Iron status and sarcopenia-related traits: a bi-directional Mendelian randomization study.

Although serum iron status and sarcopenia are closely linked, the presence of comprehensive evidence to establish a causal relationship between them remains insufficient. The objective of this study is to employ Mendelian randomization techniques to clarify the association between serum iron status and sarcopenia. We conducted a bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationship between iron status and sarcopenia. MR analyses were performed using inverse variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were conducted to verify the reliability of the causal association results. Then, we harvested a combination of SNPs as an integrated proxy for iron status to perform a MVMR analysis based on IVW MVMR model. UVMR analyses based on IVW method identified causal effect of ferritin on appendicular lean mass (ALM, ß = - 0.051, 95% CI - 0.072, - 0.031, p = 7.325 × 10-07). Sensitivity analyses did not detect pleiotropic effects or result fluctuation by outlying SNPs in the effect estimates of four iron status on sarcopenia-related traits. After adjusting for PA, the analysis still revealed that each standard deviation higher genetically predicted ferritin was associated with lower ALM (ß = - 0.054, 95% CI - 0.092, - 0.015, p = 0.006). Further, MVMR analyses determined a predominant role of ferritin (ß = - 0.068, 95% CI - 0.12, - 0.017, p = 9.658 × 10-03) in the associations of iron status with ALM. Our study revealed a causal association between serum iron status and sarcopenia, with ferritin playing a key role in this relationship. These findings contribute to our understanding of the complex interplay between iron metabolism and muscle health.

Integrative analysis of co-expression pattern of solute carrier transporters reveals molecular subtypes associated with tumor microenvironment hallmarks and clinical outcomes in colon cancer.

Recent findings have suggested that solute carrier (SLC) transporters play an important role in tumor development and progression, and alterations in the expression of individual SLC genes are critical for fulfilling the heightened metabolic requirements of cancerous cells. However, the global influence of the co-expression pattern of SLC transporters on the clinical stratification and characteristics of the tumor microenvironment (TME) remains unexplored. In this study, we identified five SLC gene subtypes based on transcriptome co-expression patterns of 187 SLC transporters by consensus clustering analysis. These subtypes, which were characterized by distinct TME and biological characteristics, were successfully employed for prognostic and chemotherapy response prediction in colon cancer patients, as well as demonstrated associations with immunotherapy benefits. Then, we generated an SLC score model comprising 113 genes to quantify SLC gene co-expression patterns and validated it as an independent prognostic factor and drug response predictor in several independent colon cancer cohorts. Patients with a high SLC score possessed distinct characteristics of copy number variation, genomic mutations, DNA methylation, and indicated an SLC-S2 subtype, which was characterized by strong stromal cell infiltration, stromal pathway activation, poor prognosis, and low predicted fluorouracil and immunotherapeutic responses. Furthermore, the analysis of the Cancer Therapeutics Response Portal database revealed that inhibitors targeting PI3K catalytic subunits could serve as promising chemosensitizing agents for individuals exhibiting high SLC scores. In conclusion, the co-expression patterns of SLC transporters aided the disease classification, and the SLC score proved to be a reliable tool for distinguishing SLC gene subtypes and guiding precise treatment in patients with colon cancer.

Co-expression pattern of SLC transporter genes associated with the immune landscape and clinical outcomes in gastric cancer.

Solute carrier (SLC) transporters play a dual role in the occurrence and progression of tumours by acting as both suppressors and promoters. However, the overall impact of SLC transcriptome signatures on the tumour microenvironment, biological behaviour and clinical stratification of gastric cancer has not been thoroughly investigated. Therefore, we comprehensively analysed the expression profiles of the SLC transporter family members to identify novel molecular subtypes in gastric cancer. We identified two distinct SLC subtypes, SLC-S1 and SLC-S2, using non-negative matrix factorization. These subtypes were markedly linked with the tumour microenvironment landscape, biological pathway activation and distinct clinical features of gastric cancer. Furthermore, a new scoring model, the SLC score, was developed to quantify the SLC subtypes. High SLC scores indicated a pattern of 'SLC-S2', characterized by stromal infiltration and activation, poor prognosis and insensitivity to chemotherapy and immunotherapy, but high sensitivity to imatinib. The SLC score could serve as a supplement to the Tumour Node Metastasis (TNM) staging system to guide personalized treatment strategies and predict prognosis for patients with gastric cancer.

Expression pattern of secretory-cell-related transcriptional signatures in colon adenocarcinomas defines tumor microenvironment characteristics and correlates with clinical outcomes.

Despite the connection of secretory cells to distinct mucus-containing colon cancer histological subtypes and the interaction of secretory cells with immune cells in the pathogenesis of intestinal inflammatory diseases, whether the secretory cell signatures are associated with tumor microenvironment (TME) heterogeneity and can aid in colon cancer patient classification have not been investigated. Here, by performing the principal component analysis and consensus clustering analysis, we identified four distinct expression patterns based on secretory cell signatures which were significantly associated with different clinical behaviors, TME landscape, pathway activation, genomic mutations, and DNA methylation characteristics. Subsequently, a 'SCS score' model was constructed. The high SCS score indicated a pattern of 'secretory cell subtype 2', which was characterized by stromal infiltration and activation, and predicted poor prognosis and low sensitivity to fluorouracil-based chemotherapy and immunotherapy, but high sensitivity to PI3K catalytic subunit inhibitors. In conclusion, our study comprehensively uncovered the tumor heterogeneity related to secretory cell signature expression patterns. Moreover, the SCS score can supplement routine histopathological assessments to guide personalized therapeutic strategies in colon cancer patients.

[Safety and efficacy of different doses of tranexamic acid in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion].

Objective: To investigate the safety and efficacy of different doses of tranexamic acid (TXA) in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion by a prospective clinical study. Methods: The middle-aged and elderly patients with cervical spondylotic myelopathy, who were admitted between January 2020 and January 2022 and scheduled to undergo posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion, were studied as the research subjects. Among them, 165 patients met the selection criteria and were included in the study. The patients were allocated into 3 groups ( n=55) by random double-blind lottery. Groups A and B were given intravenous infusion of TXA at 30 minutes before operation according to the standards of 15 and 30 mg/kg, respectively; and group C was given normal saline in the same way. There was no significant difference in gender, age, body mass index, and preoperative D-dimer, hemoglobin (Hb), and hematocrit (HCT) between groups ( P>0.05). The intraoperative bleeding, intraoperative blood transfusion, postoperative drainage volume, drainage days, and postoperative hospital stay were recorded. The Hb, HCT, and D-dimer were compared before operation and at 3 days after operation. Venous ultrasonography of the lower extremities was taken after operation to assess thrombosis; and the postoperative hematoma and epilepsy were also observed. Results: All operations were successfully completed, and the incisions healed by first intention. The differences in intraoperative bleeding volume, postoperative drainage volume, drainage days, and postoperative hospital stay between groups were significant ( P<0.05). The above indexes were significantly less in group B than in groups A and C. During operation, 14 patients in group A and 23 patients in group C were transfused, and no patient in group B had blood transfusions. Compared with groups A and C, the blood transfusion volume in group B significantly decreased ( P<0.05), and the difference between groups A and C was not significant ( P>0.05). There was no significant difference in the differences of D-dimer, Hb, and HCT before and after operation between groups ( P>0.05). At 5 days after operation, the venous ultrasonography of the lower extremities showed that the 2 cases of intermuscular venous thrombosis occurred in groups A, B, and C, respectively. No hematoma or epilepsy occurred after operation. Conclusion: The application of 15 and 30 mg/kg TXA in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion can reduce intraoperative bleeding and postoperative drainage volume, postoperative drainage days, and postoperative hospital stay. And application of 30 mg/kg TXA can reduce intraoperative blood transfusion, without increasing the risk of lower extremity venous thrombosis, hematoma, and epilepsy.

Modeling multi-opinion propagation in complex systems with heterogeneous relationships via Potts model on signed networks.

This paper investigates how the heterogenous relationships around us affect the spread of diverse opinions in the population. We apply the Potts model, derived from condensed matter physics on signed networks, to multi-opinion propagation in complex systems with logically contradictory interactions. Signed networks have received increasing attention due to their ability to portray both positive and negative associations simultaneously, while the Potts model depicts the coevolution of multiple states affected by interactions. Analyses and experiments on both synthetic and real signed networks reveal the impact of the topology structure on the emergence of consensus and the evolution of balance in a system. We find that, regardless of the initial opinion distribution, the proportion and location of negative edges in the signed network determine whether a consensus can be formed. The effect of topology on the critical ratio of negative edges reflects two distinct phenomena: consensus and the multiparty situation. Surprisingly, adding a small number of negative edges leads to a sharp breakdown in consensus under certain circumstances. The community structure contributes to the common view within camps and the confrontation (or alliance) between camps. The importance of inter- or intra-community negative relationships varies depending on the diversity of opinions. The results also show that the dynamic process causes an increase in network structural balance and the emergence of dominant high-order structures. Our findings demonstrate the strong effects of logically contradictory interactions on collective behaviors, and could help control multi-opinion propagation and enhance the system balance.

Interpretable tree-based ensemble model for predicting beach water quality.

Tree-based machine learning models based on environmental features offer low-cost and timely solutions for predicting microbial fecal contamination in beach water to inform the public of the health risk. However, many of these models are black boxes that are difficult for humans to understand, which may cause severe consequences such as unexplained decisions and failure in accountability. To develop interpretable predictive models for beach water quality, we evaluate five tree-based models, namely classification tree, random forest, CatBoost, XGBoost, and LightGBM, and employ a state-of-the-art explanation method SHAP to explain the models. When tested on the Escherichia coli (E. coli) concentration data collected from three beach sites along Lake Erie shores, LightGBM, followed by XGBoost, achieves the highest averaged precision and recall scores. For all three sites, both models suggest lake turbidity as the most important predictor, and elucidate the crucial role of accurate local data of wave height and rainfall in the model development. Local SHAP values further reveal the robustness of the importance of lake turbidity as its SHAP value increases nearly monotonically with its value and is minimally affected by other environmental factors. Moreover, we found an intriguing interaction between lake turbidity and day-of-year. This work suggests that the combination of LightGBM and SHAP has a promising potential to develop interpretable models for predicting microbial water quality in freshwater lakes.

Thrombin Aggravates Hypoxia/Reoxygenation Injury of Cardiomyocytes by Activating an Autophagy Pathway-Mediated by SIRT1.

BACKGROUND Acute myocardial infarction is the leading cause of mortality among adults worldwide. The present study aimed to investigate the role and mechanism of thrombin and SIRT1 in hypoxia/reoxygenation (H/R) injury. MATERIAL AND METHODS H9c2 cardiomyocytes were used to create an H/R model to simulate in vivo ischemia/reperfusion injury. The MTT assay was used to measure cell viability, qRT-PCR was used to detect the level of SIRT1, thrombin, and PAR-1, and western blot analysis was conducted for evaluation of thrombin, PAR-1, SIRT1, LC3I, LC3II, and Beclin1. ELISA was applied for determination of IL-1ß, IL-6, TNF-alpha, MMP-9, and ICAM-1. After the establishment of the H/R model, superoxide dismutase (SOD) activity was evaluated by the xanthine oxidase method, malondialdehyde content was detected by thiobarbituric acid assay, and reactive oxygen species generation was measured by CM-H2DCFDA. RESULTS The findings showed that thrombin enhanced inflammatory factor secretion and oxidative stress but inhibited cell viability in H/R-injured cardiomyocytes. We also observed that thrombin promoted autophagy in H/R-injured cardiomyocytes. In addition, thrombin enhanced the upregulation of SIRT1 expression by H/R. However, it was found that inhibition of SIRT1 could suppress the effect of thrombin on inflammatory factor secretion, oxidative stress, and cell viability. Moreover, downregulation of SIRT1 suppressed the inhibitory effect of thrombin on autophagy in H/R injury. CONCLUSIONS Thrombin aggravates H/R injury of cardiomyocytes by activating an autophagy pathway mediated by SIRT1. These findings might provide a potential target therapy for the treatment of ischemia/reperfusion injury in future clinical work.

A renewed understanding of anti-human globulin reagents: interference constraints using an optimization method in pretransfusion compatibility tests.

Anti-human globulin (AHG) reagents are widely applied in pretransfusion compatibility tests. The accuracy of detection with AHG reagents is mainly affected by irregular antibodies or cold agglutinins in blood samples, which are related to the human complement system. Although much has been written about various types and applications of AHG reagents, their characteristics, interference factors and optimal selection in pretransfusion compatibility tests still need to be further clarified. Here, we review clinical practice and basic studies that describe each AHG reagent, summarize the advantages and disadvantages of using different AHG reagents in the presence of cold agglutinins or complement-fixing antibodies, explore the potential mechanisms by which the complement system influences detection with AHG reagents and address the question of how to optimally select AHG reagents for clinically significant antibody detection.

Unexpected food web responses to low dissolved oxygen in an estuarine fjord.

In coastal marine ecosystems, the depletion of dissolved oxygen can cause behavioral and distributional shifts of organisms and thereby alter ecological processes. We used the spatiotemporal variation in the onset and intensity of low dissolved oxygen in Hood Canal, Washington, USA, to investigate consequences of seasonally reduced oxygen on fish-zooplankton predator-prey interactions. By simultaneously monitoring densities of zooplankton (primarily the euphausiid; Euphausia pacifica) and zooplanktivorous fish (Pacific herring, Clupea pallasii, and Pacific hake, Mercluccius productus), and the feeding of zooplanktivorous fish, we could separate the effects of dissolved oxygen on fish-zooplankton interactions from other seasonal changes. We expected that fish predators (especially Pacific herring) would be less abundant and have lower feeding rates when oxygen levels declined below biological thresholds, and that this would result in increased zooplankton abundance in areas with lowest dissolved oxygen. However, these expectations were not borne out. Overall, there was mixed evidence for an effect of dissolved oxygen on many of our response variables, and when effects were detected, they were frequently in the opposite direction of our expectations. Specifically, the pelagic fish community became more abundant (as measured by increasing acoustic backscatter), which was particularly pronounced for Pacific herring. Zooplankton had weak evidence for a response to dissolved oxygen, but the direction was negative instead of positive. Although predator feeding composition was unrelated to dissolved oxygen, stomach fullness (an index of feeding intensity) of Pacific herring declined, as per our expectations. These unexpected findings highlight the importance of in situ measurements of multiple aspects of predator-prey linkages in response to environmental stress to enhance our ability to predict ecological consequences of declining oxygen.

Improvement of Asia-Pacific colorectal screening score and evaluation of its use combined with fecal immunochemical test.

BACKGROUND: The Asia-Pacific Colorectal Screening (APCS) score is effective to screen high-risk groups of advanced colorectal neoplasia (ACN) patients but needs revising and can be combined with the fecal immunochemical test (FIT). This paper aimed to improve the APCS score and evaluate its use with the FIT in stratifying the risk of ACN. METHODS: This prospective and multicenter study enrolled 955 and 1201 asymptomatic Chinese participants to form the derivation and validation set, respectively. Participants received the risk factor questionnaire, colonoscopy and FIT. Multiple logistic regression was applied, and C-statistic, sensitivity and negative predictive values (NPVs) were used to compare the screening efficiency. RESULTS: A modified model was developed incorporating age, body mass index (BMI), family history, diabetes, smoking and drinking as risk factors, stratifying subjects into average risk (AR) or high risk (HR). In the validation set, the HR tier group had a 3.4-fold (95% CI 1.8-6.4) increased risk for ACN. The C-statistic for the modified score was 0.69 ± 0.04, and 0.67 ± 0.04 for the original score. The sensitivity of the modified APCS score combined with FIT for screening ACN high-risk cohorts was 76.7% compared with 36.7% of FIT alone and 70.0% of the modified APCS score alone. The NPVs of the modified score combined with FIT for ACN were 98.0% compared with 97.0% of FIT alone and 97.9% of the modified APCS score alone. CONCLUSIONS: The modified score and its use with the FIT are efficient in selecting the HR group from a Chinese asymptomatic population.

The synonymous 903C>G mutation in the alpha 1,4-galactosyltransferase gene in a Chinese woman with habitual abortion: A case report.

RATIONALE: Habitual abortion is caused by complex and diverse factors, such as genetic factors, immune factors, endocrine factors, viruses, bacterial infections, and so on. Allogeneic antibodies, generated due to blood-group incompatibilities between a female and her fetus, are sometimes important for habitual abortion. PATIENT CONCERNS: A 26-year-old woman had undergone abortions 3 times in July 2015 (17 weeks pregnant), March 2017 (15 weeks of gestation) and February 2018 (16 weeks pregnant) before she came to the Reproductive Medicine Center of our hospital for prenatal examinations without pregnancy. DIAGNOSES: Unexplained habitual abortion. INTERVENTIONS: A series of serological tests and nucleotide sequence of 1,4-galactosyltransferase (A4GALT) gene were performed. OUTCOMES: The patient was the rare p phenotype in P1P blood system and the patient's habitual abortion was caused by anti-PP1P antibody which was generated naturally in persons with p phenotype. There was a mutation (903C>G, CCC>CCG) in the 3rd exon of A4GALT gene, which is likely a significant contributor to p phenotype. LESSONS: This is the first case of habitual abortion caused by p phenotype due to independent 903C>G homozygous mutation with no similar record reported before, which indicates that it is a new class of mutation that leads to p phenotype.

Improvement of GH10 family xylanase thermostability by introducing of an extra α-helix at the C-terminal.

Xylanase is an important enzyme in industrial applications, which usually require the enzyme to maintain activity in high-temperature condition. In this study, a GH10 family xylanase XynAF0 from a thermophilic composting fungus, Aspergillus fumigatus Z5, was investigated to determine its thermostable mechanism. XynAF0 showed excellent thermostability, which could maintain 50% relative activity after incubation for 1 h at 70 °C. The homologous modeling structure of XynAF0 was constructed and an α-helix composed of poly-threonine has been found in the linker region between the catalytic domain and the carbohydrate-binding module domain. Both the molecular dynamics simulation and the biochemical experiments proved that the α-helix plays an important role in the thermostability of XynAF0. Introducing of this poly-threonine region to the C-terminus of another GH10 family xylanase improved its thermostability. Our results indicated that the poly-threonine α-helix at the C-terminus of the catalytic domain was important for improving the thermophilic of GH10 family xylanases, which provides a new strategy for the thermostability modification of xylanases.

Subregional differences in groundfish distributional responses to anomalous ocean bottom temperatures in the northeast Pacific.

Although climate-induced shifts in fish distribution have been widely reported at the population level, studies that account for ontogenetic shifts and subregional differences when assessing responses are rare.In this study, groundfish distributional changes in depth, latitude, and longitude were assessed at different size classes by species within nine subregions. We examined large, quality-controlled datasets of depth-stratified-random bottom trawl surveys conducted during summer in three large regions-the Gulf of Alaska and the west coasts of Canada and the United States-over the period 1996-2015, a time period punctuated by a marine "heat wave." Temporal biases in bottom temperature were minimized by subdividing each region into three subregions, each with short-duration surveys. Near-bottom temperatures, weighted by stratum area, were unsynchronized across subregions and exhibited varying subregional interannual variability. The weighted mean bottom depths in the subregions also vary largely among subregions. The centroids (centers of gravity) of groundfish distribution were weighted with catch per unit effort and stratum area for 10 commercially important groundfish species by size class and subregion. Our multivariate analyses showed that there were significant differences in aggregate fish movement responses to warm temperatures across subregions but not among species or sizes. Groundfish demonstrated poleward responses to warming temperatures only in a few subregions and moved shallower or deeper to seek colder waters. The temperature responses of groundfish depended on where they were. Under global warming, groundfish may form geographically distinct thermal ecoregions along the northeast Pacific shelf. Shallow-depth species exhibited greatly different distributional responses to temperature changes across subregions while deep-depth species of different subregions tend to have relatively similar temperature responses. Future climate studies would benefit by considering fish distributions on small subregional scales.

Signal Transducer and Activator of Transcription 3 for the Differentiation of Hepatocellular Carcinoma from Cirrhosis.

BACKGROUND: Overexpression and constitutive activation of signal transducer and activator of transcription (STAT) 3 have been suggested in the tumorigenesis of many human cancers, including multiple carcinomas, melanoma, and lymphoma. The diagnosis of hepatocellular carcinoma (HCC) in lobectomy specimens is usually straightforward, but distinguishing cirrhosis from well-differentiated HCC can be challenging in core biopsies. Our aims were to investigate the expression level of STAT3 and phosphorylated STAT3 (pSTAT3) in HCC and cirrhosis, and the application of STAT3 in the differential diagnosis of HCC and cirrhosis. METHODS: Sixty cases were divided into three groups: patients with HCC only (Group 1), HCC and cirrhosis (Group 2), and cirrhosis only (Group 3). Formalin-fixed and paraffin-embedded tissue sections were stained immunohistochemically for STAT3, pSTAT3, and CD163. The values obtained from the tissue sections of each group were compared in statistical analysis. RESULTS: STAT3 showed a high level in HCC and was a significant marker for differentiating HCC from cirrhosis (P < 0.0001). The odds ratio between HCC and cirrhosis increased 34.4 times when the intensity of STAT3 increased by 1 level. Spearman's correlation and Chi-square tests also demonstrated that expression level of STAT3 did not correlate with age, gender, or the presence of a cirrhotic background. CONCLUSIONS: STAT3 staining differs significantly in HCC and cirrhosis. The findings reinforce the role of STAT3 in the tumorigenesis of HCC and provide a useful marker to differentiate HCC from cirrhosis in challenging liver biopsies.

The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory.

Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here, we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, whereas upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2-signaling pathway and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction.

Activated p38 MAPK in Peripheral Blood Monocytes of Steroid Resistant Asthmatics.

Steroid resistance is a significant problem in management of chronic inflammatory diseases, including asthma. Accessible biomarkers are needed to identify steroid resistant patients to optimize their treatment. This study examined corticosteroid resistance in severe asthma. 24 asthmatics with forced expiratory volume in one second of less then 80% predicted were classified as steroid resistant or steroid sensitive based on changes in their lung function following a week of treatment with oral prednisone. Heparinised blood was collected from patients prior to oral prednisone administration. Phosphorylated mitogen activated kinases (MAPK) (extracellular regulated kinase (ERK), p38 and jun kinase (JNK)) were analyzed in whole blood samples using flow cytometry. Activation of phospho-p38 MAPK and phospho-mitogen- and stress-activated protein kinase 1 (MSK1) in asthmatics' peripheral blood mononuclear cells (PBMC) were confirmed by Western blot. Dexamethasone suppression of the LPS-induced IL-8 mRNA production by steroid resistant asthmatics PBMC in the presence of p38 and ERK inhibitors was evaluated by real time PCR. Flow cytometry analysis identified significantly stronger p38 phosphorylation in CD14+ monocytes from steroid resistant than steroid sensitive asthmatics (p = 0.014), whereas no difference was found in phosphorylation of ERK or JNK in CD14+ cells from these two groups of asthmatics. No difference in phosphorylated p38, ERK, JNK was detected in CD4+, CD8+ T cells, B cells and NK cells from steroid resistant vs. steroid sensitive asthmatics. P38 MAPK pathway activation was confirmed by Western blot, as significantly higher phospho-p38 and phospho-MSK1 levels were detected in the PBMC lysates from steroid resistant asthmatics. P38 inhibitor significantly enhanced DEX suppression of LPS-induced IL-8 mRNA by PBMC of steroid resistant asthmatics. This is the first report demonstrating selective p38 MAPK pathway activation in blood monocytes of steroid resistant asthmatics, suggesting that p38 and MSK1 phosphorylation can serve as blood biomarkers of steroid resistance.

Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on α-synuclein.

Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and α-synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to α-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation.