Miracle-dz/UniFAR-FTUs huggingface dataset:
The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative disease, currently affecting over 5 million Americans with projections expected to rise as the population ages. The hallmark pathologies of AD are Aβ plaques composed of aggregated beta-amyloid (Aβ), and tau tangles composed of hyperphosphorylated, aggregated tau. These pathologies are typically accompanied by an increase in neuroinflammation as an attempt to ameliorate the pathology. This idea has pushed the field toward focusing on mechanisms and the influence neuroinflammation has on disease progression. The vast majority of AD cases are sporadic and therefore, researchers investigate genetic risk factors that could lead to AD. Apolipoprotein E (ApoE) is the largest genetic risk factor for developing AD. ApoE has 3 isoforms-ApoE2, ApoE3, and ApoE4. ApoE4 constitutes an increased risk of AD, with one copy increasing the risk about 4-fold and two copies increasing the risk about 15-fold compared to those with the ApoE3 allele. ApoE4 has been shown to play a role in Aβ deposition, tau tangle formation, neuroinflammation and many subsequent pathways. However, while we know that ApoE4 plays a role in these pathways and virtually all aspects of AD, the exact mechanism of how ApoE4 impacts AD progression is murky at best and therefore the role ApoE4 plays in these pathways needs to be elucidated. This review aims to discuss the current literature regarding the pathways and mechanisms of ApoE4 in AD progression with a focus on its role in neuroinflammation.
Tumor Necrosis Factor-Alpha Signaling May Contribute to Chronic West Nile Virus Post-infectious Proinflammatory State

Background: West Nile virus (WNV) causes a spectrum of human disease ranging from a febrile illness (WNV fever) to severe neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis). Since WNV gained entry into North America in 1999, clinicians caring for WNV survivors have observed persistent neurological symptoms occurring long-after the production of neutralizing antibodies and clearance of the virus. Accordingly, alternative pathogeneses other than direct viral invasion have been hypothesized to explain these post-infectious symptoms. The dominant hypothesis is that antiviral inflammatory responses triggered initially to clear WNV may persist to promote a post-infectious proinflammatory state. Methods: In 4 serologically-confirmed WNV patients with persistent post-infectious symptoms (3 WNV fever, 1 neuroinvasive disease), we ordered a comprehensive cytokine panel at weeks 8, 10, 12, and 36 months post-onset of illness, respectively, to better understand the pathophysiology of the protracted symptoms. Results: All patients had abnormally elevated tumor necrosis factor alpha (TNF-α), a major molecule triggering antiviral cytokines and chronic inflammation in many human autoimmune diseases, but heretofore not reported to be upregulated in human WNV infection. Three patients also had elevations of other proinflammatory proteins. Major symptoms included fatigue, arthralgias, myalgias, generalized or multifocal pain or weakness, imbalance, headaches, cognitive problems, and symptoms of dysautonomia. Conclusion: The findings provide support for an extended post-infectious proinflammatory state that may contribute to chronic inflammation and long-term morbidity in some WNV survivors and further suggest that TNF-α may play a pathogenic role in initiating this inflammatory environment. Clinical trials may be warranted to determine if TNF-α inhibitors or other immunosuppressive agents can improve patient outcomes.
Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia

Essential thrombocythemia (ET) is comprised among chronic myeloproliferative neoplasms (MPN) and is caused by driver mutations in JAK2, CALR, and MPL, which lead to megakaryocyte proliferation and prominent thrombocytosis. Thrombosis remains the main cause of morbidity in ET and is driven by the interplay between blood cells, the endothelium, the clotting cascade, and host-derived inflammatory mediators. Platelet activation plays a key role in the thrombotic predisposition, although the underlying mechanisms remain poorly defined. In addition to their role in hemostasis, platelets participate in innate immunity and inflammation owing to the expression of toll-like receptors (TLR), which recognize inflammatory signals, triggering platelet functional responses. Considering the impact of inflammation on ET procoagulant state, we assessed the contribution of TLR2 and TLR4 to platelet hemostatic and inflammatory properties in ET patients, by using Pam3CSK4 and lipopolysaccharide (LPS) as specific TLR2 and TLR4 ligands, respectively. TLR2 ligation induced increased surface translocation of α-granule-derived P-selectin and CD40L, which mediate platelet interaction with leukocytes and endothelial cells, respectively, and higher levels of dense granule-derived CD63 in patients, whereas PAC-1 binding was not increased and LPS had no effect on these platelet responses. Platelet-neutrophil aggregate formation was elevated in ET at baseline and after stimulation of both TLR2 and TLR4. In addition, ET patients displayed higher TLR2- and TLR4-triggered platelet secretion of the chemokine RANTES (CCL5), whereas von Willebrand factor release was not enhanced, revealing a differential releasate pattern for α-granule-stored inflammatory molecules. TLR-mediated hyperresponsiveness contrasted with impaired or preserved responses to classic platelet hemostatic agonists, such as TRAP-6 and thrombin. TLR2 and TLR4 expression on the platelet surface was normal, whereas phosphorylation of downstream effector ERK1/2 was higher in patients at baseline and after incubation with Pam3CSK4, which may partly explain the enhanced TLR2 response. In conclusion, exacerbated response to TLR stimulation may promote platelet activation in ET, boosting platelet/leukocyte/endothelial interactions and secretion of inflammatory mediators, overall reinforcing the thromboinflammatory state. These findings highlight the role of platelets as inflammatory sentinels in MPN prothrombotic scenario and provide additional evidence for the close intertwining between thrombosis and inflammation in this setting.
The Hypoglycemic and Renal Protection Properties of Crocin via Oxidative Stress-Regulated NF-κB Signaling in db/db Mice

Background As the main ingredient of Crocus sativus L. (Iridaceae) extract, crocin- I (CR) has been reported to show various pharmacological activities. The aim of this study was to investigate the hypoglycemic and renal protection properties of CR in db/db mice. Methods Eight-week-old db/db mice were treated with metformin (Met) (100 mg/kg) and CR (50 mg/kg) for eight weeks. Results CR treatment showed hypoglycemic functions indicated by reduced bodyweight, food and water intake, plasma glucose, and serum levels of glycated hemoglobin A1c. Additionally, the CR group showed increased serum levels of insulin and pyruvate kinase, hypolipidemic functions indicated by the suppressed levels of total cholesterol and triglyceride, and enhanced levels of high-density lipoprotein cholesterol, which are also indicators of hypoglycemic functions. The renal protection function of CR was demonstrated by its protection of renal structures and its regulation of potential indicators of nephropathy. The anti-oxidation and anti-inflammation effects of CR were verified by enzyme-linked immunosorbent assay. In the kidneys of db/db mice, CR decreased the expression of phospho-IκBα and phospho-nuclear factor-κB (NF-κB), whereas it enhanced the expression of nuclear respiratory factor 2, manganese superoxide dismutase 1, heme oxygenase-1, and catalase. Conclusions The anti-diabetic and anti-diabetic nephritic effects of CR were related to its modulation of oxidative stress-mediated NF-κB signaling.
Yizhi Qingxin Formula Extract Ameliorates Cognitive Decline in Aged Rats via the Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Pathway

Cognitive impairment and decline in old age are primarily driven by the accumulation of age-related neuropathologies, and old age is thus the primary risk factor for neurodegenerative diseases such as AD. Here, we investigated the effects of Yizhi Qingxin formula (YQF) extract on cognitive impairment in aged rats and determine the role of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway underlying the neuroprotective effects of the YQF extract. Fifty male Wistar rats were randomly divided into five groups: Control group, Model group, Donepezil group, and YQF extract groups (treatment with YQF extract at two different doses). After treatment with YQF extract for 8 weeks, learning and cognitive abilities were assessed using the Morris water maze. Morphological changes in the hippocampus were observed using hematoxylin-eosin. Activated microglia and astrocytes were assessed using immunohistochemistry. Expressions of proteins and genes were examined using western blotting and real-time PCR. The results revealed that oral treatment with YQF extract dramatically improved spatial learning and memory ability and ameliorated histopathological and morphological characteristics in aged rats. YQF extract significantly increased acetylcholine and interleukin (IL)-10 levels but markedly decreased amyloid-β peptide, tumor necrosis factor alpha (TNFα), IL-2, and IL-6 levels. In addition, it inhibited the excessive activation of microglia and astrocytes, downregulated the expressions of TNFα and IL-2, and upregulated nerve growth factor, BDNF, and TrkB expressions. Furthermore, hippocampal extracellular signal-related kinase (Erk) and protein kinase B (Akt), the upstream signaling of BDNF/TrkB, were also activated by treatment with YQF extract. Our findings indicate that YQF extract activates the BDNF/TrkB pathway through the upregulation of Erk and Akt signaling, and the activated signaling pathway might contribute to the protective effects of YQF extract on cognitive impairment in aged rats.
Target the Host, Kill the Bug; Targeting Host Respiratory Immunosuppressive Responses as a Novel Strategy to Improve Bacterial Clearance During Lung Infection

The lung is under constant pressure to protect the body from invading bacteria. An effective inflammatory immune response must be tightly orchestrated to ensure complete clearance of any invading bacteria, while simultaneously ensuring that inflammation is kept under strict control to preserve lung viability. Chronic bacterial lung infections are seen as a major threat to human life with the treatment of these infections becoming more arduous as the prevalence of antibiotic resistance becomes increasingly commonplace. In order to survive within the lung bacteria target the host immune system to prevent eradication. Many bacteria directly target inflammatory cells and cytokines to impair inflammatory responses. However, bacteria also have the capacity to take advantage of and strongly promote anti-inflammatory immune responses in the host lung to inhibit local pro-inflammatory responses that are critical to bacterial elimination. Host cells such as T regulatory cells and myeloid-derived suppressor cells are often enhanced in number and activity during chronic pulmonary infection. By increasing suppressive cell populations and cytokines, bacteria promote a permissive environment suitable for their prolonged survival. This review will explore the anti-inflammatory aspects of the lung immune system that are targeted by bacteria and how bacterial-induced immunosuppression could be inhibited through the use of host-directed therapies to improve treatment options for chronic lung infections.
Injury Causes and Severity in Pediatric Traumatic Brain Injury Patients Admitted to the Ward or Intensive Care Unit: A Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study

Background: Traumatic brain injury (TBI) is the leading cause of death and disability in children. It includes a range of different pathologies that differ considerably from adult TBI. Analyzing and understanding injury patterns of pediatric TBI is essential to establishing new preventive efforts as well as to improve clinical management. Methods: The multi-center, prospectively collected CENTER-TBI core and registry databases were screened and patients were included when younger than 18 years at enrollment and admitted to the regular ward (admission stratum) or intensive care unit (ICU stratum) following TBI. Patient demographics, injury causes, clinical findings, brain CT imaging details, and outcome (GOSE at 6 months follow-up) were retrieved and analyzed. Injury characteristics were compared between patients admitted to the regular ward and ICU and multivariate analysis of factors predicting an unfavorable outcome (GOSE 1-4) was performed. Results from the core study were compared to the registry dataset which includes larger patient numbers but no follow-up data. Results: Two hundred and twenty seven patients in the core dataset and 687 patients in the registry dataset were included in this study. In the core dataset, road-traffic incidents were the most common cause of injury overall and in the ICU stratum, while incidental falls were most common in the admission stratum. Brain injury was considered serious to severe in the majority of patients and concurrent injuries in other body parts were very common. Intracranial abnormalities were detected in 60% of initial brain CTs. Intra- and extracranial surgical interventions were performed in one-fifth of patients. The overall mortality rate was 3% and the rate of unfavorable outcome 10%, with those numbers being considerably higher among ICU patients. GCS and the occurrence of secondary insults could be identified as independent predictors for an unfavorable outcome. Injury characteristics from the core study could be confirmed in the registry dataset. Conclusion: Our study displays the most common injury causes and characteristics of pediatric TBI patients that are treated in the regular ward or ICU in Europe. Road-traffic incidents were especially common in ICU patients, indicating that preventive efforts could be effective in decreasing the incidence of severe TBI in children.
Characterization of an A-Type Muscarinic Acetylcholine Receptor and Its Possible Non-neuronal Role in the Oriental Armyworm, Mythimna separata Walker (Lepidoptera: Noctuidae)

Muscarinic acetylcholine receptor (mAChR) regulates many neurophysiological functions in insects. In this report, a full-length cDNA encoding an A-type mAChR was cloned from the oriental armyworm, Mythimna separata. Pharmacological properties studies revealed that nanomolar to micromolar concentrations of carbachol or muscarine induced an increase of intracellular Ca2+ concentration ([Ca2+]i), with the EC50 values of 124.6 and 388.1 nM, respectively. The increases of [Ca2+]i can be greatly blocked by the antagonist atropine, with an IC50 value of 0.09 nM. The receptor mRNA is expressed in all developmental stages, with great differential expression between male and female adults. The tissue expression analysis identified novel target tissues for this receptor, including ovaries and Malpighian tubules. The distribution of Ms A-type mAChR protein in the male brain may suggest the neurophysiological roles that are mediated by this receptor. However, the receptor protein was found to be distributed on the membranes of oocytes that are not innervated by neurons at all. These results indicate that Ms A-type mAChR selectively mediates intracellular Ca2+ mobilization. And the high level of receptor protein in the membrane of oocytes may indicate a possible non-neuronal role of A-type mAChR in the reproductive system of M. separata.
Inhibitory Effects of Linear Lipopeptides From a Marine Bacillus subtilis on the Wheat Blast Fungus Magnaporthe oryzae Triticum

Wheat blast is a devastating fungal disease caused by a filamentous fungus, Magnaporthe oryzae Triticum (MoT) pathotype, which poses a serious threat to food security of South America and South Asia. In the course of screening novel bioactive secondary metabolites, we found that some secondary metabolites from a marine Bacillus subtilis strain 109GGC020 remarkably inhibited the growth of M. oryzae Triticum in vitro at 20 μg/disk. We tested a number of natural compounds derived from microorganisms and plants and found that five recently discovered linear non-cytotoxic lipopeptides, gageopeptides A–D (1–4) and gageotetrin B (5) from the strain 109GGC020 inhibited the growth of MoT mycelia in a dose-dependent manner. Among the five compounds studied, gageotetrin B (5) displayed the highest mycelial growth inhibition of MoT followed by gageopeptide C (3), gageopeptide D (4), gageopeptide A (1), and gageopeptide B (2) with minimum inhibitory concentrations (MICs) of 1.5, 2.5, 2.5, 10.0, and 10.0 μg/disk, respectively. Application of these natural compounds has also completely blocked formation of conidia in the MoT fungal mycelia in the agar medium. Further bioassay revealed that these compounds (1–5) inhibited the germination of MoT conidia and, if germinated, induced deformation of germ tube and/or abnormal appressoria. Interestingly, application of these linear lipopeptides (1–5) significantly suppressed wheat blast disease on detached wheat leaves. This is the first report of the inhibition of mycelial growth, conidiogenesis, conidial germination, and morphological alterations in the germinated conidia and suppression of wheat blast disease by linear lipopeptides from the strain of B. subtilis. A further study is needed to evaluate the mode of action of these natural compounds for considering them as biopesticides for managing this notorious cereal killer.
Gut Microbiome Influences the Efficacy of PD-1 Antibody Immunotherapy on MSS-Type Colorectal Cancer via Metabolic Pathway

Colorectal cancer (CRC) appears to be rather refractory to checkpoint blockers except the patient with deficient in mismatch repair (dMMR). Therefore, new advances in the treatment of most mismatch repair proficiency (pMMR) (also known as microsatellite stability, MSS) type of CRC patients are considered to be an important clinical issue associated with programmed death 1 (PD-1) inhibitors. In the present study, we evaluated the effects of gut microbiome of MSS-type CRC tumor-bearing mice treated with different antibiotics on PD-1 antibody immunotherapy response. Our results confirmed that the gut microbiome played a key role in the treatment of CT26 tumor-bearing mice with PD-1 antibody. After PD-1 antibody treatment, the injection of antibiotics counteracted the efficacy of PD-1 antibody in inhibiting tumor growth when compared with the Control group (mice were treated with sterile drinking water). Bacteroides_sp. _CAG:927 and Bacteroidales_S24-7 were enriched in Control group. Bacteroides_sp. _CAG:927, Prevotella_sp. _CAG: 1031 and Bacteroides were enriched in Coli group [mice were treated with colistin (2 mg/ml)], Prevotella_sp. _CAG:485 and Akkermansia_muciniphila were enriched in Vanc group [mice were treated with vancomycin alone (0.25 mg/ml)]. The metabolites were enriched in the glycerophospholipid metabolic pathway consistent with the metagenomic prediction pathway in Vanc group, Prevotella_sp. _CAG:485 and Akkermansia may maintain the normal efficacy of PD-1 antibody by affecting the metabolism of glycerophospholipid. Changes in gut microbiome leaded to changes in glycerophospholipid metabolism level, which may affect the expression of immune-related cytokines IFN-γ and IL-2 in the tumor microenvironment, resulting in a different therapeutic effect of PD-1 antibody. Our findings show that changes in the gut microbiome affect the glycerophospholipid metabolic pathway, thereby regulating the therapeutic potential of PD-1 antibody in the immunotherapy of MSS-type CRC tumor-bearing mice.
Nanotheranostic Applications for Detection and Targeting Neurodegenerative Diseases

Nanotechnology utilizes engineered materials and devices which function with biological systems at the molecular level and could transform the management of neurodegenerative diseases (NDs) by provoking, reacting to, and intermingling with target sites to stimulate physiological responses while minimizing side effects. Blood–brain barrier (BBB) protects the brain from harmful agents, and transporting drugs across the BBB is a major challenge for diagnosis, targeting, and treatment of NDs. The BBB provides severe limitations for diagnosis and treatment of Alzheimer’s disease (AD), Parkinson’s disease (PD), and various other neurological diseases. Conventional drug delivery systems generally fail to cross the BBB, thus are inefficient in treatment. Although gradual development through research is ensuring the progress of nanotheranostic approaches from animal to human modeling, aspects of translational applicability and safety are a key concern. This demands a deep understanding of the interaction of body systems with nanomaterials. There are various plant-based nanobioactive compounds which are reported to have applicability in the diagnosis and treatment of these NDs. This review article provides an overview of applications of nanotheranostics in AD and PD. The review also discusses nano-enabled drug delivery systems and their current and potential applications for the treatment of various NDs.
Post-mortem changes in chicken muscle

This paper details the post-mortem changes that take place in the muscular tissue of poultry and the consequences of these on the resulting meat quality at the point of consumption. The history of the development of the modern meat-type chicken, the form and function of its muscles, the factors that determine muscle growth and their effects on meat quality are all described. Past studies tend to have been concentrated on the processes occurring in mammalian tissue and those mainly on beef, with little attention being directed at the changes taking place in poultry muscle. In this context the view that modern broilers grow “at the edge of what is metabolically possible” is important. This hypothesis owes its origin to the fact that muscle, and thus protein, accretion is accomplished through a dynamic equilibrium between synthesis and degradation. Evidence is provided to show that the muscle cell reaches a certain maximum synthesis capacity, to grow beyond which requires it to decrease its rate of degradation. This property is possibly of considerable influence in meat ageing and forms the basis for the proposition that the breast muscle of poultry is especially suited to study the effects of post-mortem proteolytic degradation on meat ageing and product quality.
Hydrothermal and Cold Spring Water and Primary Productivity Effects on Magnesium Isotopes: Lake Myvatn, Iceland

Lake Myvatn, Iceland, is one of the most biologically productive lakes in the northern hemisphere, despite seasonal ice cover. Hydrothermal and groundwater springs make up the dominant source to this lake, and we investigate their Mg isotope ratio to assess the effect of mid-ocean ridge hydrothermal springs, which are the primary modern sink of seawater magnesium. We also examine a time series in the only outflow from this lake, the Laxa River, to assess the effects of seasonal primary productivity on Mg isotopes. In the hydrothermal waters, there is a clear distinction between cold waters (largely unfractionated from primary basalt) and relatively hot waters, which exhibit over 1‰ fractionation, with consequences for the oceanic mass balance if the hydrothermal removal of Mg is not fully quantitative. The outflow Mg isotopes are similar to basalts (δ26Mg = −0.2 to −0.3) during winter but reach a peak of ∼0‰ in August. This fractionation corresponds to calcite precipitation during summer in Lake Myvatn, preferentially taking up light Mg isotopes and driving the residual waters isotopically heavy as observed, meaning that overall the lake is a CO2 sink.