Miracle-dz/UniFAR-FTUs huggingface dataset:
Oncogenic KRAS engages an RSK1/NF1 complex in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways and toxicity due to the targeting of normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil new potential therapeutic targets. Here, we used proximity labelling to identify protein interactors of active KRAS in PDAC cells. Fusions of wildtype (BirA-KRAS4B), mutant (BirA-KRAS4BG12D) and non-transforming and cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase were expressed in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 was enriched among proteins that selectively interacted with membrane-bound KRASG12D. RSK1 required the NF1 and SPRED proteins to interact with KRAS-GTP at the membrane. In both murine and human PDAC lines, membrane-targeted RSK1 was tolerated but inhibited cell proliferation following oncogenic KRAS abrogation to reveal a negative feedback role for membrane-localized RSK1 on wild-type KRAS. Inhibition of the wild-type KRAS, which has been previously proposed to suppress KRAS oncogenesis, may partially explain how RSK1 has been identified as a dependency in some KRAS mutant cells and may provide an additional function for NF1 in tumorigenesis. Significance Statement For decades, KRAS interactors have been sought after as potential therapeutic targets in KRAS mutant cancers, especially pancreatic adenocarcinoma (PDAC). Our proximity labeling screen with KRAS in PDAC cells highlight RSK1 as a notable mutant-specific interactor. Functionally, we show that RSK1 mediates negative feedback on wild-type KRAS in PDAC cells.
Minimal detection and low biological fluctuation of mitochondrial CpG methylation at the single-molecule level

Cytosine DNA methylation in the CpG context (5mCpG) is associated with the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if mitochondrial DNA (mtDNA) is methylated and whether 5mCpG has a regulatory role in this context. The main aim of this work was to develop and validate a novel tool for determining methylation of mtDNA and to corroborate its existence across different biological contexts. Using long-read nanopore sequencing we found low levels of CpG methylation (with few exceptions) and little variation across biological processes: differentiation, oxidative stress, and cancer. 5mCpG was overall higher in tissues compared to cell lines, with small additional variation between cell lines of different origin. Although we do show several significant changes in all these conditions, 5mCpG is unlikely to play a major role in defining the transcriptional status of mitochondrial genes.
Let Nature Take Its Course: Cultural Adaptation and Pilot Test of Taoist Cognitive Therapy for Chinese American Immigrants With Generalized Anxiety Disorder

This report describes initial results from a multi-stage project to manualize and adapt an indigenous therapy, Chinese Taoist Cognitive Psychotherapy (CTCP), for dissemination in the United States context. Study aims were to (a) integrate cultural adaptation and implementation science frameworks to manualize and adapt the original intervention and (b) explore the feasibility, acceptability, and effectiveness of the modified intervention, renamed Taoist Cognitive Therapy (TCT), in a sample of Chinese immigrants with generalized anxiety disorder (GAD). Incorporating bottom-up and top-down adaptation approaches, we involved Chinese American clinician stakeholders and experts in Taoist philosophy, cognitive-behavioral therapy, and GAD to help identify cultural and contextual barriers and solutions to enhance treatment acceptability and implementation. Five treatment-seeking Chinese American immigrants (average age = 43.2 years) with a primary diagnosis of GAD completed 14–16 sessions of TCT. Two participants also had secondary diagnoses of major depressive disorder. Changes on primary measures of worry and anxiety were assessed for statistical and clinical significance using reliable change indices (RCIs; Jacobson and Truax, 1991) and comparisons to normative data. In this sample of patients with limited prior exposure to Taoism, results found evidence of feasibility and acceptability of the modified intervention, with strong endorsement of Taoist principles at termination. Statistically and clinically significant improvements in anxiety, worry, psychological inflexibility, and emotional avoidance were found only for the participants without comorbid depression. Results suggest that Taoist principles of acceptance and flexible adaptation to natural laws may be helpful to Chinese immigrants coping with anxiety. However, additional treatment modifications may be required to address the low self-efficacy and fatalism expressed among those with comorbid depression.
Inflammasome Deletion Promotes Anti-tumor NK Cell Function in an IL-1/IL-18 Independent Way in Murine Invasive Breast Cancer

Inflammasomes are molecular complexes that trigger an inflammatory response upon detection of pathogens or danger signals. Recent studies suggest that they are also involved in cancer progression. However, their roles during tumorigenesis remain poorly understood and controversial. Here, we investigated whether inflammasome activation supports mammary tumor growth. Using mouse models of invasive breast cancer, our results demonstrate that the absence of a functional inflammasome impairs tumor growth. Importantly, tumors implanted into inflammasome-deficient mice recruited significantly less neutrophils and more natural killer (NK) cells, and these latter cells displayed a more active phenotype. Interestingly, NK cell depletion abolished the anti-tumoral effect observed in inflammasome-deficient mice, although inflammasome-regulated cytokine neutralization had no effect. Thus, our work identifies a novel role for the inflammasome in supporting mammary tumor growth by attenuating NK cell recruitment and activity. These results suggest that inflammasome inhibition could be a putative target for treating invasive breast cancers.
Oxidative Damage and Antioxidant Defense in Ferroptosis

Many new types of regulated cell death have been recently implicated in human health and disease. These regulated cell deaths have different morphological, genetic, biochemical, and functional hallmarks. Ferroptosis was originally described as a carcinogenic RAS-dependent non-apoptotic cell death, and is now defined as a type of regulated necrosis characterized by iron accumulation, lipid peroxidation, and the release of damage-associated molecular patterns (DAMPs). Multiple oxidative and antioxidant systems, acting together autophagy machinery, shape the process of lipid peroxidation during ferroptosis. In particular, the production of reactive oxygen species (ROS) that depends on the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and the mitochondrial respiratory chain promotes lipid peroxidation by lipoxygenase (ALOX) or cytochrome P450 reductase (POR). In contrast, the glutathione (GSH), coenzyme Q10 (CoQ10), and tetrahydrobiopterin (BH4) system limits oxidative damage during ferroptosis. These antioxidant processes are further transcriptionally regulated by nuclear factor, erythroid 2-like 2 (NFE2L2/NRF2), whereas membrane repair during ferroptotic damage requires the activation of endosomal sorting complexes required for transport (ESCRT)-III. A further understanding of the process and function of ferroptosis may provide precise treatment strategies for disease.
Hemorrhagic Cerebrovascular Pathology in the Pediatric Population

Hemorrhagic cerebrovascular disease in the pediatric population can have devastating and long-term effects. Progress in the fields of genetics, neuroimaging, pharmacology, and surgical techniques has led to improved diagnosis and management of pediatric cerebrovascular diseases. In this review we discuss the current etiologies and medical and surgical treatments of hemorrhagic cerebrovascular pathology affecting infants and children. A special emphasis is placed on neuroendovascular treatment options. Increased knowledge about this unique pathology and the medical and therapeutic options will empower practitioners to more quickly and accurately identify and accurately treat hemorrhagic diseases in the pediatric population.
Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review

Gamma-aminobutyric acid (GABA) is a non-proteinogenic amino acid and is the main inhibitory neurotransmitter in the mammalian brain. GABA's stress-reducing, and sleep enhancing effects have been established. However, although several human clinical trials have been conducted, results regarding the role of natural and/or biosynthetic oral GABA intake on stress and sleep are mixed. We performed a systematic review to examine whether natural and/or biosynthetic oral GABA intake has an effect on stress and sleep. We systematically searched on PubMed database for studies published up to February 2020 following PRISMA guidelines. Only placebo-controlled human trials that assessed stress, sleep, and related psychophysiological outcomes as a response to natural GABA (i.e., GABA that is present naturally in foods) or biosynthetic GABA (i.e., GABA that is produced via fermentation) intake were included. Fourteen studies met the criteria and were included in the systematic review. Although more studies are needed before any inferences can be made about the efficacy of oral GABA consumption on stress and sleep, results show that there is limited evidence for stress and very limited evidence for sleep benefits of oral GABA intake.
Invertebrate Decline Leads to Shifts in Plant Species Abundance and Phenology

Climate and land-use change lead to decreasing invertebrate biomass and alter invertebrate communities. These biotic changes may affect plant species abundance and phenology. Using 24 controlled experimental units in the iDiv Ecotron, we assessed the effects of invertebrate decline on an artificial grassland community formed by 12 herbaceous plant species. More specifically, we used Malaise traps and sweep nets to collect invertebrates from a local tall oatgrass meadow and included them in our Ecotron units at two different invertebrate densities: 100% (no invertebrate decline) and 25% (invertebrate decline of 75%). Another eight EcoUnits received no fauna and served as a control. Plant species abundance and flowering phenology was observed weekly over a period of 18 weeks. Our results showed that invertebrate densities affected the abundance and phenology of plant species. We observed a distinct species abundance shift with respect to the invertebrate treatment. Notably, this shift included a reduction in the abundance of the dominant plant species, Trifolium pratense, when invertebrates were present. Additionally, we found that the species shifted their flowering phenology as a response to the different invertebrate treatments, e.g. with decreasing invertebrate biomass Lotus corniculatus showed a later peak flowering time. We demonstrated that in addition to already well-studied abiotic drivers, biotic components may also drive phenological changes in plant communities. This study clearly suggests that invertebrate decline may contribute to already observed mismatches between plants and animals, with potential negative consequences for ecosystem services like food provision and pollination success. This deterioration of ecosystem function could enhance the loss of insects and plant biodiversity.
Angiotensin-Converting Enzyme Gene D/I Polymorphism in Relation to Endothelial Function and Endothelial-Released Factors in Chinese Women

Many studies have investigated the relationship between angiotensin-converting enzyme (ACE) D/I polymorphism and cardiovascular disease or endothelial dysfunction; however, hardly any of these studies has taken aging or menopause into consideration. Furthermore, despite that many studies have examined the regulatory effects of endothelial-released factors (ERFs) on endothelial function, no study has evaluated the relationship between ERFs and endothelial function with respect to ACE D/I polymorphism and menopause status. To answer these questions, 391 healthy Chinese women over a wide range of ages (22–75 years) were enrolled and divided into pre-menopause group and post-menopause group. After ACE D/I genotype being identified, the women were then classified into either DI/II or DD genotype. Flow-mediated dilatation (FMD) of brachial endothelium and plasma levels of ERFs: nitric oxide (NO), endothelin-1 (ET-1), and angiotensin II (Ang II) were measured. The results showed that frequencies of ACE D/I genotypes were in accordance with the Hardy-Weinberg equilibrium, and the frequency of I allele was higher than D allele. In pre-menopause group, FMD was significantly higher in women of DI/II than DD (P = 0.032), and age-dependent in both genotypes (DD, P = 0.0472; DI/II, P < 0.0001). In post-menopause group, FMD was similar between women of DI/II and DD, and age-dependent only in women of DI/II (P < 0.0001). In pre-menopause group, Ang II level was significantly higher in women of DD than DI/II (P = 0.029), and FMD was significantly correlated with all ERFs in women of DD (NO, P = 0.032; ET-1, P = 0.017; Ang II, P = 0.002), but only with Ang II in women of DI/II (P = 0.026). In post-menopause group, no significant difference was observed in any ERF between women of DI/II and DD, and FMD was only significantly correlated with ET-1 in women of DD (P = 0.010). In summary, FMD in women of DI/II was superior to DD in pre-menopause and more age-dependent than DD in post-menopause, and FMD was closely associated with ERFs. In conclusion, Chinese women of DI/II seem to have lower risk than DD in pre-menopause, but similar risk as DD in post-menopause in developing cardiovascular disease.
Live Imaging of Innate and Adaptive Immune Responses in the Liver

Immune response in the liver is determined by the spatial organization and cellular dynamics of hepatic immune cells. The liver vasculature accommodates abundant tissue-resident innate immune cells, such as Kupffer cells, natural killer cells, and natural killer T cells, to ensure efficient intravascular immunosurveillance. The fenestrated sinusoids also allow direct contact between circulating T cells and non-canonical antigen-presenting cells, such as hepatocytes, to instruct adaptive immune responses. Distinct cellular behaviors are exploited by liver immune cells to exert proper functions. Intravital imaging enables real-time visualization of individual immune cell in living animals, representing a powerful tool in dissecting the spatiotemporal features of intrahepatic immune cells during steady state and liver diseases. This review summarizes current advances in liver immunology prompted by in vivo imaging, with a particular focus on liver-resident innate immune cells and hepatic T cells.
Eating Disorders During Gestation: Implications for Mother's Health, Fetal Outcomes, and Epigenetic Changes

Introduction: Eating disorders (EDs) have increased globally in women of childbearing age, related to the concern for body shape promoted in industrialized countries. Pregnancy may exacerbate a previous ED or conversely may be a chance for improving eating patterns due to the mother's concern for the unborn baby. EDs may impact pregnancy evolution and increase the risk of adverse outcomes such as miscarriage, preterm delivery, poor fetal growth, or malformations, but the knowledge on this topic is limited. Methods: We performed a systematic review of studies on humans in order to clarify the mechanisms underpinning the adverse pregnancy outcomes in patients with EDs. Results: Although unfavorable fetal development could be multifactorial, maternal malnutrition, altered hormonal pathways, low pre-pregnancy body mass index, and poor gestational weight gain, combined with maternal psychopathology and stress, may impair the evolution of pregnancy. Environmental factors such as malnutrition or substance of abuse may also induce epigenetic changes in the fetal epigenome, which mark lifelong health concerns in offspring. Conclusions: The precocious detection of dysfunctional eating behaviors in the pre-pregnancy period and an early multidisciplinary approach comprised of nutritional support, psychotherapeutic techniques, and the use of psychotropics if necessary, would prevent lifelong morbidity for both mother and fetus. Further prospective studies with large sample sizes are needed in order to design a structured intervention during every stage of pregnancy and in the postpartum period.
Direct Continuous EMG control of a Powered Prosthetic Ankle for Improved Postural Control after Guided Physical Training: a Case Study

Background Despite the promise of powered lower limb prostheses, the existing control of these modern devices is insufficient to assist many daily activities, such as postural control while lifting weight, that require continuous control of prosthetic joints according to human states and environments. The objective of this case study was to investigate the feasibility and potential of direct, continuous electromyographic (dEMG) control of a powered ankle prosthesis, combined with physical therapist (PT)-guided training, for improved standing postural control in an individual with transtibial amputation. Methods A powered prosthetic ankle was directly controlled by EMG signals of the residual lateral gastrocnemius and tibialis anterior muscles. The participant with transtibial amputation received 4-week PT-guided training on posture while using the dEMG control of powered ankle. A subset of activities in the mini-BESTest (a clinical balance assessment tool) were used in the training and evaluation protocol. We quantified EMG signals in the bilateral shank muscles, biomechanics that captures postural control and stability, and score for the clinical balance evaluation. Results Compared to the participant’s daily passive prosthesis, the dEMG-controlled ankle, combined with the training, yielded improved clinical balance score and reduced compensation from the intact joints. In addition, cross correlation coefficient of bilateral CoP excursions, a metric for quantifying standing postural control, increased to 0.83(±0.07) when using dEMG ankle control, compared with 0.39(±0.29) when using the passive device. Between-limb coordination was also observed as synchronized activation of homologous muscles in the shank. We witnessed rapid improvement in performance on the first day of the training for load transfer tasks, where bilateral CoP synchronization improvement was significantly related to repetition order (R=0.459, p = 0.045). Finally, the participant further improved this performance significantly across training days. Conclusion This case study showed the feasibility of dEMG control of powered prosthetic ankle by a transtibial amputee after a PT-guided training to assist postural control. This study’s training protocol and dEMG control method that lays the foundation for future study to extend these results through the inclusion of more participants and activities.
Identification and Classification of Alzheimer’s Disease Patients Using Novel Fractional Motion Model

Most diffusion magnetic resonance imaging (dMRI) techniques use the mono-exponential model to describe the diffusion process of water in the brain. However, the observed dMRI signal decay curve deviates from the mono-exponential form. To solve this problem, the fractional motion (FM) model has been developed, which is regarded as a more appropriate model for describing the complex diffusion process in brain tissue. It is still unclear in the identification and classification of Alzheimer’s disease (AD) patients using the FM model. The purpose of this study was to investigate the potential feasibility of FM model for differentiating AD patients from healthy controls and grading patients with AD. Twenty-four patients with AD and 11 healthy controls were included. The left and right hippocampus were selected as regions of interest (ROIs). The apparent diffusion coefficient (ADC) values and FM-related parameters, including the Noah exponent (α), the Hurst exponent (H), and the memory parameter (μ=H−1/α), were calculated and compared between AD patients and healthy controls and between mild AD and moderate AD patients using a two-sample t-test. The correlations between FM-related parameters α, H, μ, and ADC values and the cognitive functions assessed by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) scales were investigated using Pearson partial correlation analysis in patients with AD. The receiver-operating characteristic analysis was used to assess the differential performance. We found that the FM-related parameter α could be used to distinguish AD patients from healthy controls (P < 0.05) with greater sensitivity and specificity (left ROI, 0.917 and 0.636; right ROI, 0.917 and 0.727) and grade AD patients (P < 0.05) showed higher sensitivity and specificity (right ROI, 0.917, 0.75). The α was found to be positively correlated with MMSE (P < 0.05) and MoCA (P < 0.05) scores in patients with AD, indicating that the α values in the bilateral hippocampus were a potential MRI-based biomarker of disease severity in AD patients. This novel diffusion model may be useful for further understanding neuropathologic changes in patients with AD.
Modulating the Activity of vmPFC Regulates Informational Social Conformity: A tDCS Study

Social conformity has been evaluated in many different contexts, ranging from an emotional contagion in psychology, to speculative episodes in economics, to mass protests concerning politics. Previous neuroscience studies suggest that the ventromedial prefrontal cortex (vmPFC) participates in social conformity, especially when it comes to the value integration process, but the specific mechanism of vmPFC is still unclear. In this study, we aimed to identify a direct link between the vmPFC and conformity tendencies by means of transcranial direct current stimulation (tDCS). Conformity tendencies are measured by the probability that participants change their decisions when they observe the majority responses. In our experiment, subjects could make two decisions in each trial, once without social information and once with social information, which allowed us to directly observe the conformity tendency of subjects in different conditions. We found that cathodal stimulation of the vmPFC significantly increased conformity tendency and decreased response time when the initial decision of participants differs from the majority opinion. Based on the experimental results, our study suggests that the vmPFC mainly inhibits and regulates the informational conformity behavior. These findings complement investigations of the neural mechanism of conformity and the role of the vmPFC in the neural circuit behind conformity behavior.