Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of a Novel SARS-CoV-2 Immune Complex Vaccine Candidate (CRCx) with Broad Immune Responses: A Preclinical Trial in Animal Model

Background The ongoing pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a serious threat to global public health and imposes a severe burden on the entire human population. Faced with a virus that can mutate its structure while immunity is incapacitated, a need to develop a universal vaccine that can boost immunity to coronaviruses is highly needed. Design Five formulations of two types (CRCx2 and CRCx3) of immune complexes with an immunogen adjuvant were evaluated in a mouse model as candidate SARS CoV-2 vaccines in a pretrial prior to clinical trials in humans. CRCx3 comprises 3 different formulas and CRCx2 comprises 2. Balb/c mice were vaccinated intraperitoneally on days 0/7 with a high or low dose of CRCx2 or on days 0/7/14 with a high, medium, or low dose of CRCx3 series, and their blood was sampled for serum antibody measurements. Mice were challenged with live virus after immunization with either vaccine to evaluate prophylaxis ability or treated with them after challenge to evaluate therapeutic ability on day 15. Immunological markers and histopathological studies as well as titration of neutralizing antibodies to the vaccines were evaluated and analyzed. Results CRCx 3 and CRCx 2 vaccine candidates induced elevated levels of positive neutralizing antibodies as well as a cellular immune response with safety, efficient productivity, and good genetic stability for vaccine manufacturing to provide protection against SARS-CoV-2 with relatively higher levels with the high dose CRCx2 candidate combination. Conclusions Highly efficient protection and therapeutic effect against SARS-CoV-2 were obtained with a double-dose immunization schedule spaced at 7-day intervals using injections 0.25 of or 0.40 ml of CRCx2 vaccine formulations with a 25-mm needle. These results support further evaluation of CRCx in a clinical trial on humans.
A high-throughput approach to predict A-to-I effects on RNA structure indicates a change of double-stranded content in non-coding RNAs

RNA molecules undergo a number of chemical modifications whose effects can alter their structure and molecular interactions. Previous studies have shown that RNA editing can impact the formation of ribonucleoprotein complexes and influence the assembly of membrane-less organelles such as stress-granules. For instance, N6-methyladenosine (m6A) enhances SG formation and N1-methyladenosine (m1A) prevents their transition to solid-like aggregates. Yet, very little is known about adenosine to inosine (A-to-I) modification that is very abundant in human cells and not only impacts mRNAs but also non-coding RNAs. Here, we built the CROSSalive predictor of A-to-I effects on RNA structure based on high-throughput in-cell experiments. Our method shows an accuracy of 90% in predicting the single and double-stranded content of transcripts and identifies a general enrichment of double-stranded regions caused by A-to-I in long intergenic non-coding RNAs (lincRNAs). For the individual cases of NEAT1, NORAD and XIST, we investigated the relationship between A-to-I editing and interactions with RNA-binding proteins using available CLIP data. We found that A-to-I editing is linked to alteration of interaction sites with proteins involved in phase-separation, which suggests that RNP assembly can be influenced by A-to-I. CROSSalive is available at http://service.tartaglialab. com/new_submission/crossalive.
Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes

The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin lipid biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2ΔO/ΔO). At 6 weeks of age, normal-appearing myelin had formed in CerS2ΔO/ΔO mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2ΔO/ΔO mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2ΔO/ΔO mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2ΔO/ΔO mice. By 16 weeks, CerS2ΔO/ΔO mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2ΔO/ΔO mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases. Main Points Oligodendrocytes lacking CerS2 produce myelin using sphingolipids with C16/C18 instead of C22/C24 N-acyl chains C22/C24 myelin sphingolipids are essential for myelin stability, microglial quiescence, and survival beyond young adulthood Table of Contents Image
A human adenovirus encoding IFN-γ can transduce Tasmanian devil facial tumour cells and upregulate MHC-I

The devil facial tumour disease (DFTD) has led to a massive decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The disease is caused by two independent devil facial tumours (DFT1 and DFT2). These transmissible cancers have a mortality rate of nearly 100%. An adenoviral vector-based vaccine has been proposed as a conservation strategy for the Tasmanian devil. This study aimed to determine if a human adenovirus serotype 5 could express functional transgenes in devil cells. As DFT1 cells do not constitutively express major histocompatibility complex class I (MHC-I), we developed a replication-deficient adenoviral vector that encodes devil interferon gamma (IFN-γ) fused to a fluorescent protein reporter. Our results show that adenoviral-expressed IFN-γ was able to stimulate upregulation of beta-2 microglobulin, a component of MHC-I, on DFT1, DFT2, and devil fibroblast cell lines. This work suggests that human adenoviruses can serve as vaccine platform for devils and potentially other marsupials.
Disruption of place cell remapping by scopolamine during aversive learning

We performed in-vivo calcium imaging of hippocampal place cells in freely behaving rats (n=14) to investigate whether the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine, which is known to impair aversive learning, also disrupts place cell remapping that occurs during such learning. CA1 neurons were imaged using a large-field-of view version of the UCLA miniscope (MiniLFOV) while rats performed a shock avoidance task on a rectangular maze. Drug-free avoidance training and extinction caused place cells to remap near the shocked location, in accordance with prior studies. Systemic pre-training injections of scopolamine (1 mg/kg) did not impair immediate shock avoidance, and also did not disrupt spatial tuning properties or shock-evoked responses of place cells during training. However, the drug impaired 48 h retention of avoidance and also prevented place cells from remapping near the shocked location. In addition, when rats navigated the maze on scopolamine, CA1 population vectors showed degraded between-session similarity with drug-free maze visits on prior days, suggesting that mAChR antagonism acutely degraded the fidelity with which stored hippocampal representations were retrieved. Based upon these results, we propose that scopolamine causes amnesia by degrading the dynamics of hippocampal memory retrieval at the population level, thereby shielding stored memory representations from being modified by experience to encode new memories of events that occur under the influence of the drug. scopolamine also impaired long-term retention of avoidance learning. When rats navigated the maze on scopolamine, CA1 population vectors showed degraded between-session similarity with prior (drug-free) maze visits. These findings show for the first time that impairment of aversive learning by scopolamine is accompanied by impairment of p=. 0111), p=3.74e post-hoc paired t-tests during ‘pst’ than ‘pre’ (t 8 =4.4, p=.0022) or ‘trn’ (t 8 =4.7, p=.0015) sessions; the avoidance extinction during the ‘pst’ a on the short path after avoidance extinction. ‘trn’ sessions on scopolamine, during ‘trn’ sessions than during ‘pre’ (t 6 =5.5, p=.0015) or ‘pst’ (t 6 =5.2, p=.0019) sessions (both of drug free) the reduced running speeds on the as the
Low heritability of crossover rate in wild sticklebacks

Crossover rate is mostly studied with domesticated or lab-reared populations and little is known about its genetic variation in the wild. We studied the variation and genetic underpinnings of crossover rate in outbred wild nine- (Pungitius pungitius) and three-spined (Gasterosteus aculeatus) sticklebacks. In both species, the crossover rate of females exceeded that of males as did also its repeatability (RFemales =0.21–0.33, RMales=0.026–0.11), implying individual differences of crossover rate in females, but no or less so in males. However, in both species and sexes additive genetic variance and heritability of crossover rate were effectively zero. A review of the previously reported repeatability and heritability estimates revealed that the repeatabilities in stickleback females were moderately high, whereas those in males were very low. Genome-wide association analyses recovered a few candidate regions possibly involved with control of crossover rate. The low additive genetic variance of crossover rate in wild sticklebacks suggest limited evolvability of crossover rate.
A small DNA virus initiates replication with no more than three genome copies per cell

Cellular organisms purge lethal mutations as they occur (in haploids), or as soon as they become homozygous (in sexually reproducing diploids), thus making the mutation-carrying genomes the sole victims of lethality. How lethal mutations in viruses are purged remains an unresolved question because numerous viral genomes could potentially replicate in the same cell, sharing their encoded proteins, hence shielding lethal mutations from selection. Previous investigations by us and others suggest that viruses with plus strand (+) RNA genomes may compel such selection by bottlenecking the replicating genome copies in each cell to low single digits. However, it is unclear if similar bottlenecks also occur in cells invaded by DNA viruses. Here we investigated whether tomato yellow leaf curl virus (TYLCV), a small virus with a single-stranded DNA genome, underwent population bottlenecking in cells of its host plants. We engineered the TYLCV genome to produce two replicons that express green fluorescent protein and mCherry, respectively, in a replication-dependent manner. We found that less than 65% of cells penetrated by both replicons replicated both, whereas at least 35% of cells replicated either of them alone, illustrating an intracellular population bottleneck size of no more than three. Furthermore, sequential inoculations unveiled strong mutual exclusions of these two replicons in most cells. Collectively our data demonstrated for the first time that DNA viruses like TYLCV are subject to stringent intracellular population bottlenecks, suggesting that such population bottlenecks may be a virus-encoded, evolutionarily conserved trait that assures timely elimination of lethal mutations. Significance statement An important unresolved issue in virus life cycles is how natural selection acts on individual virus copies in the same cells. Unlike cellular organisms in which genome copies with lethal or advantageous mutations usually share their hosts with no more than one homologous genome copy, viruses could potentially reproduce with numerous sister genomes per cell, permitting sharing of protein products, thereby greatly diminishing phenotypic impacts of otherwise eventful mutations. Previous investigations suggest that (+) RNA viruses solve this problem by bottlenecking the number of replicating genome copies to low single digits. The current study reveals strikingly similar intracellular population bottlenecks for a DNA virus. Further mechanistic interrogations could avail the virus-encoded bottleneck-enforcing apparatus as targets for antiviral therapy and prevention.
Long-Range α-Synchronization as Control Signal for BCI: A Feasibility Study

Abstract Shifts in spatial attention are associated with variations in α band (α, 8–14 Hz) activity, specifically in interhemispheric imbalance. The underlying mechanism is attributed to local α-synchronization, which regulates local inhibition of neural excitability, and frontoparietal synchronization reflecting long-range communication. The direction-specific nature of this neural correlate brings forward its potential as a control signal in brain-computer interfaces (BCIs). In the present study, we explored whether long-range α-synchronization presents lateralized patterns dependent on voluntary attention orienting and whether these neural patterns can be picked up at a single-trial level to provide a control signal for active BCI. We collected electroencephalography (EEG) data from a cohort of healthy adults (n = 10) while performing a covert visuospatial attention (CVSA) task. The data show a lateralized pattern of α-band phase coupling between frontal and parieto-occipital regions after target presentation, replicating previous findings. This pattern, however, was not evident during the cue-to-target orienting interval, the ideal time window for BCI. Furthermore, decoding the direction of attention trial-by-trial from cue-locked synchronization with support vector machines (SVMs) was at chance level. The present findings suggest EEG may not be capable of detecting long-range α-synchronization in attentional orienting on a single-trial basis and, thus, highlight the limitations of this metric as a reliable signal for BCI control.
Large-scale whole-genome sequencing of migratory Bogong moths Agrotis infusa reveals genetic variants associated with migratory direction in a panmictic population

One of the most interesting macroscopic phenomena in the animal world is seasonal migration. A central goal of research into animal migration is to better understand the mechanisms that evolved to solve the complex challenges which a migratory life history presents. Each year, and with a high degree of species-level site fidelity, the Australian Bogong moth makes a return migration of up to and over 1000 km between widely distributed breeding grounds and a specific set of aestivation sites in the Australian Alps. It does this without any opportunity to learn the migratory route or the location of the aestivation sites from either older generations or repeated migrations, meaning that the information required by the moth to navigate during its migration must be inherited. The migratory direction, and therefore the inherited navigational information in Bogong moths, varies with breeding site, providing us with an opportunity to search for the source of that heritability by comparing the genomes of moths collected from different breeding areas. We successfully sequenced whole nuclear genomes of 77 Bogong moths collected from across their breeding grounds and summer range, and found that the Bogong moth population contains a large amount of (mostly rare) variation. We found no evidence of population structure, indicating that Bogong moths are panmictic. A genome-wide scan for signals of selection indicate that the Bogong population has recently recovered from a past bottleneck, however genomic regions which have likely undergone balancing selection were also detected. Despite panmixia, four genetic variants in breeding-ground-caught Bogong moths were found to be significantly associated with geographic location, and therefore migratory direction, indicating promising future avenues of research into the molecular basis of long-distance navigation.
Inferring light responses of primate retinal ganglion cells using intrinsic electrical signatures

Objective. Retinal implants are designed to stimulate retinal ganglion cells (RGCs) in a way that restores sight to individuals blinded by photoreceptor degeneration. Reproducing high-acuity vision with these devices will likely require inferring the natural light responses of diverse RGC types in the implanted retina, without being able to measure them directly. Here we demonstrate an inference approach that exploits intrinsic electrophysiological features of primate RGCs. Approach. First, ON-parasol and OFF-parasol RGC types were identified using their intrinsic electrical features in large-scale multi-electrode recordings from macaque retina. Then, the electrically inferred somatic location, inferred cell type, and average linear-nonlinear-Poisson model parameters of each cell type were used to infer a light response model for each cell. The accuracy of the cell type classification and of reproducing measured light responses with the model were evaluated. Main results. A cell-type classifier trained on 246 large-scale multi-electrode recordings from 148 retinas achieved 95% mean accuracy on 29 test retinas. In five retinas tested, the inferred models achieved an average correlation with measured firing rates of 0.49 for white noise visual stimuli and 0.50 for natural scenes stimuli, compared to 0.65 and 0.58 respectively for models fitted to recorded light responses (an upper bound). Linear decoding of natural images from predicted RGC activity in one retina showed a mean correlation of 0.55 between decoded and true images, compared to an upper bound of 0.81 using models fitted to light response data. Significance. These results suggest that inference of RGC light response properties from intrinsic features of their electrical activity may be a useful approach for high-fidelity sight restoration. The overall strategy of first inferring cell type from electrical features and then exploiting cell type to help infer natural cell function may also prove broadly useful to neural interfaces.
The combination of feedforward and feedback processing accounts for contextual effects in visual cortex

Sensory systems must combine local features with context to infer meaning. Accordingly, context profoundly influences neural responses. We developed a unified circuit model demonstrating how feedforward and feedback inputs are integrated to produce three forms of contextual effects in mouse primary visual cortex (V1). First, reanalyzing existing data, we discovered that increasing stimulus size only weakly increases the area of V1 neural response, conflicting with previous models of surround suppression (SS). Second, through modeling, we found that, in Layer 2/3, (1) SS and its contrast dependence are largely inherited from Layer 4; (2) Inverse responses (IR) – size-tuned responses to a gray “hole” in a full-field grating – are driven by feedback connections provided they are sufficiently wide; (3) Cross-orientation surround facilitation is induced by the summation of feedback input driving IR with the feedforward-driven classical center response. The model accounts for many previous findings and makes multiple testable predictions. Highlights One model explains three different types of contextual modulation The widths of spatial response patterns grow much more slowly than stimulus size. Inverse responses depend on the geometry of feedback response fields and projections Summation of classical and inverse response accounts for surround facilitation.
Characterization of Plasmodium falciparum myosin B in complex with the calmodulin-like domain of its light chain MLC-B

Myosin B (MyoB) is a class 14 myosin expressed in all invasive stages of the malaria parasite, Plasmodium falciparum. It is not associated with the glideosome complex that drives motility and invasion of host cells. During red blood cell invasion, it remains at the apical tip of the merozoite but is no longer observed once invasion is completed. MyoB is not essential for parasite survival but, when it is knocked out, merozoites are delayed in the initial stages of red blood cell invasion, giving rise to a growth defect that correlates with reduced invasion success. Here, we have expressed and purified functional MyoB with the help of parasite-specific chaperones Hsp90 and Unc45, characterized its binding to actin and its known light chain MLC-B using biochemical and biophysical methods, and determined its low-resolution structure in solution using small-angle X-ray scattering. In addition to MLC-B, four other putative regulatory light chains were found to bind to the MyoB IQ2 motif in vitro. The purified recombinant MyoB adopted the overall shape of a myosin, exhibited actin-activated ATPase activity, and moved actin filaments in vitro. The ADP release rate was faster than the ATP turnover number, and thus, does not appear to be rate-limiting. This, together with the observed high affinity to actin and the specific localization of MyoB, may point towards a role in tethering and/or force sensing during early stages of invasion.
Change point estimation by the mouse medial frontal cortex during probabilistic reward learning

There are often sudden changes in the state of environment. For a decision maker, accurate prediction and detection of change points are crucial for optimizing performance. Still unclear, however, is whether rodents are simply reactive to reinforcements, or if they can be proactive to estimate future change points during value-based decision making. In this study, we characterize head-fixed mice performing a two-armed bandit task with probabilistic reward reversals. Choice behavior deviates from classic reinforcement learning, but instead suggests a strategy involving belief updating, consistent with the anticipation of change points to exploit the task structure. Excitotoxic lesion and optogenetic inactivation implicate the anterior cingulate and premotor regions of medial frontal cortex. Specifically, over-estimation of hazard rate arises from imbalance across frontal hemispheres during the time window before the choice is made. Collectively, the results demonstrate that mice can capitalize on their knowledge of task regularities, and this estimation of future changes in the environment may be a main computational function of the rodent dorsal medial frontal cortex.
Tire Force Estimation using a Proportional Integral Observer

This paper addresses a method for detecting critical stability situations in the lateral vehicle dynamics by estimating the non-linear part of the tire forces. These forces indicate the road holding performance of the vehicle. The estimation method is based on a robust fault detection and estimation approach which minimize the disturbance and uncertainties to residual sensitivity. It consists in the design of a Proportional Integral Observer (PIO), while minimizing the well known H∞ norm for the worst case uncertainties and disturbance attenuation, and combining a transient response specification. This multi-objective problem is formulated as a Linear Matrix Inequalities (LMI) feasibility problem where a cost function subject to LMI constraints is minimized. This approach is employed to generate a set of switched robust observers for uncertain switched systems, where the convergence of the observer is ensured using a Multiple Lyapunov Function (MLF). Whilst the forces to be estimated can not be physically measured, a simulation scenario with CarSimTM is presented to illustrate the developed method.