bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineered retrovirus-like nanocarriers for messenger RNA delivery into neurons
Authors: Gu Wenchao , Luozhong Sijin , Cai Simian , Londhe Ketaki , Elkasri Nadine , Hawkins Robert , Yuan Zhefan , Su-Greene Kai , Cruz Margaret , Chang Yu-Wei , McMullen Patrick , Wu Chunyan , Seo Changwoo , Guru Akash , Gao Wenting , Sarmiento Tara , Schaffer Chris , Nishimura Nozomi , Cerione Richard , Warden Melissa , Langer Robert , Jiang Shaoyi 
Published: December 2022

AbstractSystemic delivery of mRNAs into disease neurons is first limited by the blood-brain-barrier (BBB). Leukocyte-derived extracellular vesicles (EVs) can cross the BBB at inflammatory sites, emerging as promising carriers to target the disease brain. However, efficient mRNA loading into EVs and their uptake by neurons remain challenges. Here we incorporated inside EVs the endogenous retrovirus-like Arc protein capsids, stabilized by Arc 5’UTR RNA elements, to effectively load and deliver mRNAs. Produced from self-derived leukocytes, engineered retrotransposon Arc EVs (eraEVs) are immunologically inert with minimal clearance. Equipped with endothelial adhesion molecules from donor leukocytes, circulating eraEVs enter the brain enriching at neuro-inflammatory sites. During self-assembly, Arc recruits enveloping proteins onto eraEVs further promoting neuronal uptake. Possessing high effectiveness like viral vectors and biocompatibility as natural vesicles, eraEV-nanocarriers can be produced from virtually all donor cell types, potentially leading to the development of future clinical therapies for a range of diseases.Abstract Figure
Interchromosomal segmental duplication drives translocation and loss ofP. falciparumhistidine-rich protein 3
Authors: Hathaway Nicholas J. , Kim Isaac E. , Young Neeva Wernsman , Hui Sin Ting , Crudale Rebecca , Liang Emily Y. , Nixon Christian P. , Giesbrecht David , Juliano Jonathan J. , Parr Jonathan B. , Bailey Jeffrey A. 
Published: December 2022

ABSTRACTMost malaria rapid diagnostic tests (RDTs) detectPlasmodium falciparumhistidine-rich protein 2 (PfHRP2) and PfHRP3, but deletions ofpfhrp2andphfrp3genes make parasites undetectable by RDTs. We analyzed 19,313 public whole-genome-sequenced P. falciparum field samples to understand these deletions better.Pfhrp2deletion only occurred by chromosomal breakage with subsequent telomere healing.Pfhrp3deletions involved loss frompfhrp3to the telomere and showed 3 patterns: no other associated rearrangement with evidence of telomere healing at breakpoint (Asia; Pattern 13-TARE1); associated with duplication of a chromosome 5 segment containing multidrug-resistant-1 gene (Asia; Pattern 13-5++); and most commonly, associated with duplication of a chromosome 11 segment (Americas/Africa; Pattern 13-11++). We confirmed a 13-11 hybrid chromosome with long-read sequencing, consistent with a translocation product arising from recombination between large interchromosomal ribosome-containing segmental duplications. Within most 13-11++parasites, the duplicated chromosome 11 segments were identical. Across parasites, multiple distinct haplotype groupings were consistent with emergence due to clonal expansion of progeny from intrastrain meiotic recombination. Together, these observations suggest negative selection normally removes 13-11++pfhrp3 deletions, and specific conditions are needed for their emergence and spread including low transmission, findings that can help refine surveillance strategies.
Pleiotropy of autism-associated chromatin regulators
Authors: Lasser Micaela , Sun Nawei , Xu Yuxiao , Law Karen , Gonzalez Silvano , Wang Belinda , Drury Vanessa , Drake Sam , Zaltsman Yefim , Dea Jeanselle , Bader Ethel , McCluskey Kate E. , State Matthew W. , Willsey A. Jeremy , Willsey Helen Rankin 
Published: December 2022

ABSTRACTGene ontology analyses of high confidence autism spectrum disorder (hcASD) risk genes have historically highlighted chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional workin vivohas additionally implicated microtubule biology and identified disrupted cellular proliferation as a convergent ASD phenotype. As many chromatin regulators, including ASD risk genesADNPandCHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ, andSUV420H1/KMT5B) specifically with respect to microtubule biology. We observe that all five localize to microtubules of the mitotic spindlein vitroandin vivo. Further in-depth investigation ofCHD2provides evidence that patient-derived mutations lead to a range of microtubule-related phenotypes, including disrupted localization of the protein at the mitotic spindle, spindle defects, cell cycle stalling, DNA damage, and cell death. Lastly, we observe that ASD genetic risk is significantly enriched among microtubule-associated proteins, suggesting broader relevance. Together, these results provide further evidence that the role of tubulin biology and cellular proliferation in ASD warrant further investigation and highlight the pitfalls of relying solely on annotated gene functions in the search for pathological mechanisms.
Structure of a reversible amyloid fibril formed by the CPEB3 prion-like domain reveals a core sequence involved in translational regulation
Authors: Flores Maria D. , Sawaya Michael R. , Boyer David R. , Zink Samantha , Tovmasyan Susanna , Saucedo Adrian , Zee Chih-Te , Cardenas Jorge , Fioriti Luana , Rodriguez Jose A. 
Published: December 2022

AbstractThe cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a prion-like RNA-binding polypeptide. As a functional prion, CPEB3 is thought to modulate protein synthesis at synapses and enable consolidation of long-term memory in neurons. Here, we report that the prion-like domain 1 of CPEB3 self-assembles into labile amyloid fibrilsin vitro. A cryoEM structure of these fibrils reveals an ordered 48-residue core, spanning L103 to F151. CPEB3 constructs lacking this amyloidogenic segment form abnormal puncta in cells when compared to wild type CPEB3, with reduced localization in dormant p-bodies and increased localization in stress granules. Removal of the amyloid core segment in CPEB3 also abolishes its ability to regulate protein synthesis in neurons. Collectively, this evidence suggests that the newly identified amyloidogenic segment within the CPEB3 prion domain is important for its regulated aggregation in cells and suggest its involvement in regulating translational activity and potentially long-term memory formation.
Associations of Socioeconomic Disparities With Buccal DNA-Methylation Measures Of Biological Aging
Authors: Raffington L. , Schwaba T. , Aikins M. , Richter D. , Wagner G.G. , Harden K.P. , Belsky D.W. , Tucker-Drob E.M. 
Published: December 2022

AbstractBackgroundIndividuals who are socioeconomically disadvantaged are at increased risk for aging-related diseases and perform less well on tests of cognitive function. The Weathering Hypothesis proposes that these disparities in physical and cognitive health arise from an acceleration of biological processes of aging. Theories of how life adversity is biologically embedded identify epigenetic alterations, including DNA methylation (DNAm), as a mechanistic interface between the environment and health. Consistent with the Weathering hypothesis and theories of biological embedding, recently developed DNAm algorithms have revealed profiles reflective of more advanced aging and lower cognitive function among socioeconomically-at-risk groups. These DNAm algorithms were developed using blood-DNA, but social and behavioral science research commonly collect saliva or cheek-swab DNA. This discrepancy is a potential barrier to research to elucidate mechanisms through which socioeconomic disadvantage affects aging and cognition. We therefore tested if social gradients observed in blood-DNAm measures could be reproduced using buccal-cell DNA obtained from cheek swabs.ResultsWe analyzed three DNAm measures of biological aging and one DNAm measure of cognitive performance, all of which showed socioeconomic gradients in previous studies: the PhenoAge and GrimAge DNAm clocks, DunedinPACE, and Epigenetic-g. We first computed blood-buccal cross-tissue correlations in n=21 adults (GEO111165). Cross-tissue correlations were low-to-moderate across (r=.25 tor=.48). We next conducted analyses of socioeconomic gradients using buccal DNAm data from SOEP-G (n=1128, 57% female; age mean=42 yrs, SD=21.56, range 0-72). Associations of socioeconomic status with DNAm measures of aging were in the expected direction, but were smaller as compared to reports from blood DNAm datasets (r=-.08 tor=-.13).ConclusionsOur findings are consistent with the hypothesis that socioeconomic disadvantage is associated with DNAm indicators of worse physical and cognitive health. However, relatively low cross-tissue correlations and attenuated effect-sizes for socioeconomic gradients in buccal DNAm compared with reports from analysis of blood DNAm suggest that, in order to take full advantage of buccal-DNA samples, DNAm algorithms customized to buccal DNAm are needed.
Trans-cellular control of synapse properties by a cell type-specific splicing regulator
Authors: Traunmüller Lisa , Schulz Jan , Ortiz Raul , Feng Huijuan , Furlanis Elisabetta , Gomez Andrea , Schreiner Dietmar , Bischofberger Josef , Zhang Chaolin , Scheiffele Peter 
Published: December 2022

SummaryThe recognition of synaptic partners and specification of synaptic properties are fundamental for the function of neuronal circuits. ‘Terminal selector’ transcription factors coordinate the expression of terminal gene batteries that specify cell type-specific properties. Moreover, pan-neuronal alternative splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell type-specific loss-of-function studies to uncover the contribution of the nuclear RNA binding protein SLM2 to hippocampal synapse specification. Focusing on hippocampal pyramidal cells and SST-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins, thereby generating cell type-specific isoforms. In the absence of SLM2, cell type-specification, differentiation, and viability are unaltered and neuronal populations exhibit normal intrinsic properties. By contrast, cell type-specific loss of SLM2 results in highly selective, non-cell autonomous synaptic phenotypes, altered synaptic transmission, and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.
The Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Potential Drug Candidates to Treat Acute Myeloid Leukemia
Authors: Guo Xuejiao Shirley , Chen Peng-Hsun Chase , Xu Shiqing , Liu Wenshe Ray 
Published: December 2022

ABSTRACTAcute myeloid leukemia (AML) is the second most diagnosed and the deadliest subtype of leukemia. Recently genetic loss-of-function studies have demonstrated that a human YEATS domain-containing protein named eleven-nineteen-leukaemia (ENL) functions as a transcriptional coactivator and is essential for the proliferation of AML that harbours oncogenic multiple lineage leukemia (MLL) rearrangements. We previously synthesized a series of small molecule inhibitors (1,7-9,11-15and24) that displayed significant and specific inhibitory effects against the ENL YEAST domain. In the current work, we report the development of a novel NanoBRET system that allows the analysis of cellular permeability, potency, selectivity, and stability of synthesized ENL inhibitors for their prioritization for further characterizations. Followed byin vitrometabolic stability and cell growth inhibition studies, we narrowed down to a potent and specific ENL YEATS domain inhibitor13with both highin vitrometabolic stability and strong anti-proliferation ability on MLL-fusion leukemia cell lines. A mouse pharmacokinetic (PK) analysis showed that at an oral dose of 20 mg/kg compound13had 60.9% bioavailability and 2.6 h mean residence time. With these favorable PK characteristics, compound13is ready for efficacy studies in an animal model. Cumulatively, the current study has prioritized compound13as a promising drug candidate to disrupt the pathogenic functions of ENL for the AML treatment.
Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice
Authors: Deshpande Rajashree A. , Marin-Gonzalez Alberto , Ha Taekjip , Paull Tanya T. 
Published: December 2022

SummaryThe Mre11-Rad50-Nbs1 (MRN) complex recognizes and processes DNA double-strand breaks for homologous recombination by performing short-range removal of 5ʹ strands. Endonucleolytic processing by MRN requires a stably bound protein at the break site—a role we postulate is played by DNA-dependent protein kinase (DNA-PK) in mammals. Here we interrogate the sites of MRN-dependent processing by isolating and sequencing DNA-PK-bound DNA fragments that are products of MRN cleavage. These intermediates are generated with highest efficiency when DNA-PK is catalytically blocked, yielding products within 200 bp of the break site, whereas DNA-PK products in the absence of kinase inhibition show much greater dispersal. Use of light-activated Cas9 to induce breaks facilitates temporal resolution of DNA-PK and Mre11 binding, showing that Mre11 and DNA-PK both bind to DNA ends before release of DNA-PK-bound products. These results support a sequential model of double-strand break repair involving collaborative interactions between homologous and non-homologous repair complexes.
Inductive biases of neural specialization in spatial navigation
Authors: Zhang Ruiyi , Pitkow Xaq , Angelaki Dora E 
Published: December 2022

AbstractThe brain may have evolved a modular architecture for reward-based learning in daily tasks, with circuits featuring functionally specialized modules that match the task structure. We propose that this architecture enables better learning and generalization than architectures with less specialized modules. To test this hypothesis, we trained reinforcement learning agents with various neural architectures on a naturalistic navigation task. We found that the architecture that largely segregates computations of state representation, value, and action into specialized modules enables more efficient learning and better generalization. Behaviors of agents with this architecture also resemble macaque behaviors more closely. Investigating the latent state computations in these agents, we discovered that the learned state representation combines prediction and observation, weighted by their relative uncertainty, akin to a Kalman filter. These results shed light on the possible rationale for the brain’s modular specializations and suggest that artificial systems can use this insight from neuroscience to improve learning and generalization in natural tasks.
Controlling the bioelectrical properties of neurons with ferritin-based Magnetogenetics
Authors: Hernández-Morales Miriam , Morales-Weil Koyam , Han Sang Min , Han Victor , Pegram Kelly , Benner Eric J. , Miller Evan W. , Kramer Richard H , Liu Chunlei 
Published: December 2022

AbstractMagnetogenetics promises remote control of neurons, but its validity is questioned due to controversies surrounding the underlying mechanisms and deficits in reproducibility. Recent studies discovered that ferritin, used in Magnetogenetics, transduces radiofrequency (RF) magnetic fields into biochemical signals (reactive oxygen species and oxidized lipids). Magnetic stimulation of ferritin-tethered TRPV channels induces Ca2+responses and modulates behavior but electrophysiological studies indicate that a particular channel, Magneto2.0, is ineffective in affecting the neuronal bioelectrical properties. We investigated this problem using the Magnetogenetic technique FeRIC. We resolved the electromagnetic interference caused by RF in patch-clamp recordings and supported the data with voltage imaging experiments. In neurons expressing TRPV4FeRIC, RF depolarizes the membrane potential and increases the spiking frequency. In neurons expressing the chloride-permeable TMEM16AFeRIC, RF hyperpolarizes the membrane potential and decreases the spiking frequency. Our study reveals the control of neuronal bioelectrical properties with Magnetogenetics that is non-instantaneous, long-lasting, and moderate, but effective and comparable to that induced by endogenous signaling molecules.
COVID-19 information seeking behavior versus value perception among U.S. ethnic/racial minorities: differences and vaccination implications
Authors: Kim Hyehyun , Chan-Olmsted Sylvia , Chen Huan 
Published: December 2022

PurposeThis study explores information behavior and perception and vaccination among America's three largest ethnic minorities, Hispanic, Black/African American and Asian, in COVID-19 context. Information behavior and perception are investigated from cultural and demographic characteristics, while vaccination is explored from COVID-19 related information behavior and utility/value of COVID-19 vaccine information.Design/methodology/approachUsing Qualtrics survey panel, a national survey of America's Hispanic, Black/African American and Asian population was conducted to better understand the impact of cultural and demographic factors on COVID-19 related information. Data were collected in Fall 2021. Multiple and logistic regression were conducted to analyze data.FindingsResults show that cultural factors (i.e. cultural identity, social identity, social capital and religiousness) exert significant impact on information value and seeking across all three minority groups, while some demographic factors, Republicanism and age, also significantly predict COVID-19 related information seeking and value for Black/African Americans and Hispanics, but less for Asian Americans. Lastly, information value was found to significantly predict vaccine status, willingness and eagerness, the three facets of vaccination as conceptualized in this study, for top three racial/ethic minorities.Originality/valueThe finding of this study reveal that there are variations in terms of the level and type of attachment to one's culture/social group in COVID-19 informational context. Between the three groups, granular differences were observed regarding the relationship between cultural factors and perceived COVID-19 information value. While cultural identity is most associated with African Americans, social capital is most evident for the Asian Americans, but social identity was the strongest predictor among Hispanics. Thus, this study offers important strategic insights into a unique population sample to better understand the impact of COVID-19 related information perception and vaccination implication.
Teachers' perceived usefulness of assistive technology in Ontario classrooms
Authors: Lamond Bronwyn , Mo Shimin , Cunningham Todd 
Published: December 2022

PurposeDespite the positive impact that assistive technology (AT) can have on the academic success of students with learning disabilities, it is often inconsistently implemented or abandoned. It has been established that teachers' perceived usefulness of AT can act as a barrier to classroom AT implementation. The purpose of this study is to expand the current understanding of the challenges with implementation of AT within the classroom environment to inform teacher training on AT tools, improve professional development around AT and address the systemic and practical barriers that impact AT implementation within Ontario classrooms.Design/methodology/approachThis research examined Grade 6–10 Ontario-certified teachers' (N = 111) perceptions of AT and the variables that predict perceived usefulness of AT. The study used a mixed methods design including a survey consisting of open- and closed-ended items that elicited information about teachers' AT knowledge and training, their access to AT resources, their perception of administrative support for access to and implementation of AT, the usefulness of AT and the barriers to AT use in the classroom.FindingsAn exploratory linear regression was conducted to predict perceived usefulness of AT from AT training, AT resources and AT knowledge and revealed that AT resources and AT knowledge added statistically significantly to the prediction, whereas AT training did not. A thematic analysis of open-ended survey responses and interview data further identified that access, training, Internet and student motivation may influence AT use.Originality/valueImplications for teachers’ AT training and provision of AT resources are discussed.
Impetuses and constraints in the policy formation process of the International Science and Business Belt in Korea
Authors: Lee Seunghyun 
Published: December 2022

Purpose
Korea’s Institute for Basic Science (IBS), the first research institute dedicated to basic science in Korea, started ten years ago as part of a science policy called the Science Belt. It is noteworthy that Korea, with a short history of basic science, established such a research institute exclusively for basic science within a short period of time and made it one of the representative institutions of basic science in Korea. This paper aims to uncover the impetuses and constraints surrounding the policy of Science Belt, centering on the IBS.

Design/methodology/approach
Kingdon’s stream theory is used to clarify the factors that acted as impetuses or constraints for the Science Belt. For the analysis, in-depth interviews with the active policy participants were conducted in addition to the thorough literature review. The interviews enabled an in-depth understanding of the underlying factors for the Science Belt and the actual procedures of the policy decision.

Findings
This study found that the most powerful impetus in the Science Belt policymaking process was the President and a small group composed of a few scientists who played a leading role in the political stream. The constraint of the Science Belt was that the participation of scientist experts and governmental officials, the so-called invisible participants of Kingdon, was insignificant. In particular, there was no system in place to select policy alternatives for basic science through discussion between scientists and governmental officials.

Research limitations/implications
The temporal scope of this study was limited to policy formation, that is, until the establishment of IBS. Therefore, future studies shall conduct a research on the implementation of the actual policy, IBS’s achievements and IBS’s impact of Korea’s basic science community.

Originality/value
This study applied both a theoretical framework and in-depth interviews along with the literature overview to understand a policymaking process from various angles.