bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-scale high-density brain-wide neural recording in nonhuman primates
Authors: Trautmann Eric M. , Hesse Janis K. , Stine Gabriel M. , Xia Ruobing , Zhu Shude , O’Shea Daniel J. , Karsh Bill , Colonell Jennifer , Lanfranchi Frank F. , Vyas Saurabh , Zimnik Andrew , Steinmann Natalie A. , Wagenaar Daniel A. , Andrei Alexandru , Lopez Carolina Mora , O’Callaghan John , Putzeys Jan , Raducanu Bogdan C. , Welkenhuysen Marleen , Churchland Mark , Moore Tirin , Shadlen Michael , Shenoy Krishna , Tsao Doris , Dutta Barundeb , Harris Timothy 
Published: February 2023

AbstractHigh-density, integrated silicon electrodes have begun to transform systems neuroscience, by enabling large-scale neural population recordings with single cell resolution. Existing technologies, however, have provided limited functionality in nonhuman primate species such as macaques, which offer close models of human cognition and behavior. Here, we report the design, fabrication, and performance of Neuropixels 1.0-NHP, a high channel count linear electrode array designed to enable large-scale simultaneous recording in superficial and deep structures within the macaque or other large animal brain. These devices were fabricated in two versions: 4416 electrodes along a 45 mm shank, and 2496 along a 25 mm shank. For both versions, users can programmatically select 384 channels, enabling simultaneous multi-area recording with a single probe. We demonstrate recording from over 3000 single neurons within a session, and simultaneous recordings from over 1000 neurons using multiple probes. This technology represents a significant increase in recording access and scalability relative to existing technologies, and enables new classes of experiments involving fine-grained electrophysiological characterization of brain areas, functional connectivity between cells, and simultaneous brain-wide recording at scale.
LncRNA MALAT1/microRNA-30b axis regulate macrophage polarization and function
Authors: Ahmad Imran , Naqvi Raza Ali , Valverde Araceli , Naqvi Afsar R. 
Published: February 2023

AbstractIntroductionMacrophages (Mφ) can polarize towards the proinflammatory M1 or proresolving M2 phenotype to control diverse biological processes such as inflammation, and tissue regeneration. Noncoding RNAs play critical roles in numerous biological pathways; however, their functional interaction in the regulation of Mφ polarization and immune responses remain unclear.ObjectivesTo examine relationship between lncRNA (MALAT1) and microRNA (miR-30b) in shaping macrophage polarization and immune functions.MethodsExpression of MALAT1 and miR-30b was examined in differentiating M1/M2 Mφ, human and murine inflamed gingival biopsies by RT-qPCR. MALAT1 and miR-30b direct interaction was examined by dual luciferase assays. Impact of MALAT1 knockdown and miR-30b overexpression was examined on macrophage polarization markers, bacterial phagocytosis, antigen uptake/processing and cytokine profiles.ResultsMALAT1 expression displays a time-dependent induction during Mφ differentiation and, upon challenge with TLR4 agonist (E. coliLPS). Knockdown of MALAT1 enhanced the expression of M2Mφ markers without affecting the M1Mφ markers, suggesting that MALAT1 favors the M1 phenotype by suppressing M2 polarization. MALAT1 knockdown Mφ exhibit reduced antigen uptake and processing, bacterial phagocytosis, and bactericidal activity, strongly supporting its critical role in regulating innate immune functions. Consistent with this, MALAT1 knockdown showed impaired cytokine secretion upon challenge with LPS. Importantly, MALAT1 exhibit an antagonistic expression pattern with all five members of the miR-30 family during M2Mφ differentiation. Dual-luciferase assays validated a novel sequence on MALAT1 that interacts with miR-30b, a microRNA that promotes the M2 phenotype. Phagocytosis and antigen processing assays unequivocally demonstrated that MALAT1 and miR-30b are functionally antagonistic. In human subjects with periodontal disease and murine model of ligature-induced periodontitis, we observed higher levels of MALAT1, and downregulation of miR-30b that correlates with higher M1Mφ markers expression in gingival tissues suggesting a pro-inflammatory function of MALAT1.ConclusionMALAT1/miR-30b antagonistic interaction shapes Mφ polarizationin vitroand in inflamed gingival biopsies.
High School Science Fair: School Location Trends in Student Participation and Experience
Authors: Grinnell Frederick , Dalley Simon , Reisch Joan 
Published: February 2023

AbstractThe findings reported in this paper are based on surveys of U.S. high school students who registered and managed their science and engineering fair (SEF) projects through the online Scienteer website over the three years 2019/20, 2020/21, and 2021/22. Almost 2500 students completed surveys after finishing all their SEF competitions. We added a new question in 2019/20 to our on-going surveys asking the students whether their high school location was urban, suburban, or rural. We learned that overall, 74% of students participating in SEFs indicated that they were from suburban schools. Unexpectedly, very few SEF participants, less than 4%, indicated that they were from rural schools, even though national data show that more than 20% of high school students attend rural schools. Consistent with previous findings, Asian and Hispanic students indicated more successful SEF outcomes than Black and White students. However, whereas Asian students had the highest percentage of SEF participants from suburban vs. urban schools – 81% vs. 18%, Hispanic students had the most balanced representation of participants from suburban vs. urban schools – 55% vs. 39%. Differences in students’ SEF experiences based on gender and ethnicity showed the same patterns regardless of school location. In the few items where we observed statistically significant (probability <.05) differences based on school location, students from suburban schools were marginally favored by only a few percentage points compared to students from urban schools. In conclusion, based on our surveys results most students participating in SEFs come from suburban schools, but students participating in SEFs and coming from urban schools have equivalent SEF experiences, and very few students participating in SEFs come from rural schools.
Masked superstrings as a unified framework for textualk-mer set representations
Authors: Sladký Ondřej , Veselý Pavel , Břinda Karel 
Published: February 2023

AbstractThe popularity ofk-mer-based methods has recently led to the development of compactk-mer-set representations, such as simplitigs/Spectrum-Preserving String Sets (SPSS), matchtigs, and eulertigs. These aim to representk-mer sets via strings that contain individualk-mers as substrings more efficiently than the traditional unitigs. Here, we demonstrate that all such representations can be viewed as superstrings of inputk-mers, and as such can be generalized into a unified framework that we call the masked superstring ofk-mers. We study the complexity of masked superstring computation and prove NP-hardness for bothk-mer superstrings and their masks. We then design local and global greedy heuristics for efficient computation of masked superstrings, implement them in a program called KmerCamel, and evaluate their performance using selected genomes and pan-genomes. Overall, masked superstrings unify the theory and practice of textualk-mer set representations and provide a useful framework for optimizing representations for specific bioinformatics applications.
Universal Design Principle to Enhance Enzymatic Activity using the Substrate Affinity
Authors: Ooka Hideshi , Chiba Yoko , Nakamura Ryuhei 
Published: February 2023

ABSTRACTDesign principles to improve enzymatic activity are essential to promote energy-material conversion using biological systems. For more than a century, the Michaelis-Menten equation has provided a fundamental framework of enzymatic activity. However, there is still no concrete guideline on how the parameters should be optimized to enhance enzymatic activity. Here, we demonstrate that tuning the Michaelis-Menten constant (Km) to the substrate concentration (S) maximizes enzymatic activity. This guideline (Km=S) was obtained by applying the Brønsted (Bell)-Evans-Polanyi (BEP) principle of heterogeneous catalysis to the Michaelis-Menten equation, and is robust even with mechanistic deviations such as reverse reactions and inhibition. Furthermore,KmandSare consistent to within an order of magnitude over an experimental dataset of approximately 1000 wild-type enzymes, suggesting that even natural selection follows this principle. The concept of an optimumKmoffers the first quantitative guideline towards improving enzymatic activity which can be used for highthroughput enzyme screening.
SIGNS OF CENTRAL SENSITIZATION IN PATIENTS WITH MUSCULOSKELETAL DISORDERS AND CHRONIC COMORBIDITIES: A SYSTEMATIC REVIEW AND META-ANALYSES OF OBSERVATIONAL STUDIES
Authors: Sgarbi Mattia , D’Alessandro Davide , Castaldo Matteo , Feller Daniel 
Published: February 2023

AbstractObjectivesthis review aimed to investigate the presence of signs of central sensitization in patients with musculoskeletal disorders and associated chronic comorbidities.Methodswe conducted a systematic review (prespecified protocol CRD42021228970). Two authors independently searched for primary studies published between 2000 and 2021 in Web of Science and PubMed databases. We searched for studies that investigate the presence of signs of central sensitization in patients with musculoskeletal disorder or migraine and a chronic comorbidity. Two authors independently evaluated the methodological quality of the included studies using the “The Joanna Briggs Institute Critical Appraisal tools”. When studies were judged homogenous enough, we performed a random effect meta–analysis.Resultswe included 14 observational studies. Overall, patients with musculoskeletal disorders or migraine with an associated comorbidity showed more signs of central sensitization compared with healthy subjects.The quantitative analysis showed that patients with temporomandibular disorders and chronic comorbidities, compared to patients with temporomandibular disorders without comorbidites, have a decreased pressure pain thresholds measured in the masseter area [SMD: -0.52; CI 95%: - 1.02 to -0.03; I2: 67%] and in the trapezius area [SMD: -0.55; CI 95%: -0.96 to -0.14; I2: 0%].Patients with migraine, chronic low back pain or rheumatoid arthritis and associated fibromyalgia present more signs of central sensitization, measured in different modalities, than subjects without comorbidity.Conclusionswe demonstrated that, in general, patients with musculoskeletal disorders and an associated comorbidity showed an increased incidence of signs of central sensitization compared to healthy subjects and patients with musculoskeletal disorders without comorbities.
Increasing representation and diversity in health research: A protocol of the MYHealth Research Training Program for high school students
Authors: Chuisano Samantha A. , Rafferty Jane , Allen Alison , Chang Tammy , Diemer Matthew , Harris Kara , Vaughn Lisa M. , Watkins Daphne C. , DeJonckheere Melissa 
Published: February 2023

AbstractBackgroundDespite decades of calls for increased diversity in the health research workforce, disparities exist for many populations, including Black, Indigenous, and People of Color individuals, those from low-income families, and first-generation college students. To increase representation of historically marginalized populations, there is a critical need to develop programs that strengthen their path toward health research careers. High school is a critically important time to catalyze interest and rebuild engagement among youth who may have previously felt excluded from science, technology, engineering, and mathematics (STEM) and health research careers.MethodsThe overall objective of the MYHealth program is to engage high school students in a community-based participatory research program focused on adolescent health. Investigators will work alongside community partners to recruit 9ththrough 12thgraders who self-identify as a member of a group underrepresented in STEM or health research careers (e.g., based on race and ethnicity, socioeconomic status, first generation college student, disability, etc.). MYHealth students are trained to be co-researchers who work alongside academic researchers, which will help them to envision themselves as scientists capable of positively impacting their communities through research. Implemented in three phases, the MYHealth program aims to foster a continuing interest in health research careers by developing: 1) researcher identities, 2) scientific literacy, 3) scientific self-efficacy, and 4) teamwork and leadership self-efficacy. In each phase, students will build knowledge and skills in research, ethics, data collection, data analysis, and dissemination. Students will directly collaborate with and be mentored by a team that includes investigators, community advisors, scientific advisors, and youth peers.DiscussionEach year, a new cohort of up to 70 high school students will be enrolled in MYHealth. We anticipate the MYHealth program will increase interest and persistence in STEM and health research among groups that have been historically excluded in health research careers.
Cognitive change after subthalamic deep brain stimulation for Parkinson’s disease – a systematic meta-regressive analysis
Authors: Skvarc David R. , Cartmill Tomas , McGillivray Jane A. , Berk Michael , Byrne Linda K. 
Published: February 2023

ABSTRACTParkinson’s disease is a progressive neurodegenerative disorder characterised by motor dysfunction and cognitive disruption among other non-motor symptoms. No cure for Parkinson’s disease exists. Deep Brain Stimulation of the Subthalamic Nucleus (DBS STN) has been utilised for control of motor symptoms. However, cognitive deficits are commonly reported after implantation, and few exhaustive analyses exist to quantify and explain them. Our systematic review, meta-analyses, and metaregressions examine within-subjects change across thirteen cognitive domains, from 70 studies and 3000 participants at baseline measurements. Improvement was not observed in any domain, but substantial decline at 12 months was observed for phonemic and categorical fluency, which appeared to stabilise 24 to 36 months. Meta-regression suggests that few study characteristics are predictive of longitudinal outcomes, and we propose that further research into specific surgical or placement effects is necessary to mitigate short-term cognitive change after DBS STN in Parkinson’s disease.
DESIGN AND GENERATION OF A RECOMBINANT GAMMAHERPESVIRUS ENCODING shRNA FROM NATIVE VIRAL tRNA PROMOTER
Authors: Kara Mehmet , Tibbetts Scott 
Published: February 2023

AbstractGammaherpesviruses are associated with multiple types of tumour development and understanding the pathogenesis of these viruses has been the subject of many different studies. Throughout the lytic and latent life cycle, these viruses utilize numerous virally encoded miRNAs to regulate the key mechanisms of the infected cell in their favour. Therefore it is important to understand the miRNA and their mRNA target interactions for developing better therapeutics. In this study, the strategy and design of a short hairpin encoding RNA element targeting Blimp1 transcript in the context of viral infection is evaluated. This proof of principle experiment provides a mean to study important miRNA mRNA interactionsin vivo. The very short promoter size of the Murine gammaherpesvirus 68 (MHV68) vtRNA4 and its ability to generate two shRNAs from a ~180 nucleotide sequence is useful if there is a size limit for the shRNA construct.
ClockstaRX: testing molecular clock hypotheses with genomic data
Authors: Duchêne David A. , Duchêne Sebastián , Stiller Josefin , Heller Rasmus , Ho Simon Y. W. 
Published: February 2023

AbstractPhylogenetic studies of genomic data can provide valuable opportunities for evaluating evolutionary timescales and drivers of rate variation. These analyses require statistical tools based on molecular clocks. We present ClockstaRX, a flexible platform for exploring and testing evolutionary rate signals in phylogenomic data. It implements methods that use information from gene trees in Euclidean space, allowing data transformation, visualization, and hypothesis testing. ClockstaRX implements formal tests of the dimensionality reducibility of the Euclidean space of rates, and for identifying loci and branches that have a large influence on rate variation. Using simulations to evaluate the performance of the methods implemented, we find that inferences about rates can be strongly influenced by the overall amount of rate variation in the data, the shared patterns of among-lineage rate heterogeneity across groups of loci, and missing data. In an analysis of phylogenomic data from birds, we find a higher rate of evolution in introns compared with exons across all lineages. In addition, passerine taxa are highlighted as having unique patterns of genomic evolutionary rates compared with other avian lineages. Drawing on these results, we recommend careful exploratory analyses and filtering before performing phylogenomic analyses using molecular clocks.
TLN468 changes the pattern of tRNA used to read through premature termination codons in CFTR
Authors: Karri Sabrina , Cornu David , Serot Claudia , Biri Lynda , Hatton Aurélie , Pranke Iwona , Sermet-Gaudelus Isabelle , Hinzpeter Alexandre , Bidou Laure , Namy Olivier 
Published: February 2023

ABSTRACTNonsense mutations account for 12% of cystic fibrosis (CF) cases. The presence of a premature termination codon (PTC) leads to gene inactivation, which can be countered by the use of drugs stimulating PTC readthrough, restoring production of the full-length protein. We recently identified a new readthrough inducer, TLN468, more efficient than gentamicin.We measured the readthrough induced by these two drugs with different cystic fibrosis transmembrane conductance regulator (CFTR) PTCs. We then determined the amino acids inserted at the S1196X, G542X, W846X and E1417X PTCs ofCFTRduring readthrough induced by gentamicin or TLN468. TLN468 significantly promoted the incorporation of one specific amino acid, whereas gentamicin did not greatly modify the proportions of the various amino acids incorporated relative to basal conditions. The function of the engineered missense CFTR channels corresponding to these four PTCs was assessed with and without potentiator. For the recoded CFTR, except for E1417Q and G542W, the PTC readthrough induced by TLN468 allowed the expression of CFTR variants that were correctly processed and had significant activity that was enhanced by CFTR modulators. These results suggest that it would be relevant to assess the therapeutic benefit of TLN468 PTC suppression in combination with CFTR modulators in preclinical assays.
Transcriptional Isoforms of NAD+Kinase regulate oxidative stress resistance and melanoma metastasis
Authors: Cascio Graciela , Aguirre Kelsey N. , Church Kellsey P. , Hughes Riley O. , Nease Leona A. , Delclaux Ines , Zerhouni Marwa , Piskounova Elena 
Published: February 2023

AbstractMetastasizing cancer cells encounter a multitude of stresses throughout the metastatic cascade. Oxidative stress is known to be a major barrier for metastatic colonization, such that metastasizing cancer cells must rewire their metabolic pathways to increase their antioxidant capacity. NADPH is essential for regeneration of cellular antioxidants and several NADPH-regenerating pathways have been shown to play a role in metastasis. We have found that metastatic melanoma cells have increased levels of both NADPH and NADP+suggesting increasedde novobiosynthesis of NADP+.De novobiosynthesis of NADP+occurs through a single enzymatic reaction catalyzed by NAD+kinase (NADK). Here we show that different NADK isoforms are differentially expressed in metastatic melanoma cells, with Isoform 3 being specifically upregulated in metastasis. We find that Isoform 3 is more potent in expanding the NADP(H) pools, increasing oxidative stress resistance and promoting metastatic colonization compared to Isoform 1. We have found that Isoform 3 is transcriptionally upregulated by oxidative stress through the action of NRF2. Together, our work presents a previously uncharacterized role of NADK isoforms in oxidative stress resistance and metastasis and suggests that NADK Isoform 3 is a potential therapeutic target in metastatic disease.
A multiomics approach to understanding pathology of Combined D,L-2- Hydroxyglutaric Aciduria and phenylbutyrate as potential treatment
Authors: Phua Yu Leng , D’Annibale Olivia M , Karunanidhi Anuradha , Mohsen Al-Walid , Kirmse Brian , Dobrowolski Steven F , Vockley Jerry 
Published: February 2023

AbstractCombined D, L-2-Hydroxyglutaric Aciduria (D,L-2HGA) is a rare genetic disorder caused by recessive mutations in theSLC25A1gene that encodes the mitochondrial citrate carrier protein (CIC).SLC25A1deficiency leads to a secondary increase in mitochondrial 2-ketoglutarate that, in turn, is reduced to neurotoxic 2-hydroxyglutarate. Clinical symptoms of Combined D,L-2HGA include neonatal encephalopathy, respiratory insufficiency and often with death in infancy. No current therapies exist, although replenishing cytosolic stores by citrate supplementation to replenish cytosolic stores has been proposed. In this study, we demonstrated that patient derived fibroblasts exhibited impaired cellular bioenergetics that were worsened with citrate supplementation. We hypothesized treating patient cells with phenylbutyrate, an FDA approved pharmaceutical drug, would reduce mitochondrial 2-ketoglutarate, leading to improved cellular bioenergetics including oxygen consumption and fatty acid oxidation. Metabolomic and RNA-seq analyses demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of phenylbutyrate, detected levels of phenylacetylglutamine was consistent with the drug acting as 2-ketoglutarate sink in patient cells. Our pre-clinical studies suggest citrate supplementation is unlikely to be an effective treatment of the disorder. However, cellular bioenergetics suggests phenylbutyrate may have interventional utility for this rare disease.
CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors
Authors: Wang Jiawan , Calizo Ana , Zhang Lindy , Pino James C. , Lyu Yang , Pollard Kai , Zhang Xiaochun , Larsson Alex T. , Conniff Eric , Llosa Nicolas , Wood David K. , Largaespada David A. , Moody Susan E. , Gosline Sara J. , Hirbe Angela C. , Pratilas Christine A. 
Published: February 2023

AbstractMalignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies are desperately needed. We observe anti-proliferative efficacy of genetic depletion or pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its anti-proliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable anti-tumor activity inin vitroandin vivopatient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.