bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different pharmacokinetics of lithium orotate inform why it is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania
Authors: Pacholko Anthony G. , Bekar Lane K. 
Published: May 2022

AbstractObjectiveLithium carbonate (LiCO) is a mainstay therapeutic for the prevention of mood-episode recurrences in bipolar disorder (BD). Unfortunately, its narrow therapeutic index is associated with complications that may lead to treatment non-compliance. Intriguingly, lithium orotate (LiOr) is suggested to possess uptake properties that would allow for reduced dosing and mitigation of toxicity concerns. We hypothesized that due to differences in pharmacokinetics, LiOr is more potent with reduced adverse effects.MethodsDose responses were established for LiOr and LiCO in male and female mice using an amphetamine-induced hyperlocomotion (AIH) model; AIH captures manic elements of BD and is sensitive to a dose-dependent lithium blockade. Next, the relative toxicities of LiOr and LiCO were contrasted after 14 consecutive daily administrations.ResultsLiCO maintained a partial block of AIH at doses of 15 mg/kg or greater in males and 20 mg/kg or greater in females. In contrast, LiOr elicited a near complete blockade at concentrations of just 1.5 mg/kg in both sexes, indicating improved efficacy and potency. Prior application of an organic-anion transporting polypeptide 1A2 (OATP1A2) inhibitor completely blocked the effects of LiOr on AIH while sparing LiCO, suggesting differences in transport between the two compounds. LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine levels in males, and increased serum TSH expression in females.ConclusionsLiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice as a result of select transport-mediated uptake.
Impact of shaggy aorta on intraoperative cerebral embolism during carotid artery stenting
Authors: Osipova Olesia O. , Bugurov Savr V. , Saaya Shoraan B. , Gostev Alexander A. , Cheban Alexey V. , Ignatenko Pavel V. , Karpenko Andrey A. 
Published: May 2022

AbstractBackgroundCareful selection of patients for carotid stenting is necessary. We suggest that patients with a shaggy aorta syndrome may have a higher risk of perioperative embolic complications.MethodsThe study is a subanalysis of the SIBERIA Trial. We included 72 patients undergoing transfemoral carotid artery stenting. All patients had an MRI DWI and a clinical neurological examination two days before and on the second and 30th days after the intervention.Results46 patients had shaggy aorta syndrome. Intraoperative embolisms were recorded in 82.6% and 46.1% of patients with and without shaggy aorta syndrome, respectively (p=0.001). New asymptomatic ischemic brain lesions in the postoperative period occurred in 78.3% and in 26.9% of patients with and without shaggy aorta syndrome, respectively (p=0.000). 3 (6.5%) cases of stroke within 30 days after the procedure were observed only in patients with shaggy aorta syndrome. Shaggy aorta syndrome (OR 5.54 [1.83:16.7], p=0.001) and aortic arch ulceration (OR 6.67 [1.19: 37.3], p = 0.02) were independently associated with cerebral embolism. Shaggy aorta syndrome (OR 9.77 [3.14-30.37], p=0.000) and aortic arch ulceration (OR 12.9 [2.3: 72.8], p = 0.003) were independently associated with ipsilateral new asymptomatic ischemic brain lesions.ConclusionsShaggy aorta syndrome and aortic arch ulceration significantly increase the odds of intraoperative embolism and new asymptomatic ischemic brain lesions. Carotid endarterectomy or transcervical carotid stent should be selected in the presence of aortic ulceration.
Artificial Intelligence for context-aware surgical guidance in complex robot-assisted oncological procedures: An exploratory feasibility study
Authors: Kolbinger Fiona R. , Bodenstedt Sebastian , Carstens Matthias , Leger Stefan , Krell Stefanie , Rinner Franziska M. , Nielen Thomas P. , Kirchberg Johanna , Fritzmann Johannes , Weitz Jürgen , Distler Marius , Speidel Stefanie 
Published: May 2022

AbstractIntroductionComplex oncological procedures pose various surgical challenges including dissection in distinct tissue planes and preservation of vulnerable anatomical structures throughout different surgical phases. In rectal surgery, violation of dissection planes increases the risk of local recurrence and autonomous nerve damage resulting in incontinence and sexual dysfunction. This work explores the feasibility of phase recognition and target structure segmentation in robot-assisted rectal resection (RARR) using machine learning.Materials and MethodsA total of 57 RARR were recorded and annotated with respect to surgical phases and exact locations of target structures (anatomical structures, tissue types, static structures, and dissection areas). For surgical phase recognition, three machine learning models were trained: LSTM, MSTCN, and TransSVNet. Based on pixel-wise annotations of target structures in 9037 images, individual segmentation models based on DeepLabV3 were trained. Model performance was evaluated using F1 score, Intersection-over-Union (IoU), accuracy, precision, recall, and specificity.ResultsThe best results for phase recognition were achieved with the MSTCN model (F1 score: 0.82 ± 0.01, accuracy: 0.84 ± 0.03). Mean IoUs for target structure segmentation ranged from 0.14 ± 0.22 to 0.80 ± 0.14 for organs and tissue types and from 0.11 ± 0.11 to 0.44 ± 0.30 for dissection areas. Image quality, distorting factors (i.e. blood, smoke), and technical challenges (i.e. lack of depth perception) considerably impacted segmentation performance.ConclusionMachine learning-based phase recognition and segmentation of selected target structures are feasible in RARR. In the future, such functionalities could be integrated into a context-aware surgical guidance system for rectal surgery.
A resource for generating and manipulating human microglial states in vitro
Authors: Dolan Michael-John , Therrien Martine , Jereb Saša , Kamath Tushar , Atkeson Trevor , Marsh Samuel E. , Goeva Aleksandrina , Lojek Neal M. , Murphy Sarah , White Cassandra M. , Joung Julia , Liu Bingxu , Limone Francesco , Eggan Kevin , Hacohen Nir , Bernstein Bradley E. , Glass Christopher K. , Leinonen Ville , Blurton-Jones Mathew , Zhang Feng , Epstein Charles B. , Macosko Evan Z. , Stevens Beth 
Published: May 2022

AbstractMicroglia have emerged as key players in the pathogenesis of neurodegenerative conditions such as Alzheimer’s disease (AD). In response to CNS stimuli, these cells adopt distinct transcriptional and functional subtypes known as states. However, an understanding of the function of these states has been elusive, especially in human microglia, due to lack of tools to model and manipulate this cell-type. Here, we provide a platform for modeling human microglia transcriptional states in vitro. Using single-cell RNA sequencing, we found that exposure of human stem-cell differentiated microglia (iMGLs) to brain-related challenges generated extensive transcriptional diversity which mapped to gene signatures identified in human brain microglia. We identified two in vitro transcriptional clusters that were analogous to human and mouse disease-associated microglia (DAMs), a state enriched in neurodegenerative disease contexts. To facilitate scalable functional analyses, we established a lentiviral approach enabling broad and highly efficient genetic transduction of microglia in vitro. Using this new technology, we demonstrated that MITF (Melanocyte Inducing Transcription Factor), an AD-enriched transcription factor in microglia, drives both a disease-associated transcriptional signature and a highly phagocytic state. Finally, we confirmed these results across iMGLs differentiated from multiple iPSC lines demonstrating the broad utility of this platform. Together, these tools provide a comprehensive resource that enables the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.
Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts
Authors: Fels Jasmine A. , Dash Jalia , Leslie Kent , Manfredi Giovanni , Kawamata Hibiki 
Published: May 2022

AbstractALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, Turso), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. To obtain an unbiased landscape of AMX0035 effects we investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls treated with PB, TUDCA, or PB-TUDCA combination (Combo). Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in ALS-relevant pathways, such as nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. Weighted gene coexpression network analysis showed that significant correlations between ALS gene expression modules and clinical parameters were abolished by Combo. This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared to the individual compounds and provides clues to drug targets and mechanisms of actions, which may underlie the benefits of this investigational drug combination.
Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease
Authors: Parmasad Jean-Louis A. , Ricke Konrad M. , Stykel Morgan G. , Buchner-Duby Brodie , Nguyen Benjamin , Bruce Amanda , Geertsma Haley M. , Lian Eric , Lengacher Nathalie A. , Callaghan Steve M. , Joselin Alvin , Tomlinson Julianna J. , Schlossmacher Michael G. , Stanford William L. , Ma Jiyan , Brundin Patrik , Ryan Scott D. , Rousseaux Maxime W.C. 
Published: May 2022

AbstractParkinsona’s disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractablein vitroandin vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF- challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.
Scalable sequence-informed embedding of single-cell ATAC-seq data with CellSpace
Authors: Tayyebi Zakieh , Pine Allison R. , Leslie Christina S. 
Published: May 2022

AbstractStandard scATAC-seq analysis pipelines represent cells as sparse numeric vectors relative to an atlas of peaks or genomic tiles and consequently ignore genomic sequence information at accessible loci. We present CellSpace, an efficient and scalable sequence-informed embedding algorithm for scATAC-seq that learns a mapping of DNA k-mers and cells to the same space. CellSpace captures meaningful latent structure in scATAC-seq datasets, including cell subpopulations and developmental hierarchies, and scores the activity of transcription factors in single cells based on proximity to binding motifs embedded in the same space. Importantly, CellSpace implicitly mitigates batch effects arising from multiple samples, donors, or assays, even when individual datasets are processed relative to different peak atlases. Thus, CellSpace provides a powerful tool for integrating and interpreting large-scale scATAC-seq compendia.
Comparative computational structural genomics highlights divergent evolution of fungal effectors
Authors: Seong Kyungyong , Krasileva Ksenia V 
Published: May 2022

AbstractElucidating the evolution of pathogen effector molecules is critical to understand infection mechanisms of fungal phytopathogens and ensure crop security. However, rapid diversification that diminishes sequence similarities between homologous effectors has largely concealed the roots of effector evolution. We predicted the folds of 26,653 secreted proteins from 21 species with AlphaFold and performed structure-guided comparative analyses on two aspects of effector evolution: uniquely expanded effector families and common folds present across the fungal species. Extreme expansion of nearly lineage-specific effector families was found only in several obligate biotrophs, Blumeria graminis and Puccinia graminis. The highly expanded effector families were the source of conserved sequence motifs, such as the Y/F/WxC motif. We identified additional lineage-specific effector families that include known (a)virulence factors, such as AvrSr35, AvrSr50 and Tin2. These families represented new classes of sequence-unrelated structurally similar effectors. Structural comparisons revealed that the expanded structural folds further diversify through domain duplications and fusion with disordered stretches. Sub-and neo-functionalized structurally similar effectors reconverge on regulation, expanding the functional pools of effectors in the pathogen infection cycle. We also found evidence that many effector families could have originated from ancestral folds that have been conserved across fungi. Collectively, our study highlights diverse mechanisms of effector evolution and supports divergent evolution of effectors that leads to emergence of pathogen virulence from ancestral proteins.
Selection of single domain anti-transferrin receptor antibodies for blood-brain barrier transcytosis using a neurotensin based assay and histological assessment of target engagement in a mouse model of Alzheimer’s related amyloid-beta pathology
Authors: Su Shiran , Esparza Thomas J. , Brody David L. 
Published: May 2022

AbstractThe blood-brain barrier (BBB) presents a major obstacle in developing specific diagnostic imaging agents for many neurological disorders. In this study we aimed to generate single domain anti-mouse transferrin receptor antibodies (anti-mTfR VHHs) to mediate BBB transcytosis as components of novel MRI molecular contrast imaging agents. Anti-mTfR VHHs were produced by immunizing a llama with mTfR, generation of a VHH phage display library, immunopanning, and in vitro characterization of candidates. Site directed mutagenesis was used to generate additional variants. VHH fusions with neurotensin (NT) allowed rapid, hypothermia-based screening for VHH-mediated BBB transcytosis in wild-type mice. One anti-mTfR VHH variant was fused with an anti-amyloid-beta (Aβ) VHH dimer and labeled with fluorescent dye for direct assessment of in vivo target engagement in a mouse model of AD-related Aβ plaque pathology. An anti-mTfR VHH called M1 and variants had binding affinities to mTfR of <1nM to 1.52nM. The affinity of the VHH binding to mTfR correlated with the efficiency of the VHH-NT induced hypothermia effects after intravenous injection of 600 nmol/kg body weight, ranging from undetectable for nonbinding mutants to −6°C for the best mutants. The anti-mTfR VHH variant M1P96H with the strongest hypothermia effect was fused to the anti-Aβ VHH dimer and labeled with Alexa647; the dye-labeled VHH fusion construct still bound both mTfR and Aβ plaques. However, after intravenous injection at 600 nmol/kg body weight into APP/PS1 transgenic mice, there was no detectible labeling of plaques above control levels. Thus, NT-induced hypothermia did not correlate with direct target engagement in cortex. There was a surprising dissociation between NT-induced hypothermia, presumably mediated by hypothalamus, and direct engagement with Aβ-plaques in cortex. Alternative methods to assess anti-mTfR VHH BBB transcytosis will need to be developed for anti-mTfR VHH screening and the development of novel MRI molecular contrast agents.
Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2-mutant meningiomas in mice
Authors: Szulzewsky Frank , Arora Sonali , Arakaki Aleena , Sievers Philipp , Bonnin Damian A. Almiron , Paddison Patrick J. , Sahm Felix , Cimino Patrick J , Gujral Taranjit S , Holland Eric C 
Published: May 2022

AbstractYAP1 is a transcriptional co-activator regulated by the Hippo Signaling Pathway, including NF2. Meningiomas are the most common primary brain tumors, a large percentage exhibit heterozygous loss of chromosome 22 (harboring theNF2gene) and functional inactivation of the remainingNF2copy, implicating oncogenic YAP activity in these tumors. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatricNF2-wild type meningiomas. Here, we show that humanYAP1-MAML2-positive meningiomas resembleNF2-mutant meningiomas by global and YAP-related gene expression signatures. We then show that expression ofYAP1-MAML2in mice induces tumors that resemble human YAP1 fusion-positive andNF2-mutant meningiomas by gene expression. We demonstrate that YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Treatment with YAP-TEAD inhibitors is sufficient to inhibit the viability ofYAP1-MAML2-driven mouse tumorsex vivo. Finally, we show that expression of constitutively active YAP1 (S127/397A-YAP1) is sufficient to induce similar tumors suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a causal oncogenic driver and highlight TEAD-dependent YAP activity as an oncogenic driver inYAP1-MAML2-fusion meningioma as well as NF2-mutant meningioma in general.
Genome-wide CRISPR guide RNA design and specificity analysis with GuideScan2
Authors: Schmidt Henri , Zhang Minsi , Mourelatos Haralambos , Sánchez-Rivera Francisco J. , Lowe Scott W. , Ventura Andrea , Leslie Christina S. , Pritykin Yuri 
Published: May 2022

AbstractWe present GuideScan2 for memory-efficient, parallelizable construction of high-specificity CRISPR guide RNA (gRNA) databases and user-friendly gRNA/library design in custom genomes. GuideScan2 analysis identified widespread confounding effects of low-specificity gRNAs in published CRISPR knockout, interference and activation screens and enabled construction of a ready-to-use gRNA library that reduced off-target effects in a novel gene essentiality screen. GuideScan2 also enabled the design and experimental validation of allele-specific gRNAs in a hybrid mouse genome.
Nexus between audit committee and corporate risk: evidence from Pakistan
Authors: Noor Amna , Farooq Muhammad , Tahir Zonaib 
Published: May 2022

PurposeThe purpose of this study is to investigate the impact of audit committee (AC) characteristics, such as AC size, AC independence and gender diversity on firm risk in the context of an emerging market.Design/methodology/approachThe sample data includes 102 nonfinancial Pakistan Stock Exchange listed firms from 2004 to 2018. Firm risk is measured through three proxies, namely, idiosyncratic risk, total risk and capital expenditure. Along with this, profitability, leverage, market-to-book ratio, firm age, net property plant and equipment (NPPE) and surplus cash are used as control variables. The Housman test is used to select the best model from the fixed-effect model and the random effect model to conclude the findings.FindingsAccording to the study's findings, AC characteristics have a negative and significant relationship with idiosyncratic risk. In addition, a gender-diverse AC has a significant negative relationship with capital expenditure. In connection with total risk, AC characteristics fail to shows any significant relationship. Among the control variables, the results show that profitability stand for return on asset (ROA) and NPPE have a significant negative relationship, whereas market-to-book value has a significant positive relationship with both idiosyncratic and total risk.Practical implicationsThe study's findings offer policymakers, managers and investors guidance. This study will provide new insights to the Pakistani Government, stock market, companies and accounting and auditing regulators in terms of understanding the determinants influencing risk management activities. Furthermore, this study will assist financial institutions in making credit decisions. In addition, this study provides policymakers, such as the stand for Securities and Exchange Commission of Pakistan (SECP), with guidelines for developing policies that strengthen the board governance mechanism.Originality/valueThis study investigates the impact of AC characteristics on corporate risk, which is rarely discussed in emerging economies.
How organizational justice in the hospitality industry influences proactive customer service performance through general self-efficacy
Authors: Abuelhassan Abuelhassan Elshazly , AlGassim Ali 
Published: May 2022

Purpose
Based on social exchange theory (SET) and conservation of resources (COR) theory, this study aims to examine the unique combined impact of procedural justice (PJ) and distributive justice (DJ) on proactive customer service performance (PCSP) and general self-efficacy (GSE) in the hospitality industry. It also estimates these variables’ joint effect on PCSP controlling GSE.

Design/methodology/approach
The study’s results were derived from a sample of 380 frontline supervisor–subordinate dyads, placed in 18 five-star hotels, through three-wave data collection. The hypotheses and construct validity were generated through structural equation modeling.

Findings
The combined impact of DJ and PJ on GSE and PCSP was significantly positive, and GSE mediated the relationships between DJ and PCSP as well as PJ and PCSP.

Practical implications
To improve service employees’ GSE and PCSP, hospitality management should guide and encourage managers to highlight and maintain organizational justice (OJ) in all their strategies and operations. DJ and PJ are advised to appreciate service employees’ GSE and extra-role behaviors (e.g. PCSP) through providing organizational resources.

Originality/value
This paper offers unique practical and theoretical contributions to the hospitality industry and associated literature by implementing SET and COR theory with OJ, GSE and PCSP constructs.