomas , Heindel Walter , Wildgruber Moritz , Sträter Ronald , Hanning Uta , Kemmling André , Sporns Peter B. 
Published: December 2018

Background and Purpose—
Arterial ischemic stroke (AIS) in childhood is a severe disease with potentially lifelong restrictions. Apart from cardiac or prothrombotic embolism, arteriopathy has been identified as a major cause and significant target of secondary stroke prevention. The Childhood Arterial Ischemic Stroke Standardized Classification and Diagnostic Evaluation (CASCADE) criteria facilitate a structured tool for categorizing and reporting childhood strokes according to the underlying cause. Our study aims to identify the prognostic value of CASCADE classification on admission for further course of arteriopathy and risk of stroke recurrence. Moreover, we give recommendations for follow-up imaging based on different CASCADE subgroups.

Methods—

Between 2004 and 2017, we identified 86 children with an acute arterial ischemic stroke classified in the 7-basic and 19-expanded subgroups of the acute CASCADE criteria. All included children were diagnosed and followed-up by magnetic resonance imaging. All arteriopathic strokes (basic subgroups 1–4 of acute CASCADE criteria) were further categorized into the chronic CASCADE criteria, including progressive, stable, reversible, and indeterminate course. Outcomes were defined as stroke recurrence and course of arteriopathy according to chronic CASCADE criteria. Associations between acute CASCADE criteria classification and stroke recurrence were assessed by Fisher exact test and between acute CASCADE criteria and chronic CASCADE criteria by Fisher exact test and Mann-Whitney
U
test.

Results—

A total of 86 children were included; of these, 57 presented with arteriopathic stroke (CASCADE 1–4) and 29 as nonarteriopathic. Unilateral cerebral arteriopathy (CASCADE 2;
P
=0.036) and bilateral cerebral arteriopathy (CASCADE 3;
P
=0.016) significantly correlated with stroke recurrence, and progressive arteriopathy significantly correlated with unilateral focal cerebral arteriopathy (
P
<0.001). Time points of progress of arteriopathy differed; whereas patients with unilateral focal cerebral arteriopathy presented with early median progress after 11 days, patients with bilateral cerebral arteriopathy had a significantly later median progress after 124 days (
P
=0.005).

Conclusions—
Initial CASCADE classification is associated with risk of recurrent strokes and progress of arteriopathy. Moreover, time points of arteriopathic progress vary according to the underlying cause.
Highest Lesion Growth Rates in Patients With Hyperacute Stroke
Authors: Broocks Gabriel , Rajput Furqan , Hanning Uta , Faizy Tobias Djamsched , Leischner Hannes , Schön Gerhard , Gellißen Susanne , Sporns Peter , Deb-Chatterji Milani , Thomalla Götz , Kemmling Andre , Fiehler Jens , Flottmann Fabian 
Published: December 2018

Background and Purpose—
The early growth of ischemic lesions has been described as being nonlinear, with lesion growth rates at their highest during the earliest period after stroke onset. We hypothesized that the time gap from imaging to revascularization results in higher lesion growth in patients with hyperacute presentation.

Methods—
Fifty-one patients with ischemic stroke with initial multimodal computed tomography (CT), follow-up CT after 24 hours, and successful endovascular recanalization were included and separated into 2 groups according to their median time from symptom onset to imaging (eg, hyperacute versus acute). The difference in Alberta Stroke Program Early CT Score (ASPECTS) between initial CT and follow-up CT was assessed, as well as volumetric lesion growth from early ischemic core in admission perfusion CT and total lesion volume in follow-up CT.

Results—

The median time from onset to imaging was 1.85 hours. There was no significant difference in admission ASPECTS (mean, 8.5 versus 8.2) or time from imaging to recanalization in both groups (median, 2.7 versus 2.4 hours;
P
=0.4). The mean (SD) lesion growth assessed by ASPECTS difference was 2.7 (2.3) in the hyperacute group and 1.6 (1.3) in the acute group (
P
=0.03). The mean (SD) volumetric difference in the hyperacute group was 26.6 mL (43.2 mL) and 17.2 mL (26.3 mL;
P
=0.36) in the acute group, respectively. For every passing hour after onset, ASPECTS lesion growth was reduced by 0.4.

Conclusions—
Patients in the hyperacute phase showed increased ASPECTS lesion growth from imaging to recanalization suggesting a particular benefit of faster recanalization times in this group of patients with stroke.
Self-inflicted bilateral ocular and eyelid injuries in an unsuspected individual
Authors: Samia-Aly Emma , Ha Jerome , Sagili Suresh 
Published: December 2018

Background and aims This report aims to illustrate a case of self-inflicted ocular and orbital injury, resulting in severe tissue loss and ophthalmoplegia in a patient with no known history of mental illness. Methods and results A 71-year-old male initially presented to the emergency department with significant tissue loss from his left upper and lower lids, orbital tissue loss and complete ophthalmoplegia, after reportedly tripping and falling onto his desk. He subsequently attended the emergency department on two further occasions with similar injuries, affecting the same and contralateral eye, whilst maintaining a traumatic cause for his injuries. He was eventually admitted to a psychiatric ward for mental health assessment. This report covers his progress as well as illustrating his injuries with images. Conclusion Self-harm is an important differential diagnosis in cases where the mechanism of injury does not correspond to the extent of injury or tissue loss. It can, however, be difficult to differentiate from accidental injury and even with repeated assessments, a formal psychiatric diagnosis may not be possible.
Relevance of flexibility versus radial force in rigid versus more flexible venous stents?
Authors: van Vuuren Timme MAJ , de Wolf Mark AF , Wittens Cees HA 
Published: December 2018

Introduction Deep venous stenting has gained increasing interest. More flexible venous stents are thought to gain superior clinical outcomes. This research evaluated the patency and clinical outcomes between more rigid stents and more flexible stents. Material and methods The Venous Clinical Severity Score, Villalta, complication rates and patency rates were evaluated. The more rigid stents included the Sinus XL, the Veniti VICI and the Sinus Obliquus. The flexible group included the Zilver Vena or the Sinus Venous stents. Results Differences in Venous Clinical Severity Score (p = 0.09) and Villalta score were found (p = 0.28). Tapering (0 versus 5, p = 0.03) and bad alignment were found (0 versus 5, p = 0.03). The rigid stents showed patency rates of 80, 86 and 92% compared to 88, 96 and 98% in the flexible group. Conclusion Dedicated venous stents show good patency outcomes and clinical results. Tapering and bad alignment between connecting stents are more frequently seen in more rigid stents.
Interventions to Mitigate Bias in Social Work Decision-Making: A Systematic Review
Authors: Featherston Rebecca Jean , Shlonsky Aron , Lewis Courtney , Luong My-Linh , Downie Laura E. , Vogel Adam P. , Granger Catherine , Hamilton Bridget , Galvin Karyn 
Published: December 2018

Purpose: This systematic review synthesized evidence supporting interventions aimed at mitigating cognitive bias associated with the decision-making of social work professionals. Methods: A systematic search was conducted within 10 social services and health-care databases. Review authors independently screened studies in duplicate against prespecified inclusion criteria, and two review authors undertook data extraction and quality assessment. Results: Four relevant studies were identified. Because these studies were too heterogeneous to conduct meta-analyses, results are reported narratively. Three studies focused on diagnostic decisions within mental health and one considered family reunification decisions. Two strategies were reportedly effective in mitigating error: a nomogram tool and a specially designed online training course. One study assessing a consider-the-opposite approach reported no effect on decision outcomes. Conclusions: Cognitive bias can impact the accuracy of clinical reasoning. This review highlights the need for research into cognitive bias mitigation within the context of social work practice decision-making.
Knockdown of TRPV2 channels in sensory neurons increases limb use and weight bearing but does not affect spontaneous flinching behavior in a mouse model of bone cancer
Authors: Yamamoto Katsumi , Tanaka Satoshi , Fuseya Satoshi , Ishida Takashi , Zhang Hao , Kawamata Tomoyuki , Kawamata Mikito 
Published: December 2018

Bone cancer pain is a complex pain state involving ongoing pain and movement-related pain, which are thought to be caused by different mechanisms. Transient receptor potential vanilloid subfamily 1 (TRPV1) is involved in ongoing pain but not movement-related pain. The purpose of this study was to investigate the role of transient receptor potential vanilloid subfamily 2 (TRPV2) in bone cancer pain. Proportions of TRPV1- and TRPV2-immunoreactive neurons in lumbar dorsal root ganglia innervating the femurs of male mice were examined by using Fluoro-Gold. Mice were intrathecally injected with small interfering RNA (siRNA) against TRPV2 or scrambled siRNA for three consecutive days from day 14 after sarcoma injection into the left femur. In the mice with bone cancer, the number of spontaneous flinches was quantified for assessment of ongoing pain, and limb use and weight bearing were assessed as indications of movement-related pain. Changes in TRPV2 protein levels in dorsal root ganglion were evaluated by Western blotting. We also examined the effects of intrathecal administration of siRNA against TRPV2 or scrambled siRNA on thermal and mechanical sensitivities in normal mice without tumors. The proportions of TRPV1-immunoreactive and TRPV2-immunoreactive neurons were 21% and 22% of neurons in dorsal root ganglia innervating the femur, respectively. Tumor-bearing mice exhibited an increased number of spontaneous flinches and impaired limb use and weight bearing at day 13 after sarcoma injection. TRPV2 protein level in dorsal root ganglia at day 13 was comparable to that at baseline. siRNA against TRPV2 significantly improved limb use and weight bearing but did not affect the number of spontaneous flinches compared to those in the group treated with scrambled siRNA. siRNA against TRPV2 did not affect thermal or mechanical sensitivity in normal mice. The results suggest that TRPV2 is involved in movement-related pain but not ongoing pain in mice with bone cancer.