Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Prognostic Biomarkers in Metastatic and Locally Advanced Colorectal Cancer: Micronuclei Frequency and Telomerase Activity in Peripheral Blood Lymphocytes

Purpose Due to the current practice on colorectal cancer (CRC) management, chemoresistance is most often recognized at the end of the treatment. Therefore, effective and easy-to-use prognostic biomarkers are needed. Experimental Design We evaluated the prognostic significance of two novel CRC biomarkers: a) micronuclei frequency (MNf) in 55 metastatic CRC (mCRC) and 21 locally advanced rectal cancer (laRC) patients using cytokinesis block micronucleus assay (CBMN assay) and b) telomerase activity (TA) in 23 mCRC and five laRC patients using TRAP-ELISA. Both biomarkers were evaluated in peripheral blood lymphocytes (PBLs) before, at the middle, and at the end of the therapy (approximately 0, 3, and 6 months) for mCRC patients before, at the end of the therapy, and after surgery for laRC patients. Results Overall, MNf demonstrated significant prognostic value since a decrease of MNf less than 29% between middle and initial MNf measurements can discriminate between progressive and stable/responsive disease with sensitivity of 36% and specificity of 87.0% while being able to identify responsive disease with sensitivity of 72.7% and specificity of 59.3%. On the other hand, TA presented a significant trend of increase (p = 0.07) in patients with progressive disease at the middle measurement. Conclusions The findings of this study suggest that the MN frequency may serve as a promising prognostic biomarker for the monitoring of the treatment response of patients with CRC, while TA should be evaluated in a larger group of patients to further validate its significance.
The Host Protein Aquaporin-9 is Required for Efficient Plasmodium falciparum Sporozoite Entry into Human Hepatocytes

Hepatocyte invasion by Plasmodium sporozoites represents a promising target for innovative antimalarial therapy, but the molecular events mediating this process are still largely uncharacterized. We previously showed that Plasmodium falciparum sporozoite entry into hepatocytes strictly requires CD81. However, CD81-overexpressing human hepatoma cells remain refractory to P. falciparum infection, suggesting the existence of additional host factors necessary for sporozoite entry. Here, through differential transcriptomic analysis of human hepatocytes and hepatoma HepG2-CD81 cells, the transmembrane protein Aquaporin-9 (AQP9) was found to be among the most downregulated genes in hepatoma cells. RNA silencing showed that sporozoite invasion of hepatocytes requires AQP9 expression. AQP9 overexpression in hepatocytes increased their permissiveness to P. falciparum. Moreover, chemical disruption with the AQP9 inhibitor phloretin markedly inhibited hepatocyte infection. Our findings identify AQP9 as a novel host factor required for P. falciparum sporozoite hepatocyte-entry and indicate that AQP9 could be a potential therapeutic target.
The Impact of Aging on Macroautophagy in the Pre-ovulatory Mouse Oocyte

Accompanying the precipitous age-related decline in human female fertility is an increase in the proportion of poor-quality oocytes within the ovary. The macroautophagy pathway, an essential protein degradation mechanism responsible for maintaining cell health, has not yet been thoroughly investigated in this phenomenon. The aim of this study was to characterize the macroautophagy pathway in an established mouse model of oocyte aging using in-depth image analysis-based methods and to determine mechanisms that account for the observed changes. Three autophagy pathway markers were selected for assessment of gene and protein expression in this model: Beclin 1; an initiator of autophagosome formation, Microtubule-associated protein 1 light chain 3B; a constituent of the autophagosome membrane, and lysosomal-associated membrane protein 1; a constituent of the lysosome membrane. Through quantitative image analysis of immunolabeled oocytes, this study revealed impairment of the macroautophagy pathway in the aged oocyte with an attenuation of both autophagosome and lysosome number. Additionally, an accumulation of amphisomes greater than 10 μm2 in area were observed in aging oocytes, and this accumulation was mimicked in oocytes treated with lysosomal inhibitor chloroquine. Overall, these findings implicate lysosomal dysfunction as a prominent mechanism by which these age-related changes may occur and highlight the importance of macroautophagy in maintaining mouse pre-ovulatory oocyte quality. This provides a basis for further investigation of dysfunctional autophagy in poor oocyte quality and for the development of therapeutic or preventative strategies to aid in the maintenance of pre-ovulatory oocyte health.
Synergistic Impact of Body Mass Index and Cognitive Function on All-Cause Mortality in Older Adults: A Nationwide Longitudinal Study

Background Body mass index (BMI) and cognitive function are independent predictors of mortality risk. However, little is known about the combined impact of BMI and cognitive function on the risk of all-cause mortality in older adults. In this study, we aimed to examine the associations between BMI, cognitive function, and all-cause mortality, including between-factor interactions, in the general population of older adults in China. Methods We used the data between 2011 and 2018 from the Chinese Longitudinal Healthy Longevity Survey that included adults aged ≥65 years residing in the 23 provinces of China. The association between BMI and cognitive function on all-cause mortality was examined with the Cox proportional hazards regression model. Results The study included 8,293 Chinese older adults. Low BMI (underweight) and cognitive impairment were associated with the highest risk of death after adjustments [hazard ratio (HR) = 2.18; 95% confidence interval (CI), 1.96–2.41]; this combined effect was more prominent among adults aged <100 years and women. In addition, there was an interaction effect of BMI and cognitive impairment on all-cause mortality (P <0.001). Concurrently, among older adults with normal cognition, the risk of mortality related to underweight was higher than among their cognitively impaired counterparts [55% (normal cognition) vs. 38% (cognitive impairment)]. Conclusions Low BMI (underweight) and cognitive impairment were independently and jointly associated with increased risk of all-cause mortality among Chinese older adults, and females showed a stronger effect in this association. The association between BMI and mortality was more pronounced in the participants with normal cognition than in their cognitively impaired counterparts.
Effective Stimulation Type and Waveform for Force Control of the Motor Unit System: Implications for Intraspinal Microstimulation

The input–output properties of spinal motoneurons and muscle fibers comprising motor units are highly non-linear. The goal of this study was to investigate the stimulation type (continuous versus discrete) and waveform (linear versus non-linear) controlling force production at the motor unit level under intraspinal microstimulation. We constructed a physiological model of the motor unit with computer software enabling virtual experiments on single motor units under a wide range of input conditions, including intracellular and synaptic stimulation of the motoneuron and variation in the muscle length under neuromodulatory inputs originating from the brainstem. Continuous current intensity and impulse current frequency waveforms were inversely estimated such that the motor unit could linearly develop and relax the muscle force within a broad range of contraction speeds and levels during isometric contraction at various muscle lengths. Under both continuous and discrete stimulation, the stimulation waveform non-linearity increased with increasing speed and level of force production and with decreasing muscle length. Only discrete stimulation could control force relaxation at all muscle lengths. In contrast, continuous stimulation could not control force relaxation at high contraction levels in shorter-than-optimal muscles due to persistent inward current saturation on the motoneuron dendrites. These results indicate that non-linear adjustment of the stimulation waveform is more effective in regard to varying the force profile and muscle length and that the discrete stimulation protocol is a more robust approach for designing stimulation patterns aimed at neural interfaces for precise movement control under pathological conditions.
Engendered Expressions of Anxiety: Men’s Emotional Communications With Women and Other Men

While the contemporary therapeutic discourse inveigles us to talk about our personal problems, a countervailing neo-liberal healthist discourse, aligning with conventional masculinity norms, presumes that we will manage any issues independently. This discursive tension can be difficult to navigate, especially for men confronted with still powerful traditional expectations around masculinity (e.g., self-reliance; personal control; restricted emotionality). Although qualitative research has examined how men negotiate masculinities with respect to depression, to date there has been scant attention focused on men experiencing anxiety. This article reports on an interview study with men, some with anxiety diagnoses and some without (N = 17). Thematic analysis highlights that participants can and do talk about their anxieties, most readily with significant women in their lives (e.g., partners; mothers)–although this is not always straightforward. Talking to other men was more fraught, and while participants were wary of sharing problems with male friends, or signaled issues indirectly, they also highlighted situations where they would open up e.g., workspaces where they felt safe; with best friends. Those who had gone through a therapeutic process over many years tended to me more comfortable talking to others, male or female, about their mental health–and were also keen to other support to others where they could. Our analysis suggests that despite stereotypical notions of silent, self-contained men, there are many contexts where men may feel comfortable sharing their stories of pain and suffering. This chimes with wider cultural changes and the reported experiences of some mental health initiatives.
A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

Identifying which among several in cellulo pharmacological activities is necessary for the proper in vivo activity is essential for further drug development against Alzheimer’s disease pathophysiological processes. An in-depth structure–activity relationship–based study has been carried out, and two molecules, named MAGS02-14 and PEL24-199, that share a ß-secretase modulatory effect associated or not to a lysosomotropic activity in cellulo have been identified. In terms of chemical formulas, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. The study aimed to elucidate the in vivo pharmacological effects of lysosomotropic and/or the ß-secretase modulatory activity in a tau pathology mouse model. To address this question, the THY-Tau22 transgenic model of tauopathy was treated with both compounds for 6 weeks in a curative paradigm. Short-term memory, tau burden, and inflammatory processes were analyzed using orthogonal methods, and PEL24-199, but not MAGS02-14, was shown to restore the short-term memory and reduce the neurofibrillary degenerating process. These effects were associated with a reduced phosphorylation of tau, an increased phosphatase expression, and decreased astrogliosis. Our results, therefore, suggest that the lysosomotropic activity may be nonessential for the effect on tau pathology.
Introduction of H2-Uptake Hydrogenase Genes Into Rhizobial Strains Improves Symbiotic Nitrogen Fixation in Vicia sativa and Lotus corniculatus Forage Legumes

Biological nitrogen fixation by the Rhizobium-legume symbiosis allows the conversion of atmospheric nitrogen into ammonia within root nodules mediated by the nitrogenase enzyme. Nitrogenase activity results in the evolution of hydrogen as a result of a side reaction intrinsic to the activity of this enzyme. Some rhizobia, and also other nitrogen fixers, induce a NiFe uptake hydrogenase (Hup) to recycle hydrogen produced by nitrogenase, thus improving the efficiency of the nitrogen fixation process. In this work we report the generation and symbiotic behavior of hydrogenase-positive Rhizobium leguminosarum and Mesorhizobium loti strains effective in vetch (Vicia sativa) and birsfoot trefoil (Lotus corniculatus) forage crops, respectively. The ability of hydrogen recycling was transferred to these strains through the incorporation of hup minitransposon TnHB100, thus leading to full recycling of hydrogen in nodules. Inoculation of Vicia and Lotus plants with these engineered strains led to significant increases in the levels of nitrogen incorporated into the host legumes. The level of improvement of symbiotic performance was dependent on the recipient strain and also on the legume host. These results indicate that hydrogen recycling has the potential to improve symbiotic nitrogen fixation in forage plants.
Anxiety Is Associated With DPPIV Alterations in Children With Selective Mutism and Social Anxiety Disorder: A Pilot Study

Background: Both selective mutism (SM) and social anxiety disorder (SAD) are severe pediatric anxiety disorders with the common trait of behavioral inhibition (BI). The underlying pathophysiology of these disorders remains poorly understood, however converging evidence suggests that alterations in several peripheral molecular pathways might be involved. In a pilot study, we investigated alterations in plasma molecular markers (dipeptidyl peptidase-4 [DPPIV], interleukin-6 [IL-6], tumor necrosis factor-β [TNF-β] and neuropeptide-Y [NPY]) in children with SM, SAD, and healthy controls, as well as the correlation of these markers to symptom severity. Methods: We included 51 children and adolescents (aged 5–18 years; n = 29 girls): n = 20 children in the SM-, n = 16 in the SAD- and n = 15 in the control-group (CG). Peripheral blood samples were analyzed for DPPIV, IL-6, TNF-β, and NPY concentrations. Diverse psychometric measures were used for BI, anxiety, and mutism symptoms. Results: Lower DPPIV-levels were correlated with more anxiety symptoms. However, we could not find a difference in any molecular marker between the patients with SAD and SM in comparison to the CG. Conclusion: DPPIV is proposed as relevant marker for child and adolescent anxiety. Investigating the pathophysiology of SM and SAD focusing on state and trait variables as anxiety or BI might help better understanding the underlying mechanisms of these disorders. Further studies with especially larger cohorts are needed to validate the current pilot-findings.
A Mechanistic DNA Repair and Survival Model (Medras): Applications to Intrinsic Radiosensitivity, Relative Biological Effectiveness and Dose-Rate

Variations in the intrinsic radiosensitivity of different cells to ionizing radiation is now widely believed to be a significant driver in differences in response to radiotherapy. While the mechanisms of radiosensitivity have been extensively studied in the laboratory, there are a lack of models which integrate this knowledge into a predictive framework. This paper presents an overview of the Medras model, which has been developed to provide a mechanistic framework in which different radiation responses can be modelled and individual responses predicted. This model simulates the repair of radiation-induced DNA damage, incorporating the overall kinetics of repair and its fidelity, to predict a range of biological endpoints including residual DNA damage, mutation, chromosome aberration, and cell death. Validation of this model against a range of exposure types is presented, including considerations of varying radiation qualities and dose-rates. This approach has the potential to inform new tools to deliver mechanistic predictions of radiation sensitivity, and support future developments in treatment personalization.
Deep Learning Framework for Real-Time Estimation of in-silico Thrombotic Risk Indices in the Left Atrial Appendage

Patient-specific computational fluid dynamics (CFD) simulations can provide invaluable insight into the interaction of left atrial appendage (LAA) morphology, hemodynamics, and the formation of thrombi in atrial fibrillation (AF) patients. Nonetheless, CFD solvers are notoriously time-consuming and computationally demanding, which has sparked an ever-growing body of literature aiming to develop surrogate models of fluid simulations based on neural networks. The present study aims at developing a deep learning (DL) framework capable of predicting the endothelial cell activation potential (ECAP), an in-silico index linked to the risk of thrombosis, typically derived from CFD simulations, solely from the patient-specific LAA morphology. To this end, a set of popular DL approaches were evaluated, including fully connected networks (FCN), convolutional neural networks (CNN), and geometric deep learning. While the latter directly operated over non-Euclidean domains, the FCN and CNN approaches required previous registration or 2D mapping of the input LAA mesh. First, the superior performance of the graph-based DL model was demonstrated in a dataset consisting of 256 synthetic and real LAA, where CFD simulations with simplified boundary conditions were run. Subsequently, the adaptability of the geometric DL model was further proven in a more realistic dataset of 114 cases, which included the complete patient-specific LA and CFD simulations with more complex boundary conditions. The resulting DL framework successfully predicted the overall distribution of the ECAP in both datasets, based solely on anatomical features, while reducing computational times by orders of magnitude compared to conventional CFD solvers.
The Different Faces of Insomnia

Objectives: The identification of clinically relevant subtypes of insomnia is important. Including a comprehensive literature review, this study also introduces new phenotypical relevant parameters by describing a specific insomnia cohort. Methods: Patients visiting the sleep center and indicating self-reported signs of insomnia were examined by a sleep specialist who confirmed an insomnia diagnosis. A 14-item insomnia questionnaire on symptoms, progression, sleep history and treatment, was part of the clinical routine. Results: A cohort of 456 insomnia patients was described (56% women, mean age 52 ± 16 years). They had suffered from symptoms for about 12 ± 11 years before seeing a sleep specialist. About 40–50% mentioned a trigger (most frequently psychological triggers), a history of being bad sleepers to begin with, a family history of sleep problems, and a negative progression of insomnia. Over one third were not able to fall asleep during the day. SMI (sleep maintenance insomnia) symptoms were most frequent, but only prevalence of EMA (early morning awakening) symptoms significantly increased from 40 to 45% over time. Alternative non-medical treatments were effective in fewer than 10% of cases. Conclusion: Our specific cohort displayed a long history of suffering and the sleep specialist is usually not the first point of contact. We aimed to describe specific characteristics of insomnia with a simple questionnaire, containing questions (e.g., ability to fall asleep during the day, effects of non-medical therapy methods, symptom stability) not yet commonly asked and of unknown clinical relevance as yet. We suggest adding them to anamnesis to help differentiate the severity of insomnia and initiate further research, leading to a better understanding of the severity of insomnia and individualized therapy. This study is part of a specific Research Topic introduced by Frontiers on the heterogeneity of insomnia and its comorbidity and will hopefully inspire more research in this area.
Association Between Low Handgrip Strength and 90-Day Mortality Among Older Chinese Inpatients: A National Multicenter Prospective Cohort Study

Background: The knowledge of the association between low handgrip strength and mortality among older Chinese inpatients is limited. Given China's aging society, a great number of older adults require hospital admission. Objective: To explore the association between low handgrip strength and 90-day mortality, providing evidence for clinicians to predict the risk of mortality and improve clinical outcomes for older inpatients. Materials and Methods: We conducted a national multicenter cohort study with a baseline survey from October 2018 to February 2019 and followed up for 90 days to record mortality outcomes. The assessment of handgrip strength was conducted using a hand dynamometer with the cutoff (handgrip strength < 28 kg for men and < 18 kg for women) to define low handgrip strength. Multivariable logistic regression analysis was applied to explore the association between low handgrip strength and 90-day mortality. Results: A total of 8,910 older Chinese inpatients [mean (SD) age, 72.39 (5.68) years; 3,750 women (42.09%)], with a prevalence of low handgrip strength, at 49.57%, were included. Compared to inpatients with normal handgrip strength, inpatients with low handgrip strength were older, had less education, more were female, had lower activities of daily living (ADL) score, had lower BMI, higher frailty, higher rates of depression, and poorer cognitive function (all p < 0.05). At 90 days, after adjusting for gender, age, education, frailty, depression, ADL score, malnutrition, and diagnosis, low handgrip strength was independently associated with 90-day mortality, compared to normal handgrip strength (OR = 1.64, 95% CI:1.14–2.37; P = 0.008). Additionally, subgroup and interaction analysis showed a significant interaction effect (P = 0.031) between two age groups (65–74 years older vs. ≥ 75 years old), with the OR being 3.19 (95%CI:2.07–4.93) and 1.49 (95%CI:0.87–2.55), respectively. Conclusion: Older Chinese inpatients with low handgrip strength had a 1.64-fold risk of 90-day mortality, compared to those with normal handgrip strength, indicating that clinicians need to screen early for handgrip strength and recommend corresponding interventions, such as resistance training and nutrition, as a priority for older inpatients. Clinical Trial Registration: Chinese Clinical Trial Registry, Identifier: ChiCTR1800017682.
T Cell Specificity: A Great Challenge in Chagas Disease

The CD4+ and CD8+ T cell immune response against T. cruzi, the parasite causing Chagas disease, are relevant for both parasite control and disease pathogenesis. Several studies have been focused on their phenotype and functionally, but only a few have drilled down to identify the parasite proteins that are processed and presented to these cells, especially to CD4+ T lymphocytes. Although approximately 10,000 proteins are encoded per haploid T. cruzi genome, fewer than 200 T cell epitopes from 49 T. cruzi proteins have been identified so far. In this context, a detailed knowledge of the specific targets of T cell memory response emerges as a prime tool for the conceptualization and development of prophylactic or therapeutic vaccines, an approach with great potential to prevent and treat this chronic disease. Here, we review the available information about this topic in a comprehensive manner and discuss the future challenges in the field.