Miracle-dz/UniFAR-FTUs huggingface dataset:
The modulation of acute stress on model-free and model-based reinforcement learning in gambling disorder

Background and aims Experiencing acute stress is common in behavioral addictions such as gambling disorder. Additionally, like most substance-induced addictions, aberrant decision-making wherein a reactive habit-induced response (conceptualized as a Model-free [MF] in reinforcement learning) suppresses a flexible goal-directed response (conceptualized as a Model-based [MB]) is also common in gambling disorder. In the current study we investigated the influence of acute stress on the balance between habitual response and the goal-directed system. Methods A sample of N = 116 pathological gamblers (PG) and healthy controls (HC) performed an acute stress task – the Socially Evaluated Cold pressure task (SECPT) – or a control task. Self-reported stress and salivary cortisol were collected as measures of acute stress. Following the SECPT, participants performed the Two-Step Markov Task to account for the relative contribution of MB and MF strategies. Additionally, verbal working-memory and IQ measures were collected to account for their mediating effects on the orchestration between MB/MF and the impact of stress. Results Both groups had comparable baseline and stress-induced cortisol response to the SECPT. Non-stressed PG displayed lower MB learning than HC. MANOVA and regression analyses showed a deleterious effect of stress-induced cortisol response on the orchestration between MB and MF learning in HC but not in PG. Neither working memory nor IQ mediated these effects. Discussion and Conclusions Despite normal cortisol response to stress, we found an abnormal pattern of modulation of stress on the orchestration between MB and MF learning among PG.
The PCI domains are “winged” HEAT domains

The HEAT domains are a family of helical hairpin repeat domains, composed of four or more hairpins. HEAT is derived from the names of four family members: huntingtin, eukaryotic translation elongation factor 3 (eEF3), protein phosphatase 2 regulatory A subunit (PP2A), and mechanistic target of rapamycin (mTOR). HEAT domain-containing proteins play roles in a wide range of cellular processes, such as protein synthesis, nuclear transport and metabolism, and cell signaling. The PCI domains are a related group of helical hairpin domains, with a “winged-helix” (WH) subdomain at their C-terminus, which is responsible for multi-subunit complex formation with other PCI domains. The name is derived from the complexes, where these domains are found: the Proteasome “lid” regulatory subcomplex, the COP9 signalosome (CSN), and eukaryotic translation initiation factor 3 (eIF3). We noted that in structure homology searches using HEAT domains, sometimes PCI domains appeared in the search results ahead of other HEAT domains, which indicated that the PCI domains could be members of the HEAT domain family, and not a related but separate group. Here, we report extensive structure homology analysis of HEAT and PCI domains, both within and between the two groups of proteins. We present evidence that the PCI domains as a group have greater structural homology with individual groups of HEAT domains than some of the HEAT domain groups have among each other. Therefore, our results indicate that the PCI domains have evolved from a HEAT domain that acquired a WH subdomain. The WH subdomain in turn mediated selfassociation into a multi-subunit complex, which eventually evolved into the common ancestor of the Proteasome lid/CSN/eIF3.
Network Thermodynamics of Biological Systems: A Bond Graph Approach

Edmund Crampin (1973-2021) was at the forefront of Systems Biology research and his work will influence the field for years to come. This paper brings together and summarises the seminal work of his group in applying energy-based bond graph methods to biological systems. In particular, this paper: (a) motivates the need to consider energy in modelling biology; (b) introduces bond graphs as a methodology for achieving this; (c) describes extensions to modelling electrochemical transduction; (d) outlines how bond graph models can be constructed in a modular manner and (e) describes stoichiometric approaches to deriving fundamental properties of reaction networks. These concepts are illustrated using a new bond graph model of photosynthesis in chloroplasts.
Groundfish biodiversity change in northeastern Pacific waters under projected warming and deoxygenation

In the coming decades, warming and deoxygenation of marine waters are anticipated to result in shifts in the distribution and abundance of fishes, with consequences for the diversity and composition of fish communities. Here, we combine fisheries independent trawl survey data spanning the west coast of the USA and Canada with high resolution regional ocean models to make projections of how 34 groundfish species will be impacted by changes in temperature and oxygen in British Columbia (B.C.) and Washington. In this region, species that are projected to decrease in occurrence are roughly balanced by those that are projected to increase, resulting in considerable compositional turnover. Many, but not all, species are projected to shift to deeper depths as conditions warm, but low oxygen will limit how deep they can go. Thus, biodiversity will likely decrease in the shallowest waters (< 100 m) where warming will be greatest, increase at mid depths (100—600 m) as shallow species shift deeper, and decrease at depths where oxygen is limited (> 600 m). These results highlight the critical importance of accounting for the joint role of temperature, oxygen, and depth when projecting the impacts of climate change on marine biodiversity.
Molecular basis of C9orf72 poly-PR interference with the β-karyopherin family of nuclear transport receptors

Nucleocytoplasmic transport (NCT) is affected in several neurodegenerative diseases including C9orf72-ALS. It has recently been found that arginine-containing dipeptide repeat proteins (R-DPRs), translated from C9orf72 repeat expansions, directly bind to several importins. To gain insight into how this can affect nucleocytoplasmic transport, we use coarse-grained molecular dynamics simulations to study the molecular interaction of poly-PR, the most toxic DPR, with several Kapβs (importins and exportins). We show that poly-PR–Kapβ binding depends on the net charge per residue (NCPR) of the Kapβ, salt concentration of the solvent, and poly-PR length. Poly-PR makes contact with the inner surface of most importins, which strongly interferes with Kapβ binding to cargo-NLS, IBB, and RanGTP in a poly-PR length-dependent manner. Longer poly-PRs at higher concentrations are also able to make contact with the outer surface of importins that contain several binding sites to FG-Nups. We also show that poly-PR binds to exportins, especially at lower salt concentrations, interacting with several RanGTP and FG-Nup binding sites. Overall, our results suggest that poly-PR might cause length-dependent defects in cargo loading, cargo release, Kapβ transport and Ran gradient across the nuclear envelope.
Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer’s Disease Brains and Mouse Neurodegeneration Models

Abstract Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer’s disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APPNL-G-F AD mouse model brains as well as in SOD1G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk2+ microglia preferentially accumulated close to βAmyloid plaques. Furthermore, recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicative of an anti-synaptic effect similar to that of DKK1. In stark contrast, no such microglial DKK2 upregulation was detected in the postmortem human frontal cortex from individuals diagnosed with AD or pathologic aging. In summary, the difference in microglial expression of the DAM/ARM gene DKK2 between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.
PKD autoinhibition in trans regulates activation loop autophosphorylation in cis

Phosphorylation is a ubiquitous mechanism by which signals are transduced in cells. Protein kinases, enzymes that catalyze the phospho-transfer reaction are, themselves, often regulated by phosphorylation. Paradoxically, however, a substantial fraction of the more than 500 human protein kinases are capable of catalyzing their own activation loop phosphorylation. Commonly, these kinases perform this autophosphorylation reaction in trans, whereby transient dimerization leads to the mutual phosphorylation of the activation loop of the opposing protomer. In this study, we demonstrate that Protein Kinase D (PKD) is regulated by the inverse mechanism of dimerization-mediated trans-autoinhibition, followed by activation loop autophosphorylation in cis. We show that PKD forms a stable face-to-face homodimer that is incapable of either auto- or substrate phosphorylation. Dissociation of this trans-autoinhibited dimer results in activation loop autophosphorylation, which occurs exclusively in cis. Phosphorylation serves to increase PKD activity and prevent trans-autoinhibition, thereby switching PKD on. Our findings not only reveal the mechanism of PKD regulation, but have profound implications for the regulation of many other eukaryotic kinases.
Pre-Eruptive Magma Configurations and Petrogenetic Relationships of the Rattlesnake Tuff, Oregon–Insights From Spectacularly Banded High-Silica Rhyolite Pumices

The 7.1 Ma Rattlesnake Tuff (RST) of eastern Oregon is a widespread and voluminous (>300 km3) ignimbrite composed of 99% crystal poor (≤1%) high-silica rhyolite (HSR) and <1% dacites. Basaltic andesitic to basaltic inclusions within dacites are samples of underpinned mafic magmas. The RST HSR is comprised of five increasingly evolved compositional Groups (E–A), and HSR pumices range from white to dark grey, often co-mingled in spectacular banded pumices. Previously, Groups were interpreted as rhyolites generated by crystal fractionation within a single reservoir, where more evolved rhyolite melts formed from relatively less evolved rhyolite parents. To reassess compositional HSR Groups and their implications for tapping a single or multiple rhyolite reservoirs as well as reevaluating the petrological relationships among groups, we focus on large banded pumices for geochemical analysis. Statistical analysis of existing and new data verified these five compositional Groups and gaps, best characterized by variations in Ba, Eu/Eu*, Eu, FeO*, Hf, and Zr. Wet-liquidus temperatures, storage temperatures, and storage pressures calculated for all HSR Groups indicate similar pre-eruptive conditions (∼6.1–7.5 km depth; storage temperatures of ∼805–895°C). Differentiation trends, trends in storage pressure and temperature, and lack of crystal-rich tuff or country rock corroborate existing models for HSRs that involve a single, density-stratified magma reservoir prior eruption. Density differences are sufficient to prevent convection between layers of HSRs in a single reservoir when water content increases from 2–4 wt% from Groups E–A. However, if HSRs do not represent a liquid line, it is possible to generate HSRs through batch melting of various regional country rock. Yet, HSRs would still accumulate within the same storage zone, where density variations kept HSRs from mixing until eruption when these banded pumices formed. In either scenario, our study underscores the significance of water content and density variations for accumulating rhyolite magmas in a contiguous magma body without mixing. This has implications for other compositionally heterogenous rhyolitic ignimbrites where natural samples do not provide comparable evidence to argue for pre-eruptive confocal storage of different rhyolite magmas as is the case for the Rattlesnake Tuff.
Side Effects of Endocrine Therapy Are Associated With Depression and Anxiety in Breast Cancer Patients Accepting Endocrine Therapy: A Cross-Sectional Study in China

Objective Hormone positive breast cancer patients bear side effects of endocrine therapy and that may be related to depression and anxiety. We sought to find an association between mental health and side effects of endocrine therapy. Methods A total of 398 patients participated. Sociodemographic, disease profile, and side effects questionnaires were administered. We screened for depressive and anxiety disorders by using the SDS (Self-Rating Depression Scale) and SAS (Self-Rating Anxiety Scale). Results The prevalence of depression and anxiety in our study were 33.4% (133) and 13.3% (53), respectively. Depression was linked to education level (≤8 years, OR = 3.59, 95% CI: 2.22–5.78), night sweats (yes, OR = 1.90, 95% CI: 1.17–3.09), vaginal dryness (yes, OR = 2.22, 95% CI: 1.19–4.16), and fatigue (yes, OR = 1.94, 95% CI: 1.21–3.11); anxiety was associated with education level (≤8 years, OR = 3.13, 95% CI: 1.62–6.08), time to diagnosis (≤ 3 years, OR = 2.14, 95% CI: 1.13–4.07), osteopenia (yes, OR = 2.43, 95% CI: 1.26–4.70), loss of hair (yes, OR = 2.80, 95% CI: 1.10–7.15), and fatigue (yes, OR = 2.89, 95% CI: 1.54–5.43). A stratified analysis according to age (≤45 years and > 45 years) was performed as an exploratory. None of factor-age interactions was statistically significant. Conclusion Side effects of endocrine therapy were significantly associated with anxiety and depression. Side effects deserve greater emphasis and clinical interventions are needed to reduce anxiety and depression in breast cancer patients accepting ET.
Beetle elytra as role models for lightweight building construction

Being natural lightweight constructions, elytra of beetles constitute promising role models for biomimetic development. In 2014, a multi-disciplinary team led by scientists from the University of Stuttgart constructed a research pavilion in order to evaluate fi ber composites for architecture and to develop fabrication methods for fi ber-reinforced polymer structures. Functional principles of the elytra of the Colorado potato beetle (Leptinotarsa decemlineata) and the Green tortoise beetle (Cassida viridis) were analyzed, abstracted and transferred into a modular pavilion. Two collaborating industrial robots were employed to wind 36 individual glass and carbon fi ber-reinforced elements, which were assembled into the fi nal prototype.
Cost-Effectiveness of Tislelizumab Versus Docetaxel for Previously Treated Advanced Non-Small-Cell Lung Cancer in China

Background: Tislelizumab, a new high-affinity programmed cell death protein-1 (PD-1) inhibitor, significantly prolonged the overall survival in pretreated non-small-cell lung cancer (NSCLC). This study aimed to assess the cost-effectiveness of tislelizumab versus docetaxel for this population in China. Methods: A three-state partitioned survival model was developed to simulate advanced NSCLC. Efficacy and safety data were based on a global phase 3 clinical trial (RATIONALE 303). Utilities were mainly extracted from previously published resources. Costs were calculated from the Chinese healthcare system’s perspective, and only direct medical costs were covered. The main outcomes included total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were carried to test the uncertainty of the modeling results. In addition, several scenarios including tislelizumab price before negotiation, different docetaxel price calculation, 50-year time horizon, and alternative utility values were assessed. Results: The model predicted an average gain of 0.62 LYs and 0.51 QALY for tislelizumab vs. docetaxel, at the additional cost of $9,219. The resulting ICER was $15,033.92/LY and $18,122.04/QALY, both below the cost-effective threshold (CET) of three times gross domestic product (GDP) per capita in China. Sensitivity analyses showed that the results are robust over a plausible range for majority of inputs. Utility of progression-free survival (PFS), followed by the price of tislelizumab, had the greatest impact on the ICER. The probability of being cost-effective for tislelizumab was 96.79% at the CET we set. Conclusion: Tislelizumab improves survival, increases QALYs, and can be considered a cost-effective option at current price compared with docetaxel for pretreated advanced NSCLC in China.
Mechanical Stretch Triggers Epithelial-Mesenchymal Transition in Keratinocytes Through Piezo1 Channel

The epithelial-mesenchymal transition (EMT) process has emerged as a central regulator of embryonic development, tissue repair and tumor malignancy. In recent years, researchers have specifically focused on how mechanical signals drive the EMT program in epithelial cells. However, how epithelial cells specifically leverage mechanical force to control the EMT process remains unclear. Here, we show that the bona fide mechanically activated cation channel Piezo1 plays a critical role in the EMT. The Piezo1 is expressed in human primary epidermal keratinocytes (HEKs) and is responsible for the mechanical stretch-induced Ca2+ concentration. Inhibition of Piezo1 activation by the inhibitor GsMTx4 or by siRNA-mediated Piezo1 knockdown influenced the morphology and migration of HEKs. Moreover, Piezo1 activity also altered EMT-correlated markers expression in response to mechanical stretch. We propose that the mechanically activated cation channel Piezo1 is an important determinant of mechanical force-induced EMT in keratinocytes and might play similar roles in other epithelial cells.
Feed Insects as a Reservoir of Granadaene-Producing Lactococci

Insects are a component of the diet of different animal species and have been suggested as the major source of human dietary protein for the future. However, insects are also carriers of potentially pathogenic microbes that constitute a risk to food and feed safety. In this study, we reported the occurrence of a hemolytic orange pigmented producing phenotype of Lactococcus garvieae/petauri/formosensis in the fecal microbiota of golden lion tamarins (Leontopithecus rosalia) and feed larvae (Zophobas atratus). Feed insects were identified as a regular source of L. garvieae/petauri/formosensis based on a reanalysis of available 16S rRNA gene libraries. Pan-genome analysis suggested the existence of four clusters within the L. garvieae/petauri/formosensis group. The presence of cyl cluster indicated that some strains of the L. garvieae/petauri/formosensis group produced a pigment similar to granadaene, an orange cytotoxic lipid produced by group B streptococci, including Streptococcus agalactiae. Pigment production by L. garvieae/petauri/formosensis strains was dependent on the presence of the fermentable sugars, with no pigment being observed at pH <4.7. The addition of buffering compounds or arginine, which can be metabolized to ammonium, restored pigment formation. In addition, pigment formation might be related to the source of peptone. These data suggest that edible insects are a possible source of granadaene-producing lactococci, which can be considered a pathogenic risk with zoonotic potential.
Self-Assembling Nanovaccine Confers Complete Protection Against Zika Virus Without Causing Antibody-Dependent Enhancement

The Zika virus (ZIKV) epidemic poses a substantial threat to the public, and the development of safe and effective vaccines is a demanding challenge. In this study, we constructed a kind of self-assembling nanovaccine which confers complete protection against ZIKV infection. The ZIKV envelop protein domain III (zEDIII) was presented on recombinant human heavy chain ferritin (rHF) to form the zEDIII-rHF nanoparticle. Immunization of mice with zEDIII-rHF nanoparticle in the absence of an adjuvant induced robust humoral and cellular immune responses. zEDIII-rHF vaccination conferred complete protection against lethal infection with ZIKV and eliminated pathological symptoms in the brain. Importantly, the zEDIII-rHF nanovaccine induced immune response did not cross-react with dengue virus-2, overcoming the antibody-dependent enhancement (ADE) problem that is a safety concern for ZIKV vaccine development. Our constructed zEDIII-rHF nanovaccine, with superior protective performance and avoidance of ADE, provides an effective and safe vaccine candidate against ZIKV.
Global Transcriptome Analysis Revealed the Molecular Regulation Mechanism of Pigment and Reactive Oxygen Species Metabolism During the Stigma Development of Carya cathayensis

Hickory (Carya cathayensis Sarg.) is a monoecious plant of the genus Carya of the Juglandaceae family. Its nuts contain a number of nutritional compounds and are deeply loved by consumers. Interestingly, it was observed that the color of hickory stigma changed obviously from blooming to mature. However, the molecular mechanism underlying color formation during stigma development and the biological significance of this phenomenon was mostly unknown. In this work, pigment content, reactive oxygen species (ROS) removal capacity, and transcriptome analysis of developing stigma of hickory at 4 differential sampling time points (S1, S2, S3, and S4) were performed to reveal the dynamic changes of related pigment, antioxidant capacity, and its internal molecular regulatory mechanism. It was found that total chlorophyll content was decreased slightly from S1 to S4, while total carotenoids content was increased from S1 to S3 but decreased gradually from S3 to S4. Total anthocyanin content continued to increase during the four periods of stigma development, reaching the highest level at the S4. Similarly, the antioxidant capacity of stigma was also gradually improved from S1 to S4. Furthermore, transcriptome analysis of developing hickory stigma identified 31,027 genes. Time-series analysis of gene expressions showed that these genes were divided into 12 clusters. Cluster 5 was enriched with some genes responsible for porphyrin and chlorophyll metabolism, carotenoid metabolism, and photosynthesis. Meanwhile, cluster 10 was enriched with genes related to flavonoid metabolism, including anthocyanin involved in ROS scavenging, and its related genes were mainly distributed in cluster 12. Based on the selected threshold values, a total of 10432 differentially expressed genes were screened out and enriched in the chlorophyll, carotenoid, anthocyanin, and ROS metabolism. The expression trends of these genes provided plausible explanations for the dynamic change of color and ROS level of hickory stigma with development. qRT-PCR analyses were basically consistent with the results of RNA-seq. The gene co-regulatory networks of pigment and ROS metabolism were further constructed and MYB113 (CCA0887S0030) and WRKY75 (CCA0573S0068) were predicted to be two core transcriptional regulators. These results provided in-depth evidence for revealing the molecular mechanism of color formation in hickory stigma and its biological significance.