bluuebunny/crossref_metadata_2025 huggingface dataset:
A CXCL12 morphogen gradient uncovers lung endothelial heterogeneity and promotes distal vascular growth
Authors: Chandrasekaran Prashant , Negretti Nicholas M. , Sivakumar Aravind , Peers de Nieuburgh Maureen , Wang Joanna , Michki Nigel S. , Chaudhry Fatima N. , Wen Hongbo , Kaur Sukhmani , Lu MinQi , Zepp Jarod A. , Young Lisa R. , Sucre Jennifer M.S. , Frank David B.
Published: May 2022

In adults, there is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury, however, molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to a large number of lung diseases in children, indicating a need to uncover fetal programs that promote pulmonary vascular growth. To address this, we used a transgenic mouse reporter for expression ofCxcl12, an arterial hallmark gene, and performed single-cell RNA sequencing on isolatedCxcl12-DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation, gene ontology analysis, and spatial transcriptomics allowed us to segregate the developing artery into spatially and functionally distinct novel subpopulations. In addition, expression ofCxcl12suggests a morphogen gradient from arteries to capillaries, suggesting directed cell migration for pulmonary vascular development. Disruption of this gradient led to abnormal branching and pulmonary vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development.
Toxicology assessment of manganese oxide nanomaterials with enhanced electrochemical properties using human in vitro models representing different exposure routes
Authors: Fernández-Pampin Natalia , Plaza Juan José González , García Alejandra , Peña Elisa , Rumbo Carlos , Barros Rocío , Martel Sonia , Aparicio Santiago , Tamayo-Ramos Juan Antonio
Published: May 2022

In the present study, a comparative human toxicity assessment between newly developed Mn3O4 nanoparticles with enhanced electrochemical properties (GNA35) and their precursor material (Mn3O4) was performed, employing different in vitro cellular models representing alveolar, oral and dermal exposure routes, namely the human alveolar carcinoma epithelial cell line (A549), the human colorectal adenocarcinoma cell line (HT29), and the reconstructed 3D human epidermal model EpiDerm™ (RhE). The obtained results showed that Mn3O4 and GNA35 harbour similar morphological characteristics, while differences were observed in relation to their thermal stability and electrochemical properties. In regard to their toxicological properties, both nanomaterials induced oxidative stress in the A549 and HT29 cell lines that have demonstrated that manganese oxide nanoparticles reduce the cell viability in A549 cells while they do not produce any negative effect on that of HT29 cells. On the other hand, it was observed that Mn3O4 and GNA35 induce oxidative stress in both cell lines. Finally, it was noticed that none of the nanoparticles caused a reduction of the viability on the skin tissue so that they could not be classified as irritants. Our findings demonstrate that the evaluation of the toxicity of nanoparticles using different models is a critical aspect to increase the knowledge on their potential impact on human health.
Hippocampal cAMP-dependent synaptic potentiation, ERK-dependent immediate-early gene activation, and context-dependent fear conditioning in mice are linked through dependence on the guanine nucleotide exchange factor RapGEF2
Authors: Jiang Sunny Zhihong , Shahoha Meishar , Tejeda Hugo A. , Ashery Uri , Eiden Lee E.
Published: May 2022

The MAP kinase ERK is important for neuronal plasticity underlying associative learning, yet specific molecular pathways for ERK activation in hippocampus are still largely undetermined. RapGEF2 has emerged as a neuron-specific cAMP sensor that mediates ERK activation. We investigated whether RapGEF2 might also be required for cAMP-dependent ERK activation leading to synaptic potentiation, and how this involvement might be penetrant to hippocampus-dependent learned behavior. We demonstrate that conditional knockout of Rapgef2 in forebrain neurons, specifically in dentate gyrus and CA1 of the hippocampus, leads to an attenuation of context-dependent fear conditioning, but not of cue-dependent fear conditioning, in mice. RapGEF2 knockout is associated with a reduction in cAMP-dependent synaptic potentiation at two central hippocampal synapses-the entorhinal cortex-granule cell synapse and the CA3-CA1 synapse. Furthermore, cAMP-induced postsynaptic potentiation requires both RapGEF2 and activation of ERK. Induction of Egr-1/Zif268 (and pERK), but not of c-Fos, immediately following fear conditioning, was abolished in CA1 and detate gyrus, in the absence of RapGEF2 expression in these hippocampal regions, thus revealing a link between learning (conditioning) and molecular pathways activated during conditioned fear memory formation. Hence, we suggest that contextual fear conditioning is mediated via RapGEF2-dependent ERK activation and downstream induction of Egr-1, via an underlying mechanism of cAMP-dependent long-term potentiation at hippocampal synapses. Cyclic AMP-dependent GEFs have been genetically associated as risk factors for schizophrenia, a disorder associated with cognitive deficits. This study provides a functional link between one of these cAMP-dependent GEFs, RapGEF2, and cognitive processes involved in associative learning.
Continued Emergence and Evolution of Omicron in South Africa: New BA.4 and BA.5 lineages
Authors: Tegally Houriiyah , Moir Monika , Everatt Josie , Giovanetti Marta , Scheepers Cathrine , Wilkinson Eduan , Subramoney Kathleen , Moyo Sikhulile , Amoako Daniel G. , Baxter Cheryl , Althaus Christian L. , Anyaneji Ugochukwu J. , Kekana Dikeledi , Viana Raquel , Giandhari Jennifer , Lessells Richard J. , Maponga Tongai , Maruapula Dorcas , Choga Wonderful , Matshaba Mogomotsi , Mayaphi Simnikiwe , Mbhele Nokuzola , Mbulawa Mpaphi B. , Msomi Nokukhanya ,   NGS-SA consortium, Naidoo Yeshnee , Pillay Sureshnee , Sanko Tomasz Janusz , San James E. , Scott Lesley , Singh Lavanya , Magini Nonkululeko A. , Smith-Lawrence Pamela , Stevens Wendy , Dor Graeme , Tshiabuila Derek , Wolter Nicole , Preiser Wolfgang , Treurnicht Florette K. , Venter Marietjie , Davids Michaela , Chiloane Georginah , Mendes Adriano , McIntyre Caitlyn , O’Toole Aine , Ruis Christopher , Peacock Thomas P. , Roemer Cornelius , Williamson Carolyn , Pybus Oliver G. , Bhiman Jinal , Glass Allison , Martin Darren P. , Rambaut Andrew , Gaseitsiwe Simani , Gottberg Anne von , de Oliveira Tulio
Published: May 2022

South Africa’s fourth COVID-19 wave was driven predominantly by three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern. We have now identified two new lineages, BA.4 and BA.5. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure with the TaqPath™ COVID-19 qPCR assay. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa from the first week of April 2022 onwards. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.07 - 0.09) and 0.12 (95% CI: 0.09 - 0.15) per day respectively over BA.2 in South Africa.
Predicting longitudinal brain atrophy in Parkinson’s disease using a Susceptible-Infected-Removed agent-based model
Authors: Abdelgawad Alaa , Rahayel Shady , Zheng Ying-Qiu , Tremblay Christina , Vo Andrew , Misic Bratislav , Dagher Alain
Published: May 2022

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in PD: in its misfolded pathologic state it favours the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal or synaptic damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation and toxicity of alpha-synuclein molecules in the brain. Here we test this model with longitudinal MRI collected over four years from the Parkinson Progression Markers Initiative (1068 T1 MRI scans, 790 PD, 278 matched controls). We find that brain deformation progresses in subcortical and cortical regions. The SIR model, using structural connectivity from diffusion MRI, recapitulates the spatiotemporal distribution of brain atrophy observed in PD. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in PD is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.
A transcriptional mechanism involving R-loop, m6A modification and RNA abasic sites regulates an enhancer RNA of APOE
Authors: Watts Jason A. , Grunseich Christopher , Rodriguez Yesenia , Liu Yaojuan , Li Dongjun , Burdick Joshua T , Bruzel Alan , Crouch Robert J. , Mahley Robert W. , Wilson Samuel H. , Cheung Vivian G.
Published: May 2022

The DNA genetic code and the RNA regulatory code determine phenotypes from gene expression to disease susceptibility. DNA sequence variants lead to phenotypic differences among individuals, while within an individual, RNA dynamically confers cell identity and responds to cellular and environmental signals. To provide regulation for different cell types and conditions, the nucleotides of RNA are modified by hundreds of chemical reactions, and RNA folds into innumerable shapes. To decipher the RNA regulatory code is to understand how RNA sequence and structure respond to cellular needs. Here, we deciphered one part of the RNA code where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We uncovered an enhancer RNA, AANCR, that regulates the transcription and expression of APOE. When AANCR is folded into an R-loop, which is then modified by N6-adenine methylation and N-glycosidic cleavage, it is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in some cell types and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. By genetic analysis, we confirmed that AANCR regulates APOE expression. DNA sequence variants in AANCR are associated with APOE expression and also with Alzheimer’s disease. Our data show that DNA and RNA sequence and structure jointly regulate gene expression that influence disease risk.

Highlights

m6A, RNA abasic sites and R-loops jointly regulate transcription by pausing RNA Polymerase II.

An enhancer RNA regulates APOE expression.

Enhancer RNA of APOE modifies susceptibility to Alzheimer’s disease.
Building a knowledge graph to enable precision medicine
Authors: Chandak Payal , Huang Kexin , Zitnik Marinka
Published: May 2022

Developing personalized diagnostic strategies and targeted treatments requires a deep understanding of disease biology and the ability to dissect the relationship between molecular and genetic factors and their phenotypic consequences. However, such knowledge is fragmented across publications, non-standardized research repositories, and evolving ontologies describing various scales of biological organization between genotypes and clinical phenotypes. Here, we present PrimeKG, a precision medicine-oriented knowledge graph that provides a holistic view of diseases. PrimeKG integrates 20 high-quality resources to describe 17,080 diseases with 4,050,249 relationships representing ten major biological scales, including disease-associated protein perturbations, biological processes and pathways, anatomical and phenotypic scale, and the entire range of approved and experimental drugs with their therapeutic action, considerably expanding previous efforts in disease-rooted knowledge graphs. PrimeKG supports drug-disease prediction by including an abundance of ‘indications’, ‘contradictions’ and ‘off-label use’ edges, which are usually missing in other knowledge graphs. We accompany PrimeKG’s graph structure with text descriptions of clinical guidelines for drugs and diseases to enable multimodal analyses.
Genome-wide identification ofSINAgene family in sugarcane and functional analysis ofSsSINA1ain drought response
Authors: Zhang Jinxu , Jiang Xialan , Xiao Shenghua , Jiang Shuo , Yao Wei , Zhang Muqing
Published: May 2022

Sugarcane (Saccharumspp. hybrid) is a crucial sugar and energy crop that provides majority of the raw material for sugar and ethanol production globally. Drought represents one of the most critical constraints of sugarcane production in the subtropical parts of China. SEVEN IN ABSENTIA (SINA) act as an important E3 ubiquitin ligase and play a significant role in plant stress responses. However, the characteristics of the sugarcaneSINAgene family have not been previously studied currently. Here, we identified 15SsSINAinSaccharum spontaneum, 5ShSINAinSaccharum spp. hybrid and 6SbSINAinSorghum bicolorbased on their conserved N□terminal RING and C-terminal SINA domains, and these genes were distributed into three phylogenetic groups (I, □ and □). Collinearity analysis showed a close genetic relationship between theSINAgenes ofS. spontaneumandS. bicolor. The cis-regulatory elements in the promoter regions of theSINAgenes were involved in a variety of plant physiological responses. Further, we identified aSINAgeneSsSINA1athat significantly induced by drought stress. Overexpression ofSsSINA1aenhanced drought tolerance in Arabidopsis through reducing leaf water loss rate. These finding indicate that SsSINA1a mediates plant drought tolerance and this study provides a new potential candidate gene for sugarcane drought-resistant breeding.
Tension-Tuned SynNotch Receptors for Synthetic Mechanotranduction and Intercellular Force Detection
Authors: Sloas D. Christopher , Tran Jeremy C. , Marzilli Alexander M. , Ngo John T.
Published: May 2022

Cells can sense and interpret mechanical stimuli from their environments and neighbors, but the ability to engineer customized mechanosensing capabilities has remained a synthetic and mechanobiology challenge. Here, we introduce tension-tuned synthetic Notch (SynNotch) receptors that can be used to convert extracellular and intercellular forces into specifiable gene expression changes. By elevating the tension requirements of SynNotch activation, in combination with structure-guided mutagenesis, we designed a set of receptors with mechanical sensitivities spanning the physiologically relevant picoNewton (pN) range. Cells expressing these receptors can distinguish between varying tensile forces and respond by enacting customizable transcriptional programs. The synthetic utility of these tools is demonstrated by designing a decision-making circuit, through which fibroblasts can be made to differentiate into myoblasts upon stimulation with distinct tension magnitudes. Mechanobiological utility is also demonstrated by characterizing cell-generated forces transmitted between cells during Notch signaling. Overall, this work provides insight regarding how mechanically induced changes in protein structure can be used to transduce physical forces into biochemical signals. The system should facilitate the further programming and dissection of force-related phenomena in biological systems.
A role for the anterior hippocampus in autobiographical memory construction regardless of temporal distance
Authors: Audrain Sam , Gilmore Adrian W. , Wilson Jenna M. , Schacter Daniel L. , Martin Alex
Published: May 2022

Mounting evidence suggests distinct functional contributions of the anterior and posterior hippocampus to autobiographical memory retrieval, but how these subregions function under different retrieval demands as memories age is not yet understood. Specifically, autobiographical memory retrieval is not a homogenous process, rather, it is thought to consist of multiple stages: an early stage of memory construction and a later stage of detailed elaboration, which may differently engage the hippocampus over time. In the present study, we analyzed data from 40 participants who constructed and overtly elaborated upon recent and remote memories in response to picture cues in the fMRI scanner. We previously reported a temporal gradient in the posterior hippocampus during the elaboration period of autobiographical retrieval, with posterior hippocampal activation observed for recent but not remote timepoints. Here, we consider the previously unanalyzed construction stage of retrieval, where participants searched for and selected a memory. We found no evidence of a temporal gradient during memory construction, instead observing strong anterior hippocampus activity regardless of memory remoteness. Our findings suggest a unique contribution of the anterior hippocampus to the construction process of autobiographical retrieval over time. These findings highlight that retrieval processes, which have yet to be considered in current models of systems consolidation, offer novel insights to hippocampal subregion function over time.
Coordinated control of neuronal differentiation and wiring by a sustained code of transcription factors
Authors: Özel Mehmet Neset , Gibbs Claudia Skok , Holguera Isabel , Soliman Mennah , Bonneau Richard , Desplan Claude
Published: May 2022

The enormous diversity of cell types in nervous systems presents a challenge in identifying the genetic mechanisms that encode it. Here, we report that nearly 200 distinct neurons in the Drosophila visual system can each be defined by unique combinations of ∼10 transcription factors that are continuously expressed by them. We show that targeted modifications of this ‘selector’ code induce predictable conversions of cell fates between neurons in vivo. These conversions appear morphologically and transcriptionally complete, arguing for a conserved gene regulatory program that jointly instructs both the type-specific development and the terminal features of neurons. Cis-regulatory sequence analysis of open chromatin links one of these selectors to an upstream patterning gene in stem cells that specifies neuronal fates. Experimentally validated network models show that selectors interact with ecdysone signaling to regulate downstream effectors controlling brain wiring. Our results provide a generalizable framework of how specific fates are initiated and maintained in postmitotic neurons.
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

Objective

Lithium 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.

Methods

Dose 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.

Results

LiCO 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.

Conclusions

LiOr 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

Background

Careful 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.

Methods

The 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.

Results

46 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.

Conclusions

Shaggy 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

Introduction

Complex 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 Methods

A 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.

Results

The 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.

Conclusion

Machine 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

Microglia 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

ALS 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

Parkinsona’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

Standard 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

Elucidating 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

The 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

YAP1 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

We 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

Purpose

The 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/approach

The 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.

Findings

According 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 implications

The 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/value

This 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.
Knowledge, risk perceptions and practices surrounding chronic inflammatory diseases among first and second generation South Asian immigrants parents and children
Authors: Rishworth Andrea C. , Niraula Ashika , Cao Tiffany , Carrillo Lay Jimena , Ferrari Justin , Zaman Sarah , Wilson Kathi
Published: May 2022

Purpose

The purpose of this study is to examine knowledge and perceptions of risk surrounding chronic inflammatory diseases (CIDs) and intergenerational development, as well as practices used to acquire CID information among unaffected first- and second-generation South Asian immigrant parents and children in the Greater Toronto Area, Ontario.

Design/methodology/approach

Fifty-four in-depth interviews with parents and children (18 parents, 36 children) were conducted by trained facilitators, recorded, transcribed and analyzed qualitatively.

Findings

Findings reveal that although CIDs disproportionately affect South Asian immigrants, this group has low knowledge and awareness of CID symptoms, risk factors and conditions. Yet when equipped with some knowledge about CIDs, participants linked their increased risk of CIDs to perceived risks in their broader environments such as climate variations, pollution, unhealthy food environments and health system neglect, that although yearning to change these factors, felt unable to modify their risks as factors were beyond their control. Although information is critical to manage CIDs, the findings reveal important and divergent knowledge pathways and practices used among first- and second-generation parents and children, particularly related to health-care settings and academic resources, underscoring generational disparities in knowledge acquisition.

Originality/value

The findings suggest that a multi-sector, multi-tiered approach built around a series of structural interventions, programs and policy changes is needed to address CID knowledge and awareness gaps and entrenched culturally insensitive health care to create more equitable access to healthy, safe and responsive environments and care systems for CID management.
Severe graft‐versus‐host disease‐like enterocolitis accompanied with cytomegalovirus‐reactivation in drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms
Authors: Takamiyagi Saeko , Iriki Hisato , Asahina Yasuhiko , Furuichi Yuki , Funakoshi Takeru , Ichikawa Masataka , Mikami Yohei , Okita Hajime , Sakiyama Tomo , Inazumi Toyoko , Amagai Masayuki , Takahashi Hayato
Published: May 2022

Drug‐induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug adverse reaction with skin eruption and visceral organ involvement. The characteristic clinical features of DIHS/DRESS are reactivation of human herpesviruses (HHV) and the development of autoimmune diseases, but their pathogenesis and associations are not yet understood. Here, we report a 66‐year‐old man who presented with fever, generalized erythema, diffuse lymphadenopathy, and diarrhea after 3 weeks of treatment with zonisamide. Reactivation of HHV‐6 and cytomegalovirus (CMV) was detected during the clinical course. The patient was diagnosed with DIHS/DRESS and treated with systemic prednisolone, i.v. immunoglobulin therapy, and ganciclovir. However, severe enterocolitis persisted for 6 months. A series of examinations revealed features of both CMV enterocolitis, as indicated by identification of a few CMV‐positive cells on immunohistochemical analysis, and graft‐versus‐host disease (GVHD)‐like enterocolitis indicated by orange‐peel appearance on endoscopic examination and histopathological loss of goblet cells. Intractable enterocolitis continued and the patient finally died of pneumonia. An autoimmune predisposition in DIHS/DRESS patients in combination with CMV reactivation was considered to trigger the severe enterocolitis of this case that showed GVHD‐like features of the gastrointestinal tract. GVHD‐like organ damage is a pathological condition rarely observed in DIHS/DRESS but should be recognized as one of the most severe complications of the disease.
China's Global Finance Footprint 2005–2014: Comparing AidData and CGIT
Authors: Ahmed Salma , Rasmussen Bruce , Sheehan Peter
Published: May 2022

The growth of Chinese global official finance has stimulated great interest among foreign aid advocates. Yet, until now, a lack of systematic data reporting has limited our understanding of Chinese official finance. Against this background, this article describes and compares two internationally comparable Chinese datasets from 2005 to 2014: AidData and the China Global Investment Tracker (CGIT). This study summarises China's priority areas of investment and the actual volume of Chinese finance, including a breakdown of these estimates by region and sector. Despite significant disparities between the two databases, this study shows that Chinese investment preferences in terms of locality and priority sectors are broadly consistent with the existing pattern.