Level Of Activation Research Articles

Mild therapeutic hypothermic protection activates the PI3K/AKT signaling pathway to inhibit TRPM7 and suppress ferroptosis induced by myocardial ischemia‑reperfusion injury.

The present study aimed to investigate the role of PI3K‑mediated ferroptosis signaling induced by mild therapeutic hypothermia (MTH), which was defined as a temperature of 34˚C, in protecting against myocardial ischemia-reperfusion (I/R) injury (MIRI). To meet this aim, H9C2 cells underwent hypoxia‑reperfusion (H/R) and/or MTH. The MTT assay was used to assess cell viability, cytotoxicity was measured using a lactate dehydrogenase cytotoxicity assay, and Annexin V‑FITC/PI flow cytometric analysis was used to analyze early and late cell apoptosis. In addition, 84 healthy adult male Sprague‑Dawley rats were randomly divided into seven groups (n=12), and underwent I/R and various treatments. Hemodynamics were monitored, and the levels of myocardial injury marker enzymes and oxidative stress markers in myocardial tissue were measured using ELISA. The expression levels of PI3K, AKT, transient receptor potential cation channel subfamily M member 7 (TRPM7), glutathione peroxidase 4 (GPX4) and acyl‑CoA synthetase long chain family member 4 (ACSL4) in animals and cells were measured using western blot analysis. These experiments revealed that MTH could effectively reduce myocardial infarct size, improve hemodynamic performance following MIRI and suppress myocardial apoptosis, thereby contributing to the recovery from H/R injury. Mechanistically, MTH was revealed to be able to activate the PI3K/AKT signaling pathway in cells, upregulating GPX4, and downregulating the expression levels of TRPM7 and ACSL4. Treatment with 2‑aminoethoxydiphenyl borate (an inhibitor of TRPM7) could further strengthen the myocardial protective effects of MTH, whereas treatment with erastin (promoter of ferroptosis) and wortmannin (inhibitor of PI3K) led to the effective elimination of the myocardial protective effects of MTH. Compared with in the I/R group, the PI3K/AKT activation level and the expression levels of GPX4 were both significantly increased, whereas the expression levels of TRPM7 and ACSL4 were significantly decreased in the I/R + MTH group. Taken together, the results of the present study indicated that MTH may activate the PI3K/AKT signaling pathway to inhibit TRPM7 and suppress ferroptosis induced by MIRI.

Upper limb movement control strategy of top-tier elite male badminton players when smashing for different distances

PurposeMastering the skill of smashing in a game can be quite challenging. Unfortunately, it’s not always easy to control the distance of the smash. The present study investigated the impact of different smashing distances on muscle activation patterns and kinematics of the upper limbs.Material and methodsTen collegiate athletes from a top-ranked team in Korea participated in the present study with a mean age, weight, and height of 21 ± 1 years, 71.9 ± 9.1 kg, and 1.78 ± 2.24 m, respectively. Three valid data points for each subject at three different distances were analyzed using a one-way analysis of variance (ANOVA).ResultsThe results demonstrated that with increasing smashing distance, the internal rotation angle of the elbow and wrist joints decreased, while the angular velocity of flexion and internal rotation of the shoulder, elbow, and wrist joints increased. Muscle activation increased for all muscles except the biceps brachii (BICLO) with increasing distance. The greatest changes in activation levels were observed in the anterior deltoid (DELTA), extensor carpi radialis (ECR), and flexor carpi ulnaris (FCU).ConclusionsDuring tasks with different smashing distances, muscle activation in the upper limbs (except the biceps) increased with increasing distances. Additionally, the internal rotation angle of the upper limbs decreased with increased distances, while the angular velocity of flexion and internal rotation of the shoulder, elbow, and wrist joints increased.

The Role of the Orbitofrontal Cortex in the Regulation of Fear Coping Strategies.

Under threats, individuals exhibit freezing behavior and prepare for active coping. The ability to flexibly shift between freezing and active coping increases survival chances in animals and decreases susceptibility to mental disorders among human beings. For example, patients with psychiatric disorders, such as obsessive-compulsive disorder and posttraumatic stress disorder, often show maladaptive coping behaviors. The orbitofrontal cortex (OFC) is a critical hub to process higher cognitive functions, sensory inputs, reward learning, and decision-making. It also regulates negative emotions and its aberrant activation level often correlates with numerous mental disorders. The rodent OFC comprises different subdivisions with varying connections to cortical and subcortical regions. Among these subdivisions, the medial orbital area (MO) and the lateral orbital area (LO) have distinct functions in the regulation of fear. Here, we updated the existing rodent literature studying the function of the OFC, with a particular focus on the MO and the LO in different coping strategies of animals. By examining the role of the OFC in the mediation of defensive coping strategies, we aim to deepen the understanding of its functional importance on mental health.

Lapatinib-induced enhancement of mitochondrial respiration in HER2-positive SK-BR-3 cells: mechanism revealed by analysis of proteomic but not transcriptomic data.

Dual inhibitors of HER2 and EGFR, such as lapatinib, have shown significant efficacy for the therapy of HER2-positive breast cancer. Previous experiments showed that in cell cultures, the efficacy of lapatinib was significantly reduced by exposure to human serum and human epidermal growth factor (EGF). At the proteomic and transcriptomic levels, we examined the changes in the HER2-positive breast cancer cell line SK-BR-3 profiles upon treatment with lapatinib, either alone or in combination with human serum or EGF. Proteomic profiling revealed 350 differentially expressed proteins (DEPs) in response to lapatinib treatment at concentrations that induced cell growth arrest. Addition of human serum or EGF in combination with lapatinib prevented cell growth inhibition, and this combination treatment returned the expression of ∼93% of DEPs to drug-free levels for both human serum and EGF. Gene ontology enrichment and OncoboxPD pathway activation level analysis showed that lapatinib addition influenced mostly common functional processes revealed in RNA- and protein-based assays. However, a specific feature was observed at the proteome level: addition of lapatinib increased the expression of proteins associated with mitochondrial function and cellular respiration. This feature was not observed when using RNA sequencing data for the same experiments. However, it is consistent with the results of the resazurin test, which showed a 1.8-fold increase in SK-BR-3 cellular respiration upon exposure to lapatinib. Thus, we conclude that enhanced cellular respiration is a novel additional mechanism of action of lapatinib on HER2-positive cancer cells.

Electromyographic comparison of exercises for scapulothoracic muscle activation in men with upper crossed syndrome: A cross-sectional study

ObjectiveThis study aimed to determine the optimal exercise for improving Upper Crossed Syndrome (UCS) using electromyographic (EMG) activity of upper trapezius (UT), middle trapezius (MT), lower trapezius (LT), and serratus anterior (SA) during ten exercises. MethodA cross-sectional study involved 30 male students (mean age: 25.3 ± 2.5 years; height: 176.8 ± 7.2 cm; weight: 77.7 ± 2.5 kg; BMI: 23.8 ± 0.72 kg/m2) with UCS. Participants were selected based on postural assessments (forward head posture ≥44°, rounded shoulder ≥49°, thoracic kyphosis ≥42°). EMG was used to measure activation levels of UT, MT, LT, and SA, and the UT activation ratio relative to MT, LT, and SA during ten exercises. One-way ANOVA was applied for data analysis. ResultsSide-lying external rotation, standing diagonal flexion with Thera-band, and lying prone “V” demonstrated the least UT activity, with the highest MT and LT activation. The standing diagonal flexion with Thera-band elicited the highest SA activity. UT/MT, UT/LT, and UT/SA ratios were less than one in multiple exercises. Significant differences in muscle activation levels and ratios were observed across all exercises (P ≤ 0.05). ConclusionThe findings suggest significant clinical implications for UCS rehabilitation. The identified exercises effectively engage MT and LT while minimizing UT activation, addressing muscular imbalances. Favorable UT/MT, UT/LT, and UT/SA ratios further support these exercises in correcting UCS. These exercises may help counteract the underlying muscular imbalance in UCS by promoting a more balanced activity ratio among the shoulder girdle muscles, potentially improving posture and reducing UCS symptoms.

Liver mechanosignaling as a natural anti-hepatitis B virus mechanism

The mechanisms underlying the natural control of hepatitis B virus (HBV) infection have long been an intriguing question. Given the wide physiological range of liver stiffness and the growing attention to the role of mechanical microenvironment in homeostasis and diseases, we investigated how physical matrix cues impact HBV replication. High matrix stiffness significantly inhibited HBV replication and activated YAP in primary hepatocyte culture system, a key molecule in mechanosignaling. YAP activation notably suppressed HBV transcription and antigen expression. Several YAP-induced genes exhibited strong anti-HBV effects. Single-cell analysis of liver tissue from male individuals with active HBV replication revealed a strong significant negative correlation between YAP signature activation and HBV transcript levels. Intraperitoneal administration of YAP small molecule agonist potently controls HBV in male mouse models. These findings unveil a mechanism that involves the mechanical environment of hepatocytes and YAP to clear hepatotropic viral infection in the liver, providing new perspectives for HBV cure studies and antiviral development.

Harmaline attenuates chemotherapy-induced peripheral neuropathy: Modulation of Nrf-2 pathway and NK-1 receptor signaling

Peripheral neuropathy, resulting from damage to peripheral nerves, manifests as weakness, numbness, and pain, primarily affecting extremities and significantly impairing quality of life, especially in the elderly. Current treatments often entail severe side effects, necessitating the exploration of alternative therapies. Harmaline, a β-carboline alkaloid derived from Peganum harmala, exhibits promising antioxidant and anti-inflammatory properties. This study aimed to assess the efficacy of harmaline in a vincristine-induced mouse model of peripheral neuropathy. Swiss albino mice received vincristine (0.1 mg/kg, i.p.) for 10 days to induce neuropathy. Harmaline (5 and 10 mg/kg, i.p.) was administered 30 min before vincristine and continued until day 14 to evaluate its protective effects. Behavioral assessments were conducted on days 7 and 14. Vincristine treatment significantly heightened sensitivity to cold, measured by cold plate and acetone drop tests, and to heat, assessed via the hot plate test, while also impairing motor coordination. Biochemical analyses revealed decreased levels of GSH and Nrf-2, alongside elevated TBARS and IL-1β levels in sciatic nerve tissue. Harmaline administration markedly alleviated both behavioral and biochemical alterations induced by vincristine, with the 10 mg/kg dose exhibiting the most pronounced effects. Notably, harmaline treatment elevated GSH and Nrf-2 levels while reducing TBARS and IL-1β. Furthermore, substance-P treatment reversed the protective effects of harmaline, implicating the NK-1 receptor in its mechanism of action. In conclusion, harmaline demonstrates significant potential in mitigating vincristine-induced peripheral neuropathy by reducing oxidative stress through Nrf-2 activation and lowering IL-1β levels, likely via NK-1 receptor inhibition.

Ebola Virus Infection of Flt3-Dependent, Conventional Dendritic Cells and Antigen Cross-presentation Leads to High Levels of T-Cell Activation.

Previous studies have described that Ebola virus (EBOV) infection of human monocyte-derived dendritic cells (moDCs) inhibits dendritic cell (DC) maturation, resulting in poor T-cell activation. However, it is unknown how other DC subsets distinct from moDCs respond to EBOV infection. To better understand how DCs initiate T-cell activation during EBOV infection, we assessed the response of conventional mouse DCs (cDCs) to EBOV infection utilizing a recombinant EBOV expressing the model antigen ovalbumin. In contrast to moDCs, mouse cDC2s and cDC1s were poorly infected with EBOV but were highly activated. DCs were able to prime CD8 T cells via cross-presentation of antigens obtained from cell debris of EBOV-infected cells. EBOV infection further enhanced DC cross-presentation. Our findings indicate that EBOV infection of cDCs results in activation rather than inhibition, leading to high levels of T-cell activation. With that we propose a mechanistic explanation for the excess T-cell activation observed in human Ebola virus disease.

Functional activation of the AKT-mTOR signalling axis in a real-world metastatic breast cancer cohort.

Mutations of the PIK3CA/AKT/mTOR axis are common events in metastatic breast cancers (MBCs). This study was designed to evaluate the extent to which genetic alterations of the PIK3CA/AKT/mTOR can predict protein activation of this signalling axis in MBCs. Molecular profiles were generated by CLIA-certified laboratories from a real-world evidence cohort of 171 MBC patients. Genetic alterations of the PIK3CA pathway were measured using next-generation sequencing. Activation levels of AKT and downstream signalling molecules were quantified using two orthogonal proteomic methods. Protein activity was correlated with underlying genomic profiles and response to CDK4/6 inhibition in combination with endocrine treatment (ET). Oncogenic alterations of the PIK3CA/AKT/PTEN pathway were identified in 49.7% of cases. Genomic profiles emerged as poor predictors of protein activity (AUC:0.69), and AKT phosphorylation levels mimicked those of mutant lesions in 76.9% of wild-type tumours. High phosphorylation levels of the PI3K/AKT/mTOR downstream target p70S6 Kinase (T389) were associated with shorter PFS in patients treated with CDK4/6 inhibitors in combination with ET (HR:4.18 95%CI:1.19-14.63); this association was not seen when patients were classified by mutational status. Phosphoprotein-based measurements of drug targets and downstream substrates should be captured along with genomic information to identify MBCs driven by the PI3K/AKT/mTOR signalling.

Tailoring a CRISPR/Cas-based Epigenome Editor for Programmable Chromatin Acylation and Decreased Cytotoxicity.

Engineering histone acylation states can inform mechanistic epigenetics and catalyze therapeutic epigenome editing opportunities. Here, we developed engineered lysine acyltransferases that enable the programmable deposition of acetylation and longer-chain acylations. We show that targeting an engineered lysine crotonyltransferase results in weak levels of endogenous enhancer activation yet retains potency when targeted to promoters. We further identify a single mutation within the catalytic core of human p300 that preserves enzymatic activity while substantially reducing cytotoxicity, enabling improved viral delivery. We leveraged these capabilities to perform single-cell CRISPR activation screening and map enhancers to the genes they regulate in situ. We also discover acylation-specific interactions and find that recruitment of p300, regardless of catalytic activity, to prime editing sites can improve editing efficiency. These new programmable epigenome editing tools and insights expand our ability to understand the mechanistic role of lysine acylation in epigenetic and cellular processes and perform functional genomic screens.

Extracellular DNA from the blood plasma of patients with schizophrenia stimulates the TLR9-NF-kB signaling pathway in cultured human lymphocytes

Schizophrenia is a mental illness of complex etiology. Recently, there has been increased interest in the role of the immune system in the pathophysiology of mental disorders. The concept of neuroinflammation in neurodevelopmental disorders is gaining widespread interest, including the role of Toll-like receptors.Schizophrenia is associated with an increase in the concentration of cfDNA in human blood, and the composition of cfDNA fragments changes significantly compared to cellular DNA: GC-rich fragments of the ribosomal repeat accumulate and base oxidation occurs. Similar changes, but less pronounced, also occur for cfDNA from healthy donors.To confirm the hypothesis about the possible participation of cfDNA in the inflammation induction, we studied the effect of cfDNA samples on cultured mononuclear cells.Unlike cellular DNA, cfDNA(SZ) and cfDNA(K) stimulate transcription of the TLR9 gene in mononuclear cells. After 1 hour the amount of TLR9 RNA increases by 2.9 and 3.3 times compared to the control. After 24 hours, the TLR9 RNA level decreases slightly, but is still 2-3 times higher than the control level. After 1 hour, TLR9 protein increases by 1.5 and 1.7 times, respectively, and further increased after 24h of culture.An increase TLR9 protein expression correlates with an increase of the transcription factor NF-kB in lymphocytes and is accompanied by an increase in proinflammatory cytokine IL8 RNA, the transcription of IL8 is controlled by the NF-kB factor.Thus, cfDNA(SZ) and cfDNA(K) stimulate the TLR9-NF-kB-proinflammatory cytokine signaling pathway in lymphocytes. The effect of cfDNA also depends on the concentration of these fragments in the extracellular environment. Since the concentrations of cfDNA in the blood of patients with schizophrenia are significantly increased compared to healthy donors, we should expect a much higher level of activation of the TLR9-NF-kB signaling pathway in the body cells of sick people.Samples of cfDNA from patients with schizophrenia have a pronounced biological effect on cells of the immune system, stimulating the synthesis of pro-inflammatory cytokines by activating the TLR9-NF-kB-proinflammatory cytokines signaling pathway. High levels of cfDNA in blood plasma may be one of the reasons for the induction and maintenance of low-level inflammation in schizophrenia.

Characterization of Patient Activation among Childhood Cancer Survivors in the St. Jude Lifetime Cohort Study (SJLIFE).

Patient activation describes a willingness to take action to manage health and is associated with health outcomes. The purpose of this study was to characterize patient activation and its association with psychological outcomes and health behaviors in childhood cancer survivors. Participants were from the St. Jude Lifetime Cohort Study (SJLIFE). Activation levels (1-4, 4 = highest activation) were measured with the Patient Activation Measure (PAM). Psychological outcomes and health behaviors were obtained via self-report. Cognitive function was assessed by trained examiners. ANOVA or chi-squared tests were utilized to assess group-level differences in activation. Multivariable regression models were used to assess associations between PAM scores and outcomes of interest. Among 2708 survivors and 303 controls, more survivors endorsed lower activation levels than the controls (11.3 vs. 4.7% in level 1) and fewer survivors endorsed the highest level of activation than the controls (45.3 vs. 61.5% in level 4). Not endorsing depression (OR: 2.37, 95% CI 1.87-2.99), anxiety (OR: 2.21, 95% CI 1.73-2.83), and somatization symptoms (OR: 1.99, 95% CI 1.59-2.50), general fear (OR: 1.45, 95% CI 1.23-1.71) and body-focused (OR: 2.21, 95% CI 1.83-2.66), cancer-related worry, and physical (OR: 2.57, 95% CI 2.06-3.20) and mental (OR: 2.08, 95% CI 1.72-2.52) HRQOL was associated with higher levels of activation. Lower activation was associated with not meeting physical activity guidelines (OR: 2.07, 95% CI 1.53-2.80). Survivors endorsed lower activation levels than peers. Interventions to improve physical and psychological health outcomes could leverage these results to identify survivors who benefit from support in patient activation.

Reduction characteristics and mechanism of mechanically activated iron ore powder by lignin

As a primary constituent of renewable biomass fuel, lignin can be effectively utilized as a reducing agent in the ironmaking process, thereby significantly mitigating CO2 emissions throughout the procedure. This study meticulously evaluates the impact of lignin on the reduction of iron ore powder across diverse levels of mechanical activation through thermogravimetric analysis. It elucidates the intricate reduction mechanism at play. The reduction process is characterized by two pivotal stages: the initial reduction of pyrolysis gases followed by the reduction of fixed carbon, which predominantly drives the transformation of iron ore powder. While mechanical activation exhibits a negligible influence on the first stage, it exerts a pronounced effect on the second. An extended activation time elevates the depth of reduction in the latter stage. Furthermore, the heating rate plays a crucial role in the reduction process, with slower rates favoring the reduction of pyrolysis gases and faster rates boosting carbon fixation reduction. Enhanced activation durations lead to improve linear regression fits for the reduction reaction data. Utilizing the carbon gasification model for iron ore powder treated with 480 min of activation yields a calibration variance of 0.99, with the derived activation energy of 48.75 kJ/mol aligning closely with empirical values. This research provides a thorough analysis of the reduction kinetics and mechanism, underscoring the transformative potential of lignin as a reducer in ironmaking processes, thus contributing to the development of sustainable, low-carbon technologies.

The Impact of Different Telerehabilitation Methods on Peripheral Muscle Strength and Aerobic Capacity in COPD Patients: A Randomized Controlled Trial.

Lung diseases have profound effects on the aging population. We aimed to hypothesize and investigate the effect of remote pulmonary telerehabilitation and motor imagery (MI) and action observation (AO) methods on the clinical status of elderly chronic obstructive pulmonary disease (COPD) patients. Twenty-six patients were randomly assigned to pulmonary telerehabilitation (PtR) or cognitive telerehabilitation (CtR) groups. The programs were carried out 3 days a week for 8 weeks. The 6-min walk test (6MWT), modified Medical Research Council dyspnea score, blood lactate level (BLL), measurement of peripheral muscle strength (PMS), and electromyography activation levels of accessory respiratory muscles were the main outcomes. There was a statistically significant improvement (p < 0.05) in both groups in the 6MWT distance and in secondary results, except for BLL. Generally, in the mean muscle activity obtained from the electromyography measurement after the program, there were statistically significant increases in the PtR group and decreases in the CtR group (p < 0.05). There was a statistically significant increase in PMS in both groups. An active muscle-strengthening program has the same benefits as applying the muscle-strengthening program to the patient as MI and AO. CtR can be a powerful alternative rehabilitation method in respiratory patients who cannot tolerate active exercise programs.

Miniaturized protein profiling permits targeted signaling pathway analysis in individual circulating tumor cells to improve personalized treatment

BackgroundTraditional genomic profiling and mutation analysis of single cells like Circulating Tumor Cells (CTCs) fails to capture post-translational and functional alterations of proteins, often leading to limited treatment efficacy. To overcome this gap, we developed a miniaturized ‘protein analysis on the single cell level’ workflow—baptized ZeptoCTC. It integrates established technologies for single-cell isolation with sensitive Reverse Phase Protein Array (RPPA) analysis, thus enabling the comprehensive assessment of multiple protein expression and activation in individual CTCs.MethodsThe ZeptoCTC workflow involves several critical steps. Firstly, individual cells are labeled and isolated. This is followed by cell lysis and the printing of true single cell lysate preparations onto a ZeptoChip using a modified micromanipulator, CellCelector™. The printed lysates then undergo fluorescence immunoassay RPPA protein detection using a ZeptoReader. Finally, signal quantification is carried out with Image J software, ensuring precise measurement of multiple protein levels.ResultsThe efficacy of ZeptoCTC was demonstrated through various applications. Initially, it was used for measuring EpCAM protein expression, a standard marker for CTC detection, revealing higher levels in single MCF-7 over MDA-MB-231 tumor cells. Furthermore, in Capivasertib (Akt-inhibitor)-treated MCF-7 single cells, ZeptoCTC detected a 2-fold increase in the pAkt/Akt ratio compared to control cells, and confirmed co-performed bulk-cell western blot analysis results. Notably, when applied to individual CTCs from metastasized breast cancer patients, ZeptoCTC revealed significant differences in protein activation levels, particularly in measured pAkt and pErk levels, compared to patient-matched WBCs. Moreover, it successfully differentiated between CTCs from patients with different Akt1 genotypes, highlighting its potential to determine the activation status of druggable cancer driving proteins for individual and targeted treatment decision making.ConclusionsThe ZeptoCTC workflow represents a valuable tool in single cell cancer research, crucial for personalized medicine. It permits detailed analysis of key proteins and their activation status of targeted, cancer-driven signaling pathways in single cell samples, aiding in understanding tumor response, progression, and treatment efficacy beyond bulk analysis. The method significantly advances clinical investigations in cancer, improving treatment precision and effectiveness. The workflow will be applicable to protein analysis on other types of single cells like relevant in stem cell, neuropathology and hemopoietic cell research.

Effects of seatback angles on passenger kinematics among the longitudinal braking scenario

With the development of autonomous vehicles and zero gravity seats, the passengers are more likely to sit in their preferred postures, such as the high reclined positions. This study aims to analyse the passenger kinematics under different seatback angles by volunteer experiments, which is beneficial for future smart restraint system development. For this study, four volunteers were selected to participate in the longitudinal braking experiments from 80 km/h to 0 km/h, and each volunteer repeated 3 times. Among the tests, three seatback angles (25°, 45°, and 60° from the vertical) were introduced, while the seat pan angles were the same. The seatbelt forces, as well as the volunteers’ motions were recorded among the experiments. The experimental results indicated that both head displacement and the first thoracic vertebrae (T1) displacement increased gradually with the increase of the seatback angle. The average T1 displacements for four volunteers under 25° seatback angle were between 180.2 mm to 245.5 mm, while the T1 displacements for 45° seatback angle and 60° seatback angle were between 291.4 mm to 374.3 and 366.2 mm to 444.5 mm respectively. Both shoulder belt force and lap belt force increased with the increase of seatback angle, except for the 60° case of No.1 volunteer, which might due to the muscle activation level difference. In this study, there was no significant correlation between the seatback inclination angle and the amount of seat belt outlet amount. The study is beneficial for active human model validation and future smart restraint system development.

Serum inflammatory biomarkers associated with disease severity and response to dupilumab treatment in bullous pemphigoid: A cluster analysis

BackgroundDupilumab, a novel therapy targeting the T helper (Th) 2-mediated inflammation, is showing clinical benefits in treating bullous pemphigoid (BP). However, limited research investigated the serum biomarkers that reflect the inflammation alterations throughout the disease course. ObjectivesTo explore the changes of the serum inflammatory biomarkers under dupilumab therapy in BP and establish their correlations with disease severity and clinical outcomes. MethodsThis exploratory study evaluated serum samples from 40 patients with BP at baseline, 30 of these patients following 16-week dupilumab therapy, and 20 senior healthy controls. Serum levels of 29 cytokines and chemokines were quantified using the Magnetic Luminex Assay. ResultsTwo distinct clusters based on serum inflammatory profiles were identified. The first cluster, characterized by elevated levels of inflammatory activation, exhibited worse disease severity and poorer remission outcomes. Following the 16-week dupilumab therapy regimen, a significant suppression of Th2-mediated inflammation in the serum was observed, alongside a relative upregulation of Th1 responses. Patients treated with adjuvant systemic steroids exhibited an enhanced suppression of B cell activating factor compared to those receiving dupilumab alone. Significant correlations were unveiled between Th2 biomarkers and clinical scores, eosinophil counts, and anti-BP180 immunoglobulin G levels. Baseline levels of CCL18, Periostin, interleukin (IL)-6, and IL-16 constitute an optimal combination to distinguish between inflammatory clusters. ConclusionsCluster analysis of serum inflammatory biomarkers provided novel insights into the heterogeneity of the inflammation profiles in BP. Baseline levels of CCL18, Periostin, IL-6, IL-16 emerged as effective predictors for disease severity and therapy response to dupilumab.

Effect of morningness-eveningness chronotype on academic performance of undergraduate students

BackgroundCircadian rhythms are crucial for physiological functioning, and they vary among people. There are three distinct chronotypes: morning, evening, and neither type. Morning types experience their highest level of activation during the early part of the day and tend to be more conscientious and focused on achieving their goals. Evening types, on the other hand, reach their peak performance during the latter portion of the day and exhibit a higher level of intelligence. University class schedules may occasionally clash with evening-type individuals’ circadian preferences, potentially impacting their academic performance in comparison to their morning-type peers. Therefore, this study was done to investigate if morningness-eveningness can affect college students’ academic performance as sleeping late or sleep deprivation can lead to disease in the young population.Materials and methodsA sample of 100 collegiate students aged 18–30 years were recruited via convenience sampling from Jamia Hamdard, Delhi, and informed consent was obtained from the subjects. The morningness-eveningness questionnaire (MEQ) was used to assess students’ chronotype, and the mean of the last three academic years percentage was used to assess the academic performance of the students.ResultsThe total academic performance score was better in the morning category (75.53 ± 7.28) as compared to the evening (66.42 ± 10.08) and intermediate (73.72 ± 6.46) categories. There was a low degree of positive correlation between total academic performance and TMEQ (total morning-evening questionnaire) score (ρ = 0.204).ConclusionThe academic performance of morning chronotype students was better than that of evening chronotype students.

Scaleable production of highly loaded protein nanoparticles for immune modulation

Immune modulation and desensitization is a growing field of research and clinical investigation that requires precise delivery of antigens to immune system cells. Nanoparticles (NPs) have emerged as excellent candidates for antigen delivery, particularly in immune desensitization applications. NP-encapsulated protein antigens enable the delivery of protein and co-encapsulated adjuvant to antigen-presenting cells without systemic exposure and allergic response. Here, we show a method for producing poly(lactide-co-glycolide) (PLG) NPs in an efficient, high-yield, and large-scale inhomogeneous precipitation process. The process enables the production of compositionally complex PLG NPs containing protein while also incorporating DNA and E. coli phospholipids as integral adjuvants in the NP vehicle. Orally delivered PLG NPs activate the murine immune system, and encapsulated peanut allergen protein elicits approximately 10-fold lower levels of basophil activation than does unencapsulated protein in basophils isolated from peanut-allergic patients. This efficacy and safety evidence makes these PLG NPs excellent candidates for clinical applications.

Consequences of the perivascular niche remodeling for tumoricidal T-cell trafficking into metastasis of ovarian cancer.

The treatment-induced activation level within the perivascular tumor microenvironment (TME) that supports T-cell trafficking and optimal T-cell differentiation is unknown. We investigated the mechanisms by which inflammatory responses generated by tumor-specific T cells delivered to ovarian tumor-bearing mice alone or after oncolytic vaccinia virus-driven immunogenic cancer cell death affect antitumor efficacy. Analyses of the perivascular TME by spatially resolved omics technologies revealed reduced immunosuppression and increased tumoricidal T-cell trafficking and function after moderate inflammatory responses driven by a CXCR4 antagonist-armed oncolytic virus. Neither weak nor high inflammation created a permissive TME for T-cell trafficking. Notably, treatment-mediated differences in T-cell effector programs acquired within the perivascular TME contrasted with comparable antigenic priming in the tumor-draining lymph nodes regardless of the activation mode of antigen-presenting cells. These findings provide new insights into combinatorial treatment strategies that enable tumor-specific T cells to overcome multiple barriers for enhanced trafficking and control of tumor growth. .