The Danger Is Growing! A New Paradigm for Immune System Activation and Peripheral Tolerance

Successful immune defense is a complex balancing act. In order to protect a host against invasion by harmful pathogens, an immune response must be rapid and vigorous, and must eliminate foreign invaders before their populations grow beyond control. That same immune response, however, must be selective enough to recognize and ignore commensal bacteria, environmental antigens and host tissue itself. How the immune system makes the crucial decision whether or not to attack a particular antigen has been a long-standing question central to the study of immunology. Here we show that the structure of the signaling network between regulatory T-cells and type 17 helper T-cells allows the immune system to selectively attack pathogens based on whether or not the pathogens represent a growing, and thus dangerous population. We term this mechanism for immune system activation the ‘Growth Detection Paradigm’, because it offers an entirely new explanation for immune system regulation and peripheral tolerance

Research Progress in the Effect of Glycosylation on Functional Properties and Allergenicity of Dairy Products

In recent years, milk allergy has attracted more and more attention because of its increasing incidence and in-depth research on it. The glycosylation modification of milk proteins not only can improve the functional properties of dairy products, but also reduce the allergenicity of dairy products by destroying or shielding the epitope of allergen proteins. This modification has found applications in various fields such as food flavor, antioxidants and carriers. This paper introduces common glycosylation reactions in the dairy industry, discusses their advantages and disadvantages and the pattern of changes in functional properties and allergenicity of milk proteins after glycosylation, and summarizes the methods to avoid the negative effects of glycosylation reactions. This review provides a reference for the research, development and application of glycosylation modification in milk allergy and dairy processing

Transcriptomic signatures of severe acute mountain sickness during rapid ascent to 4,300 m

IntroductionAcute mountain sickness (AMS) is a common altitude illness that occurs when individuals rapidly ascend to altitudes ≥2,500 m without proper acclimatization. Genetic and genomic factors can contribute to the development of AMS or predispose individuals to susceptibility. This study aimed to investigate differential gene regulation and biological pathways to diagnose AMS from high-altitude (HA; 4,300 m) blood samples and predict AMS-susceptible (AMS+) and AMS-resistant (AMS─) individuals from sea-level (SL; 50 m) blood samples.MethodsTwo independent cohorts were used to ensure the robustness of the findings. Blood samples were collected from participants at SL and HA. RNA sequencing was employed to profile gene expression. Differential expression analysis and pathway enrichment were performed to uncover transcriptomic signatures associated with AMS. Biomarker panels were developed for diagnostic and predictive purposes.ResultsAt HA, hemoglobin-related genes (HBA1, HBA2, and HBB) and phosphodiesterase 5A (PDE5A) emerged as key differentiators between AMS+ and AMS− individuals. The cAMP response element-binding protein (CREB) pathway exhibited contrasting regulatory patterns at SL and HA, reflecting potential adaptation mechanisms to hypoxic conditions. Diagnostic and predictive biomarker panels were proposed based on the identified transcriptomic signatures, demonstrating strong potential for distinguishing AMS+ from AMS− individuals.DiscussionThe findings highlight the importance of hemoglobin-related genes and the CREB pathway in AMS susceptibility and adaptation to hypoxia. The differential regulation of these pathways provides novel insights into the biological mechanisms underlying AMS. The proposed biomarker panels offer promising avenues for the early diagnosis and prediction of AMS risk, which could enhance preventive and therapeutic strategies

Clinical and Pathological Characteristics of Autoimmune Hepatitis with Acute Presentation

Aim. To study the differences between acute presentation-autoimmune hepatitis (A-AIH) and chronic autoimmune hepatitis (C-AIH). Methods. Through long-term follow-up, 80 patients were included in our study by using the revised international autoimmune hepatitis group (IAIHG) score and were divided into acute and chronic groups for comparison. Results. No significant difference was found in the gender, age, IAIHG score (pretreatment/posttreatment), definite diagnosis rate, extrahepatic autoimmune disease, onset time, or treatment before biopsy between the acute and chronic groups. In terms of clinical symptoms, A-AIH patients were more prone to jaundice, anorexia, yellow urine, and detesting oil than C-AIH patients, but melena only occurred in chronic group (P<0.05). The acute group exhibited more severe injury upon histological evaluation, with lobular inflammation and bile duct injury, especially central necrosis of the lobule, more pronounced in this group (P<0.05). Conclusion. A-AIH had manifestations of acute hepatitis and presented cholestasis. Serum indicators could preliminarily distinguish A-AIH and C-AIH. Histologically, the primary manifestation of A-AIH was lobular inflammation, which was usually accompanied by lobular central necrosis. For the diagnosis of A-AIH, more attention should be paid to long-term follow-up. This study was registered at ClinicalTrials.gov (identifier: NCT02994537)

Effects of atmospheric pressure air plasma pretreatment on the seed germination and early growth of andrographis paniculata

The objective of this paper is to demonstrate whether air plasma can change the seed germination characteristics, seedling emergence, as well as biochemical reactivity, in Andrographis paniculata (A. paniculata) seedlings by modifying the seed coat and finding a beneficial treatment dose. Eight treatment doses and one control were used to conduct electrical conductivity determination, a germination test, a seedling emergence test and a biochemical assay. The results showed that after being treated with air plasma excited at 5950 V for 10 s, the permeability of the seeds was improved significantly, resulting in the acceleration of seed germination and seedling emergence. In the meantime, the catalase activity and catalase isoenzyme expression were also improved, while the malondialdehyde content in the seedlings was decreased (which means greater counteraction with environmental stress). After being treated with 4250 V for 10 s and 5950 V for 20 s, the seed germination was enhanced, but without an obvious change in seedling emergence. However, after treatment with 3400 V for 20 s and 5100 V for 10 s, the permeability of the seeds was decreased, resulting in a delay in seedling emergence. These results indicate that air plasma can change the physiological and biochemical characteristics of Andrographis paniculata seeds by modifying the seed coat, combined with the effects of the active plasma species, and that different treating doses have different effects

Impact of dietary changes on retinal neuronal plasticity in rodent models of physical and psychological trauma

IntroductionBlast injury has been implicated as the major cause of traumatic brain injury (TBI) and ocular system injury, in military operations in Iraq and Afghanistan. Soldiers exposed to traumatic stress also have undiagnosed, chronic vision problems. Here we hypothesize that excessive intake of ω-6 fatty acid linoleic acid (LA) and insufficiency of dietary long chain ω-3 polyunsaturated fatty acids (PUFAs, e.g., docosahexaenoic acid; DHA) would dysregulate endocannabinoid-mediated neuronal plasticity and immune response. The study objective was to determine the effect of blast-TBI and traumatic stress on retinal gene expression and assess the role of dietary deficiency of long chain ω-3 PUFAs on the vulnerability to these injury models.MethodsLinoleic acid was used as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% present in the current western diets, and these custom LA diets were also devoid of long chain ω-3 PUFAs. Animals were exposed to a simulated blast overpressure wave followed by a weight drop head-concussion to induce TBI. A Separate group of rats were subjected to traumatic stress by a forced immersion underwater.ResultsOur findings showed that blast-TBI exposure, post 14 days, produced significant neuropathological changes such as axonal degeneration in the brain optic tracts from all the three diet groups, especially in rats fed the DHA-deprived 1 en% LA diet. Transcriptomic analysis showed that presence of DHA in the house chow diet prevented blast-induced disruption of neuronal plasticity by activating molecular networks like SNARE signaling, endocannabinoid pathway, and synaptic long-term depression when compared to DHA-deprived 8 en% LA diet group. Under traumatic stress, retinal synaptic function, neurovascular coupling, and opioid signaling mechanisms were dysregulated in rodents fed DHA-deficient diets (i.e., 8 en% LA and 1 en% LA), where reducing the levels of ω-6 linoleic acid from 8 en% to 1 en% was associated with increased neuronal plasticity and suppressed immune signaling.ConclusionThe findings of our study suggest that deprivation of long chain ω-3 PUFAs in the diet affects endocannabinoid-mediated neuronal plasticity, vascular function and inflammatory response that could influence the resistance of veterans to TBI and psychological trauma

External Control of the GAL Network in S. cerevisiae: A View from Control Theory

While there is a vast literature on the control systems that cells utilize to regulate their own state, there is little published work on the formal application of control theory to the external regulation of cellular functions. This paper chooses the GAL network in S. cerevisiae as a well understood benchmark example to demonstrate how control theory can be employed to regulate intracellular mRNA levels via extracellular galactose. Based on a mathematical model reduced from the GAL network, we have demonstrated that a galactose dose necessary to drive and maintain the desired GAL genes' mRNA levels can be calculated in an analytic form. And thus, a proportional feedback control can be designed to precisely regulate the level of mRNA. The benefits of the proposed feedback control are extensively investigated in terms of stability and parameter sensitivity. This paper demonstrates that feedback control can both significantly accelerate the process to precisely regulate mRNA levels and enhance the robustness of the overall cellular control system

Core module biomarker identification with network exploration for breast cancer metastasis

<p>Abstract</p> <p>Background</p> <p>In a complex disease, the expression of many genes can be significantly altered, leading to the appearance of a differentially expressed "disease module". Some of these genes directly correspond to the disease phenotype, (i.e. "driver" genes), while others represent closely-related first-degree neighbours in gene interaction space. The remaining genes consist of further removed "passenger" genes, which are often not directly related to the original cause of the disease. For prognostic and diagnostic purposes, it is crucial to be able to separate the group of "driver" genes and their first-degree neighbours, (i.e. "core module") from the general "disease module".</p> <p>Results</p> <p>We have developed COMBINER: COre Module Biomarker Identification with Network ExploRation. COMBINER is a novel pathway-based approach for selecting highly reproducible discriminative biomarkers. We applied COMBINER to three benchmark breast cancer datasets for identifying prognostic biomarkers. COMBINER-derived biomarkers exhibited 10-fold higher reproducibility than other methods, with up to 30-fold greater enrichment for known cancer-related genes, and 4-fold enrichment for known breast cancer susceptible genes. More than 50% and 40% of the resulting biomarkers were cancer and breast cancer specific, respectively. The identified modules were overlaid onto a map of intracellular pathways that comprehensively highlighted the hallmarks of cancer. Furthermore, we constructed a global regulatory network intertwining several functional clusters and uncovered 13 confident "driver" genes of breast cancer metastasis.</p> <p>Conclusions</p> <p>COMBINER can efficiently and robustly identify disease core module genes and construct their associated regulatory network. In the same way, it is potentially applicable in the characterization of any disease that can be probed with microarrays.</p

Rare copy number variation in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further