Miracle-dz/UniFAR-FTUs huggingface dataset:
Slowing of Frontocentral Beta Oscillations in Atypical Parkinsonism

Diagnosis of atypical parkinsonian syndromes mostly relies on clinical presentation as well as structural and molecular brain imaging. It has not been investigated whether cortical oscillatory activity exhibits features distinguishing these syndromes. Therefore, we measured resting-state magnetoencephalography in 13 patients with corticobasal syndrome, 10 patients with progressive supranuclear palsy, 23 patients with idiopathic Parkinson’s disease and 23 healthy controls. We compared spectral power as well as amplitude and frequency of power peaks between the groups. Atypical Parkinsonism was associated with spectral slowing, distinguishing both corticobasal syndrome and progressive supranuclear palsy from age-matched healthy controls and Parkinson’s disease. Patients with atypical Parkinsonism showed a shift of beta peaks (13-30 Hz) towards lower frequencies in frontal and central areas bilaterally. A concomitant increase in theta/alpha power relative to controls was observed in both atypical parkinsonian syndromes and in Parkinson’s disease. Our results demonstrate that slowing of frontocentral beta oscillations is characteristic of atypical Parkinsonism. Spectral slowing with a different topography has previously been observed in other neurodegenerative disorders, such as Alzheimer’s disease, suggesting that spectral slowing might be an electrophysiological marker of cortical neurodegeneration. As such, it might support differential diagnosis of parkinsonian syndromes in the future. Highlights Slowing of beta oscillations distinguishes atypical parkinsonian syndromes from healthy controls and idiopathic Parkinson’s disease Spectral slowing is most pronounced in frontocentral areas Beta oscillations are shifted towards lower frequencies independent of their amplitude
Chemogenetic Disconnection between the Orbitofrontal Cortex and the Rostromedial Caudate Nucleus Disrupts Motivational Control of Goal-Directed Action

The orbitofrontal cortex (OFC) and its major downstream target within the basal ganglia—the rostromedial caudate nucleus (rmCD)—are involved in reward-value processing and goal-directed behavior. However, a causal contribution of the pathway linking these two structures to goal-directed behavior has not been established. Using the chemogenetic technology of designer receptors exclusively activated by designer drugs with a crossed inactivation design, we functionally and reversibly disrupted interactions between the OFC and rmCD in two male macaque monkeys. We injected an adeno-associated virus vector expressing an inhibitory designer receptor, hM4Di, into the OFC and contralateral rmCD, the expression of which was visualized in vivo by positron emission tomography and confirmed by postmortem immunohistochemistry. Functional disconnection of the OFC and rmCD resulted in a significant and reproducible loss of sensitivity to the cued reward value for goal-directed action. This decreased sensitivity was most prominent when monkeys had accumulated a certain amount of reward. These results provide causal evidence that the interaction between the OFC and the rmCD is needed for motivational control of action on the basis of the relative reward value and internal drive. This finding extends the current understanding of the physiological basis of psychiatric disorders in which goal-directed behavior is affected, such as obsessive-compulsive disorder. SIGNIFICANCE STATEMENT In daily life, we routinely adjust the speed and accuracy of our actions on the basis of the value of expected reward. Abnormalities in these kinds of motivational adjustments might be related to behaviors seen in psychiatric disorders such as obsessive-compulsive disorder. In the current study, we show that the connection from the orbitofrontal cortex to the rostromedial caudate nucleus is essential for motivational control of action in monkeys. This finding expands our knowledge about how the primate brain controls motivation and behavior and provides a particular insight into disorders like obsessive-compulsive disorder in which altered connectivity between the orbitofrontal cortex and the striatum has been implicated.
Circular mRNA encoded PROTAC (RiboPROTAC) as a new platform for the degradation of intracellular therapeutic targets

Although proteolysis targeting chimera (PROTAC) technology that hijacking the ubiquitin-proteasome system (UPS) to artificially degrade protein is an emerging promising technology for many undruggable targets, it still faces several challenges, such as the difficulty to select high specificity molecule to protein of interest (POI), and only few of the E3-ligase are suitable for PROTAC mediated protein degradation. Protein-based PROTAC, termed BioPROTAC, owns the advantage of specificity but lacks membrane permeability. Here, we develop a new targeted protein degrading platform, which we termed RiboPROTAC, by encoding BioPROTAC protein degraders with circular mRNA (cmRNA) and delivering intracellularly. In this way, intracellular protein GFP and nuclear protein PCNA were successfully degraded. For PCNA targeting, not only the level of target protein is strongly decreased, but also the cell function related is strongly interfered, such as cell proliferation, apoptosis, as well as the cell cycle. What is more, for the first time, we observed that degrading PCNA with RiboPROTAC causes immunogenic cell death (ICD), although not strong, but was verified in vivo. Importantly, our in vivo results demonstrated that cmRNA encoded PCNA degrader exhibited significant tumor suppression effect, thus we provide the first proof of concept for the application of RiboPROTAC as potential mRNA therapeutic. We consider that RiboPROTAC is a new and superior PROTAC technology for targeting the undruggable targets.
The licorice metabolite enoxolone attenuates Clostridioides difficile pathophysiology by corrupting its metabolic and toxin production networks

Toxins TcdA and TcdB are the main virulence factors of Clostridioides difficile, a leading cause of hospital-acquired diarrhea. We investigated the therapeutic potential of inhibiting the biosynthesis of TcdA and TcdB. Accordingly, screening of structurally diverse phytochemicals with medicinal properties identified 18β-glycyrrhetinic acid (enoxolone) as an inhibitor of TcdA and TcdB biosynthesis. Enoxolone also inhibited sporulation. In a CDI colitis model, enoxolone when combined with vancomycin protected mice from becoming moribund and the combination was more effective than vancomycin alone, a standard of care antibiotic for CDI. While enoxolone alone reduced the in vivo load of toxins, the monotherapy did not protect mice from CDI. Affinity based proteomics identified ATP synthase subunit alpha (AtpA) and adenine deaminase (Ade) as possible molecular targets for enoxolone. Silencing of mRNA for Ade and AtpA also reduced toxin biosynthesis, while molecular interaction analysis showed that enoxolone directly bound to Ade. Ade converts adenine to hypoxanthine as an early step in the purine salvage pathway. Metabolomics revealed enoxolone caused cells to accumulate adenosine and deplete hypoxanthine and ATP. Accordingly, supplementation with hypoxanthine partly restored toxin production. Enoxolone also impacted phosphate metabolism by reducing the amounts of cellular phosphate. Thus, supplementation with triethyl phosphate as a source of phosphate also partly restored toxin production. When hypoxanthine and triethyl phosphate were combined, toxin production was fully restored in the presence of enoxolone. Taken together, studies with enoxolone revealed metabolic pathways that affect C. difficile toxin production and could represent potential anti-virulence drug targets. IMPORTANCE Clostridioides difficile, a leading cause of hospital-acquired diarrhea, produces two co-regulated toxins (TcdA and TcdB) that are the focus of most anti-virulence discovery efforts for C. difficile infection (CDI). Exploration of an alternate anti-virulence strategy led to the discovery that the licorice metabolite enoxolone inhibits C. difficile virulence by blocking the cellular biosynthesis of TcdA and TcdB. Blockage of toxin production by enoxolone was associated with multiple effects on cells, including inhibiting adenine deaminase and ATP synthase leading to disruption of purine biosynthesis and phosphate metabolism. In mice infected with C. difficile, the efficacy of enoxolone in combination with vancomycin was superior to vancomycin alone. These findings contribute to establishing toxin biosynthesis inhibition as a newer therapeutic concept for CDI.
Comparative transcriptomics and metabolomics reveal specialized metabolite drought stress responses in switchgrass (Panicum virgatum)

Summary Switchgrass (Panicum virgatum) is a bioenergy model crop valued for its energy efficiency and drought tolerance. The related monocot species rice (Oryza sativa) and maize (Zea mays) deploy species‐specific, specialized metabolites as core stress defenses. By contrast, specialized chemical defenses in switchgrass are largely unknown. To investigate specialized metabolic drought responses in switchgrass, we integrated tissue‐specific transcriptome and metabolite analyses of the genotypes Alamo and Cave‐in‐Rock that feature different drought tolerance. The more drought‐susceptible Cave‐in‐Rock featured an earlier onset of transcriptomic changes and significantly more differentially expressed genes in response to drought compared to Alamo. Specialized pathways showed moderate differential expression compared to pronounced transcriptomic alterations in carbohydrate and amino acid metabolism. However, diterpenoid‐biosynthetic genes showed drought‐inducible expression in Alamo roots, contrasting largely unaltered triterpenoid and phenylpropanoid pathways. Metabolomic analyses identified common and genotype‐specific flavonoids and terpenoids. Consistent with transcriptomic alterations, several root diterpenoids showed significant drought‐induced accumulation, whereas triterpenoid abundance remained predominantly unchanged. Structural analysis verified select drought‐responsive diterpenoids as oxygenated furanoditerpenoids. Drought‐dependent transcriptome and metabolite profiles provide the foundation to understand the molecular mechanisms underlying switchgrass drought responses. Accumulation of specialized root diterpenoids and corresponding pathway transcripts supports a role in drought stress tolerance.
A Hybrid Method for Ultrasound-Based Tracking of Skeletal Muscle Architecture

Tracking skeletal muscle architecture using B-mode ultra-sound is a widely used method in the field of human movement science and biomechanics. Sequential methods based on optical flow algorithms allow for smooth and coherent muscle tracking but are known to drift over time. Non-sequential feature detection methods on the other hand, do not suffer from drift, but are limited to tracking only lower-dimensional features. They are also known to be sensitive to image noise, and therefore often result in highly irregular tracking patterns. Building on the complimentary nature of both approaches, we present a novel fully automated hybrid muscle tracking approach that combines a sequential feature-point tracking method and a non-sequential method based on Hough transform. Tibialis anterior fascicle pennation angle and length, and central aponeurosis displacement, were measured in five healthy individuals during isometric contractions at five different ankle angles. Our hybrid method was demonstrated to significantly (p < 0.001) reduce drift compared to two sequential methods, and curve irregularity was significantly (p < 0.001) decreased compared to a non-sequential method. These findings suggest that the proposed hybrid approach can uniquely mitigate drift and irregularity limitation of individual methods used for tracking skeletal muscle architecture. Fully automated muscle tracking allows for convenient analysis of large datasets, whereas automatic drift correction opens the door for tracking muscle architecture in long ultrasound recordings during common movements, such as walking, running, and jumping without the need for manual intervention.
Metatranscriptomic Comparison of Viromes in Endemic and Introduced Passerines in New Zealand

New Zealand has many endemic passerine birds vulnerable to emerging infectious diseases. Yet little is known about viruses in passerines, and in some countries, including New Zealand, the virome of wild passerines has received little research attention. Using metatranscriptomic sequencing we characterised the virome of New Zealand endemic and introduced species of passerine. Accordingly, we identified 34 possible avian viruses from cloacal swabs of 12 endemic and introduced bird species not showing signs of disease. These included a novel siadenovirus, iltovirus and avastrovirus in the Eurasian blackbird (Turdus merula, an introduced species), song thrush (Turdus philomelos, introduced) and silvereye (Zosterops lateralis, introduced), respectively. This is the first time novel viruses from these genera have been identified in New Zealand, likely reflecting prior undersampling. It also represents the first identification of an iltovirus and siadenovirus in blackbirds and thrushes globally. These three viruses were found only in introduced species and may pose a risk to endemic species if they were to jump species boundaries, particularly the iltoviruses and siadenoviruses that have a prior history of disease associations. Further virus study and surveillance is needed in New Zealand avifauna, particularly in Turdus populations and endemic species.
Individual prediction tendencies facilitate cortical speech tracking

Listening can be conceptualized as a process of active inference, in which the brain forms internal models to predict and integrate auditory information in a complex interaction of bottom-up and top-down processes. Whether inter-individual “prediction tendencies” shape listening experiences of real-world stimuli such as speech is, however, unknown. In the current study, we used a passive paradigm presenting tone sequences of varying entropy level, to independently quantify auditory prediction tendency (as the tendency to anticipate low-level acoustic features according to their contextual probability) for each individual. This measure was then used to predict the magnitude of cortical speech (envelope) tracking in a multi speaker listening task, where participants listened to audiobooks narrated by a target speaker in isolation or interfered by 1 or 2 distractors. Furthermore, rare semantic violations were introduced into the story, enabling us to also examine effects of word surprisal during continuous speech processing. Our results show that individual prediction tendency facilitates cortical speech tracking. Furthermore, we find interactions between individual prediction tendency and background noise as well as word surprisal in disparate brain regions. In sum, our findings suggest that individual prediction tendencies are generalizable across different listening situations and may serve as a valuable element to explain interindividual differences in natural listening experience.
The physics of liquid-to-solid transitions in multi-domain protein condensates

Many RNA-binding proteins (RBPs) that assemble into membraneless organelles, have a common architecture including disordered prion-like domain (PLD) and folded RNA-binding domain (RBD). An enrichment of PLD within the condensed phase gives rise to formation, on longer time scales, amyloid-like fibrils (aging). In this study, we employ coarse-grained Langevin dynamics simulations to explore the physical basis for the structural diversity in condensed phases of multi-domain RBPs. We discovered a highly cooperative first order transition between disordered structures and an ordered phase whereby chains of PLD organize in fibrils with high nematic orientational order. An interplay between homo-domain (PLD-PLD) and hetero-domain (PLD-RBD) interactions results in variety of structures with distinct spatial architectures. Interestingly, the different structural phases also exhibit vastly different intra-cluster dynamics of proteins, with diffusion coefficients 5 (disordered structures) to 50 times (ordered structures) lower than that of the dilute phase. Cooperativity of this liquid-solid transition makes fibril formation highly malleable to mutations or post-translational modifications. Our results provide a mechanistic understanding of how multi-domain RBPs could form assemblies with distinct structural and material properties. Significance Statement Assembly of proteins and nucleic acids into dense, liquid-like pockets is associated with several key functions including stress response, gene-regulation, DNA-repair and RNA processing. Several RNA binding proteins such as FUS are known to form liquid-like condensates that progressively harden into more dynamically, solid-like structures, a phenomenon that gets accelerated by disease mutations. In this study, we discover the mechanistic origins of this transition and show that small mutational or posttranslational modifications could result in sharp disorder-order transitions that could characterize accelerated liquid-solid transition in disease mutants.
A monogenean parasite reveals the widespread translocation of the African Clawed Frog in its native range

The management of bio-invasions relies upon the development of methods to trace their origin and expansion. Co-introduced parasites, especially monogenean flatworms, are ideal tags for the movement of their hosts due to their short generations, direct life cycles and host specificity. However, they are yet to be applied to trace the intraspecific movement of host lineages in their native ranges. As proof of this concept, we conducted a comparative phylogeographic analysis based upon two mitochondrial markers of a globally invasive frog Xenopus laevis and its monogenean parasite Protopolystoma xenopodis in its native range in southern Africa and invasive range in Europe. Translocation of lineages was largely masked in the frog’s phylogeography. However, incongruent links between host and parasite phylogeography indicated host switches from one host lineage to another after these were brought into contact in the native range. Thus, past translocation of host lineages is revealed by the invasion success of its co-introduced parasite lineage. This study demonstrates that parasite data can serve as an independent line of evidence in invasion biology, also on the intraspecific level, shedding light on previously undetected invasion dynamics. Based upon the distribution of these invasive parasite lineages, we infer that there is widespread anthropogenic translocation of this frog, not only via official export routes, but also facilitated by the frog’s use as live bait by angling communities. Synthesis and applications. Data from co-introduced, host-specific parasites, as tags for translocation, can add value to investigations in invasion biology and conservation. A better understanding of the translocation history and resulting genetic mixing of host and parasite lineages in the native range can shed light on the genetic make-up of parasite assemblages co-introduced to the invasive range. Knowledge of the intraspecific movement of different lineages of animals in their native ranges also has conservation implications, since contact between divergent lineages of hosts and parasites can facilitate host switches and altered parasite dynamics in both native and invasive populations. Therefore, we recommend the inclusion of parasite data as a more holistic approach to the invasion ecology of animals on the intraspecific level.
Comparison of Fracture Cracking Parameters from Monotonic Loading Tests: Indirect Tension and Monotonic Overlay Tester Tests

Cracking is one of the major structural distresses that occur in hot-mix asphalt (HMA) pavements and is undesirable. Cracking often leads to costly maintenance and rehabilitation activities. Various laboratory test methods, including the indirect tension (IDT) test, semicircular bend test, Texas Overlay Test (OT), and bending beam fatigue test, are typically used to characterize and quantify the resistance of HMA to cracking. Recently, the OT test in monotonic loading configuration was explored as a supplement or surrogate to the traditional repeated loading OT test for evaluating the cracking resistance potential of HMA mixes in the laboratory. The basic analysis parameters from the monotonic OT test include the tensile strength, failure tensile strain, fracture energy (FE), and FE index, which are essentially the same fracture parameters obtainable from the IDT test. In this study, the crack resistance potentials of 15 different HMA mixes were comparatively evaluated with two monotonic loading tests: the IDT and monotonic OT. Statistical analysis with analysis of variance and Tukey’s honestly significant difference methods was performed to characterize the test methods’ comparative potential to discriminate and screen mixes. For the mixes evaluated and the test conditions considered, the corresponding results indicate that the FE index was the most effective fracture parameter in capturing the test loading history and differentiating the crack resistance potential of the HMA mixes. The statistical comparisons between the IDT and monotonic OT tests showed plausible correlations for all the fracture parameters that were evaluated, with the FE index being the best.
Upregulation of RGS4 expression in a model of neuropathic pain and insensitivity to morphine

We hypothesized that the upregulated expression of one or more members of the RGS (regulator of G-protein signalling) family can cause an attenuation of signalling via Gi/Go-coupled opioid receptors, and thereby play a role in the development of hyperalgesia and accompanying insensitivity to morphine observed in animal models of neuropathic pain. Accordingly we examined the mRNA expression of several RGS genes in a rat model of chronic neuropathic pain induced by partial ligation of the sciatic nerve. During the development of hyperalgesia, RGS4 was the only isoform examined whose mRNA levels increased significantly (up to 230%) in the lumbar spinal cord. In situ hybridization studies confirmed that RGS4 is present in the dorsal horn of the spinal cord where mu-opioid receptors (MOR) are also expressed. This inhibitory effect was overcome partially at high agonist concentrations, supporting the view that morphine insensitivity is promoted by RGS4 overexpression. These studies provide evidence that the upregulation of RGS4 expression may contribute to changes in pain signal processing which lead to the development of hyperalgesia, and further effect its modulation by morphine.