Miracle-dz/UniFAR-FTUs huggingface dataset:
Crossroads+

As vehicles become autonomous and connected, intelligent management techniques can be utilized to operate an intersection without a traffic light. When a Connected Autonomous Vehicle (CAV) approaches an intersection, it shares its status and intended direction with the Intersection Manager (IM), and the IM checks the status of other CAVs and assigns a target velocity/reference trajectory for it to maintain. In practice, however, there is an unknown delay between the time a CAV sends a request to the IM and the moment it receives back the response, namely, the Round-Trip Delay (RTD). As a result, the CAV will start tracking the target velocity/reference trajectory later than when the IM expects, which may lead to accidents. In this article, we present a time-aware approach, Crossroads+, that makes CAVs’ behaviors deterministic despite the existence of the unknown RTD. In Crossroads+, we use timestamping and synchronization to ensure that both the IM and the CAVs have the same notion of time. The IM will also set a fixed start time to track the target velocity/reference trajectory for each CAV. The effectiveness of the proposed Crossroads+ technique is illustrated by experiments on a 1/10 scale model of an intersection with CAVs. We also built a simulator to demonstrate the scalability of Crossroads+ for multi-lane intersections. Results from our experiments indicate that our approach can reduce the position uncertainty by 15% in comparison with conventional techniques and achieve up to 36% better throughputs.
CAIRO

Three-dimensional (3D)-stacking technology and the memory-wall problem have popularized processing-in-memory (PIM) concepts again, which offers the benefits of bandwidth and energy savings by offloading computations to functional units inside the memory. Several memory vendors have also started to integrate computation logics into the memory, such as Hybrid Memory Cube (HMC), the latest version of which supports up to 18 in-memory atomic instructions. Although industry prototypes have motivated studies for investigating efficient methods and architectures for PIM, researchers have not proposed a systematic way for identifying the benefits of instruction-level PIM offloading. As a result, compiler support for recognizing offloading candidates and utilizing instruction-level PIM offloading is unavailable. In this article, we analyze the advantages of instruction-level PIM offloading in the context of HMC-atomic instructions for graph-computing applications and propose CAIRO, a compiler-assisted technique and decision model for enabling instruction-level offloading of PIM without any burden on programmers. To develop CAIRO, we analyzed how instruction offloading enables performance gain in both CPU and GPU workloads. Our studies show that performance gain from bandwidth savings, the ratio of number of cache misses to total cache accesses, and the overhead of host atomic instructions are the key factors in selecting an offloading candidate. Based on our analytical models, we characterize the properties of beneficial and nonbeneficial candidates for offloading. We evaluate CAIRO with 27 multithreaded CPU and 36 GPU benchmarks. In our evaluation, CAIRO not only doubles the speedup for a set of PIM-beneficial workloads by exploiting HMC-atomic instructions but also prevents slowdown caused by incorrect offloading decisions for other workloads.
Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy

Survivin is a cancer-associated protein that is pivotal for cellular life and death: it is an essential mitotic protein and an inhibitor of apoptosis. In cancer cells, a small pool of survivin localises to the mitochondria, the function of which remains to be elucidated. Here, we report that mitochondrial survivin inhibits the selective form of autophagy, called “mitophagy”, causing an accumulation of respiratory defective mitochondria. Mechanistically the data reveal that survivin prevents recruitment of the E3-ubiquitin ligase Parkin to mitochondria and their subsequent recognition by the autophagosome. The data also demonstrate that, as a consequence of this blockade, cells expressing high levels of survivin have an increased dependency on anaerobic glycolysis. As these effects were found exclusively in cancer cells they suggest that the primary act of mitochondrial survivin is to force cells to implement the “Warburg Effect” by inhibiting mitochondrial turnover.
RiboDiPA: a novel tool for differential pattern analysis in Ribo-seq data

Ribosome profiling (also known as Ribo-seq) has become an important technique to investigate changes in translation across a wide variety of contexts. Ribo-seq data not only provides the abundance of ribosomes bound to transcripts, but also positional information across transcripts that could be indicative of differences in translation dynamics between conditions. While many computational tools exist for the analysis of Ribo-seq data, including those that assess differences in translational efficiency between conditions, no tool currently exists for rigorous test of the pattern differences in ribosome footprint. In this paper we propose a novel approach together with an R package, RiboDiPA, for Differential PPattern Analysis of Ribo-seq data. RiboDiPA allows for quick identification of genes with statistically significant differences in ribosome occupancy patterns for model organisms ranging from yeast to mammals. We show that differential pattern analysis reveals information that is distinct and complimentary to the existing methods that focus on translational efficiency analysis. Using both simulated Ribo-seq footprint data and two benchmark data sets, we illustrate that RiboDiPA can not only uncover meaningful global translational differences between conditions, but also the detailed differential ribosome binding patterns to a single codon resolution.
Elucidating the differences in the molecular mechanism of receptor binding between 2019-nCoV and the SARS-CoV viruses using computational tools

The outbreak of the 2019-nCoV coronavirus causing severe acute respiratory syndrome which can be fatal, especially in elderly population, has been declared a pandemic by the World Health Organization. Many biotechnology laboratories are rushing to develop therapeutic antibodies and antiviral drugs for treatment of this viral disease. The viral CoV spike (S) glycoprotein is one of the main targets for pharmacological intervention. Its receptor-binding domain (RBD) interacts with the human ACE2 receptor ensuring the entry of the viral genomes into the host cell. In this work, we report on the differences in the binding of the RBD of the previous coronavirus SARS-CoV and of the newer 2019-nCoV coronavirus to the human ACE2 receptor using atomistic molecular dynamics techniques. Our results show major mutations in the 2019-nCoV RBD with respect to the SARS-CoV RBD occurring at the interface of RBD-ACE2 complex. These mutations make the 2019-nCoV RBD protein backbone much more flexible, hydrophobic interactions are reduced and additional polar/charged residues appear at the interface. We observe that higher flexibility of the 2019-nCoV RBD with respect to the SARS-CoV RBD leads to a bigger binding interface between the 2019-nCoV RBD and ACE2 and to about 20% more contacts between them in comparison with SARS-CoV. Taken together, the 2019-nCoV RBD shows more stable binding interface and higher binding affinity for the ACE2 receptor. The mutations not only stabilize the binding interface, they also lead to overall more stable 2019-nCoV RBD protein structure, even far from the binding interface. Our results on the molecular differences in the binding between the two viruses can provide important inputs for development of appropriate antiviral treatments of the new viruses, addressing the necessity of ongoing pandemics.
SARS-CoV-2 Encodes a PPxY Late Domain Motif Known to Enhance Budding and Spread in Enveloped RNA Viruses

The current COVID-19 (Coronavirus Disease-2019) pandemic is affecting the health and/or socioeconomic welfare of almost everyone in the world. Finding vaccines and therapeutics is therefore urgent, but elucidation of the molecular mechanisms that allow some viruses to cross host species boundaries, becoming a threat to human health, must also be given close attention. Here, analysis of all proteins of SARS-CoV-2 revealed a unique PPxY Late (L) domain motif, 25PPAY28, in a spike (S) protein inside a predicted hot disordered loop subject to phosphorylation and binding. PPxY motifs in enveloped RNA viruses are known to recruit Nedd4 E3 ubiquitin ligases and ultimately the ESCRT complex to enhance virus budding and release, resulting in higher viral loads, hence facilitating new infections. Interestingly, proteins of SARS-CoV-1 do not feature PPxY motifs, which could explain why SARS-CoV-2 is more contagious than SARS-CoV-1. Should an experimental assessment of this hypothesis show that the PPxY motif plays the same role in SARS-CoV-2 as it does in other enveloped RNA viruses, this motif will become a promising target for the development of novel host-oriented antiviral therapeutics for preventing S proteins from recruiting Nedd4 E3 ubiquitin ligase partners.
Endophilin A2 regulates B cell protein trafficking and humoral responses

Antigen-specific B cell responses require endosomal trafficking to regulate antigen uptake and presentation to helper T cells, and to control expression and signaling of immune receptors. However, the molecular composition of B cell endosomal trafficking pathways and their specific roles in B cell responses have not been systematically investigated. Here we report high-throughput identification of genes regulating B cell receptor (BCR)-mediated antigen internalization using genome-wide functional screens. We show that antigen internalization depends both on clathrin-coated pits and on clathrin-independent endocytosis mediated by endophilin A2. Although endophilin A2 is dispensable for presentation of the endocytosed antigen, it is required for metabolic support of germinal center (GC) B cell proliferation, in part through regulation of iron uptake. Consequently, endophilin A2 deficient mice show selective defects in GC B cell responses and production of high-affinity IgG. The requirement for endophilin A2 highlights a unique importance of clathrin-independent intracellular trafficking in GC B cell clonal expansion and antibody responses. HIGHLIGHTS Genome-wide CRISPR screens comprehensively identify genes regulating antigen uptake in B cells B cell receptor-mediated antigen internalization is mediated by both epsin1- dependent clathrin-coated pits and a novel fast endophilin A2-mediated endocytosis. Endophilin A2 is required for peripheral B cell development, antigen-specific germinal center responses and high-affinity IgG production. Endophilin A2 is broadly essential for B cell intracellular trafficking pathways providing metabolic support of germinal center B cell proliferation, in part through regulation of iron uptake.
ZBTB18 interacts with CTBP2 and represses SREBP genes to inhibit fatty acid synthesis in glioblastoma

Abstract Enhanced fatty acid synthesis is a hallmark of tumors, including glioblastoma. SREBF1/2 regulates the expression of enzymes involved in fatty acid and cholesterol synthesis. Yet, little is known about the precise mechanism regulating SREBP gene expression in glioblastoma. Here, we show that a novel interaction between the co-activator/co-repressor CTBP2 and the tumor suppressor ZBTB18 regulates the expression of SREBP genes. Our study points at CTBP2 as a co-activator of SREBP genes whose complex activity is impaired by ZBTB18. ZBTB18 binding to the SREBP gene promoters is associated with reduced LSD1 activity leading to increased di-methylation of lysine 9 (H3K9me2), and concomitant decrease of H3K4me3 with consequent repression of the SREBP genes. In line with our findings, lipidomics analysis shows a reduction of several phospholipid species upon ZBTB18 expression. Our results thus outline a new epigenetic mechanism enrolled by ZBTB18 and its cofactors to regulate fatty acid synthesis which could be targeted to treat glioblastoma patients. Statement of Significance De novo lipogenesis is a hallmark of many cancers, including glioblastoma; therefore, revealing how fatty acid synthesis enzymes are regulated may open up new venues in therapy. Moreover, understanding how epigenetic control of key cancer genes occurs may contribute to shed light on common regulatory mechanisms shared by other tumor suppressors in different cancers.
Constraints on the deformation of the vibrissa within the follicle

Nearly all mammals have a vibrissal system specialized for tactile sensation, composed of whiskers growing from sensor-rich follicles in the skin. Because a whisker has no sensors along its length, an open question is how mechanoreceptors in the follicle transduce sensory signals. These mechanoreceptors are activated by whisker deflection, so it is essential to understand how the whisker deforms within the follicle and so how it may activate different populations of mechanoreceptors in different ways. During active whisking behaviors, muscle contractions and increases in blood pressure in the ring sinus will likely affect the whisker deformation profile. Directly recording from mechanoreceptors under these conditions is difficult due to their small size, location within intricate and delicate membranes, and movement during sensation. Using data from a previous experimental study on whisker deflection, and from histological analysis of follicle tissue, we develop a mechanical model of the follicle sinus complex. With this model we first simulate passive whisker contact, replicating previous results of ex vivo experiments on deformation of a whisker within the follicle. We then simulate whisker deformation within the follicle during active whisking. Results of these simulations predict that both intrinsic muscle contraction and elevated hydrostatic pressure within the ring sinus may be regulatory mechanisms to enhance tactile sensitivity during active whisking. The mechanical model presented in this study is an important first step in simulating mechanical interactions within whisker follicles, and aids in the development of artificial robotic follicles. Author summary Many mammals rely on whiskers as a mode of tactile sensation, especially when exploring in darkness. Active, rhythmic protraction and retraction of the whiskers, commonly referred to as whisking, is observed among many whisker specialist animals. Whisker-based sensing requires the forces and moments generated by external stimuli to be transduced into neural signals inside the follicle, which holds the base of the whisker shaft. Within the follicle, the interaction between the whisker’s deformation and the surrounding tissue determines how different groups of mechanoreceptors along the inside of a follicle will deformed. However, experimental measurement of this interaction is challenging to perform in active animals. We therefore created a mechanical model for the follicle sinus complex to simulate whisker deformation within the follicle resulting from external whisker deflection. Our simulations replicate results from previous ex vivo experiments that have monitored whisker deformation in the follicle ring sinus. We extend these results by predicting whisker deformation profiles during active whisking. Our results suggest that both intrinsic muscle contraction and an increase in blood pressure will affect the whisker deformation profile within the follicle, and in turn, the tactile sensitivity of the whisker system.
Dendrites decrease the synaptic weight resolution necessary to implement linearly separable computations

In theory, neurons modelled as single layer perceptrons can implement all linearly separable computations. In practice, however, these computations may require arbitrarily precise synaptic weights. This is a strong constraint since both, biological neurons and their artificial counterparts, have to cope with limited precision. Here, we explore how the non-linear processing in dendrites helps overcoming this constraint. We start by finding a class of computations which requires increasing precision with the number of inputs in a perceptron and show that it can be implemented without this constraint in a neuron with sub-linear subunits. Then, we complement this analytical study by a simulation of a biophysical neuron model with two passive dendrites and a soma, and show that it can implement this computation. This works demonstrates a new role of dendrites in neural computation: by distributing the computation across independent subunits, the same computation can be performed more efficiently with less precise tuning of the synaptic weights. We hope that this works not only offers new insight into the importance of dendrites for biological neurons, but also paves the way for new, more efficient architectures of artificial neuromorphic chips. Author Summary In theory, we know how much neurons can compute, in practice, the number of possible synaptic weights values limits their computation capacity. Such a limitation holds true for artificial and synthetic neurons. We introduce here a computation where the required means evolve significantly with the number of inputs, this poses a problem as neurons receive multiple thousands of inputs. We study here how the neurons’ receptive element-called dendrites-can mitigate such a problem. We show that, without dendrites, the largest synaptic weight need to be multiple orders of magnitude larger than the smallest to implement the computation. Yet a neuron with dendrites implements the same computation with constant synaptic weights whatever the number of inputs. This study paves the way for the use of dendritic neurons in a new generation of artificial neural network and neuromorphic chips with a considerably better cost-benefit balance.
Evidence for transposable element control by Argonautes in a parasitic flatworm lacking the piRNA pathway

Transposable elements (TEs) are mobile parts of the genome that can jump or self-replicate, posing a threat to the stability and integrity of the host genome. TEs are prevented from causing damage to the host genome by defense mechanisms such as nuclear silencing, where TE transcripts are targeted for degradation in an RNAi-like fashion. These pathways are well characterised in model organisms but very little is known about them in other species. Parasitic flatworms present an opportunity to investigate evolutionary novelties in TE control because they lack canonical pathways identified in model organisms (such as the piRNA pathways) but have conserved central players such as Dicer and Ago (argonaute) enzymes. Notably, parasitic flatworm Ago proteins are phylogenetically distinct from classical Ago, raising the question of whether they play special roles in these organisms. In this report, we investigate the role of Ago proteins in the parasitic flatworm Schistosoma mansoni. We show that transcript abundance of two retrotransposable elements increases upon silencing of S. mansoni Ago genes. We further demonstrate that SmAgo2 protein is primarily localised in the germ line of adult worms and its sub-cellular localisation is both nuclear and cytoplasmic. These findings provide further evidence of active TE control under a yet not fully unveiled pathway.
Broad and differential animal ACE2 receptor usage by SARS-CoV-2

The COVID-19 pandemic has caused an unprecedented global public health and economy crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, comparing to the SARS-CoV-2-like CoVs identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human ACE2 as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2 from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activity, respectively. Among the remaining species, ACE2 from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models. Importance SARS-CoV-2 uses human ACE2 as primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologues and found that wild type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models and molecular basis of receptor binding for SARS-CoV-2.
Open database searching enables the identification and comparison of bacterial glycoproteomes without defining glycan compositions prior to searching

Mass spectrometry has become an indispensable tool for the characterisation of glycosylation across biological systems. Our ability to generate rich fragmentation of glycopeptides has dramatically improved over the last decade yet our informatic approaches still lag behind. While glycoproteomic informatics approaches using glycan databases have attracted considerable attention, database independent approaches have not. This has significantly limited high throughput studies of unusual or atypical glycosylation events such as those observed in bacteria. As such, computational approaches to examine bacterial glycosylation and identify chemically diverse glycans are desperately needed. Here we describe the use of wide-tolerance (up to 2000 Da) open searching as a means to rapidly examine bacterial glycoproteomes. We benchmarked this approach using N-linked glycopeptides of Campylobacter fetus subsp. fetus as well as O-linked glycopeptides of Acinetobacter baumannii and Burkholderia cenocepacia revealing glycopeptides modified with a range of glycans can be readily identified without defining the glycan masses prior to database searching. Utilising this approach, we demonstrate how wide tolerance searching can be used to compare glycan utilisation across bacterial species by examining the glycoproteomes of eight Burkholderia species (B. pseudomallei; B. multivorans; B. dolosa; B. humptydooensis; B. ubonensis, B. anthina; B. diffusa; B. pseudomultivorans). Finally, we demonstrate how open searching enables the identification of low frequency glycoforms based on shared modified peptides sequences. Combined, these results show that open searching is a robust computational approach for the determination of glycan diversity within bacterial proteomes.