Miracle-dz/UniFAR-FTUs huggingface dataset:
Inference of Subpathway Activity Profiles Reveals Metabolism Abnormal Subpathway Regions in Glioblastoma Multiforme

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most malignant form of glioma and represents 81% of malignant brain and central nervous system (CNS) tumors. Like most cancers, GBM causes metabolic recombination to promote cell survival, proliferation, and invasion of cancer cells. In this study, we propose a method for constructing the metabolic subpathway activity score matrix to accurately identify abnormal targets of GBM metabolism. By integrating gene expression data from different sequencing methods, our method identified 25 metabolic subpathways that were significantly abnormal in the GBM patient population, and most of these subpathways have been reported to have an effect on GBM. Through the analysis of 25 GBM-related metabolic subpathways, we found that (S)-2,3-Epoxysqualene, which was at the central region of the sterol biosynthesis subpathway, may have a greater impact on the entire pathway, suggesting a potential high association with GBM. Analysis of CCK8 cell activity indicated that (S)-2,3-Epoxysqualene can indeed inhibit the activity of U87-MG cells. By flow cytometry, we demonstrated that (S)-2,3-Epoxysqualene not only arrested the U87-MG cell cycle in the G0/G1 phase but also induced cell apoptosis. These results confirm the reliability of our proposed metabolic subpathway identification method and suggest that (S)-2,3-Epoxysqualene has potential therapeutic value for GBM. In order to make the method more broadly applicable, we have developed an R system package crmSubpathway to perform disease-related metabolic subpathway identification and it is freely available on the GitHub (https://github.com/hanjunwei-lab/crmSubpathway).
Frondoside A Attenuates Amyloid-β Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation

Oligomeric assembly of Amyloid-β (Aβ) is the main toxic species that contribute to early cognitive impairment in Alzheimer’s patients. Therefore, drugs that reduce the formation of Aβ oligomers could halt the disease progression. In this study, by using transgenic Caenorhabditis elegans model of Alzheimer’s disease, we investigated the effects of frondoside A, a well-known sea cucumber Cucumaria frondosa saponin with anti-cancer activity, on Aβ aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 µM significantly delayed the worm paralysis caused by Aβ aggregation as compared with control group. In addition, the number of Aβ plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of Aβ species in the transgenic C. elegans were significantly reduced upon treatment with frondoside A, whereas the level of Aβ monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of Aβ. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express Aβ. Taken together, these data suggested that low dose of frondoside A could protect against Aβ-induced toxicity by primarily suppressing the formation of Aβ oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-Aβ aggregation should be studied and elucidated in the future.
Designing Clinical Trials for Anti-Inflammatory Therapies in Cystic Fibrosis

The inflammatory response in the CF airway begins early in the disease process and becomes persistent through life in most patients. Inflammation, which is predominantly neutrophilic, worsens airway obstruction and plays a critical role in the development of structural lung damage. While cystic fibrosis transmembrane regulator modulators will likely have a dramatic impact on the trajectory of CF lung disease over the coming years, addressing other important aspects of lung disease such as inflammation will nevertheless remain a priority. Considering the central role of neutrophils and their products in the inflammatory response, potential therapies should ultimately affect neutrophils and their products. The ideal anti-inflammatory therapy would exert a dual effect on the pro-inflammatory and pro-resolution arms of the inflammatory cascade, both of which contribute to dysregulated inflammation in CF. This review outlines the key factors to be considered in the design of clinical trials evaluating anti-inflammatory therapies in CF. Important lessons have been learned from previous clinical trials in this area and choosing the right efficacy endpoints is key to the success of any anti-inflammatory drug development program. Identifying and validating non-invasive biomarkers, novel imaging techniques and sensitive lung function tests capable of monitoring disease activity and therapeutic response are important areas of research and will be useful for the design of future anti-inflammatory drug trials.
Gut Ischemia Reperfusion Injury Induces Lung Inflammation via Mesenteric Lymph-Mediated Neutrophil Activation

Gut ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidities that result from systemic inflammation and remote organ dysfunction, typically acute lung injury. The mechanisms underlying the dissemination of gut-derived harmful mediators into the circulation are poorly understood. The objective of our study was to determine the role of mesenteric lymphatic circulation in the systemic and pulmonary inflammatory response to gut I/R. Using a murine intestinal I/R model, we evaluated whether and how blocking mesenteric lymph flow affects the inflammatory response in local tissues (gut) and remote organs (lungs). We further explored the mechanisms of post-I/R lymph-induced systemic inflammation by examining neutrophil activity and interaction with endothelial cells in vitro. Mice subjected to intestinal I/R displayed a significant inflammatory response in local tissues, evidenced by neutrophil infiltration into mucosal areas, as well as lung inflammation, evidenced by increased myeloperoxidase levels, neutrophil infiltration, and elevated microvascular permeability in the lungs. Mesenteric lymph duct ligation (MLDL) had no effect on gut injury per se, but effectively attenuated lung injury following gut I/R. Cell experiments showed that lymph fluid from post-I/R animals, but not pre-I/R, increased neutrophil surface CD11b expression and their ability to migrate across vascular endothelial monolayers. Moreover, post-I/R lymph upregulated neutrophil expression of pro-inflammatory cytokines and chemokines, which was mediated by a mechanism involving nuclear factor (NF)-κB signaling. Consistently, gut I/R activated NF-κB in lung neutrophils, which was alleviated by MLDL. In conclusion, all these data indicate that mesenteric lymph circulation contributes to neutrophil activation and lung inflammation following gut I/R injury partly through activating NF-κB.
Effects of Survival Processing on Item and Context Memory: Enhanced Memory for Survival-Relevant Details

Due to the natural selection pressure, certain aspects of memory may have been selected to give humans a survival advantage. Research has demonstrated that processing information for survival relevance leads to better item memory (i.e., the content of information) compared to control conditions. The current study investigates the effects of survival processing on context memory (i.e., memory for peripheral episodic details) and item memory to better understand when the survival processing memory advantage emerges. In this study, participants studied pictures of objects in either a survival or moving (control) condition. Objects were presented in either a plausible color, for example, a red apple, or in an implausible color, such as a green pie. We chose this color plausibility manipulation because color is a detail that conveys information about the fitness (and other diagnostic information) about an item. After studying items, participants made item memory judgments (did you see this item before? ) and two context memory judgments: color context (in which color did you see this item? ) and source context (in which condition did you see this item? ). Results indicated better item memory for materials processed in the survival relative to moving condition. Critically, for color context, there was a condition by plausibility interaction, where memory was best for plausibly colored items in the survival processing condition. There was no difference, however, in source context memory between the survival and moving conditions. These results suggest the survival processing memory advantage extends to contextual details that particularly reflect the survival utility of items such as color.
Distinct Functions of Acyl/Alkyl Dihydroxyacetonephosphate Reductase in Peroxisomes and Endoplasmic Reticulum

Plasmalogens are a subclass of ether glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position of the glycerol backbone. Plasmalogen biosynthesis is initiated in peroxisomes. At the third step of plasmalogen synthesis, alkyl-dihydroxyacetonephosphate (DHAP) is enzymatically reduced to 1-alkyl-sn-glycero-3-phospate by acyl/alkyl DHAP reductase (ADHAPR), whose activity is found in both peroxisomes and microsomes. We herein show that knockdown of ADHAPR in HeLa cells reduced the synthesis of ethanolamine plasmalogen (PlsEtn), similar to the Chinese hamster ovary cell mutant FAA.K1B deficient in ADHAPR activity. Endogenous ADHAPR and ectopically expressed FLAG-tagged ADHAPR were localized to peroxisomes and endoplasmic reticulum (ER) as a type I integral membrane protein in HeLa cells. ADHAPR targets to peroxisomes via a Pex19p-dependent class I pathway. In addition, it is also inserted into the ER via the SRP-dependent mechanism. The ADHAPR mutant lacking the N-terminal domain preferentially targets to the ER, restoring the reduced level of PlsEtn synthesis in FAA.K1B cell. In contrast, the expression of full-length ADHAPR in the mutant cells elevates the synthesis of phosphatidylethanolamine, but not PlsEtn. Taken together, these results suggest that the third step of plasmalogen synthesis is mediated by ER-localized ADHAPR.
Melanopsin retinal ganglion cell-driven contribution to visual and cognitive brain responses in LHON

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive photoreceptors contributing to visual and non-image-forming functions of the eye. Isolating mRGC roles in humans is challenging, therefore mRGCs functions remains to be fully characterized. We explored mRGCs contribution to light-driven visual and cognitive brain responses in Leber’s Hereditary Optic Neuropathy (LHON), given mRGC relative sparing in LHON. Twelve patients and twelve matched healthy controls (HC) participated in an fMRI protocol including visual and visual-cognitive paradigms under blue (480nm) and red light (620nm). Higher occipital activation was found in response to sustained blue vs. red stimulation in LHON vs. HC. Similarly, brain responses to the executive task were larger under blue vs. red light in LHON over lateral prefrontal cortex. These findings are in line with LHON mRGCs relative sparing and support mRGCs contribution to non-visual and visual functions in humans, with potential implication for visual rehabilitation in optic neuropathy patients.
Detection and Recognition of Fearful Facial Expressions During the Coronavirus Disease (COVID-19) Pandemic in an Italian Sample: An Online Experiment

In this observational study, the psychological ability to recognize the others’ fearful expressions in Italian individuals during the pandemic COVID-19 lockdown was explored through a behavioral task performed online. An implicit version of the traditional facial emotion recognition task, grounded on the attentional and unconscious mechanism of the redundant target effect, was used. The experiment was scripted through the free software OpenSesame (Mathôt et al., 2012) and published on the Internet through the free software Jatos (Lange et al., 2015). The Reaction Time and level of Accuracy in detecting fearful expressions were computed. Overall, the data of 86 Italian individuals were collected. When their performance was scored in terms of Reaction Time, the redundant target effect did not emerge; instead, the expected effect was observed when the level of Accuracy was considered. Overall, the performance registered in this Italian sample in terms of accuracy was in line with previous results reported in Scarpina et al. (2018), in which a long extended version of the same behavioral task was used in a traditional experimental setting. This study might offer some considerations regarding the adoption of online experiments – together with self-report surveys – to assess the psychological and behavioral functioning during social restriction measures.
Altered Functional Hubs and Connectivity in Type 2 Diabetes Mellitus Without Mild Cognitive Impairment

Background: Type 2 diabetes mellitus (T2DM)-related cognitive decline is associated with neuroimaging changes. However, only a few studies have focused on early functional alteration in T2DM prior to mild cognitive impairment (MCI). This study aimed to investigate the early changes of global connectivity patterns in T2DM by using a resting-state functional magnetic resonance imaging (rs-fMRI) technique. Methods: Thirty-four T2DM subjects and 38 age-, sex-, and education-matched healthy controls (HCs) underwent rs-fMRI in a 3T MRI scanner. Degree centrality (DC) was used to identify the functional hubs of the whole brain in T2DM without MCI. Then the functional connectivity (FC) between hubs and the rest of the brain was assessed by using the hub-based approach. Results: Compared with HCs, T2DM subjects showed increased DC in the right cerebellum lobules III–V. Hub-based FC analysis found that the right cerebellum lobules III–V of T2DM subjects had increased FC with the right cerebellum crus II and lobule VI, the right temporal inferior/middle gyrus, and the right hippocampus. Conclusions: Increased DC in the right cerebellum regions III–V, as well as increased FC within cerebellar regions and ipsilateral cerebrocerebellar regions, may indicate an important pathophysiological mechanism for compensation in T2DM without MCI.
Attenuated P. falciparum Parasite Shows Cytokine Variations in Humanized Mice

A recently developed humanized mouse has been used to assess the immune response evoked against the isolated attenuated C9 parasite clone (C9-M; carrying a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500) of Plasmodium falciparum. Significant human RBC engraftment was achieved by ameliorating the residual non-adaptive immune response using clodronate-loaded liposome treatment. Controlled reactive professional phagocytic leukocytes in immunodeficient mice allowed for sizeable human blood chimerism and injected huRBCs acted as bona fide host cells for P. falciparum. huRBC-reconstituted immunodeficient mice received infectious challenge with attenuated P. falciparum C9 parasite mutants (C9-M), complemented (C9-C), and wild type (NF54) progenitors to study the role of immune effectors in the clearance of the parasite from mouse circulation. C9-M and NF54 parasites grew and developed in the huRBC-reconstituted humanized NSG mice. Further, the presence of mutant parasites in deep-seated tissues suggests the escape of parasites from the host's immune responses and thus extended the survival of the parasite. Our results suggest an evasion mechanism that may have been employed by the parasite to survive the mouse's residual non-adaptive immune responses. Collectively, our data suggest that huRBCs reconstituted NSG mice infected with attenuated P. falciparum is a valuable tool to explore the role of C9 mutation in the growth and survival of parasite mutants and their response to the host's immune responses. This mouse might help in identifying novel chemotherapeutic targets to develop new anti-malarial drugs.
Phloem loading via the abaxial bundle sheath cells in maize leaves

Leaves are asymmetric, with differential functionalization of abaxial and adaxial tissues. The bundle sheath (BS) surrounding the vasculature of the C3 crop barley is dorsoventrally differentiated into three domains: adaxial structural, lateral S-type, and abaxial L-type. S-type cells seem to transfer assimilates towards the phloem. Here we used single-cell RNA sequencing to investigate BS differentiation in C4 maize. Abaxial BS (abBS) cells of rank-2 intermediate veins specifically expressed three SWEET sucrose uniporters (SWEET13a, b, and c) and UmamiT amino acid efflux transporters. SWEET13a, b, c were also identified in the phloem parenchyma (PP). Thus maize acquired a unique mechanism for phloem loading in which abBS cells provide the main pathway for apoplasmic sucrose transfer towards the phloem. This pathway predominates in veins responsible for phloem loading (rank-2 intermediate), while rank-1 intermediate and major veins export sucrose from the phloem parenchyma (PP) adjacent to the sieve element companion cell (SE/CC) complex, as in Arabidopsis. We surmise that abBS identity is subject to dorsoventral patterning and has components of PP identity. These observations provide first insights into the unique transport-specific properties of abBS cells and support for a modification to the canonical phloem loading pathway of maize, which may be generalizable to other C4 monocots.
Geometric and Electronic Properties of Li2GeO3

The 3D ternary Li2GeO3 compound, which could serve as the electrolyte material in Li+-based batteries, exhibits an unusual lattice symmetry (orthorhombic crystal), band structure, charge density distribution and density of states. The essential properties are fully explored through the first-principles method. In the delicate calculations and analyses, the main features of atom-dominated electronic energy spectrum, space-charge distribution, and atom-/orbital-projected density of states are sufficient to identify the critical multi-orbital hybridizations of the chemical bonds: 2s-(2px, 2py, 2pz) and (4s, 4px, 4py, 4pz)-(2s, 2px, 2py, 2pz), respectively, for Li-O and Ge-O. This system possesses a large indirect gap of Eg = 3.77 eV. There exist a lot of significant covalent bonds, with an obvious non-uniformity and anisotropy. In addition, spin-dependent magnetic configurations are completely absent. The theoretical framework could be developed to investigate the important features of anode and cathode materials related to lithium oxide compounds.
Prevalence and Description of Hyponatremia in a Swiss Tertiary Care Hospital: An Observational Retrospective Study

Background: Hyponatremia (serum sodium concentration <135 mEq/L) is the most common electrolyte abnormality among hospitalized patients. Our aim was to study the epidemiology of hyponatremia in hospitalized patients, as well as the short-term mortality rates, the length of stay (LOS), and associated hospital costs. Methods: This retrospective cohort study included 6,539 hospitalizations in the internal medicine ward of a Swiss tertiary-care teaching hospital between January 1, 2012, and December 31, 2018 (42.7% women, mean age 69 years). Using serum sodium concentration, we identified hospitalizations with hyponatremia and calculated the prevalence of overall hyponatremia, admission hyponatremia (AH), hospital-acquired hyponatremia (HAH), and persistent hyponatremia (PH) at discharge. We also studied the impact of hyponatremia on 30-day readmissions, in-hospital and 30-day mortality, and hospital LOS and costs, using multivariable logistic regression and Cox proportional hazards models, with normal natremia as reference. Results: Prevalence of overall hyponatremia was 32.5% [95% confidence interval (CI), 31.3–33.6%], while prevalence of PH among hospitalizations with AH and HAH was 33.7% (31.7–35.8%). After multivariable adjustment, hyponatremia was associated with increased hospital costs (CHF 19,025 ± 485 vs. 14,962 ± 341, p < 0.001) and LOS (13.4 ± 0.2 vs. 10.7 ± 0.2 days, p < 0.001). Increased severity of hyponatremia was associated with higher hospital costs and LOS (p for trend <0.001). There was a trend toward more frequent 30-day readmissions associated with hyponatremia [adjusted odds ratio (OR), 1.15 (1.01–1.31), p = 0.032], mainly with PH: adjusted OR = 1.41 (1.17–1.71), p < 0.001. No association was found between severity of hyponatremia and readmissions. Hyponatremia was associated with an increase of in-hospital [adjusted OR = 1.94 (1.49–2.53), p < 0.001] and 30-day mortality: adjusted OR = 1.80 (1.44–2.24), p < 0.001. Increased severity of hyponatremia was associated with higher in-hospital and 30-day mortality (p for trend < 0.001). Conclusions: Hyponatremia is highly prevalent among hospitalized patients and associated with an increase of LOS, early hospital readmission, in-hospital and 30-day mortality, and hospital costs. PH was associated with a substantial increase of the risk of early hospital readmission and 30-day mortality.
Sense organ formation and identity are controlled by divergent mechanisms in insects

Insects and other arthropods utilise external sensory structures for mechanosensory, olfactory and gustatory reception. These sense organs have characteristic shapes related to their function, and in many cases are distributed in a fixed pattern so that they are identifiable individually. In Drosophila melanogaster, the identity of sense organs is regulated by specific combinations of transcription factors. In other arthropods, however, sense organ subtypes cannot be linked to the same code of gene expression. This raises the questions of how sense organ diversity has evolved in arthropods, and if the D. melanogaster subtype identity principle is representative for insects. To address these questions, we analyse sense organ development in another insect, the flour beetle Tribolium castaneum. We show that in contrast to D. melanogaster, T. castaneum sense organs cannot be categorised based on their requirement for individual or combinations of the conserved sense organ transcription factors such as cut and pox-neuro and members of the Achaete-Scute (Tc ASH, Tc asense) and Atonal family (Tc atonal, Tc cato, Tc amos). Rather, these genes are required for the specification of sense organ precursors and the development and differentiation of sensory cell types in diverse external sensilla. Based on our findings and past research, we present an evolutionary scenario suggesting that sensory organs have diversified from a default state through subsequent recruitment of sensory genes to the different sense organ specification processes. A specific role for genes in subtype identity has evolved as a secondary effect of the function of these genes in individual or subsets of sense organs, which can largely not be aligned with morphological or functional categories.