bluuebunny/crossref_metadata_2025_split huggingface dataset:
mRNA Treatment Rescues Niemann-Pick Disease Type C1 in Patient Fibroblasts
Authors: Furtado Denzil , Cortez-Jugo Christina , Hung Ya Hui , Bush Ashley I. , Caruso Frank 
Published: February 2022

AbstractMessenger RNA (mRNA) holds great potential as a disease-modifying treatment for a wide array of monogenic disorders. Niemann-Pick disease type C1 (NP-C1) is an ultra-rare monogenic disease that arises due to loss-of-function mutations in theNPC1gene, resulting in the entrapment of unesterified cholesterol in the lysosomes of affected cells and a subsequent reduction in their capacity for cholesterol esterification. This causes severe damage to various organs including the brain, liver, and spleen. In this work, we describe the use of NPC1-encoded mRNA to rescue the protein insufficiency and pathogenic phenotype caused by biallelicNPC1mutations in cultured fibroblasts derived from an NP-C1 patient. We first evaluated engineering strategies for the generation of potent mRNAs capable of eliciting high protein expression across multiple cell types. We observed that “GC3” codon optimization, coupled with N1-methylpseudouridine base modification, yielded an mRNA that was approximately a thousand-fold more potent than wildtype, unmodified mRNA in a luciferase reporter assay, and consistently superior to other mRNA variants. Our data suggest that the improved expression associated with this design strategy was due in large part to the increased secondary structure of the designed mRNAs. Both codon optimization and base modification appear to contribute to increased secondary structure. Applying these principles to the engineering of NPC1-encoded mRNA, we observed a normalization in NPC1 protein levels after mRNA treatment, as well as a rescue of the mutant phenotype. Specifically, mRNA treatment restored the cholesterol esterification capacity of patient cells to wildtype levels, and induced a significant reduction in both unesterified cholesterol levels (>57% reduction compared to Lipofectamine-treated control in a cholesterol esterification assay) and lysosome size (157 μm2reduction compared to lipofectamine-treated control). These findings show that engineered mRNA can correct the deficit caused byNPC1mutations. More broadly, they also serve to further validate the potential of this technology to correct diseases associated with loss-of-function mutations in genes coding for large, complex, intracellular proteins.
The immune profile of Major Dysmood Disorder: proof of concept and mechanism using the precision nomothetic psychiatry approach
Authors: Maes Michael , Rachayon Muanpetch , Jirakran Ketsupar , Sodsai Pimpayao , Klinchanhom Siriwan , Gałecki Piotr , Sughondhabirom Atapol 
Published: February 2022

AbstractMajor depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class namely Major Dysmood Disorder, a new pathway phenotype namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD’s features and IRS, CIRS, M1, T helper (Th)1, Th2, Th17, Tregulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into one a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS / CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase triggered STAT protein phosphorylation, TLR/NF-κB, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD’s heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers.
Spinning Disk Multifocal Microscopy for Dynamic Arbitrarily Shaped Surface Imaging at Centimetre Scale and Micrometre Resolution
Authors: Xie Hao , Han Xiaofei , Xiao Guihua , Xu Hanyun , Zhang Yuanlong , Zhang Guoxun , Li Qingwei , He Jin , Zhu Dan , Yu Xinguang , Dai Qionghai 
Published: February 2022

ABSTRACTThe large-scale fluorescence microscopy has enabled the observation of dynamic physiological activities at the single cellular level across the mouse cortex, such as distributed neuronal population representations. However, video-rate high-resolution microscopy at sophisticated biological surfaces in nature keeps a challenging task for the tradeoff between the speed, resolution, and field of view. Here we propose Spinning Disk Multifocal Microscopy (SDiM) for arbitrarily shaped surfaces, which enables imaging at centimeter field-of-view, micrometer resolution and up to 30 frames per second across the depth range of 450 µm. We apply this technique in various microscopic systems, including customized macroscopic systems and the Real-time Ultra-large-Scale imaging at High resolution macroscopy (RUSH), in both the reflective mode and the fluorescence mode, and in the study of cortex-wide single-neuron imaging and immune cell tracking. SDiM provides an opportunity for studying the cortex-wide multi-scale cellular interactions in biological tissues.
Odorant receptor orthologues in conifer-feeding beetles display conserved responses to ecologically relevant odors
Authors: Roberts Rebecca E. , Biswas Twinkle , Yuvaraj Jothi Kumar , Grosse-Wilde Ewald , Powell Daniel , Hansson Bill S. , Löfstedt Christer , Andersson Martin N. 
Published: February 2022

AbstractInsects are able to detect a plethora of olfactory cues using a divergent family of odorant receptors (ORs). Despite the divergent nature of this family, related species frequently express several evolutionarily conserved OR orthologues. In the largest order of insects, Coleoptera, it remains unknown whether OR orthologues have conserved or divergent functions in different species. Using HEK293 cells, we addressed this question through functional characterization of two groups of OR orthologues in three species of the Curculionidae (weevil) family, the conifer-feeding bark beetlesIps typographusL. (‘Ityp’) andDendroctonus ponderosaeHopkins (‘Dpon’) (Scolytinae), and the pine weevilHylobius abietisL. (‘Habi’; Molytinae). The ORs ofH. abietiswere annotated from antennal transcriptomes. Results show highly conserved response specificities, with one group of orthologues (HabiOR3/DponOR8/ItypOR6) responding exclusively to 2-phenylethanol (2-PE), and the other group (HabiOR4/DponOR9/ItypOR5) responding to angiosperm green leaf volatiles (GLVs). Both groups of orthologues belong to the coleopteran OR subfamily 2B, and share a common ancestor with OR5 in the cerambycidMegacyllene caryae, also tuned to 2-PE, suggesting a shared evolutionary history of 2-PE receptors across two beetle superfamilies. The detected compounds are ecologically relevant for conifer-feeding curculionids, and are probably linked to fitness, with GLVs being used to avoid angiosperm non-host plants, and 2-PE being important for intraspecific communication and/or playing a putative role in beetle-microbe symbioses. To our knowledge, this study is the first to reveal evolutionary conservation of OR functions across several beetle species and hence sheds new light on the functional evolution of insect ORs.
Confirming Multiplex Q-PCR Use in COVID-19 with Next Generation Sequencing: Strategies for Epidemiological Advantage
Authors: Carpenter Rob E. , Tamrakar Vaibhav , Chahar Harendra , Vine Tyler , Sharma Rahul 
Published: February 2022

AbstractRapid classification and tracking of emerging SARS-CoV-2 variants are critical for understanding the transmission dynamics and developing strategies for interrupting the transmission chain. Next-Generation Sequencing (NGS) is an exceptional tool for whole-genome analysis and deciphering new mutations. The technique has been instrumental in identifying the Variants of Concern and tracking this pandemic. However, NGS remains expensive and time-consuming for large-scale monitoring of COVID-19. This study analyzed a total of 78 de-identified samples that screened positive for SARS-CoV-2 from two timeframes, August 2020 and July 2021. All 78 samples were classified into WHO lineages by whole genome sequencing then compared with two commercially available Q-PCR assays for spike protein mutation(s). The data showed good concordance with Q-PCR and NGS analysis for specific SARS-COV-2 lineages and characteristic mutations.Deployment of Q-PCR testing to detect known SARS-COV-2 variants may be extremely beneficial. These assays are quick and cost-effective, thus can be implemented as an alternative to sequencing for screening known mutations of SARS-COV-2 for clinical and epidemiological interest. The findings support the great potential for Q-PCR to be an effective strategy offering several COVID-19 epidemiological advantages.
Sensory-motor computations in a cortico-pontine pathway
Authors: Darlington Timothy R. , Lisberger Stephen G. 
Published: February 2022

SummarySubcortical circuits decode the output from multiple cortical areas to create commands for movement. By recording during monkeys’ smooth pursuit eye movements, we reveal how the dorsolateral pontine nucleus (DLPN) and nucleus reticularis tegmenti pontis (NRTP) decode cortical output. Preparatory activity is inherited from the smooth eye movement region of the frontal eye fields (FEFSEM). Consistent with its effects on eye movement responses to visual motion, preparatory activity modulates the gain of pontine responses to visual motion input from visual area MT. Furthermore, the “place” code for target speed in area MT becomes the motor command’s “rate” code in the pons, through linear weighting of MT’s output. The division into decoding that happens in the pons and residual computations that occur downstream reveals that the pons is neither a relay nor the source of a final motor command. It is part of a complex, distributed cortical decoder for motor control.
Trends in Arabidopsis Research post genome sequencing- A Scientometric study
Authors: Kumar Sandeep , Kushwaha Amar Kant , Thribhuvan R , Balakrishnan M , Krishnan P 
Published: February 2022

1.AbstractArabidopsis thaliana, a model plant, is intensively researched because of the intrinsic advantages associated with its life cycle, genetics, and other characteristics. In the present study, we analysed the publication data of research work done on A. thaliana during 2001-2020, a period when the whole genome sequence of the plant was available to the researchers. The current meta-analysis showed that 31965 research papers were published globally on Arabidopsis during the study period. The USA topped the countries with the maximum share of publications (28.97%), followed by China, Japan, and West European countries. The analysis showed a temporal shift in the number of publications from different countries and their research focus. After 2013, the research output from China was higher than that from the USA, and there was a shift in focus from developmental biology to stress-related topics. Plant Physiology journal carried the most research work (2490 publications) on Arabidopsis, which was followed by Plant Cell (2376), the Plant Journal (2260) and the Journal of Experimental Botany (1121). However, there was a progressive decline in the publication in these journals, and a shift was evident in favour of open access journals like Frontiers in Plant Science. The publication and citation numbers also show ongoing Arabidopsis research’s relevance to plant sciences, particularly curiosity-driven and discovery-based science. This article delves into the patterns in the prominence of research areas, ideas and foci for the future Arabidopsis research roadmap.
Frequency dependent growth of bacteria in living materials
Authors: Lewis Daniel D. , Gong Ting , Xu Yuanwei , Tan Cheemeng 
Published: February 2022

AbstractThe fusion of living bacteria and man-made materials represents a new frontier in medical and biosynthetic technology. However, the principles of bacterial signal processing inside three dimensional and fluctuating environments of synthetic materials remain elusive. Here, we study bacterial growth in a three-dimensional hydrogel. We find that bacteria expressing an antibiotic resistance module can take advantage of ambient kinetic disturbances to improve growth while encapsulated. We show that these changes in bacterial growth are specific to disturbance frequency and hydrogel density. This remarkable specificity is consistent with stochastic resonance theory, which we leverage to explain how bacteria can integrate spatial and temporal information to control growth. This research provides a quantitative foundation for the control of living materials and a systematic framework towards understanding bacterial information processing in three-dimensional environments.
Condensin II is required for efficient Spindle Assembly Checkpoint activation in Drosophila male meiosis
Authors: Horta Cintia , Tavares Alexandra , Oliveira Raquel A. 
Published: February 2022

AbstractReductional nuclear division in meiosis is essential for diploid life. A fundamental event in meiosis is chromatin condensation, through mechanisms not yet fully understood. Current data suggest that Condensins are key players in building and sustaining mitotic and meiotic chromosome structure. In Drosophila, Condensin II appears to be dispensable for faithful mitosis in somatic tissues yet essential in the germline. Previous work has demonstrated that in Drosophila male meiosis, Condensin II is required for the segregation of homologous chromosomes into distinct territories during prophase I, possibly through the resolution of chromosomal intertwines. Here we show that in addition to this well-established function in meiotic chromatin assembly, Condensin II is required for robust Spindle Assembly Checkpoint (SAC) signaling in male meiosis. In the absence of Condensin II, spermatocytes undergo faster meiotic divisions and display reduced ability to prolong meiosis in the presence of spindle poisons. This is attributed to the inability to recruit a key SAC component (Mad1) to the kinetochore. Importantly, we demonstrate that the absence of a robust SAC response in Condensin II mutants, and consequent accelerated meiosis, is a strong contributor to the meiotic defects associated with these mutants. We show that artificial prolongation of meiotic divisions, using conditions that delay anaphase onset in a SAC-independent manner, is sufficient to rescue segregation defects and aneuploidy associated with Condensin II mutations. We therefore conclude that Condensin II can be dispensable for the resolution of topological problems and chromosome condensation if cells are able to prolong meiosis. Yet, the newly found role of this complex in the robustness of the SAC reduces meiotic timing leading to severe chromosome segregation defects.
Topologically frustrated dynamics in an uncharged Tetra-PEG gel
Authors: Jia Di , Tsuji Yui , Shibayama Mitsuhiro , Muthukumar Murugappan 
Published: February 2022

AbstractBased on our previous discovery of non-diffusive topologically frustrated dynamics in a charged system where electrostatic interactions between the charged guest and the charged host gel play a role (Nature Communications, 2018, 9, 2248; Physical Review Letters, 2021, 126, 057802), we have investigated the onset of this effect in an uncharged gel matrix. Using sodium (polystyrene sulfonate) as the guest macromolecule and the ideal tetra-PEG gel, we find the emergence of the non-diffusive topologically frustrated dynamical state with a hierarchy of segmental dynamics represented by a stretched exponential of exponent β around 1/3. Our results demonstrate the universal behavior of the topologically frustrated dynamical state.
Human septins in cells organize as octamer-based filaments mediating actin-membrane anchoring
Authors: Martins Carla Silva , Taveneau Cyntia , Castro-Linares Gerard , Baibakov Mikhail , Buzhinsky Nicolas , Eroles Mar , Milanović Violeta , Iv Francois , Bouillard Léa , Llewellyn Alex , Gomes Maxime , Belhabib Mayssa , Kuzmić Mira , Verdier-Pinard Pascal , Lee Stacey , Badache Ali , Kumar Sanjay , Chandre Cristel , Brasselet Sophie , Rico Felix , Rossier Olivier , Koenderink Gijsje H. , Wenger Jerome , Cabantous Stéphanie , Mavrakis Manos 
Published: February 2022

AbstractSeptins are cytoskeletal proteins conserved from algae and protists to mammals. Septin knock-out animals have established that septins are essential for animal physiology, but their molecular function remains elusive. A unique feature of septins is their presence as heteromeric complexes that polymerize into filaments in solution and on lipid membranes. Although animal septins associate extensively with actin-based structures in cells, whether actin-decorating septins organize as filaments and if septin organization impacts septin function is not known. Customizing a tripartite split-GFP complementation assay for probing the presence and composition of septin filamentsin situin cells, we show that all septins decorating actin stress fibers are present as filaments whose integrity depends on octameric septin protomers. Atomic force microscopy nanoindentation measurements on cells confirmed that cell stiffness depends on the presence of octamer-containing septin filaments. Super-resolution structured illumination microscopy revealed septin fibers with widths compatible with their organization as paired septin filaments. Nanometer-resolved distance measurements and single-protein tracking further showed that actin-associated septin filaments are membrane-bound and largely immobilized. Finally, reconstitution assays on supported lipid bilayers showed that septin filaments mediate actin-membrane anchoring. We propose that septin organization as octamer-based filaments is essential for septin function in anchoring and stabilizing actin fibers at the plasma membrane.
Epidermal basal domains organization highlights skin robustness to environmental exposure
Authors: Ghuwalewala Sangeeta , Lee Seon A , Jiang Kevin , Baidya Joydeep , Chovatiya Gopal , Kaur Pritinder , Shalloway David , Tumbar Tudorita 
Published: February 2022

AbstractAdult interfollicular epidermis (IFE) renewal is likely orchestrated by physiological demands of its complex tissue architecture comprising spatial and cellular heterogeneity. Mouse tail and back skin display two kinds of basal IFE spatial domains that regenerate at different rates. Here we elucidate the molecular and cellular states of basal IFE domains by marker expression and single cell transcriptomics in mouse and human skin. We uncover two paths of basal cell differentiation that reflect in part the IFE spatial domain organization. We unravel previously unrecognized similarities between mouse tail IFE basal domains defined as scales and interscales versus human rete ridges and inter-ridges, respectively. Second, our basal IFE transcriptomics and gene targeting in mice provide evidence supporting a physiological role of IFE domains: adaptation to differential UV exposure. We identify Sox6 as a novel UV-induced and interscale/inter-ridge basal IFE-domain transcription factor, important for IFE proliferation and survival. The spatial, cellular, and molecular organization of IFE basal domains underscores skin adaptation to environmental exposure and its unusual robustness in adult homeostasis.Synopsis
RNA-based vaccine demonstrates prophylactic efficacy against Mycobacterium tuberculosis challenge in a mouse model
Authors: Larsen Sasha E. , Erasmus Jesse H. , Reese Valerie A. , Pecor Tiffany , Archer Jacob , Kandahar Amit , Hsu Fan-Chi , Reed Steven G. , Baldwin Susan L. , Coler Rhea N. 
Published: February 2022

AbstractMycobacterium tuberculosis (Mtb) is an opportunistic bacterial pathogen that causes tuberculosis disease (TB) and exerts an extensive burden on global health. The complex intra- and extracellular nature of this bacterium, coupled with different disease stages have made mechanistic studies evaluating the contributions of innate and adaptive host immunity challenging. In this work we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low dose and ultra-low dose aerosol challenge with Mtb H37Rv in C57BL/6 mice. Our proof-of-concept TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a replicating-RNA (repRNA) formulated in a nanostructured lipid carrier (NLC). Results from this work demonstrate that protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to controls. Excitingly, in prime-boost strategies, groups that received heterologous RNA-prime, protein-boost or combination (simultaneous in different sites) immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high priority Mtb antigens containing CD4+ and CD8+ T cell epitopes.
Resolving tricky nodes in the tree of life through amino acid recoding
Authors: Giacomelli Mattia , Rossi Maria Eleonora , Lozano-Fernandez Jesus , Feuda Roberto , Pisani Davide 
Published: February 2022

AbstractGenomic data allowed for a detailed resolution of the tree of life. Yet, tricky nodes such as the root of the animal, plants, eukaryotes, bacterial and archaeal trees remain unresolved. Genomic datasets are heterogeneous as genes and species evolve under different selective pressures, impending the efficacy of evolutionary analyses. Amino acid recodings were developed to reduce heterogeneity, but clear evidence to justify their use is missing. We use simulated genomic-scale datasets and show that recodings can substantially improve phylogenetic accuracy when tackling tricky nodes. We apply our findings to address the root of the animal tree where the debate centers on whether sponges (Porifera) or comb jellies (Ctenophora) branched out first. We show that results from real data follow predictions from simulated data and indicate that a placement of the ctenophores as the first branching animal lineage is most likely artifactual.