bluuebunny/crossref_metadata_2025 huggingface dataset:
Vulnerable Brain Networks Associated with Risk for Alzheimer’s Disease
Authors: Mahzarnia Ali , Stout Jacques A , Anderson Robert J , Moon Hae Sol , Han Zay Yar , Beck Kate , Browndyke Jeffrey N , Dunson David B. , Johnson Kim G , O’Brien Richard J , Badea Alexandra
Published: June 2022

Brain connectomes provide untapped potential for identifying individuals at risk for Alzheimer’s disease (AD), and can help provide novel targets based on selective circuit vulnerability. Age, APOE4 genotype, and female sex are thought to contribute to the selective vulnerability of brain networks in Alzheimer’s disease, in a manner that differentiates pathological versus normal aging. These brain networks may predict pathology otherwise hard to detect, decades before overt disease manifestation and cognitive decline. Uncovering network based biomarkers at prodromal, asymptomatic stages may offer new windows of opportunity for interventions, either therapeutic or preventive. We used a sample of 72 people across the age span to model the relationship between Alzheimer’s disease risk and vulnerable brain networks. Sparse Canonical Correlation analysis (SCCA) revealed relationships between brain subgraphs and AD risk, with bootstrap based confidence intervals. When constructing a composite AD risk factor based on sex, age, genotype, the highest weight was associated with genotype. Next, we mapped networks associated with auditory, visual, and olfactory memory, and identified networks extending beyond the main nodes known to be involved in these functions. The inclusion of cognitive metrics in a composite risk factor pointed to vulnerable networks, and associated with the specific memory tests. These regions with the highest cumulative degree of connectivity in our studies were the pericalcarine, insula, banks of the superior sulcus and cerebellum. To help scale up our approach, we extended Tensor Network Principal Component Analysis (TNPCA) to evaluate AD risk related subgraphs, introducing CCA components and sparsity. When constructing a composite AD risk factor based on sex, age, and genotype, and family risk factor the most significant risk was associated with age. Our sparse regression based predictive models revealed vulnerable networks associated with known risk factors. The prediction error was 17% for genotype, 24% for family risk factor, and 5 years for age. Age prediction in groups including MCI and AD subjects involved several regions that were not prominent for age prediction otherwise. These regions included the middle and transverse temporal, paracentral and superior banks of temporal sulcus, as well as the amygdala and parahippocampal gyrus. The joint estimation of AD risk and connectome based mappings involved the cuneus, temporal, and cingulate cortices known to be associated with AD, and add new candidates, such as the cerebellum, whose role in AD is to be understood. Our predictive modeling approaches for AD risk factors represent a stepping stone towards single subject prediction, based on distances from normative graphs.
A loss of crAssphage stability in the human gut virome is associated with obesity and metabolic syndrome
Authors: Cervantes-Echeverría Melany , Gallardo-Becerra Luigui , Cornejo-Granados Fernanda , Leyva Adrian Ochoa
Published: June 2022

Viral metagenomics studies of the human gut microbiota unravel differences in phage populations between healthy and disease, stimulating interest in the role that phages play in bacterial ecosystem regulation. CrAssphages are not only the most abundant viruses but also are a common component of the gut phageome across human populations. However, the role of crAssphages in obesity (O) and obesity with metabolic syndrome (OMS) remains largely unknown. Therefore, we explored the role that crAssphages have on both diseases in a children’s cohort. We found decreased crAssphage abundance, prevalence, richness, and diversity in O and OMS compared to normal-weight (NW), suggesting a loss of crAssphages stability in the human phageome associated with the disease. Interestingly, when we analyzed the abundance of host crAssphages bacteria, we found that Bacteroidetes, Bacteroidia, and Bacteroidales were significantly decreased in O and OMS, suggesting a possible relation with the loss of crAssphages stability. Regarding crAssphage taxonomy, a significantly decreased abundance of the crAssphage Alpha subfamily and the Alpha_1 and Alpha_4 genus and a significant overabundance of the Delta_8 was found in OMS. A strong taxonomical signature of obesity is the over-abundance of Bacilli, which also were significantly increased in O and OMS. Notably, we found a significant negative correlation between crAssphages and Bacilli abundances, suggesting an association between the decreased abundance of crAssphage and the over-abundance of Bacilli in OMS. Furthermore, we found a loss of crAssphage stability in the human virome associated with the presence of obesity, having a more significant impact on obesity with metabolic syndrome, suggesting that these bacteriophages could play an essential role in inhibiting metabolic syndrome in obese individuals. Our results open a promising treatment for these diseases through fecal crAssphage transplantation.
A Mechanistic Study on the Cellular Uptake, Intracellular Trafficking, and Antisense Gene Regulation of Bottlebrush Polymer-Conjugated Oligonucleotides
Authors: Zhang Lei , Wang Yuyan , Chen Peiru , Wang Dali , Zhang Zheyu , Wang Ruimeng , Kang Xi , Fang Yang , Lu Hao , Cai Jiansong , Ren Mengqi , Dong Sijia , Zhang Ke
Published: June 2022

We have developed a non-cationic transfection vector in the form of a bottlebrush polymer-antisense oligonucleotide (ASO) conjugate. Termed pacDNA (polymer-assisted compaction of DNA), these agents show improved biopharmaceutical characteristics and antisense potency in vivo while suppressing non-antisense side effects. Nonetheless, there still lacks a mechanistic understanding regarding the cellular uptake, subcellular trafficking, and gene knockdown with pacDNA. Here, we show that the pacDNA enters human non-small cell lung cancer cells (NCI-H358) predominantly by scavenger receptor-mediated endocytosis and macropinocytosis, and trafficks via the endolysosomal pathway within the cell. The pacDNA significantly reduces a target gene expression (KRAS) in the protein level but not in the mRNA level, despite that the transfection of free ASOs causes ribonuclease H1 (RNase H)-dependent degradation of KRAS mRNA. In addition, the antisense activity of pacDNA is independent of ASO chemical modification, suggesting that the pacDNA functions as a steric blocker.

TOC
High Mortality among Older Patients Hospitalized with COVID-19 during the First Pandemic Wave
Authors: Kempker Russell R , Rebolledo Paulina A , Rollin Francois , Gurbani Saumya , Schechter Marcos C. , Wilhoite David , Bogard Sherri N. , Watkins Stacey , Duggal Aarti , John Nova , Kapuria Malavika , Terry Charles , Yang Philip , Dale Gordon , Mora Ariana , Preslar Jessica , Sandor Kaitlin , Wang Yun F (Wayne) , Woodworth Michael H , Kempker Jordan A
Published: June 2022

Background

Understanding the local epidemiology, including mortality, of COVID-19 is important for guiding optimal mitigation strategies such as vaccine implementation, need for study of more effective treatment, and redoubling of focused infection control measures.

Methods

A retrospective observational cohort study design was utilized. We included adult patients diagnosed in the hospital or emergency department with COVID-19 from March 8, 2020 through May 17, 2020 at Grady Memorial Hospital (Atlanta, GA). Medical chart data abstraction was performed to collect clinical, laboratory and outcome data. Death, defined as inpatient mortality or discharge to hospice, was the primary outcome.

Results

Among 360 persons with laboratory-confirmed COVID-19, 50% were ≥ 60 years, and most (80%) were Black and had a BMI ≥25 kg/m2 (64%). A total of 53 patients (15%) had an outcome of death with the majority (n=46, 88%) occurring in persons ≥ 60 years. Persons ≥ 60 years were less likely to have typical COVID-19 symptoms while more likely to have multiple comorbidities, multifocal pneumonia, and to be admitted to intensive care. The death rate was 27% among persons ≥60 years versus 4% in those <60 years (p<.01). Furthermore, most deaths (n=40, 75%) occurred among residents of long-term care facilities (LCFs).

Conclusions

We describe early COVID-19 cases among predominantly Black and older patients from a single center safety net hospital. COVID-19 related mortality occurred predominantly among older patients from LCFs highlighting the need for improved preparedness and supporting prioritization of vaccination efforts in such settings.
The layered costs and benefits of translational redundancy
Authors: Raval Parth K , Ngan Wing Yui , Gallie Jenna , Agashe Deepa
Published: June 2022

The rate and accuracy of translation hinges upon multiple components – including transfer RNA (tRNA) pools, tRNA modifying enzymes, and rRNA molecules – many of which are redundant in terms of gene copy number or function. It has been hypothesized that the redundancy evolves under selection, driven by its impacts on growth rate. However, we lack empirical measurements of the fitness costs and benefits of redundancy, and we have poor understanding of how this redundancy is organized across components. We manipulated redundancy in multiple translation components of Escherichia coli by deleting 28 tRNA genes, 3 tRNA modifying systems, and 4 rRNA operons in various combinations. We find that redundancy in tRNA pools is beneficial when nutrients are plentiful, and costly under nutrient limitation. This nutrient-dependent cost of redundant tRNA genes stems from upper limits to translation capacity and growth rate, and therefore varies as a function of the maximum growth rate attainable in a given nutrient niche. The loss of redundancy in rRNA genes and tRNA modifying enzymes had similar nutrient-dependent fitness consequences. Importantly, these effects are also contingent upon interactions across translation components, indicating a layered hierarchy from copy number of tRNA and rRNA genes to their expression and posttranscriptional modification. Overall, our results indicate both positive and negative selection on redundancy in translation components, depending on a species’ evolutionary history with feasts and famines.
Evaluation of targeted oxidative stress induced by oxygen-ozone gas mixtures in vitro after ischemic induction
Authors: Orlandin Jessica Rodrigues , Santos Sarah Ingrid Pinto , Machado Luciana Cristina , Neto Paulo Fantinato , Bressan Fabiana Fernandes , Pieri Naira Caroline Godoy , Recchia Kaiana , Coutinho Meline de Paula , Ferreira Pinto Priscilla Avelino , Santucci Annalisa , Travagli Valter , Ambrosio Carlos Eduardo
Published: June 2022

Encephalic vascular accident, or stroke, is the most common pathology of the central nervous system in humans. It is the second leading cause of death, as well as physical and cognitive disabilities, in developing countries. It is a vascular disorder that may present in an ischemic (more common) or hemorrhagic form. Ozone is a gas capable of oxidizing double bonds of organic molecules, thereby producing lipoperoxides and aldehydes. Stimulation of the immune and antioxidant system, and improvement in tissue vascularization and oxygenation, are few among several effects exerted by ozone. Ozone therapy has previously been shown to be effective in neuromodulation, neuroprotection, and nerve regeneration. The present study aimed to evaluate the effect of targeted mild ozone after inducing cerebral ischemia in vitro. The experiment was divided into two steps; in the first step, neuroblastoma lineage cells (SH-SY5Y) were subjected to 24 hours of hypoxia in an incubator culture chamber. Treatment with different concentrations of ozone (2–10 µg/mL), followed by an 2,5-diphenyl-2H-tetrazolium bromide assay, indicated a possible neuroregenerative effect at low concentrations. The same protocol was applied to canine amniotic membrane stem cells that were evaluated via colorimetric assay spectrophotometry, fluorescence microscopy, and flow cytometry. The metabolic conditions and cellular regeneration in cells at low ozone concentrations (3–8 µg/mL) correlated with lower levels of apoptosis and oxidative stress compared to cells not subjected to hypoxia. High concentrations of ozone (18–30 µg/mL) promoted an increase in rate of apoptosis and cell death. Therefore, we developed a novel protocol that mimics ozone therapy for ischemic stroke, using ozonized culture medium after hypoxia induction. Although more studies are needed to open new avenues for translational medicine, we conclude that ozone has a dose-dependent hormetic effect and can reverse the effect of ischemia in vitro at low concentrations.
Early and lifelong effects of APOE4 on neuronal gene expression networks relevant to Alzheimer’s disease
Authors: Grone Brian P. , Zalocusky Kelly A. , Hao Yanxia , Yoon Seo Yeon , Arriola Patrick , Huang Yadong
Published: June 2022

Apolipoprotein E4 (APOE4) genotype and aging are critical risk factors for Alzheimer’s disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mice showed prominent alterations, relative to APOE3-KI mice, in neuronal transcriptome related to synaptic function, calcium signaling, and MAPK/Rap1/Pld signal transduction, starting by 5 months and persisting during aging. Mice with the APOE4 gene removed specifically from neurons failed to show most of these neuronal transcriptomic changes, suggesting a specific effect of neuron-derived APOE4 on the transcriptome. APOE4 affects similar cellular pathways in induced pluripotent stem cell-derived human neurons transplanted into APOE4-KI mouse hippocampus and in cortical neurons from aged human brains. Thus, neuronal APOE4 has early and persistent effects on neuronal transcriptomes, suggesting the requirement of early interventions for successfully treating APOE4-related AD.
Identification of chemo-sensory genes from antennae of female banana pseudostem weevil, Odoiporous longicollis by transcriptomics approach
Authors: Mani Kannan , Balakrishnan Padmanaban , Soroker Victoria
Published: June 2022

In the present study, the female O. longicollis antennal transcriptome was constructed by Illumina Hiseq 2500™ sequencing, with the aim of discovering olfaction-related genes. Totally 12, 411 unigenes were identified from the transcriptome assembly and the putative genes functions were annotated using gene ontology tools. We identified 46 putative chemosensory unigenes likely essential for insect olfaction including 19 odorant binding proteins, 3 Niemann–Pick type C (NPC) protein, 6 odorant receptors, 15 ionotropic receptors, and 3 sensory neuron membrane proteins. The key function of these chemosensory genes in the antennae are discussed. Phylogenetic analysis of NPC revealed that the identified proteins had a close relationship with Coleopterans than other insects. This is the first ever report on identification of olfactory genes from O. longicollis which may provide new leads for control of this major pest.
Smart-design of universally decorated nano-particles for drug delivery applications driven by active transport
Authors: Halbi Gal , Fayer Itay , Aranovich Dina , Brik Ashraf , Granek Rony , Bernheim-Groswasser Anne
Published: June 2022

Targeting the cell nucleus remains a challenge for drug delivery. Here we present a universal platform for smart design of nano-particles (NPs) decoration that allows recruitment of multiple dynein motors to drive their active motion towards the nucleus. The uniqueness of our approach is based on using: (i) a spacer polymer, commonly Biotin-Polyethylene-glycol-thiol (B-PEG-SH), whose grafting density and molecular weight can be tuned thereby allowing NP transport optimization, and (ii) protein binding peptides, like cell penetrating, NLS, or cancer targeting, peptides. Universal chemistry is employed to link peptides to the PEG free-end. To manifest our platform, we use a SV40T large antigen-originating NLS peptide. Our modular design allows tuning the number of recruited motors, and to replace the NLS by a variety of other localization signal molecules. Our control of the NP decoration scheme, and the modularity of our platform, carries great advantage for nano-carrier design for drug delivery applications.
Structural basis for activation of DNMT1
Authors: Kikuchi Amika , Onoda Hiroki , Yamaguchi Kosuke , Kori Satomi , Matsuzawa Shun , Chiba Yoshie , Tanimoto Shota , Yoshimi Sae , Sato Hiroki , Yamagata Atsushi , Shirouzu Mikako , Adachi Naruhiko , Sharif Jafar , Koseki Haruhiko , Nishiyama Atsuya , Nakanishi Makoto , Defossez Pierre-Antoine , Arita Kyohei
Published: June 2022

DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA recognition helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.
Revealing invisible cell phenotypes with conditional generative modeling
Authors: Lamiable Alexis , Champetier Tiphaine , Leonardi Francesco , Cohen Ethan , Sommer Peter , Hardy David , Argy Nicolas , Massougbodji Achille , Del Nery Elaine , Cottrell Gilles , Kwon Yong-Jun , Genovesio Auguste
Published: June 2022

Biological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and observation. Aside from dramatic events such as cell division or cell death, most cell phenotypic changes that keep cells alive are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. While we show that deep learning models can leverage invisible features from microscopy images, to discriminate between close conditions, these features can yet hardly be observed and therefore interpreted. In this work, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases such as high concentration drug treatments, nuclear translocation and golgi apparatus assays. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs or low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to the accessible discovery of biological and disease biomarkers.
Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer
Authors: Kandala Sridhar , von Voithenberg Lena Voith , Chocarro Sara , Ramos Maria , Keding Johanna , Brors Benedikt , Imbusch Charles D. , Sotillo Rocio
Published: June 2022

Chromosomal instability (CIN), the inability to correctly segregate chromosomes during cell division, is a common characteristic of solid tumors. CIN contributes to tumor evolution by promoting intratumor heterogeneity, thus facilitating resistance to cancer therapies.In vitrostudies have demonstrated that cells with complex karyotypes are recognized and eliminated by natural killer (NK) cells. Paradoxically, it has also been observed that human tumors with high levels of CIN have an immunosuppressive phenotype. It remains unclear which CIN-associated molecular features alter immune recognition during tumor evolution.

Previous studies with Polo-like kinase 1 (Plk1) overexpression in Her2-positive breast tumors, resulted in increased levels of CIN and delayed tumorigenesis. Using this mouse model, we show that high CIN tumors activate a senescence-associated secretory phenotype (SASP) and become immune evasive by activating RELB signaling and upregulating PD-L1 in a non-cell-autonomous manner. Single-cell RNA sequencing of immune cells from early-stage induced mammary glands revealed that macrophages, NK cells, B cells and regulatory T cells are programmed to a suppressive phenotype during tumor development. In human tumors, we further establish the importance of RELB/p38 signaling in understanding the interplay between CIN and the immune system, highlighting the need for novel adjuvant therapies in the context of chromosomally unstable tumors.
Structural and mechanistic insights into the DNA glycosylase AAG-mediated base excision in nucleosome
Authors: Zheng Lvqin , Tsai Bin , Gao Ning
Published: June 2022

DNA glycosylase engaging with damaged base marks the initiation of base excision repair. Nucleosome-based packaging of eukaryotic genome obstructs DNA accessibility, and how DNA glycosylases locate the substrate site on nucleosomes is currently unclear. Here, we report cryo-electron microscopy structures of nucleosomes bearing a deoxyinosine (DI) in various geometric positions and structures of them in complex with DNA glycosylase AAG. The apo nucleosome structures show that the presence of a deoxyinosine alone perturbs nucleosomal DNA globally, leading to a general weakening of the interface between DNA and the histone core and a greater flexibility to the exit/entry of the nucleosomal DNA. AAG makes use of this nucleosomal plasticity and imposes further local deformation of the DNA through the formation of the stable enzyme-substrate complex. Mechanistically, local distortion augment, translation/rotational register shift and partial opening of the nucleosome are employed by AAG to cope with substrate sites in fully exposed, occluded and complete buried positions, respectively. Our findings reveal the molecular basis for the DI-induced modification on the structural dynamics of the nucleosome and elucidate how DNA glycosylase AAG accesses damaged sites on the nucleosome with different solution accessibility.
Schedule-dependent production of stereotyped sequences of actions
Authors: Follman Emma G. , Chevée Maxime , Kim Courtney J. , Johnson Amy R. , Tat Jennifer , Calipari Erin S.
Published: June 2022

Concatenating actions into automatic routines is evolutionarily advantageous as it allows organisms to efficiently use time and energy under predictable conditions. However, over reliance on inflexible behaviors can be life-threatening in a changing environment and can become pathological in disease states such as obsessive-compulsive disorder (OCD) and substance use disorder (SUD). Understanding the conditions under which stereotypical sequences of actions are produced is crucial to studying how these behaviors can become maladaptive. Here, we investigated the ability of operant conditioning schedules and contingencies to promote reproducible sequences of five lever presses. We found that signaling reinforcer delivery with a visual cue was effective at increasing learning rates but resulted in mice pressing the lever in fast succession until the cue turned on, rather than pressing it five times. We also found that requiring mice to collect their reinforcer between sequences had little effect on both rate of behavior and on quantitative metrics of reproducibility such as interresponse interval (IRI) variance, and that a training strategy that directly reinforced sequences with low variance IRIs was not more effective than a traditional fixed ratio schedule at promoting reproducible action execution. Together, our findings provide insights into the parameters of behavioral training that promote reproducible sequences and serve as a roadmap to investigating the neural substrates of automatic behaviors.
Columnar scale lesions in barrel cortex degrade tactile discrimination but not detection
Authors: Ryan Lauren , Laughton Maya , Sun-Yan Andrew , Pancholi Ravi , Peron Simon
Published: June 2022

Primary sensory cortices typically display functional topography, suggesting that even small cortical volumes may underpin perception of specific stimuli. Because traditional loss-of-function approaches have a relatively large radius of effect (>1 mm), the behavioral necessity of smaller cortical volumes remains unclear. In the mouse primary vibrissal somatosensory cortex (vS1), ‘barrels’ with a radius of ∼150 μm receive input predominantly from a single whisker, partitioning vS1 into a topographic map of well-defined columns. Here, we train animals implanted with a cranial window over vS1 to perform single-whisker perceptual tasks. We then use high-power laser exposure centered on the barrel representing the spared whisker to produce lesions with an average volume of ∼2 barrels. These columnar scale lesions impair performance on object location discrimination tasks without disrupting vibrissal kinematics. Animals with degraded discrimination performance can immediately perform a detection task with high accuracy. Animals trained de novo on both simple and complex detection tasks showed no behavioral deficits following columnar scale lesions. Thus, vS1 barrels are necessary for performing object location discrimination but not simple or complex object detection behaviors.
FUN-PROSE: A Deep Learning Approach to Predict Condition-Specific Gene Expression in Fungi
Authors: Nambiar Ananthan , Dubinkina Veronika , Liu Simon , Maslov Sergei
Published: June 2022

mRNA levels of all genes in a genome is a critical piece of information defining the overall state of the cell in a given environmental condition. Being able to reconstruct such condition-specific expression in fungal genomes is particularly important for the task of metabolic engineering of these organisms to produce desired chemicals in industrially scalable conditions. Most of the previous deep learning approaches focused on predicting the average expression levels of a gene based on its promoter sequence, ignoring its variation across different conditions. Here we present FUN-PROSE - a deep learning model trained to predict differential expression of individual genes across various conditions using their promoter sequences and expression levels of all transcription factors. We train and test our model on three fungal species:Saccharomyces cerevisiae,Neurospora crassaandIssatchenkia orientalisand get the correlation between predicted and observed condition-specific gene expression as high as 0.85. We then interpret our model to extract promoter sequence motifs responsible for variable expression of individual genes. We also carried out input feature importance analysis to connect individual transcription factors to their gene targets. A sizeable fraction of both sequence motifs and TF-gene interactions learned by our model agree with previously known biological information, while the rest corresponds to either novel biological facts or indirect correlations.
CDK6 activity in a recurring convergent kinase network motif
Authors: Gangemi Christina , Sabapathy Rahkesh T , Janovjak Harald
Published: June 2022

More than 500 kinases phosphorylate ∼15% of all human proteins. The architecture of the phosphorylation network has been studied extensively, for instance to compile global interaction maps, trace signal transduction pathways or identify chemical intervention points. In contrast, systematic investigation of local motifs is rare but may provide a complementary understanding of network and kinase function. Here, we report on the occurrence, topology and experimental analysis of convergent kinase-substrate relationships (cKSRs) in which ≥two kinases phosphorylate the same substrate. Through bioinformatics analysis we found that human cKSRs are frequent and involve >80% of all kinases and >24% of all substrates. We show that cKSRs occur over a wide range of stoichiometries harnessing converging kinases that are in many instances recruited from the same family subgroup and co-expressed. Experimentally, we demonstrate at the prototypical convergent CDK4/6 kinase pair how multiple inputs at the major tumor suppressor retinoblastoma protein (RB) can hamper in situ analysis of individual kinases. We hypothesized that overexpression of one kinase combined with a CDK4/6 inhibitor can dissect convergence. In breast cancer cells that express high levels of CDK4, we confirmed this hypothesis and developed a high throughput compatible assay that sensitively quantifies genetically modified CDK6 variants and small molecule or protein inhibitors. Collectively, our work provides deeper insights into the phosphorylation network through the identification and analysis of kinase convergence.
Leveraging the CSF proteome toward minimally-invasive diagnostics and biological characterization of brain malignancies
Authors: Mikolajewicz Nicholas , Khan Shahbaz , Trifoi Mara , Skakdoub Anna , Ignatchenko Vladmir , Mansouri Sheila , Zuccatto Jeffrey , Zacharia Brad E. , Glantz Michael , Zadeh Gelareh , Moffat Jason , Kislinger Thomas , Mansouri Alireza
Published: June 2022

1

Background

Diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk.

Objective

To identify diagnostic and prognostic cerebrospinal fluid (CSF) proteomic signatures in glioblastoma (GBM), brain metastases (BM), and primary central nervous system lymphoma (CNSL).

Methods

CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics. Proteomic signatures were identified using machine learning classifiers and survival analyses.

Results

Using 30 µL CSF volumes, we recovered 755 unique proteins across 73 samples. Proteomic-based classifiers identified malignancy with area under the receiver operating characteristic (AUROC) of 0.94 and distinguished between tumor entities with AUROC ≥0.95. More clinically relevant triplex classifiers, comprised of just 3 proteins, distinguished between tumor entities with AUROC of 0.75-0.89. Novel biomarkers were identified, including GAP43, TFF3 and CACNA2D2, and characterized using single-cell RNA sequencing. Survival analyses validated previously implicated prognostic signatures, including blood brain barrier disruption.

Discussion

Reliable classification of intra-axial malignancies using low CSF volumes is feasible, allowing for longitudinal tumor surveillance. Based on emerging evidence, upfront implantation of CSF reservoirs in brain tumor patients warrants consideration.

2

Statement of Significance

Current approaches to diagnosing brain tumors risk morbidity. The CSF may be an ideal liquid biopsy matrix for mitigating this risk. We report feasibility of high-throughput CSF proteomics on limited volumes from brain tumor patients with intraventricular reservoirs, demonstrate diagnostic and prognostic utility, and explore its applications in practice.
Environmental regulation of gene expression mediated by Long non-coding RNAs
Authors: Kang Jingliang , Chung Arthur , Suresh Sneha , Bonzi Lucrezia L. , Sourisse Jade M. , Ramirez Sandra , Romeo Daniele , Petit-Marty Natalia , Pegueroles Cinta , Schunter Celia
Published: June 2022

The majority of the transcribed genome does not have coding potential but is composed of non-coding transcripts that are involved in transcriptional and post-transcriptional regulation of protein-coding genes. Regulation of gene expression is important in determining the response of organisms to changes in the environment, and therefore their persistence as population or species under global change. However, long non-coding RNAs (lncRNAs) are scarcely studied especially in non-model organisms due to the lack of a reliable pipeline for their accurate identification and annotation. Here, we present a pipeline which uses a combination of alignment-dependent and independent methods for the identification of conserved and species-specific lncRNAs from RNA-Seq data. Validation of this pipeline was performed using existing RNA-Seq data fromAcanthochromis polyacanthusbrain tissue, identifying a total of 4,728 lncRNAs across the genome, the majority of which (3,272) are intergenic. To investigate the possible implications of these intergenic lncRNAs (lincRNAs), we estimated the expression changes of lincRNAs and coding genes in response to ocean acidification. We found lincRNAs which neighbour or possibly trans-regulate differentially expressed coding genes related to pH regulation, neural signal transduction and ion transport, which are known to be important in the response to ocean acidification in fish. Overall, this pipeline enables the use of existing RNA sequencing data to reveal additional underlying molecular mechanisms involved in the response to environmental changes by integrating the study of lncRNAs with gene expression.
Estimating population split times and migration rates from historical effective population sizes
Authors: Shchur Vladimir , Brandt Débora Y. C. , Ilina Anna , Nielsen Rasmus
Published: June 2022

The estimation of effective population sizes (Ne) through time is of fundamental interest in population genetics, but the interpretation of Ne as the effective number of breeding individuals in the population is challenged by the effect of population structure. In fact, variation in Ne reported in many studies may be a consequence of changes in migration rates between populations rather than changes in actual population size. We address this long-standing problem here by constructing joint models of population size changes, migration, and divergence that can adjust temporal estimates of Ne and estimate the actual Ne of a local deme connected to another population through migration. We also develop a method for estimating divergence times and migration rates taking into account complex scenarios of changing population sizes. We apply the method to previously published data from humans, and show that, when taking migration and changes in Ne into account, the estimated divergence between the San and Dinka populations is approximately 108 kya, and not 255 kya as reported in a previous study. Using simulations, we demonstrate that the previously reported and surprisingly old estimates of divergence between San and Dinka is in fact caused by a quantifiable estimation bias due to changes in Ne through time.
Euler–Lagrange method for low-frequency metamaterials
Authors: Gong Zhi , Yang Shiyou , Guan Chongxi
Published: June 2022

Purpose

The purpose of this paper is to develop a modeling method for the analysis of low-frequency metamaterials (MTMs) and their near-field applications.

Design/methodology/approach

The Euler–Lagrange method is introduced. An MTM is modeled as a multi-degree-of-freedom system without homogenization. The properties and the responses of the MTM in a near-field device are readily and rigorously studied through the motion equation derived from the Lagrange equations. The resonance frequencies and the corresponding resonance modes are solved from the characteristic equation.

Findings

The numerical results of the proposed method show good agreement with the experimental ones. A measurement of MTM-core coil resistance and inductance shows high accuracy of the proposed method.

Originality/value

The proposed Euler–Lagrange method provides a new study perspective and enables more flexible, rigorous and straightforward analysis of low-frequency MTMs in near-field applications. Consequently, the presented work greatly facilitates further explorations and studies on various novel MTM-based low-frequency near-field devices and systems.
Hidden multiwing chaotic attractors with multiple stable equilibrium points
Authors: Deng Quanli , Wang Chunhua , Wu Yazheng , Lin Hairong
Published: June 2022

Purpose

The purpose of this paper is to construct a multiwing chaotic system that has hidden attractors with multiple stable equilibrium points. Because the multiwing hidden attractors chaotic systems are safer and have more dynamic behaviors, it is necessary to construct such a system to meet the needs of developing engineering.

Design/methodology/approach

By introducing a multilevel pulse function into a three-dimensional chaotic system with two stable node–foci equilibrium points, a hidden multiwing attractor with multiple stable equilibrium points can be generated. The switching behavior of a hidden four-wing attractor is studied by phase portraits and time series. The dynamical properties of the multiwing attractor are analyzed via the Poincaré map, Lyapunov exponent spectrum and bifurcation diagram. Furthermore, the hardware experiment of the proposed four-wing hidden attractors was carried out.

Findings

Not only unstable equilibrium points can produce multiwing attractors but stable node–foci equilibrium points can also produce multiwing attractors. And this system can obtain 2N+ 2-wing attractors as the stage pulse of the multilevel pulse function isN. Moreover, the hardware experiment matches the simulation results well.

Originality/value

This paper constructs a new multiwing chaotic system by enlarging the number of stable node–foci equilibrium points. In addition, it is a nonautonomous system that is more suitable for practical projects. And the hardware experiment is also given in this article which has not been seen before. So, this paper promotes the development of hidden multiwing chaotic attractors in nonautonomous systems and makes sense for applications.
Analysis of forced convective nanofluid flow through a wavy channel with linearly varying amplitude at the entrance
Authors: Kumar Ajit , Mehta Sumit Kumar , Pati Sukumar , Baranyi László
Published: June 2022

Purpose

The purpose of this paper is to analyze the heat and momentum transfer for steady two-dimensional incompressible nanofluid flow through a wavy channel with linearly varying amplitude in the entrance region.

Design/methodology/approach

The mass, momentum and energy conservation equations for laminar flow of Cu-water nanofluids are computationally solved using the finite element method. A parametric study is carried out by varying the dimensionless length of the channel section with varying amplitude (EL), Reynolds number (Re) and nanoparticle volume fraction (Φ) in the ranges 0 ≤ EL ≤ 25.5, 105 ≤ Re ≤ 900 and 0 ≤ Φ ≤ 0.04.

Findings

A higher heat transfer rate is seen in the wavy channel compared to a plane channel beyond a critical value of Re (Recrit) whose value varies with EL; moreover, the overall heat transfer decreases with EL. The heat transfer rate increases with phi for all EL values investigated. The combined effects of the increase in the overall heat transfer and the associated pressure drop in the wavy channel compared to the parallel plate channel are presented as performance factor (PF) against EL. For the highest value of EL (= 25.5), PF monotonically decreases with Re. For smaller values of EL (= 5.5 and 11.5) and also for EL = 0, PF decreases with Re in the lower and the higher Re regimes, while it increases in the intermediate Re regime. In all cases, PF is higher for φ = 0.04 than for the base fluid. The sensitivity of the average Nusselt number to nanoparticle volume fraction follows a non-monotonic trend with the change in Re, φ and EL.

Practical implications

This study finds relevance in several applications such as solar collectors, heat exchangers and heat sinks.

Originality/value

To the best of the authors’ knowledge, the analysis of forced convection flow of nanofluid through a wavy channel with linearly varying amplitude is reported for the first time in the literature.
Foreign investment horizons, corporate governance and payout policy
Authors: Lee Eun Jung , Kim Sungmin , Jang Yongwon
Published: June 2022

This paper examines whether long-term foreign investors may force firms to use a costly dividend to mitigate inefficient managerial behavior. The authors also hypothesize that the relation between foreign investment horizons and payout policy depends upon the extent of the corporate governance. The authors find that firms held by long-term foreign investors make dividend more often in the subsequent years. The authors also find that foreign investors with long-term investments do not cause firms to pay dividends when firms have strong corporate governance. It suggests that long-term foreign investors serve as a substitute for strong corporate governance with respect to controlling agency conflicts.
A systematic review on halal cosmetic consumption: application of theory method context – attributes decision outcome framework
Authors: Herjanto Halimin , Amin Muslim , Karmagatri Mulyani
Published: June 2022

Purpose

This study aims to offer a holistic halal cosmetic consumption framework by describing the current knowledge about halal cosmetics and presenting new directions for future research.

Design/methodology/approach

The theory, method and context–attributes, decision and outcome systematic review framework was used in this study. This study addresses the halal cosmetics literature published in the Scopus database: nonpredatory journals between 2010 and 2021.

Findings

This study found seven antecedent categories that affect four halal cosmetics consumption decisions. Those decisions led to three outcomes. In addition, behavioral theories were identified as the most frequent theory used to explain this phenomenon in personal and business settings.

Originality/value

To the best of the authors’ knowledge, this is the first systematic review of halal cosmetics consumption. This study explores the relevant theories, contexts, methods, antecedents and consumer decisions. Therefore, this study offers important insights into this phenomenon.
The impact of income gap on regional green economic growth – evidence from 283 prefecture-level cities in China
Authors: Hou Shiying , Song Liangrong , Dai Wanrui
Published: June 2022

Purpose

This paper aims to research the relationship between income gap (IG) and green economic growth based on the perspective of economic inequality.

Design/methodology/approach

Based on the panel data of 283 prefecture-level cities in China from 2011 to 2020, this paper uses the super slack based model (Super-SBM) to measure the efficiency of regional green economic growth, and constructs a regression model of the IG and regional green economic growth.

Findings

Firstly, the IG has an inhibitory effect on the growth of regional green economy (GE). Secondly, the relationship between the IG and regional green economic growth will be affected by the threshold value of income level. Thirdly, environmental regulation and government competition will increase the inhibitory effect of the IG.

Originality/value

According to the characteristics of China's regional economy, the researchers construct an empirical model of the IG and green economic growth to study their relationship, the threshold effect of income level and the moderating effect of environmental regulation and local government competition. The research content, methods and conclusions of this paper provide new evidence for the sustainable growth of China's regional GE.
Establishing novel experimental operation teaching by a click-and-mortar environment
Authors: Wu Hsin-Te , Chung Kuo Cheng
Published: June 2022

Purpose

This study aims to focus on the Artificial Intelligence of Things (AIoT) course. As AIoT has many theoretical theories and students usually have little interest in learning the protocols, the experiments can help stimulate their curiosity. Due to the environmental factor, the teaching requires assistive videos and Problem-Based Learning (PBL) to understand students' learning conditions.

Design/methodology/approach

The experimental design generally follows the course theories going from easy to complex, and students can extend the acquired concepts to other project development, yet, without in-depth knowledge about the experiment, resulting in limited creativity.

Findings

The assessment analysis can reveal whether students have grown from the teaching. The final analysis at the end of the term can show learners' conditions; meanwhile, students can deliver their level of satisfaction. The click-and-mortar teaching environment provided in this research can improve learning setting and quality, solidifying learners' proficiency.

Originality/value

The research result has proved the feasibility of the proposed method. Apart from showing the experimental steps, the video also explains the corresponding theories, helping students reinforce experimental knowledge and boost learning willingness.
Aspects of contextual architecture regarding traditional/contemporary architecture, physical/cultural and place identity: a systematic literature review
Authors: Al-Hammadi Nessma A. Q. , Grchev Kokan
Published: June 2022

Purpose

Adopting Mapping Literature, the purpose of this study is to notice the tendency in defining contextualism through extrinsic aspects neglecting the intrinsic ones generating three theoretical gaps in understanding contextualism, especially in terms of (1) physical/cultural aspects (P/C); (2) traditional vs contemporary architecture (T/C); and (3) place identity (PI).

Design/methodology/approach

A directed systematic literature review (SLR) was conducted to investigate the Web of Science and Google Scholar engines for the related studies, resulting in 66 texts of book chapters, conferences, articles and practitioners’ texts. Using the PRISMA reporting method, the study presented the SLR procedure that narrowed the related studies to 66 texts of book chapters, conferences, articles and practitioners’ texts. Both consensus and debates in understanding the relation between contextualism and (T/C, P/C and PI) were re-visited (see Appendix).

Findings

According to the findings, the studies tend to address contextualism through either extrinsic or intrinsic values. The undefined balance between extrinsic and intrinsic aspects in understanding and creating contextual architecture seems to be the common reason why the three theoretical gaps exist.

Originality/value

This paper did not only conduct an SLR investigation on the topic, which is limited in the field, but it also highlighted the need for further and constant discussions despite the previous one to improve the understanding of contextual architecture.