bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycobacterial RNase E cleaves with a distinct sequence preference and controls the degradation rates of mostMycolicibacterium smegmatismRNAs
Authors: Zhou Ying , Sun Huaming , Vargas-Blanco Diego A. , Martini Maria Carla , Rapiejko Abigail R. , Chase Michael R. , Joubran Samantha R. , Davis Alexa B. , Dainis Joseph P. , Kelly Jessica M. , Ioerger Thomas R. , Roberts Louis A. , Fortune Sarah M. , Shell Scarlet S. 
Published: March 2023

ABSTRACTThe mechanisms and regulation of RNA degradation in mycobacteria have been subject to increased interest following the identification of interplay between RNA metabolism and drug resistance. Mycobacteria encode multiple ribonucleases that are predicted to participate in mRNA degradation and/or processing of stable RNAs. RNase E is an endoribonuclease hypothesized to play a major role in mRNA degradation due to its essentiality in mycobacteria and its role in mRNA degradation in gram- negative bacteria. Here, we defined the impact of RNase E on mRNA degradation rates transcriptome- wide in the non-pathogenic modelMycolicibacterium smegmatis. RNase E played a rate-limiting role in the degradation of at least 89% of protein-coding genes, with leadered transcripts generally being more affected by RNase E repression than leaderless transcripts. There was an apparent global slowing of transcription in response to knockdown of RNase E, suggesting thatM. smegmatisregulates transcription in responses to changes in mRNA degradation. This compensation was incomplete, as the abundance of most transcripts increased upon RNase E knockdown. We assessed the sequence preferences for cleavage by RNase E transcriptome-wide in bothM. smegmatisandM. tuberculosis, and found a consistent bias for cleavage in C-rich regions. Purified RNase E had a clear preference for cleavage immediately upstream of cytidines, distinct from the sequence preferences of RNase E in gram-negatives. We furthermore report a high-resolution map of mRNA cleavage sites inM. tuberculosis, which occur primarily within the RNase E-preferred sequence context, confirming RNase E as a broad contributor toM. tuberculosistranscriptome structure.
Su(var)3-9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration
Authors: Marzullo Marta , Romano Giulia , Pellacani Claudia , Riccardi Federico , Ciapponi Laura , Feiguin Fabian 
Published: March 2023

AbstractAging progressively modifies the physiological balance of the organism increasing susceptibility to both genetic and sporadic neurodegenerative diseases. These changes include epigenetic chromatin remodeling events that may modify gene transcription. However, how aging interconnects with disease-causing genes is not well known. Here, we found that Su(var)3-9 causes increased methylation of histone H3K9 in the promoter region of TDP-43, the most frequently altered factor in amyotrophic lateral sclerosis (ALS), affecting the mRNA and protein expression levels of this gene through epigenetic modifications in chromatin organization that appear to be conserved in agedDrosophilabrains, mouse and human cells. Remarkably, augmented Su(var)3-9 activity causes a decrease in TDP-43 expression followed by early defects in locomotor activities. In contrast, decreasing Su(var)3-9 action promotes higher levels of TDP-43 expression and reinvigorates motility parameters in old flies, uncovering a novel role of this enzyme in regulating TDP-43 expression and locomotor senescence. The data indicate how conserved epigenetic mechanisms may link aging with neuronal diseases and suggest that Su(var)3-9 may play a role in the pathogenesis of ALS.
Free long chain fatty acid solitarily primes early postembryonic development inCaenorhabditis elegansunder starvation
Authors: Ruan Meiyu , Xu Fan , Li Na , Teng Fukang , Zhu Huanhu 
Published: March 2023

AbstractPostembryonic development of animals is long considered an internal predetermined program, while macronutrient is essential only because they provide biomatters and energy to support this process. However, in this study, by using a nematodeCaenorhabditis elegansmodel, we surprisingly found that dietary supplementation of palmitic acid alone, but not other essential nutrients of abundance such as glucose or amino acid mixture, sufficiently initiated the early postembryonic development under complete macronutrient deprivation. Such a development was indicated by changes in morphology, cellular markers in multiple tissues, behaviors and the global transcription pattern. Mechanistically, palmitate doesn’t function as a biomatter/energy provider, but as a ligand to activate the nuclear hormone receptor NHR-49/80 and generate an obscure peroxisome-derived secretive hormone in the intestine. Such a hormonal signal was received by chemosensory neurons in the head in regulating the insulin-like neuropeptide secretion and its downstream nuclear receptor to orchestrate the global development. Moreover, the nutrient-sensing hub mTORC1 played a negative role in this process. In conclusion, our data indicate that free fatty acid acts as a prime nutrient signal to launch the early development inC. elegans;and implicate that specific nutrient rather than the internal genetic program is the first impetus of postembryonic development.
SafeMut: UMI-aware variant simulator incorporating allele-fraction overdispersion in read editing
Authors: Zhao Xiaofei , Guo Jingyu , Wang Sizhen 
Published: March 2023

AbstractNext-generation sequencing (NGS) has been widely used for calling biological variants. The gold-standard methodology for accessing the ability of a computational method to call a specific variant is to perform NGS wet-lab experiments on samples known to harbor this variant. Nevertheless, wet-lab experiments are both labor-intensive and time-consuming, and rare variants may not be present in a sample of population. Moreover, these two issues are exacerbated in SafeSeqS which enabled liquid biopsy and minimum-residual disease (MRD) detection with cell-free DNA by using unique molecular identifier (UMI) to detect and/or correct NGS error. Hence, we developed the first UMI-aware NGS small-variant simulator named SafeMut which also considered the overdispersion of allele fraction. We used the tumor-normal paired sequencing runs from the SEQC2 somatic reference sets and cell-free DNA data sets to assess the performance of BamSurgeon, VarBen, and SafeMut. We observed that, unlike BamSurgeon and VarBen, the allele-fraction distribution of the variants simulated by SafeMut closely resembles such distribution generated by technical replicates of wet-lab experiments. SafeMut is able to provide accurate simulation of small variants in NGS data, thereby helping with the assessment of the ability to call these variants in a bioinformatics pipeline.
Extracellular vesicle-localized miR-203 mediates neural crest-placode communication required for trigeminal ganglia formation
Authors: Bernardi Yanel E , Sanchez-Vasquez Estefania , Piacentino Michael L. , Urrutia Hugo , Rossi Izadora , Saraiva Karina Lidianne Alcântara , Pereira-Neves Antonio , Ramirez Marcel Ivan , Bronner Marianne E. , de Miguel Natalia , Strobl-Mazzulla Pablo H. 
Published: March 2023

ABSTRACTWhile interactions between neural crest and placode cells are critical for the proper formation of the trigeminal ganglion, the mechanisms underlying this process remain largely uncharacterized. Here, we show that the microRNA-(miR)203, whose epigenetic repression is required for neural crest migration, is reactivated in coalescing and condensing trigeminal ganglion cells. Overexpression of miR-203 induces ectopic coalescence of neural crest cells and increases ganglion size. Reciprocally, loss of miR-203 function in placode, but not neural crest, cells perturbs trigeminal ganglion condensation. Demonstrating intercellular communication, overexpression of miR-203 in the neural crestin vitroorin vivorepresses a miR-responsive sensor in placode cells. Moreover, neural crest-secreted extracellular vesicles (EVs), visualized using pHluorin-CD63 vector, become incorporated into the cytoplasm of placode cells. Finally, RT-PCR analysis shows that small EVs isolated from condensing trigeminal ganglia are selectively loaded with miR-203. Together, our findings reveal a critical role in vivo for neural crest-placode communication mediated by sEVs and their selective microRNA cargo for proper trigeminal ganglion formation.SIGNIFICANCE STRATEMENTCellular communication during early development plays a critical role. In this study, we demonstrate a unique role for a microRNA in cell-cell communication between the neural crest (NC) and placode cells (PC) during trigeminal ganglia (TG) formation. By utilizing loss and gain of function experiments in vivo, we demonstrate a requirement for miR-203 during cellular condensation to form the TG. We revealed that NC produces extracellular vesicles, selectively carrying miR-203, which is then taken up by the PC and regulates a sensor vector exclusively expressed in the placode. Taken together, our findings reveal a critical role in TG condensation for miR-203, produced by post-migratory NC and taken up by PC via extracellular vesicles.
Nanobodies against SARS-CoV-2 reduced virus load in the brain of challenged mice and neutralized Wuhan, Delta and Omicron Variants
Authors: Pavan María Florencia , Bok Marina , Juan Rafael Betanzos San , Malito Juan Pablo , Marcoppido Gisela Ariana , Franco Diego Rafael , Militello Daniela Ayelen , Schammas Juan Manuel , Bari Sara ,   Argentinian AntiCovid Consortium, Stone William B. , López Krisangel , Porier Danielle L. , Muller John , Auguste Albert J. , Yuan Lijuan , Wigdorovitz Andrés , Parreño Viviana , Ibañez Lorena Itatí 
Published: March 2023

AbstractIn this work, we developed llama-derived nanobodies (Nbs) directed to the receptor binding domain (RBD) and other domains of the Spike (S) protein of SARS-CoV-2. Nanobodies were selected after the biopanning of two VHH-libraries, one of which was generated after the immunization of a llama (lama glama) with the bovine coronavirus (BCoV) Mebus, and another with the full-length pre-fused locked S protein (S-2P) and the RBD from the SARS-CoV-2 Wuhan strain (WT). Most of the neutralizing Nbs selected with either RBD or S-2P from SARS-CoV-2 were directed to RBD and were able to block S- 2P/ACE2 interaction. Three Nbs recognized the N-terminal domain (NTD) of the S-2P protein as measured by competition with biliverdin, while some non-neutralizing Nbs recognize epitopes in the S2 domain. One Nb from the BCoV immune library was directed to RBD but was non-neutralizing. Intranasal administration of Nbs induced protection ranging from 40% to 80% against COVID-19 death in k18-hACE2 mice challenged with the WT strain. Interestingly, protection was not only associated with a significant reduction of virus replication in nasal turbinates and lungs, but also with a reduction of virus load in the brain. Employing pseudovirus neutralization assays, we were able to identify Nbs with neutralizing capacity against the Alpha, Beta, Delta and Omicron variants. Furthermore, cocktails of different Nbs performed better than individual Nbs to neutralize two Omicron variants (B.1.529 and BA.2). Altogether, the data suggest these Nbs can potentially be used as a cocktail for intranasal treatment to prevent or treat COVID-19 encephalitis, or modified for prophylactic administration to fight this disease.
A lymph node-to-tumour PDL1+macrophage circuit antagonizes dendritic cell immunotherapy
Authors: Sprooten Jenny , Vanmeerbeek Isaure , Datsi Angeliki , Govaerts Jannes , Borràs Daniel M , Naulaerts Stefan , Laureano Raquel S. , Calvet Anna , Kuballa Marc , Sabel Michael C. , Rapp Marion , Knobbe-Thomsen Christiane , Liu Peng , Zhao Liwei , Kepp Oliver , Kroemer Guido , Boon Louis , Tejpar Sabine , Borst Jannie , Schlenner Susan , Vleeschouwer Steven De , Sorg Rüdiger V. , Garg Abhishek D 
Published: March 2023

ABSTRACTImmune-checkpoint blockers (ICB) provide limited benefit against T cell-depleted tumours, calling for therapeutic innovation. Here, we aimed at designing a new type of dendritic cell (DC) vaccine by unbiased computational integration of multi-omics data from cancer patients. In a first attempt, a DC vaccine designed to present tumor antigens from cancer cells succumbing to immunogenic cancer cell death (ICD) and to elicit high type I interferon (IFN) responses failed to induce the regression of mouse tumors lacking T cell infiltrates. In lymph nodes (LNs), instead of activating CD4+and CD8+T cells, DCs stimulated immunosuppressive PD-L1+LN-associated macrophages (LAMs) via a type I IFN response. Moreover, DC vaccines of this type stimulated pre-existing, T cell-suppressive, PD-L1+tumour-associated macrophages (TAMs). This created a T cell-suppressive circuit of PD-L1+macrophages, spanning across LNs and tumours. Accordingly, DC vaccines synergised with PD-L1 blockade to deplete PD-L1+macrophages, suppress myeloid inflammation affecting the tumor bed and draining lymph nodes, and de-inhibit effector/stem-like memory T cells, eventually causing tumour regression. The synergistic interaction between the DC vaccine and PD-L1 blockade was lost when DCs were manipulated to loseIfnar1orCcr7or when macrophages were depleted. Interestingly, clinical DC vaccines also potentiated lymphocyte-suppressive PD-L1+TAMs in patients bearing T cell-depleted tumours. Altogether, our results reveal the existence of a novel PD-L1+LAM/TAM-driven immunosuppressive pathway that can be elicited by DC vaccines, yet can be subverted for improving the outcome of immunotherapy.
Reverse genetic screen identifies malaria parasite genes required for gametocyte-to-sporozoite development in its mosquito host
Authors: Ukegbu Chiamaka Valerie , Gomes Ana Rita , Giorgalli Maria , Campos Melina , Bailey Alexander J. , Besson Tanguy Rene Balthazar , Billker Oliver , Vlachou Dina , Christophides George K. 
Published: March 2023

SummaryMalaria remains one of the most devastating infectious diseases. Reverse genetic screens offer a powerful approach to identify genes and molecular processes governing malaria parasite biology. However, sexual reproduction and complex regulation of gene expression and genotype-phenotype associations in the mosquito have hampered the development of screens in this key part of the parasite lifecycle. We designed a genetic approach in the rodent parasitePlasmodium berghei, which in conjunction with barcode sequencing allowed us to overcome the fertilization roadblock and screen for gametocyte-expressed genes required for parasite infection of the mosquitoAnopheles coluzzii. The results confirmed previous findings, validating our approach for scaling up, and identified new genes required for ookinete motility and mosquito midgut infection and for sporozoite development and oocyst egress and salivary gland infection. Our findings can assist efforts to study malaria transmission biology and develop new interventions to control disease transmission.
Unraveling the role ofSlc10a4in auditory processing and sensory motor gating: implications for neuropsychiatric disorders?
Authors: Ciralli Barbara , Malfatti Thawann , Hilscher Markus M. , Leao Richardson N. , Cederroth Christopher R. , Leao Katarina E. , Kullander Klas 
Published: March 2023

AbstractBackgroundPsychiatric disorders, such as schizophrenia, are complex and challenging to study, partly due to the lack of suitable animal models. However, the absence of theSlc10a4gene, which codes for a monoaminergic and cholinergic associated vesicular transporter protein, in knockout mice (Slc10a4-/-), leads to the accumulation of extracellular dopamine. This makes them a potential animal model for schizophrenia, a disorder known to be associated with altered dopamine signaling in the brain.MethodsThe locomotion, auditory sensory filtering and prepulse inhibition (PPI) ofSlc10a4-/-mice were quantified and compared to wildtype (WT) littermates. Intrahippocampal electrodes were used to record auditory event-related potentials (aERPs) for quantifying sensory filtering in response to paired-clicks. The channel above aERPs phase reversal was chosen for reliably comparing results between animals, and aERPs amplitude and latency of click responses were quantified. WT andSlc10a4-/-mice were also administered subanesthetic doses of ketamine to provoke psychomimetic behavior.ResultsBaseline locomotion during auditory stimulation was similar betweenSlc10a4-/-mice and WT littermates. In WT animals, normal auditory gating was observed after i.p saline injections, and it was maintained under the influence of 5 mg/kg ketamine, but disrupted by 20 mg/kg ketamine. On the other hand,Slc10a4-/-mice did not show significant differences between N40 S1 and S2 amplitude responses in saline or low dose ketamine treatment. Auditory gating was considered preserved since the second N40 peak was consistently suppressed, but with increased latency. The P80 component showed higher amplitude, with shorter S2 latency under saline and 5 mg/kg ketamine treatment inSlc10a4-/-mice, which was not observed in WT littermates. Prepulse inhibition was also decreased inSlc10a4-/-mice when the longer interstimulus interval of 100 ms was applied, compared to WT littermates.ConclusionTheSlc10a4-/-mice responses indicate that cholinergic and monoaminergic systems participate in the PPI magnitude, in the temporal coding (response latency) of the auditory sensory gating component N40, and in the amplitude of aERPs P80 component. These results suggest thatSlc10a4-/-mice can be considered as potential models for neuropsychiatric conditions.
Modeling and dissociation of intrinsic and input-driven neural population dynamics underlying behavior
Authors: Vahidi Parsa , Sani Omid G. , Shanechi Maryam M. 
Published: March 2023

AbstractNeural dynamics can reflect intrinsic dynamics or dynamic inputs, such as sensory inputs or inputs from other regions. To avoid misinterpreting temporally-structured inputs as intrinsic dynamics, dynamical models of neural activity should account for measured inputs. However, incorporating measured inputs remains elusive in joint dynamical modeling of neural-behavioral data, which is important for studying neural computations of a specific behavior. We first show how training dynamical models of neural activity while considering behavior but not input, or input but not behavior may lead to misinterpretations. We then develop a novel analytical learning method that simultaneously accounts for neural activity, behavior, and measured inputs. The method provides the new capability to prioritize the learning of intrinsic behaviorally relevant neural dynamics and dissociate them from both other intrinsic dynamics and measured input dynamics. In data from a simulated brain with fixed intrinsic dynamics that performs different tasks, the method correctly finds the same intrinsic dynamics regardless of task while other methods can be influenced by the change in task. In neural datasets from three subjects performing two different motor tasks with task instruction sensory inputs, the method reveals low-dimensional intrinsic neural dynamics that are missed by other methods and are more predictive of behavior and/or neural activity. The method also uniquely finds that the intrinsic behaviorally relevant neural dynamics are largely similar across the three subjects and two tasks whereas the overall neural dynamics are not. These input-driven dynamical models of neural-behavioral data can uncover intrinsic dynamics that may otherwise be missed.
The Electrophysiological Markers of Statistically Learned Attentional Enhancement: Evidence for a Saliency Based Mechanism
Authors: Duncan Dock H. , van Moorselaar Dirk , Theeuwes Jan 
Published: March 2023

AbstractIt has been well established that attention can be sharpened through the process of statistical learning - whereby visual search is optimally adapted to the spatial probabilities of a target in visual fields. Specifically, attentional processing becomes more efficient when targets appear at high relatively to low probability locations. Statistically learned attentional enhancement has been shown to differ behaviorally from the more well studied top-down and bottom-up forms of attention; and while the electrophysiological characteristics of top-down and bottom-up attention have been well explored, relatively little work has been done to characterize the electrophysiological correlates of statistically learned attentional enhancement. In the current study, EEG data was collected while participants performed the additional singleton task with an unbalanced target distribution. Encephalographic data was then analyzed for two well-known correlates of attentional processing – alpha lateralization and the N2pc component. Our results showed that statistically learned attentional enhancement is not characterized by alpha lateralization, thereby differentiating it from top-down enhancement. Yet targets at high probability locations did reliably produce larger N2pc amplitudes, a known marker of increased bottom-up capture due to higher target-distractor contrasts. These results support an interpretation of the probability cuing effects where the improved processing of targets at expected locations is mediated by a saliency-based mechanism – boosting the salience of targets appearing at high-probability locations relative to those at low-probability locations.Significance statementThings are easier to find when you have a good idea of where they should be – e.g. shoes on the floor and birds in the sky. Expectations of where things are likely to be found can be implicitly learned without much, if any, awareness. Until now, little was known about how these implicit spatial biases change the representation of items in the brain. In the current work, we present EEG recordings which suggest that the brain may represent items in common locations as more salient than in other locations in space. These findings inform how the brain represents implicit search expectations; supporting a model where items in expected areas in space capture attention more frequently because they are represented by the brain as more salient.
The ancestry of Antennapedia-like homeobox genes
Authors: Copley Richard R. 
Published: March 2023

AbstractI show that broad evolutionarily significant sub-groups of Antennapedia-like homeobox genes can be distinguished by consideration of 4 amino acids. The absence of proline at position 26 is a synapomorphy of the class; HOX-like homeodomains contain a 19,30 salt-bridge of inverted polarity with respect to the same residues in typical NK-like homeodomains, and residue 28 is highly conserved within but not necessarily between orthologous groups. None of these residues has an obvious role in sequence specific DNA recognition. The EH1 and hexapeptide sequence motifs outside the homeodomain are not well correlated with sub-type. From the discovery of a hexapeptide motif in a sponge NK-like gene, and identification of new instances of longer engrailed-like (EH2) variants of the hexapeptide, I infer that scattered motif distribution is unlikely to be due to convergent evolution, but rather multiple independent loss events. I reconcile these features and the species distribution of current genes to propose a scheme for the ordering of duplication events in the cnidarian-bilaterian stem group.