bluuebunny/crossref_metadata_2025_split huggingface dataset:
COGNITIVE ADVERSE EFFECTS OF LACOSAMIDE IN PATIENTS WITH LOCALIZATION RELATED
EPILEPSY - A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Modi Sophia B , Asha S , Iype Thomas , Libu G K , Rajan Reeja 
Published: May 2021

Abstract
Newer antiepileptic drugs (AEDs) offer favourable safety profiles than the
previously used AEDs. Despite the introduction of many AEDs, a large number of
patients continue to suffer from uncontrolled partial-onset seizures which have
considerable impact on a patient’s quality of life. Lacosamide (LCM) is a third
generation AED approved for adjunctive use in partial-onset seizures. Patients
with epilepsy frequently experience cognitive dysfunctions due to a variety of
factors. Because AEDs are the major therapeutic modality for epilepsy, the
adverse effects of AEDs on cognition are important.

Objectives
To assess the adverse effects of lacosamide on cognition among patients
with localization related epilepsy to whom lacosamide is given as adjuvant
therapy.

METHODOLOGY
An open labelled prospective observational study in 22 patients who
suffered from localization related epilepsy.

Results
Average Initial seizure frequency per month was 3.56 (SD 2.58) and
median frequency 2.5 seizures per month. Range being 1-8 per month. At the
final followup at 6months, only 2 persons experienced seizure and that too
only single episodes. The difference in frequency is statistically
significant (Wilcoxon Signed Ranks TestP <0.001). All the pre and post
lacosamide cognition scores showed statistically significant positive
correlation in this study.

Conclusion
Excellent seizure control is observed in patients with refractory
localization related epilepsy treated with lacosamide. Also, lacosamide has
no serious adverse effects or drug interactions. In this study, it is
observed that unlike many AEDs, lacosamide contributed to significant
improvement in cognition and can improve the quality of life in such
patients.
Global mapping of RNA homodimers in living cells
Authors: Gabryelska Marta M , Kudla Grzegorz 
Published: May 2021

AbstractRNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, RNA subcellular localization, and packaging of viral genomes. However, understanding of RNA homodimerization has been hampered by the lack of systematicin vivodetection methods. Here we show that PARIS, COMRADES, and other RNA proximity ligation methods can detect RNA homodimers transcriptome-wide as “overlapping” chimeric reads that contain more than one copy of the same sequence. Analysing published proximity ligation datasets, we show that RNA:RNA homodimers mediated by direct base-pairing interactions are rare across the transcriptome, but highly enriched in specific transcripts, including U8 snoRNA, U2 snRNA and a subset of tRNAs. Analysis of data from virus-infected cells reveals homodimerization of SARS-CoV-2 and Zika genomes, mediated by specific palindromic sequences located within protein-coding regions of N protein in SARS-CoV-2 and NS2A gene in Zika. We speculate that regions of viral genomes involved in homodimerization may constitute effective targets for antiviral therapies.
Short 5′ UTR enables optimal translation of plant virus tricistronic RNA via leaky scanning
Authors: Fujimoto Yuji , Keima Takuya , Hashimoto Masayoshi , Hagiwara-Komoda Yuka , Hosoe Naoi , Nishida Shuko , Nijo Takamichi , Oshima Kenro , Verchot Jeanmarie , Namba Shigetou , Yamaji Yasuyuki 
Published: May 2021

AbstractRegardless of the general model of translation in eukaryotic cells, a number of studies suggested that many of mRNAs encode multiple proteins. Leaky scanning, which supplies ribosomes to downstream open reading frames (ORFs) by read-through of upstream ORFs, is the most major regulatory mechanism to translate polycistronic mRNAs. However, the general regulatory factors controlling leaky scanning and their biological relevance have rarely been elucidated, with exceptions such as the Kozak sequence. Here, we have analyzed the strategy of a plant RNA virus to translate three movement proteins from a single RNA molecule through leaky scanning. The in planta and in vitro results indicate that significantly shorter 5′ UTR of the most upstream ORF promotes leaky scanning, potentially finetuning the translation efficiency of the three proteins in a single RNA molecule to optimize viral propagation. Moreover, in plant endogenous mRNAs, we found that shorter UTRs were more frequently observed in uORFs of polycistronic mRNAs. We propose that the promotion of leaky scanning induced by a short 5′ UTR (LISH), together with the Kozak sequence, is a conserved gene regulation mechanism not only in viruses but also in eukaryotes.
Genome and transcriptome analysis of the beet armywormSpodoptera exiguareveals targets for pest control
Authors: Simon Sabrina , Breeschoten Thijmen , Jansen Hans J. , Dirks Ron P. , Schranz M. Eric , Ros Vera I.D. 
Published: May 2021

AbstractBackgroundThe genusSpodoptera(Lepidoptera: Noctuidae) includes some of the most infamous insect pests of cultivated plants includingSpodoptera frugiperda,Spodoptera lituraandSpodoptera exigua. To effectively develop targeted pest control strategies for diverseSpodopteraspecies, genomic resources are highly desired. To this aim, we provide the genome assembly and developmental transcriptome comprising all major life stages ofS. exigua, the beet armyworm.Spodoptera exiguais a polyphagous herbivore that can feed from > 130 host plants including several economically important crops.ResultsThe 419 Mb beet armyworm genome was sequenced from a femaleS. exiguapupa. Using a hybrid genome sequencing approach (Nanopore long read data and Illumina short read), a high-quality genome assembly was achieved (N50=1.1 Mb). An official gene set (OGS, 18,477 transcripts) was generated by automatic annotation and by using transcriptomic RNA-seq data sets of 18S. exiguasamples as supporting evidence. In-depth analyses of developmental stage-specific expression in combination with gene tree analyses of identified homologous genes across Lepidoptera genomes revealed potentialSpodoptera-specific genes of interest such as mg7 and REPAT46 upregulated during 1stand 3rdinstar larval stages for targeted pest-outbreak management.ConclusionsThe beet armyworm genome sequence and developmental transcriptome covering all major developmental stages provides critical insights into the biology of this devastating polyphagous insect pest species with a worldwide distribution. In addition, comparative genomic analyses across Lepidoptera significantly advance our knowledge to further control other invasiveSpodopteraspecies and reveals potential lineage-specific target genes for pest control strategies.
SCOUR: A stepwise machine learning framework for predicting metabolite-dependent regulatory interactions
Authors: Lee Justin Y. , Nguyen Britney , Orosco Carlos , Styczynski Mark P. 
Published: May 2021

AbstractBackgroundThe topology of metabolic networks is both well-studied and remarkably well-conserved across many species. The regulation of these networks, however, is much more poorly characterized, though it is known to be divergent across organisms – two characteristics that make it difficult to model metabolic networks accurately. While many computational methods have been built to unravel transcriptional regulation, there have been few approaches developed for systems-scale analysis and study of metabolic regulation. Here, we present a stepwise machine learning framework that applies established algorithms to identify regulatory interactions in metabolic systems based on metabolic data: Stepwise Classification Of Unknown Regulation, or SCOUR.ResultsWe evaluated our framework on both noiseless and noisy data, using several models of varying sizes and topologies to show that our approach is generalizable. We found that, when testing on data under the most realistic conditions (low sampling frequency and high noise), SCOUR could identify reaction fluxes controlled only by the concentration of a single metabolite (its primary substrate) with high accuracy. The positive predictive value (PPV) for identifying reactions controlled by the concentration of two metabolites ranged from 32-88% for noiseless data, 9.2-49% for either low sampling frequency/low noise or high sampling frequency/high noise data, and 6.6-27% for low sampling frequency/high noise data, with results typically sufficiently high for lab validation to be a practical endeavor. While the PPVs for reactions controlled by three metabolites were lower, they were still in most cases significantly better than random classification.ConclusionsSCOUR uses a novel approach to synthetically generate the training data needed to identify regulators of reaction fluxes in a given metabolic system, enabling metabolomics and fluxomics data to be leveraged for regulatory structure inference. By identifying and triaging the most likely candidate regulatory interactions, SCOUR can drastically reduce the amount of time needed to identify and experimentally validate metabolic regulatory interactions. As high-throughput experimental methods for testing these interactions are further developed, SCOUR will provide critical impact in the development of predictive metabolic models in new organisms and pathways.
Sequence and functional characterization of a public HIV-specific antibody clonotype
Authors: Murji Amyn A. , Raju Nagarajan , Qin Juliana S , Kaldine Haajira , Janowska Katarzyna , Fechter Emilee Friedman , Mapengo Rutendo , Scheepers Cathrine , Setliff Ian , Acharya Priyamvada , Morris Lynn , Georgiev Ivelin S. 
Published: May 2021

SummaryPublic antibody clonotypes shared among multiple individuals have been identified for several pathogens. However, little is known about the limits of what constitutes a public clonotype. Here, we characterize the sequence and functional properties of antibodies from a public HIV-specific clonotype comprising sequences from 3 individuals. Our results showed that antigen specificity for the public antibodies was modulated by the VH, but not VL, germline gene. Non-native pairing of public heavy and light chains from different donors resulted in antibodies with consistent antigen specificity, suggesting functional complementation of sequences within the public antibody clonotype. The strength of antigen recognition appeared to be dependent on the specific antibody light chain used, but not on other sequence features such as germline or native-antibody sequence identity. Understanding the determinants of antibody clonotype “publicness” can provide insights into the fundamental rules of host-pathogen interactions at the population level, with implications for clonotype-specific vaccine development.
Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin
Authors: Ocsenas Oliver , Reimand Jüri 
Published: May 2021

ABSTRACTBackgroundRegional distribution of somatic mutations in cancer genomes associates with DNA replication timing (RT) and chromatin accessibility (CA), however normal tissues and cell lines have contributed these insights while associations with the epigenomes of primary cancers remain uncharacterized.ResultsHere we model megabase-scale mutation burden in whole cancer genomes using ∼900 CA and RT profiles of primary cancers, normal tissues, and cell lines. CA profiles of primary cancers, rather than normal tissues, predict regional mutagenesis in most cancer types. Regional mutation burden associates with the CA profiles of matching cancer types, indicating tissue-specific determinants of mutagenesis. However, mutagenesis in squamous cell and lymphoid cancers instead associates with RT profiles. Mutational signatures also show tissue-specific associations with cancer epigenomes, especially for carcinogen-induced and unannotated signatures. Lastly, while each cancer type includes certain frequently-mutated genomic regions exceeding epigenome-informed predictions of mutation burden, these regions show a pan-cancer convergence to biological processes involved in development and cancer. Thus, modelling excess mutations using epigenomes highlights known cancer driver genes as well as frequently mutated non-coding regions.ConclusionsThe dominant association of regional mutation burden with cancer epigenomes suggests that many passenger mutations are determined by the epigenetic landscapes of transformed cells and may occur later in tumor evolution. CA-informed models help find cancer genes and pathways with positive selection and highlight regions where additional mutation burden is contributed by local mutational processes. This study underlines the complex interplay of mutational processes, genome function and evolution in cancer and tissues of origin.
Lukea gen. nov. (Monodoreae-Annonaceae) with two new species of shrub from the forests of the Udzungwas, Tanzania & Kaya Ribe, Kenya
Authors: Cheek Martin , Luke W.R. Quentin , Gosline George 
Published: May 2021

SummaryA new genus, Lukea Gosline & Cheek (Annonaceae), is erected for two new species to science, Lukea quentinii Cheek & Gosline from Kaya Ribe, S.E. Kenya, and Lukea triciae Cheek & Gosline from the Udzungwa Mts, Tanzania. Lukea is characterised by a flattened circular bowl-shaped receptacle-calyx with a corolla of three petals that give the buds and flowers a unique appearance in African Annonaceae. Both species are extremely rare shrubs of small surviving areas of lowland evergreen forest under threat of habitat degradation and destruction and are provisionally assessed as Critically Endangered and Endangered respectively using the IUCN 2012 standard. Both species are illustrated and mapped. Material of the two species had formerly been considered to be possibly Uvariopsis Engl. & Diels, and the genus Lukea is placed in the Uvariopsis clade of the Monodoreae (consisting of the African genera Uvariodendron (Engl. & Diels) R.E.Fries, Uvariopsis, Mischogyne Exell, Dennettia Bak.f., and Monocyclanthus Keay).The clade is characterised by often conspicuous, finely reticulate quaternary nervation and incomplete or absent connective shields (in Annonaceae the connective shield is usually complete). Morphologically Lukea is distinct for its broad, turbinate, fleshy pedicel, a synapomorphy. It appears closest to the West African monotypic Monocyclanthus, sharing a trait unusual in the Annonaceae: the calyx in both genera forms a shallow bowl (calyx lobes are absent or vestigial), barely enclosing the base of the petals at anthesis, and persisting as a living, leathery disc at least until the fruit is mature. The placement of Lukea within the Uvariopsis clade is discussed.
Early Detection of Tau Pathology
Authors: Parekh Parag , Badachhape Andrew , Mu Qingshan , Bhavane Rohan , Srivastava Mayank , Stupin Igor , Bhandari Prajwal , Devkota Laxman , Eriksen Jason , Tanifum Eric , Ghaghada Ketan , Annapragada Ananth 
Published: May 2021

AbstractWhile a definitive Alzheimer’s disease (AD) diagnosis remains a post-mortem exercise, the ATN Research Framework proposed by the National Institute on Aging and the Alzheimer’s Association utilizes a score representing the presence of amyloid deposits (A), tau deposits (T) and neuronal degeneration markers (N), with A+T+ necessary for a positive diagnosis. Current detection of tau pathology lags amyloid detection by years and by the time both markers are detected the disease is fairly advanced. We describe the development of a new generation of molecular imaging probes forin vivodetection of cells undergoing abnormal phosphorylation representing the initial stages of pTau pathology, potentially enabling a very early stage diagnosis of AD. We describe a novel nanoparticle formulation that binds such abnormally phosphorylating cells in a mouse model of tau pathology, enabling invivovisualization of the hyperphosphorylative state by magnetic resonance imaging. Our results demonstrate the potential of this novel platform to identify a correlative marker signifying the development of future tau pathology, and has implications for early-stage diagnosis of Alzheimer’s disease.
Error minimization and specificity could emerge in a genetic code as by-products of prebiotic evolution
Authors: Janzen Evan , Shen Yuning , Liu Ziwei , Blanco Celia , Chen Irene A. 
Published: May 2021

AbstractThe emergence of the genetic code was a major transition in the evolution from a prebiotic RNA world to the earliest modern cells1. A prominent feature of the standard genetic code is error minimization, or the tendency of mutations to be unusually conservative in preserving biophysical features of the amino acid2–6. While error minimization is often assumed to result from natural selection, it has also been speculated that error minimization may be a by-product of emergence of the genetic code3. During establishment of the genetic code in an RNA world, self-aminoacylating ribozymes would enforce the mapping of amino acids to anticodons. Here we show that expansion of the genetic code, through co-option of ribozymes for new substrates, could result in error minimization as an emergent property. Using self-aminoacylating ribozymes previously identified during an exhaustive search of sequence space7, we measured the activity of thousands of candidate ribozymes on alternative substrates (activated analogs for tryptophan, phenylalanine, leucine, isoleucine, valine, and methionine). Related ribozymes exhibited preferences for biophysically similar substrates, indicating that co-option of existing ribozymes to adopt additional amino acids into the genetic code would itself lead to error minimization. Furthermore, ribozyme activity was positively correlated with specificity, indicating that selection for increased activity would also lead to increased specificity. These results demonstrate that by-products of the evolution and functional expansion of a ribozyme system could lead to adaptive properties of a genetic code. Such ‘spandrels’ could thus underlie significant prebiotic developments.
C. elegansDSB-3 Reveals Conservation and Divergence among Protein Complexes Promoting Meiotic Double-Strand Breaks
Authors: Hinman Albert W. , Yeh Hsin-Yi , Roelens Baptiste , Yamaya Kei , Woglar Alexander , Bourbon Henri-Marc G. , Chi Peter , Villeneuve Anne M. 
Published: May 2021

AbstractMeiotic recombination plays dual roles in the evolution and stable inheritance of genomes: recombination promotes genetic diversity by reassorting variants, and it establishes temporary connections between pairs of homologous chromosomes that ensure for their future segregation. Meiotic recombination is initiated by generation of double-strand DNA breaks (DSBs) by the conserved topoisomerase-like protein Spo11. Despite strong conservation of Spo11 across eukaryotic kingdoms, auxiliary complexes that interact with Spo11 complexes to promote DSB formation are poorly conserved. Here, we identify DSB-3 as a DSB-promoting protein in the nematodeCaenorhabditis elegans. Mutants lacking DSB-3 are proficient for homolog pairing and synapsis but fail to form meiotic crossovers. Lack of crossovers indsb-3mutants reflects a requirement for DSB-3 in meiotic DSB formation. DSB-3 concentrates in meiotic nuclei with timing similar to DSB-1 and DSB-2 (predicted homologs of yeast/mammalian Rec114/REC114), and DSB-1, DSB-2, and DSB-3 are interdependent for this localization. Bioinformatics analysis and interactions among the DSB proteins support the identity of DSB-3 as a homolog of MEI4 in conserved DSB-promoting complexes. This identification is reinforced by colocalization of pairwise combinations of DSB-1, DSB-2, and DSB-3 foci in structured illumination microscopy images of spread nuclei. However, unlike yeast Rec114, DSB-1 can interact directly with SPO-11, and in contrast to mouse REC114 and MEI4, DSB-1, DSB-2 and DSB-3 are not concentrated predominantly at meiotic chromosome axes. We speculate that variations in the meiotic program that have co-evolved with distinct reproductive strategies in diverse organisms may contribute to and/or enable diversification of essential components of the meiotic machinery.Significance StatementFaithful inheritance of chromosomes during meiosis depends on the formation and repair of double-strand DNA breaks (DSBs), which are generated through the activity of a topoisomerase-like protein known as Spo11. Spo11 exhibits strong conservation throughout eukaryotes, presumably reflecting constraints imposed by its biochemical activity, but auxiliary proteins that collaborate with Spo11 to promote and regulate DSB formation are less well conserved. Here we investigate a cohort of proteins comprising a complex required for meiotic DSB formation inCaenorhabditis elegans, providing evidence for both conservation with and divergence from homologous complexes in other organisms. This work highlights the evolutionary malleability of protein complexes that serve essential, yet auxiliary, roles in fundamental biological processes that are central to reproduction.
Density Fluctuations Yield Distinct Growth and Fitness Effects in Single Bacteria
Authors: Nemati Shahla , Singh Abhyudai , Dhuey Scott D. , McDonald Armando , Weinreich Daniel M. , Vasdekis Andreas. E. 
Published: May 2021

AbstractSingle-cells grow by increasing their biomass and size. Here, we report that while mass and size accumulation rates of single Escherichia coli cells are exponential, their density fluctuates during growth. As such, the rates of mass and size accumulation of a single-cell are generally not the same, but rather cells differentiate into increasing one rate with respect to the other. This differentiation yields a previously unknown density homeostasis mechanism, which we support mathematically. Further, growth differentiation challenges ongoing efforts to predict single-cell reproduction rates (or fitness-levels), through the accumulation rates of size or mass. In contrast, we observe that density fluctuations can predict fitness, with only high fitness individuals existing in the high density fluctuation regime. We detail our imaging approach and the ‘invisible’ microfluidic arrays that critically enabled increased precision and throughput. Biochemical production, infections, and natural communities start from few, growing, cells, thus, underscoring the significance of density-fluctuations when considering non-genetic variability.