Miracle-dz/UniFAR-FTUs huggingface dataset:
Quantitative study of alpha-synuclein prion-like spreading in fully oriented reconstructed neural networks reveals non-synaptic dissemination of seeding aggregates

The trans-neuronal spread of protein aggregates in a prion-like manner underlies the progression of neuronal lesions in the brain of patients with synucleinopathies such as Parkinson’s disease. Despite being studied actively, the mechanisms of alpha-synuclein (aSyn) aggregates propagation remain poorly understood. This hinders the development of therapeutic approaches aiming at preventing the spatial progression of intracellular inclusions in neural networks. To assess the role of synaptic structures and neuron characteristics in the transfer efficiency of aggregates with seeding propensity, we developed a novel microfluidic culture system which allows for the first time to reconstruct in vitro fully oriented and synaptically connected neural networks. This is achieved by filtering axonal growth with unidirectional “axon valves” microchannels. We exposed the presynaptic compartment of reconstructed networks to well characterized human aSyn aggregates differing in size: Fibrils and Oligomers. Both aggregates were transferred to postsynaptic neurons through active axonal transport, albeit with poor efficiency. By manipulating network maturity, we compared the transfer rate of aggregates in networks with distinct levels of synaptic connectivity. Surprisingly, we found that transfer efficiency was lower in mature networks with higher synaptic connectivity. We then investigated the seeding efficiency of endogenous aSyn in the postsynaptic population. We found that exposure to Fibrils, and not Oligomers, resulted in low efficiency trans-neuronal seeding which was restricted to postsynaptic axons. Finally, we assessed the impact of neuron characteristics and aSyn expression on the propagation of aSyn aggregates. By reconstructing chimeric networks, we found that neuron characteristics, such as the brain region from which they originate or aSyn expression levels, did not significantly impact aggregates transfer, and observed no trans-neuronal seeding where the presynaptic population did not express aSyn. Overall, we demonstrate that this novel platform uniquely allows the quantitative interrogation of original aspects of the trans-neuronal propagation of seeding pathogenic entities.
Can DNA help trace the local trade of pangolins? A genetic assessment of white-bellied pangolins from the Dahomey Gap (West Africa)

We conducted in the Dahomey Gap (DG) a pioneer study on the genetic tracing of the African pangolin trade. We sequenced and genotyped 189 white-bellied pangolins from 18 forests and 12 wildlife markets using one mitochondrial fragment and 20 microsatellites loci. Tree-based assignment procedure showed the ‘endemicity’ of the pangolin trade, as strictly fed by the lineage endemic to the DG (DGL). DGL populations were characterized by low levels of genetic diversity, an overall absence of equilibrium, inbreeding depression and lack of geographic structure. We identified a 92-98% decline in DGL effective population size 200-500 ya –concomitant with major political transformations along the ‘Slave Coast’– leading to contemporaneous estimates inferior to minimum viable population size. Genetic tracing suggested that wildlife markets from the DG sourced through the entire DGL range. Our loci provided the necessary power to distinguish among all the genotyped pangolins, tracing the dispatch of same individuals on the markets and within local communities. We developed an approach combining rarefaction analysis of private allele frequencies and cross-validation with observed data that could trace five traded pangolins to their forest origin, c. 200-300 km away from the markets. Although the genetic toolkit that we designed from traditional markers can prove helpful to trace the pangolin trade, our tracing ability was limited by the lack of population structure within DGL. Given the deleterious combination of genetic, demographic and trade-related factors affecting DGL populations, the conservation status of white-bellied pangolins in the DG should be urgently re-evaluated.
Broad-scale puma connectivity could restore genomic diversity to fine-scale coastal populations

Urbanization is decreasing wildlife habitat and connectivity worldwide, including for apex predators, such as the puma (Puma concolor). Puma populations along California’s central and southern coastal habitats have experienced rapid fragmentation from development, leading to calls for demographic and genetic management. To address urgent conservation genomic concerns, we used double-digest restriction-site associated DNA (ddRAD) sequencing to analyze 16,285 genome-wide single-nucleotide polymorphisms (SNPs) from 401 broadly sampled pumas. Our analyses indicated support for 4–10 geographically nested, broad- to fine-scale genetic clusters. At the broadest scale, the 4 genetic clusters had high genetic diversity and exhibited low linkage disequilibrium, indicating pumas have retained statewide genomic diversity. However, multiple lines of evidence indicated substructure, including 10 fine-scale genetic clusters, some of which exhibited allelic fixation and linkage disequilibrium. Fragmented populations along the Southern Coast and Central Coast had particularly low genetic diversity and strong linkage disequilibrium, indicating genetic drift and close inbreeding. Our results demonstrate that genetically at-risk populations are typically nested within a broader-scale group of interconnected populations that collectively retains high genetic diversity and heterogeneous fixations. Thus, extant variation at the broader scale has potential to restore diversity to local populations if management actions can enhance vital gene flow and recombine locally sequestered genetic diversity. These state- and genome-wide results are critically important for science-based conservation and management practices. Our broad- and fine-scale population genomic analysis highlights the information that can be gained from population genomic studies aiming to provide guidance for fragmented population conservation management.
Retrograde adenosine/A2A receptor signaling facilitates excitatory synaptic transmission and seizures

Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2A receptor (A2AR) as a novel retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity. Highlights Postsynaptic firing induces presynaptic LTP at mossy cell to granule cell synapses Postsynaptic TrkB activation induces adenosine release from granule cells Presynaptic adenosine A2A receptors are necessary and sufficient to induce LTP Adenosine/A2AR signaling within the dentate gyrus is pro-convulsant In Brief Nasrallah et al. report a novel retrograde signaling pathway at hippocampal synapses that involves postsynaptic TrkB-dependent release of adenosine and the activation of presynaptic A2A receptors. This pathway mediates presynaptic long-term potentiation at a key hippocampal excitatory synapse and can also promote epileptic seizures.
Connexins evolved after early chordates lost innexin diversity

Gap junction channels are formed by two unrelated protein families. Non-chordates use the primordial innexins, while chordates use connexins that superseded the gap junction function of innexins. Chordates retained innexin-homologs, but N-glycosylation prevents them from forming gap junctions. It is puzzling why chordates seem to exclusively use the new gap junction protein and why no chordates should exist that use non-glycosylated innexins to form gap junctions. Here, we identified glycosylation sites of 2270 innexins from 152 non-chordate and 274 chordate species. Among all chordates, we found not a single innexin without glycosylation sites. Surprisingly, the glycosylation motif is also widespread among non-chordate innexins indicating that glycosylated innexins are not a novelty of chordates. In addition, we discovered a loss of innexin diversity during the early chordate evolution. Most importantly, the most basal living chordates, which lack connexins, exclusively possess innexins with glycosylation sites. A bottleneck effect might thus explain why connexins have become the only protein used to form chordate gap junctions.
Endoglin deficiency elicits hypoxia-driven congestive heart failure in zebrafish

Hereditary hemorrhagic Telangiectasia (HHT) is a rare genetic disease relying on mutations affecting components of Bone Morphogenetic Protein and Transforming Growth Factor-β (BMP/TGF-β) signaling pathway in endothelial cells. This disorder is characterized by arterio-venous malformations prone to rupture. and ensuing hemorrhages are responsible for iron deficiency anemia. Along with Activin receptor-like kinase ALK1, Endoglin is involved in the vast majority of HHT cases. In this report, we characterized zebrafish endoglin locus and demonstrated that it produces two phylogenetically conserved protein isoforms using a distinctive alternative splicing mechanism. Functional analysis of a Crispr/Cas9 zebrafish Endoglin mutant revealed that Endoglin deficiency results in massive death during the course from juvenile stage to adulthood. Endoglin deficient fish develop a cardiomegaly resulting in heart failure and hypochromic anemia which both stem from chronic hypoxia. Histological analysis and confocal imaging evidenced structural alterations of the developing gill and its underlying vascular network that tally with hypoxia. Finally, phenylhydrazine treatment demonstrated that lowering hematocrit/blood viscosity alleviates heart failure and enhances survival of Endoglin deficient fish. Altogether, our data indicate that Endoglin is crucial for gill vascular development and that further studies using zebrafish in general and this endoglin mutant in particular will provide crucial hints regarding the molecular and cellular events altered in HHT for the development of new therapeutic strategies. Summary Statement Endoglin deficiency in zebrafish recapitulates critical aspects of Hereditary Hemorrhagic Telangiectasia (HHT) and will thus constitute a valuable model in large scale screens for HHT-active drugs.
WUSCHEL-Related Homeobox Genes Cooperate with Cytokinin Signalling to Promote Bulbil Formation in Lilium lancifolium

The bulbil is an important vegetative reproductive organ in triploid Lilium lancifolium. Based on our previously obtained transcriptome data, we screened two WUSCHCEL-related homeobox (WOX) genes closely related to bulbil formation, LlWOX9 and LlWOX11. However, the biological functions and regulatory mechanisms of LlWOX9 and LlWOX11 are unclear. In this study, we cloned the full-length coding sequences of LlWOX9 and LlWOX11. Transgenic Arabidopsis showed increased branch numbers, and the overexpression of LlWOX9 and LlWOX11 in stem segments promoted bulbil formation, while the silencing of LlWOX9 and LlWOX11 inhibited bulbil formation, indicating that LlWOX9 and LlWOX11 are positive regulators of bulbil formation. Cytokinins acting through type-B response regulators (type-B RRs) could bind to the promoters of LlWOX9 and LlWOX11 and promote their transcription. LlWOX11 could enhance cytokinin pathway signalling by inhibiting the transcription of type-A LlRR9. Our study enriches the understanding of the regulation of plant development by the WOX gene family and lays a foundation for further research on the molecular mechanism of bulbil formation in lily.
Growth and development of trabecular structure in the calcaneus of Japanese macaques (Macaca fuscata) reflects locomotor behavior, life history, and neuromuscular development

We aim to broaden the analysis of bone structure by suggesting a new way to incorporate the interactions between behavior, neuromuscular development, and life-history. We examine the associations between these variables and age-related variation in trabecular structure in the calcaneus of Japanese macaques (Macaca fuscata). If skeletal markers linking these variables can be established, our inferences of the biology and behavior of fossil species would be significantly improved. We µCT scanned the calcaneus in a cross-sectional sample of 36 juveniles aged between 0 and 7 years old and 5 adults at the Primate Research Institute, Japan. We calculated whole bone averages of standard trabecular properties and generated whole-bone morphometric maps of bone volume fraction and Young’s modulus. Trabecular structure is increasingly heterogeneous in older individuals. BV/TV decreases during the first month of life and increases afterwards, coinciding with the onset of independent locomotion. At birth, primary Young’s modulus is oriented orthogonal to the ossification center, but after locomotor onset bone structure becomes stiffest in the direction of joint surfaces and muscle attachments. Age-related variation in bone volume fraction is best predicted by an interaction between neuromaturation, body mass, and locomotor independence. Results support the common assumption that trabecular structure dynamically adapts to novel joint loading conditions during ontogeny. The timing of independent locomotion, body size, and neuromuscular development, are all correlated to age-related variation in the trabecular structure of the macaque calcaneus. The causal mechanisms behind the observed patterns cannot be directly inferred from our cross-sectional study. If the model presented in this paper holds up under longitudinal experimental conditions, trabecular structure can be used both to infer behavior from fossil morphology and to serve as a valuable proxy for neuromuscular maturation and life history events like locomotor onset and the achievement of an adult-like gait.
A Conserved uORF Regulates APOBEC3G Translation and Is Targeted by HIV-1 Vif Protein to Repress the Antiviral Factor

The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular restriction factors APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutation during reverse transcription. Vif counteracts A3G at several levels (transcription, translation and protein degradation) that together reduce the levels of A3G in cells and prevent its incorporation into viral particles. How Vif affects A3G translation remains unclear. Here, we uncovered the importance of a short conserved uORF (upstream ORF) located within two critical stem-loop structures of the 5’ untranslated region (5’UTR) of A3G mRNA for this process. A3G translation occurs through a combination of leaky-scanning and translation re-initiation and the presence of an intact uORF decreases the extent of global A3G translation under normal conditions. Interestingly, the uORF is also absolutely required for Vif-mediated translation inhibition and redirection of A3G mRNA into stress granules. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific feature to repress its translation.
Platinum Chemotherapy Induces Lymphangiogenesis in Cancerous and Healthy Tissues That Can be Prevented With Adjuvant Anti-VEGFR3 Therapy

Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drugs drain via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used class of chemotherapeutics, to directly induce systemic lymphangiogenesis and activation. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We saw similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increases cancer metastasis as compared to no pre-treatment. These platinum-induced phenomena could be blocked by VEGFR3 inhibition. These findings have implications for cancer patients receiving platinums and may support the inclusion of anti-VEGFR3 therapy into treatment regimens or differential design of treatment regimens to alter these potential effects. Summary Platinum chemotherapy induces VEGFR3-dependent lymphangiogenesis, priming tissues for metastasis of breast cancer. Inhibition of VEGFR3 via antibody blockade can reverse these effects.
PBDT: Python Backdoor Detection Model Based on Combined Features

Application security is essential in today’s highly development period. Backdoor is a means by which attackers can invade the system to achieve illegal purposes and damage users’ rights. It has posed a serious threat to network security. Thus, it is urgent to take adequate measures to defend such attacks. Previous research work was mainly focused on numerous PHP webshells, with less research on Python backdoor files. Language differences make the method not entirely applicable. This paper proposes a Python backdoor detection model named PBDT based on combined features. The model summarizes the common functional modules and functions in the backdoor files and extracts the number of calls in the text to form sample features. What is more, we consider the text’s statistical characteristics, including the information entropy, the longest string, etc., to identify the obfuscated Python code. Besides, the opcode sequence is used to represent code characteristics, such as TF-IDF vector and FastText classifier, to eliminate the influence of interference items. Finally, we introduce the Random Forest algorithm to build a classifier. Covering most types of backdoors, some samples are obfuscated, the model achieves an accuracy of 97.70%, and the TNR index is as high as 98.66%, showing a good classification performance in Python backdoor detection.
Multislice Spiral Computed Tomography under Hybrid Iterative Reconstruction Algorithm in Staging Diagnosis of Bladder Cancer and Ceramide Glycosylation

This study was to discuss the application of multislice spiral computed tomography (CT) in the staging diagnosis of bladder cancer and the effect of ceramide glycosylation. The hybrid iterative reconstruction algorithm was applied. Immunohistochemistry and western blot were used to detect the normal bladder tissues (30 cases) of GCS in group 1 (100 cases) and group 2. The scanned images of all the research objects were obtained, the images with the iterative reconstruction algorithm were reconstructed, and statistical analysis on the CT value under the algorithm was conducted. The results showed that the image quality, blood vessel sharpness, average image score, signal-to-noise ratio, and radiation dose after the spiral CT and iterative reconstruction algorithm all increased, while the noise value decreased. The optical density value of glucosylceramide synthase in group 2 patients increased by 71%, and the optical density value of group 1 increased by 29%. The optical density expression of glucosylceramide synthase in group 1 patients was significantly higher than that in the control group, and there was a statistical difference between the two ( P < 0.05 ). Among the results of multislice spiral CT for tumor staging, the lesions larger than 5 cm and in the range of 1.1–2 cm in diameter were more sensitive. In 41 patients, there were multiple lesions. A total of 142 cancer lesions were found. The diameter of the tissue ranged from 0.5 to 6.8 cm, with an average diameter of 2.03 ± 0.35 cm. The optical density of glucosylceramide synthase in the group 1 was 5526, and the optical density in group 2 was 2576. The OD expression of GCS in group 1 was greatly higher in contrast to that in group 2, and there was a statistical difference between the two groups ( P < 0.05 ). The multislice spiral CT examination under this algorithm found that the diagnosis and staging accuracy of lesions with a diameter greater than 5 cm and tumor diameters in the range of 1.1 to 2 cm was higher. The image processed by the hybrid iterative reconstruction algorithm had good effect, high definition, and accuracy.
A Provably Secure Authentication and Key Agreement Protocol in Cloud-Based Smart Healthcare Environments

The wide applications of the Internet of Things and cloud computing technologies have driven the development of many industries. With the improvement of living standards, health has become the top priority of people’s attention. The emergence of the wireless body area network (WBAN) enables people to master their physical condition all the time and make it more convenient for patients and doctors to communicate with each other. Doctors can provide real-time online treatment with cloud-based smart healthcare environments for patients. In this process, patients, health records, and doctors need to maintain security and privacy. Recently, Kumari et al. proposed a secure framework for the smart medical system. However, we found that their framework cannot provide the anonymity of patients and doctors, data confidentiality, and patient unlinkability and also is subject to impersonation attacks and desynchronization attacks. In order to ensure the security and privacy of patients and doctors, we propose an authentication and key exchange protocol in cloud-based smart healthcare environments. Formal and informal security analyses, as well as performance analysis, demonstrated that our protocol is suitable for these environments.
A Hybrid Association Rule-Based Method to Detect and Classify Botnets

Nowadays, botnet has become a threat in the area of cybersecurity, and, worse still, it is difficult to be detected in complex network environments. Thus, traffic analysis is adopted to detect the botnet since this kind of method is practical and effective; however, the false rate is very high. The reason is that normal traffic and botnet traffic are quite close to the border, making it so difficult to be recognized. In this paper, we propose an algorithm based on a hybrid association rule to detect and classify the botnets, which can calculate botnets’ boundary traffic features and receive effects in the identification between normal and botnet traffic ideally. First, after collecting the data of different botnets in a laboratory, we analyze botnets traffic features by processing a data mining on it. The suspicious botnet traffic is filtered through DNS protocol, black and white list, and real-time feature filtering methods. Second, we analyze the correlation between domain names and IP addresses. Combining with the advantages of the existing time-based detection methods, we do a global correlation analysis on the characteristics of botnets, to judge whether the detection objects can be botnets according to these indicators. Then, we calculate these parameters, including the support, trust, and membership functions for association rules, to determine which type of botnet it belongs to. Finally, we process the test by using the public dataset and it turns out that the accuracy of our algorithm is higher.