bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebellar–Motor Cortex Connectivity: One or Two Different Networks?
Authors: Spampinato Danny A. , Celnik Pablo A. , Rothwell John C. 
Published: April 2020

Anterior–posterior (AP) and posterior–anterior (PA) pulses of transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) appear to activate distinct interneuron networks that contribute differently to two varieties of physiological plasticity and motor behaviors (Hamada et al., 2014). The AP network is thought to be more sensitive to online manipulation of cerebellar (CB) activity using transcranial direct current stimulation. Here we probed CB–M1 interactions using cerebellar brain inhibition (CBI) in young healthy female and male individuals. TMS over the cerebellum produced maximal CBI of PA-evoked EMG responses at an interstimulus interval of 5 ms (PA-CBI), whereas the maximum effect on AP responses was at 7 ms (AP-CBI), suggesting that CB–M1 pathways with different conduction times interact with AP and PA networks. In addition, paired associative stimulation using ulnar nerve stimulation and PA TMS pulses over M1, a protocol used in human studies to induce cortical plasticity, reduced PA-CBI but not AP-CBI, indicating that cortical networks process cerebellar inputs in distinct ways. Finally, PA-CBI and AP-CBI were differentially modulated after performing two different types of motor learning tasks that are known to process cerebellar input in different ways. The data presented here are compatible with the idea that applying different TMS currents to the cerebral cortex may reveal cerebellar inputs to both the premotor cortex and M1. Overall, these results suggest that there are two independent CB–M1 networks that contribute uniquely to different motor behaviors.SIGNIFICANCE STATEMENTConnections between the cerebellum and primary motor cortex (M1) are essential for performing daily life activities, as damage to these pathways can result in faulty movements. Therefore, developing and understanding novel approaches to probe this pathway are critical to advancing our understanding of the pathophysiology of diseases involving the cerebellum. Here, we show evidence for two distinct cerebellar–cerebral interactions using cerebellar stimulation in combination with directional transcranial magnetic stimulation (TMS) over M1. These distinct cerebellar–cerebral interactions respond differently to physiological plasticity and to distinct motor learning tasks, which suggests they represent separate cerebellar inputs to the premotor cortex and M1. Overall, we show that directional TMS can probe two distinct cerebellar–cerebral pathways that likely contribute to independent processes of learning.
Frequency-Specific Optogenetic Deep Brain Stimulation of Subthalamic Nucleus Improves Parkinsonian Motor Behaviors
Authors: Yu Chunxiu , Cassar Isaac R. , Sambangi Jaydeep , Grill Warren M. 
Published: April 2020

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy for the motor symptoms of Parkinson's disease (PD). However, the neural elements mediating symptom relief are unclear. A previous study concluded that direct optogenetic activation of STN neurons was neither necessary nor sufficient for relief of parkinsonian symptoms. However, the kinetics of the channelrhodopsin-2 (ChR2) used for cell-specific activation are too slow to follow the high rates required for effective DBS, and thus the contribution of activation of STN neurons to the therapeutic effects of DBS remains unclear. We quantified the behavioral and neuronal effects of optogenetic STN DBS in female rats following unilateral 6-hydroxydopamine (6-OHDA) lesion using an ultrafast opsin (Chronos). Optogenetic STN DBS at 130 pulses per second (pps) reduced pathologic circling and ameliorated deficits in forelimb stepping similarly to electrical DBS, while optogenetic STN DBS with ChR2 did not produce behavioral effects. As with electrical DBS, optogenetic STN DBS exhibited a strong dependence on stimulation rate; high rates produced symptom relief while low rates were ineffective. High-rate optogenetic DBS generated both increases and decreases in firing rates of single neurons in STN, globus pallidus externa (GPe), and substantia nigra pars reticular (SNr), and disrupted β band oscillatory activity in STN and SNr. High-rate optogenetic STN DBS can indeed ameliorate parkinsonian motor symptoms through reduction of abnormal oscillatory activity in the STN-associated neural circuit, and these results highlight that the kinetic properties of opsins have a strong influence on the effects of optogenetic stimulation.SIGNIFICANCE STATEMENTWhether STN local cells contribute to the therapeutic effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) remains unclear. We re-examined the role of STN local cells in mediating the symptom-relieving effects of STN DBS using cell type-specific optogenetic stimulation with a much faster opsin, Chronos. Direct optogenetic stimulation of STN neurons was effective in treating the symptoms of parkinsonism in the 6-hydroxydopamine (6-OHDA) lesion rat. These results highlight that the kinetic properties of opsins can have a strong influence on the effects of optogenetic activation/inhibition and must be considered when employing optogenetic to study high-rate neural stimulation.
The Arabidopsis lncRNA ASCO modulates the transcriptome through interaction with splicing factors
Authors: Rigo Richard , Bazin Jérémie , Romero‐Barrios Natali , Moison Michaël , Lucero Leandro , Christ Aurélie , Benhamed Moussa , Blein Thomas , Huguet Stéphanie , Charon Céline , Crespi Martin , Ariel Federico 
Published: April 2020

AbstractAlternative splicing (AS) is a major source of transcriptome diversity. Long noncoding RNAs (lncRNAs) have emerged as regulators of AS through different molecular mechanisms. In Arabidopsis thaliana, the AS regulators NSRs interact with the ALTERNATIVE SPLICING COMPETITOR (ASCO) lncRNA. Here, we analyze the effect of the knock‐down and overexpression of ASCO at the genome‐wide level and find a large number of deregulated and differentially spliced genes related to flagellin responses and biotic stress. In agreement, ASCO‐silenced plants are more sensitive to flagellin. However, only a minor subset of deregulated genes overlaps with the AS defects of the nsra/b double mutant, suggesting an alternative way of action for ASCO. Using biotin‐labeled oligonucleotides for RNA‐mediated ribonucleoprotein purification, we show that ASCO binds to the highly conserved spliceosome component PRP8a. ASCO overaccumulation impairs the recognition of specific flagellin‐related transcripts by PRP8a. We further show that ASCO also binds to another spliceosome component, SmD1b, indicating that it interacts with multiple splicing factors. Hence, lncRNAs may integrate a dynamic network including spliceosome core proteins, to modulate transcriptome reprogramming in eukaryotes.
Gi‐coupled receptor activation potentiates Piezo2 currents via Gβγ
Authors: Del Rosario John Smith , Yudin Yevgen , Su Songxue , Hartle Cassandra M , Mirshahi Tooraj , Rohacs Tibor 
Published: April 2020

AbstractMechanically activated Piezo2 channels are key players in somatosensory touch, but their regulation by cellular signaling pathways is poorly understood. Dorsal root ganglion (DRG) neurons express a variety of G‐protein‐coupled receptors that modulate the function of sensory ion channels. Gi‐coupled receptors are generally considered inhibitory, as they usually decrease excitability. Paradoxically, activation of Gi‐coupled receptors in DRG neurons sometimes induces mechanical hypersensitivity, the mechanism of which is not well understood. Here, we find that activation of Gi‐coupled receptors potentiates mechanically activated currents in DRG neurons and heterologously expressed Piezo2 channels, but inhibits Piezo1 currents in heterologous systems in a Gβγ‐dependent manner. Pharmacological inhibition of kinases downstream of Gβγ, phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) also abolishes the potentiation of Piezo2 currents. Local injection of sumatriptan, an agonist of the Gi‐coupled serotonin 1B/1D receptors, increases mechanical sensitivity in mice, and the effect is abolished by inhibiting PI3K and MAPK. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents and alter mechanosensitivity after activation of Gi‐coupled receptors.
Controlling Smad4 signaling with a Wip
Authors: ten Dijke Peter , Baker David 
Published: April 2020

Members of the transforming growth factor‐β (TGF‐β) family play key roles in embryogenesis and in maintaining tissue homeostasis, and their perturbation can result in a broad range of diseases. One way TGF‐β family signaling pathways are kept in check is by reversible (de)phosphorylation of intracellular Smad effectors. In this issue of EMBO Reports, Park et al [1] identify the phosphatase wild‐type p53‐induced phosphatase 1 (Wip1) as a negative regulator of TGF‐β family signaling. Mechanistically, Wip1 constrains TGF‐β family signaling through direct dephosphorylation of Thr277, an activating MAP kinase phosphorylation site located in the linker region of the common mediator Smad4.
Hepatitis C-vírus- (HCV-) infekció és malignus lymphomák: az ellátás szempontjai egy HCV-pozitív, marginalis zóna lymphomás beteg esete kapcsán
Authors: Folhoffer Anikó , Tárkányi Ilona , Németh Dániel , Csernus Balázs , Rajnai Hajnalka , Matolcsy András , Kaposi Novák Pál , Abonyi† Margit , Tóth Tamás , Szalay Ferenc , Demeter Judit 
Published: April 2020

Absztrakt:
Bevezetés: A hepatitis C-vírus (HCV) krónikus májgyulladáshoz,
májcirrhosishoz, májrákhoz vezethet. A Flaviviridae csoportba tartozó RNS vírus
nemcsak hepatotrop, de lymphotrop tulajdonsággal is rendelkezik. Számos
extrahepatikus manifesztációja között jelentős a lymphoproliferatív eltérés. A
főként B-sejtes betegségek közül leggyakoribb az alacsony malignitású marginalis
zóna lymphoma, a diffúz nagy B-sejtes lymphoma, valamint a follicularis
lymphoma. Beteg: A hypertoniás, visszérműtéten átesett 54 éves
férfi beteg thrombopeniájának, indirekt, Coombs-pozitív hyperbilirubunaemiájának
és hepatosplenomegaliájának hátterében HCV-infekció talaján kialakult Child B
stádiumú májcirrhosis igazolódott. Az inhomogén szerkezetű, megnagyobbodott,
lobulált felszínű májban körülírt eltérés nem látszott. A portalis keringés
megtartott volt. A máj fokozott keménysége (26 kPa, IQR/med. 18%) F4 cirrhosisra
utalt. A homogén szerkezetű lépet jelentősen nagyobbnak (20×9 cm) mértük. A
perifériás vérkenet alapján lymphoma gyanúja merült fel, amit a crista-biopsia
eredménye megerősített, CD5/CD10-negatív marginális zóna lymphomát (MZL)
diagnosztizáltunk. A fenti májbetegségnek és a HCV 1b genotípusnak megfelelően,
sofosbuvir/ledipasvir direkt antivirális kezelést indítottunk. A 12 hetes
kezelés tartós vírusmentességet eredményezett. Mind a májbetegség, mind a
lymphoma tünetei mérséklődtek, a beteg testsúlya nőtt, fáradékonysága megszűnt.
Megbeszélés: Az irodalomból is ismert, hogy a krónikus C
hepatitisben a B-sejtes lymphomák előfordulása gyakoribb. Az antiviralis kezelés
hatására lymphoma javulását is leírták, esetünkben a társuló immunhaemolysis
mértékének csökkenését észleltük. Lymphomaspecifikus kezelés jelenleg nem
szükséges, a beteg tünetmentes és stabil, progresszió esetén rituximab
monoterápia jön szóba. Következtetés: A fenti eset példa a
HCV-pozitív betegekben előforduló B-sejtes lymphomára. Bár az irodalomból
ismert, hogy a hepatitis C-vírus eradikációjával a B-sejtes non-Hodgkin-lymphoma
regrediálhat, esetünkben az eddig eltelt vírusmentes időszakban ezt még nem
észleltük, igaz, hogy progressziót sem.
The Benefits of Adjuvant Trastuzumab for HER-2-Positive Salivary Gland Cancers
Authors: Hanna Glenn J. , Bae Ji Eun , Lorch Jochen H. , Haddad Robert I. , Jo Vickie Y. , Schoenfeld Jonathan D. , Margalit Danielle N. , Tishler Roy B. , Goguen Laura A. , Annino Donald J. , Chau Nicole G. 
Published: April 2020

Abstract

Background
Although high-grade salivary gland cancers (SGCs) often express androgen receptor (AR) and/or HER-2/neu, therapeutically targeting these receptors in SGC remains investigational. We investigated the prevalence of receptor expression and the benefit of adjuvant HER-2 directed therapy in the high-risk postoperative setting and explored the clinical utility of sequentially targeting these receptors in the setting of advanced disease.

Materials and Methods
We clinically annotated 95 patients with SGC (excluding adenoid cystic carcinoma) treated at our institution from 2002 to 2019 and recorded AR, HER-2/neu status, and tumor genomic profiling results when available. Clinicopathologic information was then integrated with outcomes.

Results
Of 95 patients, most had high-risk histologies, with salivary duct carcinoma (SDC) as the most frequent diagnosis (43, 45%). Thirty-five (37%) experienced recurrence (51% SDC). HER-2/neu was positive (1–3+) by immunostaining in 34 of 52 (65%) evaluable cases. There was no difference in survival based on HER-2/neu or AR expression. Nine of 17 (53%) patients with HER-2+ SDC received adjuvant chemoradiation with trastuzumab. Median disease-free survival (DFS) and overall survival (OS) were longer among patients with HER-2/neu 3+ staining tumors who received adjuvant trastuzumab versus those who did not (DFS, 117 vs. 9 months; p = .02; OS, 74 vs. 43 months; p = .02), with no difference among other HER-2/neu subgroups (0–2+). Two of nine (22%) patients treated with adjuvant trastuzumab demonstrated recurrence, both with low HER-2/neu staining intensity (1+). Longer time to recurrence (hazard ratio, 0.94; p = .01) predicted improved outcomes. Both androgen deprivation and HER-2-directed therapies had clinical benefit beyond the first-line metastatic setting, with partial response observed beyond second-line use.

Conclusion
Although prospective data are lacking, the use of adjuvant trastuzumab in high-risk patients with SGC appears beneficial, particularly among patients with tumors exhibiting HER-2/neu 3+ immunostaining.

Implications for Practice
Results of this study showed an improved disease-free and overall survival in patients treated with adjuvant trastuzumab for high-risk salivary gland cancers with strong HER-2/neu staining intensity. Following recurrence or metastatic spread, sequential HER-2, and androgen-directed therapies may benefit certain patients with salivary gland cancer.
A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors
Authors: Weekes Colin , Lockhart Albert , LoRusso Patricia , Murray Elaine , Park Erica , Tagen Mike , Singh Jatinder , Sarkar Indrani , Mueller Lars , Dokainish Hatem , Shapiro Geoffrey , Burris Howard 
Published: April 2020

Abstract

Lessons Learned
Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug–drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1.

Background
Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors.

Methods
Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle.

Results
In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1–2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug–drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response.

Conclusion
The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor–related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.
Molecular diagnostics of the Krabbe disease in Russian children
Authors: Pushkov Alexander A. , Mazanova Nataliya N. , Kuzenkova Lyudmila M. , Zhurkova Nataliya V. , Globa Oksana V. , Alexeeva Alina Yu. , Migali Alla V. , Sukhozhenko Aleksey V. , Varichkina Mariya A. , Chernyaev Vasily V. , Asanov Aliy Yu. , Fisenko Andrey P. , Savostyanov Kirill V. 
Published: April 2020

Introduction. Krabbe disease (KD) is the lysosomal storage disease developed due to the decline of the galactocerebrosidase activity associated with mutations in the GALC gene. It leads to the development of oligodendrocytes and lemmocytes (Schwann cells) myelin-forming dysfunction. Nowadays the only possible treatment of KD is hemopoietic cell transplantation which should be performed before the manifestation of any signs of disease. That is why laboratory diagnostics has special significance.
The aim of the study. To elaborate the algorithm of a molecular diagnostics of the Krabbe disease (KD) in Russian children.
Material and methods. 190 patients were diagnosed for the exclusion of KD during the period from 2012 to 2019. In all cases, there was measured a galactocerebrosidase activity in dry blood spots. In cases with the declined enzyme activity, there was performed a further search of pathogenic variants in the GALC gene. The concentration of glycosyl sphingosine (Lyso-GL1) biomarker was measured in 90 patients included in the study since 2016.
Results. The enzyme activity was decreased in all patients in comparison with the control group (0.330.05; 2.950.24 mol/l/h, (p0.001; CI: 95%) in 9 patients. Also, we revealed an increased concentration of Lyso-GL1 biomarker in matched controls (12.501.57 ng/ml; 1.80.33 ng/ml, (p0.005; CI: 95%) in 5 patients. During molecular genetic testing of KD, three novel pathogenic variants of the GALC gene were revealed in 3 out of 9 patients: c.265-2AG, c.1036del and c.2037_2040del.
Conclusion. The Lyso-GL1 concentration measurement can be used as an additional diagnostics method of KD. The high efficiency of the presented algorithm for the KD diagnostics in Russian children is presented.
Study on the transformation and upgrading path and countermeasures of Zhejiang's foreign trade promoted by cross-border e-commerce
Authors: Zhang Yifan 
Published: April 2020

<p>In recent years, with the continuous rise of cross-border e-commerce, traditional foreign trade has been affected to some extent, but it is still developing steadily. How to promote the development of traditional foreign trade with the help of cross-border e-commerce is the focus of this paper. Taking Zhejiang province as an example, this paper studies the path and countermeasures of promoting the transformation and upgrading of Zhejiang's foreign trade by cross-border e-commerce.</p>
Gamma glutamyl transferase – an underestimated marker for cardiovascular disease and the metabolic syndrome
Authors: Neuman Manuela G , Malnick Stephen , Chertin Lucy 
Published: April 2020

Gamma glutamyl transferase (GGT) is an enzyme in glutathione and cysteine metabolism. GGT is a standard liver enzyme test reflecting biliary tract involvement. It also has a prooxoidant activity and a modulating influence on endothelia dysfunction. GGT is associated with the metabolic syndrome and is often elevated in patients with NAFLD.
There is also a role for GGT activity in several aspects cardiovascular disease. There is an association between elevated GGT and cardiovascular mortality, atrial fibrillation, exacerbation of congestive heart failure . In addition there is an association with obstructive sleep apnea.
We review the evidence available and suggest that there is a need for further assessing the use of GGT, together with the presence of the metabolic syndrome as a prognostic marker.
Dealing with Feeling: Emotion, Affect, and the Qualitative Research Encounter
Authors: Rau Asta 
Published: April 2020

Emotion and affect are different, yet intricately interwoven. Emotions such as fear, joy, or sadness are biological in as far as they are physically felt, but they are relational in as far as they are more fully experienced. Affect arises out of the relational quality of emotion—it consists of the myriad ways in which emotions are embodied, expressed, and enacted.
Emotion and affect are influenced by their physical and symbolic contexts. In terms of physical context, data for this article were collected from two different research studies and several sites in the Free State Province of South Africa. Two forms of data were collected: verbal data and images/artworks. In terms of symbolic context, these verbal and visual forms of language and their functioning were explored to generate insights on the social construction of emotion and affect.
Margaret Wetherell’s work provides a theoretical basis for analyzing emotion and affect. Rather than conceptualizing emotion in terms of obscure or esoteric formulations, her “practice-based” approach grounds the study of emotion by examining its manifestation in actions. When taken together, action and practice imply pattern and order, form and function, process and consequence.
Both projects featured in this paper are sensitive studies that stir emotion. This is fertile ground for exploring emotion and affect in participants’ narratives. It is also fertile ground for exploring how emotion and affect may influence the qualitative researcher and the research process itself. Accordingly, this paper offers an additional layer of analysis on the functioning of intersubjectivity, power, emotion, and affect in the research encounter. Concluding insights endorse the practice of mindfulness as a fruitful approach to manage researcher subjectivity in the qualitative research encounter.
Reliability, Validity and Empirical Dimensionality of the Minnesota Nurses' Perceptions of Nursing Diagnoses Scale Among Italian Nursing Students
Authors: Di Sarra Luca , D'Agostino Fabio , Scialò Gennaro , Rocco Gennaro , Ghezzi Valerio , Vellone Ercole , Macale Loreana , Alvaro Rosaria 
Published: April 2020

Background and PurposePerceptions toward nursing diagnosis (ND) may represent core drivers of its adoption within clinical practice. Few studies have investigated perceptions toward ND within nursing academic contexts. The study was conducted to validate the Italian version of the Minnesota Nurses' Perceptions of Nursing Diagnoses (MNPND) scale on a sample of Italian nursing students and explore the psychometric structure of perceptions in a sample drawn from this population.MethodsA cross-sectional survey with an online self-administered questionnaire was used. The study used exploratory factor analysis (EFA) and confirmatory factor analysis (CFA).ResultsA three-factorstructure was obtained from parallel analysis and EFA. This was confirmed using CFA; fit statistics: MLRχ² (132) = 230.150, p <. 001; CFI = 0.94; TLI = 0.93; RMSEA = 0.05 [90% CI = 0.041–0.064]; SRMR = 0.056).ConclusionsThe MNPND scale is a useful instrument to measure nursing students' perceptions of ND