Adaptation of STIM1 structure-function relationships for optogenetic control of calcium signaling.

In cellular contexts, the oscillation of calcium ions (Ca2+) is intricately linked to various physiological processes, such as cell proliferation, metabolism, and survival. Stromal interaction molecule 1 (STIM1) proteins form a crucial regulatory component in the store-operated calcium entry (SOCE) process. The structural attributes of STIM1 are vital for its functionality, encompassing distinct domains situated in the endoplasmic reticulum (ER) lumen and the cytoplasm. The intraluminal domain enables the timely detection of diminishing Ca2+ concentrations, prompting structural modifications that activate the cytoplasmic domain. This activated cytoplasmic domain undergoes conformational alterations and engages with membrane components, opening a channel that facilitates the influx of Ca2+ from the extracellular environment. Given its multiple domains and interaction mechanisms, STIM1 plays a foundational role in cellular biology. This review focuses on the design of optogenetic tools inspired by the structure and function of STIM1. These tools offer a groundbreaking approach for studying and manipulating intracellular Ca2+ signaling with precisely spatiotemporal control. We further explore the practical applications of these tools, spanning fundamental scientific research, clinical studies, and their potential for translational research.

Ginsenoside Rg1 in neurological diseases: From bench to bedside.

Ginseng has been used in China as a superior medicinal material for thousands of years that can nourish the five internal organs, calm the mind and benefit wisdom. Due to its anti-inflammatory, antioxidant and neuroprotective activities, one of the active components of ginseng, ginsenoside Rg1, has been extensively investigated in the remedy of brain disorders, especially dementia and depression. In this review, we summarized the research progress on the action mechanisms of Rg1 ameliorating depression-like behaviors, including inhibition of hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis, regulation of synaptic plasticity and gut flora. Rg1 may alleviate Alzheimer's disease in the early phase, as well as in the middle-late phases through repairing dendrite, axon and microglia- and astrocyte-related inflammations. We also proposed that Rg1 could regulate memory state (the imbalance of working and aversive memory) caused by distinct stimuli. These laboratory studies would further the clinical trials on Rg1. From the prospective of drug development, we discussed the limitations of the present investigations and proposed our ideas to increase permeability and bioavailability of Rg1. Taken together, Rg1 has the potential to treat neuropsychiatric disorders, but a future in-depth investigation of the mechanisms is still required. In addition, drug development will benefit from the clinical trials in one specific neuropsychiatric disorder.

Proteomic mapping and optogenetic manipulation of membrane contact sites.

Membrane contact sites (MCSs) mediate crucial physiological processes in eukaryotic cells, including ion signaling, lipid metabolism, and autophagy. Dysregulation of MCSs is closely related to various diseases, such as type 2 diabetes mellitus (T2DM), neurodegenerative diseases, and cancers. Visualization, proteomic mapping and manipulation of MCSs may help the dissection of the physiology and pathology MCSs. Recent technical advances have enabled better understanding of the dynamics and functions of MCSs. Here we present a summary of currently known functions of MCSs, with a focus on optical approaches to visualize and manipulate MCSs, as well as proteomic mapping within MCSs.

[Effect of Gegen Qinlian Decoction on gut microbiota of irritable bowel syndrome with diarrhea rats].

This study aims to explore the effect of Gegen Qinlian Decoction on gut microbiota of irritable bowel syndrome with diarrhea(IBS-D) rats. A total of 36 male SD rats were randomly classified into the control group, model group, rifaximin group(150 mg·kg~(-1)), and high-dose(8.125 g·kg~(-1)), medium-dose(4.062 5 g·kg~(-1)) and low-dose(2.031 3 g·kg~(-1)) Gegen Qinlian Decoction groups with the random number table method, 6 in each group. After modeling, rats were treated for 8 days. The general state, bristol stool chart(BSC) score, and the minimum volume threshold for abdominal withdrawal reflex were recorded. Pathological changes of colon tissues were observed based on hematoxylin and eosin(HE) staining, and gut microbiota was analyzed based on 16 S rRNA sequencing. Compared with the model group, rifaximin group and high-dose and medium-dose Gegen Qinlian Decoction groups showed low BSC score(P<0.01) and high minimum volume threshold for abdominal lifting(P<0.05). HE staining showed that Gegen Qinlian Decoction could relieve intestinal inflammation. 16 S rRNA sequencing suggested obvious variation of gut microbiota in IBS-D rats. Gegen Qinlian Decoction significantly raised the richness index and diversity index of gut microbiota, regulated the number of the flora, and improved alpha diversity and beta diversity. Species composition of gut microbiota and LEfSe analysis showed that Gegen Qinlian Decoction could significantly increase the ratio of Bacteroidota to Firmicutes, elevate the abundance of probiotics such as Clostridia and Lachnospirales, and reduce the abundance of conditional pathogens such as Bacteroidales, and Prevotellaceae. PICRUSt2 analysis indicated that Gegen Qinlian Decoction was mainly related to multiple metabolic pathways such as carbohydrate metabolism and amino acid metabolism. In summary, Gegen Qinlian Decoction can significantly reduce visceral hypersensitivity of IBS-D rats, alleviate intestinal inflammation, and relieve clinical symptoms such as diarrhea. The mechanism is the likelihood that it regulates the composition and structure of gut microbiota and improves its metabolic pathway as well.

TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.

Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10-mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled-coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer.

A molecular toolbox for interrogation of membrane contact sites.

Membrane contact sites (MCSs) are specialized subcellular compartments formed by closely apposed membranes from two organelles. The intermembrane gap is separated by a distance ranging from 10 to 35 nm. MCSs are typically maintained through dynamic protein-protein and protein-lipid interactions. These intermembrane contact sites constitute important intracellular signalling hotspots to mediate a plethora of cellular processes, including calcium homeostasis, lipid metabolism, membrane biogenesis and organelle remodelling. In recent years, a series of genetically encoded probes and chemogenetic or optogenetic actuators have been invented to aid the visualization and interrogation of MCSs in both fixed and living cells. These molecular tools have greatly accelerated the pace of mechanistic dissection of membrane contact sites at the molecular level. In this review, we present an overview on the latest progress in this endeavour, and provide a general guide to the selection of methods and molecular tools for probing interorganellar membrane contact sites.

STIM2 interacts with AMPK and regulates calcium-induced AMPK activation.

AMPK is a crucial regulator of energy homeostasis that acts downstream of its upstream kinase liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase 2 (CaMKK2). LKB1 primarily phosphorylates AMPK after energy stress, whereas calcium-mediated activation of AMPK requires CaMKK2, although the regulatory mechanisms of calcium-mediated AMPK activation remain unclear. Using biochemical, microscopic, and genetic approaches, we demonstrate that the stromal interaction molecule (STIM)2, a calcium sensor, acts as a novel regulator of CaMKK2-AMPK signaling. We reveal that STIM2 interacts with AMPK and CaMKK2 and that the increase in intracellular calcium levels promotes AMPK colocalization and interaction with STIM2. We further show that STIM2 deficiency attenuates calcium-induced but not energy stress-induced AMPK activation, possibly by regulating the CaMKK2-AMPK interaction. Together, our results identify a previously unappreciated mechanism that modulates calcium-mediated AMPK activation.-Chauhan, A. S., Liu, X., Jing, J., Lee, H., Yadav, R. K., Liu, J., Zhou, Y., Gan B. STIM2 interacts with AMPK and regulates calcium-induced AMPK activation.

Red Cell Distribution Width as a Prognostic Factor in Patients with Hepatocellular Carcinoma.

BACKGROUND: The red blood cell distribution width (RDW) was reported to be related to the severity of liver diseases, but its clinical significance in patients with hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to explore the clinical significance of RDW in HCC patients. METHODS: For the retrospective study, 422 HCC patients were enrolled in this study. Hematological parameters and liver biochemical indexes were analyzed. Child-Pugh grade and Barcelona Clinic Liver Cancer (BCLC) stages of the HCC patients were calculated. The diagnostic accuracy was evaluated according to the area under the receiver operating characteristic (ROC) curve. The medical records of HCC patients who were admitted to The Second Affiliated Hospital of Nanjing University of Chinese Medicine from January 2006 to August 2015 were retro-spectively reviewed. RESULTS: Subgroup analysis showed that RDW level of HCC patients with tumor size more than 10 cm were higher than those of HCC patients with tumor size smaller than 3 cm, 3 - 5 cm, and 5 - 10 cm (14.77 ± 2.35%, 15.27 ± 2.65%, 15.32 ± 2.40% vs. 15.97 ± 2.39%, p < 0.001). RDW level significantly increased with worsening Child-Pugh grade and BCLC stages. In addition, RDW level were negatively correlated with red blood cell (RBC) counts, hematocrit (HCT), lymphocyte (LY) counts, hemoglobin (Hb), blood platelet (PLT) counts, and positively correlated with aspartate-aminotransferase (AST), and total bile acid (TBA). ROC curve analysis showed that RDW level was 14.15% was the optimal prognostic cutoff point to determine the survival rate of HCC patients. In the univariate analysis followed by multivariate analysis, RDW level below 14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor size were prognostic indicators for HCC patients. This indicated HCC patients with RDW level below 14.15% [hazard ratio of 0.530 (95% confidence interval, 0.395 - 0.710; p < 0.001)] had the lower mortality. CONCLUSIONS: RDW level was positively associated with tumor size. The prognosis was better for HCC patients with RDW levels below14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor lesions. It suggested RDW level might be an easily obtainable and inexpensive prognostic indicator for HCC patients.

[Magnetic resonance-ultrasound fusion guided transperineal prostate biopsy for the diagnosis of prostate cancer].

OBJECTIVE: To investigate the application value of magnetic resonance-ultrasound fusion (MR-USF) guided transperineal prostate biopsy (TPPB) in the diagnosis of prostate cancer. METHODS: Relevant data were collected retrospectively from 77 patients undergoing MR-USF guided TPPB (n = 22) or 12-core systematic prostate biopsy (SPB) (n = 55) in Binhai People's Hospital from May to July 2019 and statistically analyzed using the software Graphad Prism 7.0 and SPSS 22.0. RESULTS: The patients were aged 51－91 (70.5 ± 9.7) years, with a mean PSA level of (35.1 ± 115.4) µg/L (1.02－959 µg/L) and an average prostate volume of (48.81 ± 38.4) cm3 (7.54－307.61 cm3). There were no statistically significant differences in age, PSA, and BMI between the two groups of patients (P > 0.05). Prostate cancer was confirmed in 31 of the cases, with a positive rate of 40.26% (31/77), significantly higher in the TPPB (45.45% ï¼»10/22ï¼½ than in the SPB group (38.18% ï¼»21/55ï¼½, P < 0.01). Based on the PI-RADS scores, the Gleason grade was also higher in the former than in the latter group. CONCLUSIONS: MR-USF guided TPPB can improve the biopsy performance. Whether it should be used is based on the patient's PSA level and PI-RADS scores.

Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1.

Store-operated calcium entry (SOCE) modulates cytosolic calcium in multiple cells. Endoplasmic reticulum (ER)-localized STIM1 and plasma membrane (PM)-localized ORAI1 are two main components of SOCE. STIM1:ORAI1 association requires STIM1 oligomerization, its re-distribution to ER-PM junctions, and puncta formation. However, little is known about the negative regulation of these steps to prevent calcium overload. Here, we identified Tmem178 as a negative modulator of STIM1 puncta formation in myeloid cells. Using site-directed mutagenesis, co-immunoprecipitation assays and FRET imaging, we determined that Tmem178:STIM1 association occurs via their transmembrane motifs. Mutants that increase Tmem178:STIM1 association reduce STIM1 puncta formation, SOCE activation, impair inflammatory cytokine production in macrophages and osteoclastogenesis. Mutants that reduce Tmem178:STIM1 association reverse these effects. Furthermore, exposure to plasma from arthritic patients decreases Tmem178 expression, enhances SOCE activation and cytoplasmic calcium. In conclusion, Tmem178 modulates the rate-limiting step of STIM1 puncta formation and therefore controls SOCE in inflammatory conditions.

α2-Adrenergic receptor activation promotes long-term potentiation at excitatory synapses in the mouse accessory olfactory bulb.

The formation of mate recognition memory in mice is associated with neural changes at the reciprocal dendrodendritic synapses between glutamatergic mitral cell (MC) projection neurons and GABAergic granule cell (GC) interneurons in the accessory olfactory bulb (AOB). Although noradrenaline (NA) plays a critical role in the formation of the memory, the mechanism by which it exerts this effect remains unclear. Here we used extracellular field potential and whole-cell patch-clamp recordings to assess the actions of bath-applied NA (10 µM) on the glutamatergic transmission and its plasticity at the MC-to-GC synapse in the AOB. Stimulation (400 stimuli) of MC axons at 10 Hz but not at 100 Hz effectively induced N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation (LTP), which exhibited reversibility. NA paired with subthreshold 10-Hz stimulation (200 stimuli) facilitated the induction of NMDA receptor-dependent LTP via the activation of α2-adrenergic receptors (ARs). We next examined how NA, acting at α2-ARs, facilitates LTP induction. In terms of acute actions, NA suppressed GC excitatory postsynaptic current (EPSC) responses to single pulse stimulation of MC axons by reducing glutamate release from MCs via G-protein coupled inhibition of calcium channels. Consequently, NA reduced recurrent inhibition of MCs, resulting in the enhancement of evoked EPSCs and spike fidelity in GCs during the 10-Hz stimulation used to induce LTP. These results suggest that NA, acting at α2-ARs, facilitates the induction of NMDA receptor-dependent LTP at the MC-to-GC synapse by shifting its threshold through disinhibition of MCs.

Axonal chronic injury in treatment-naïve HIV+ adults with asymptomatic neurocognitive impairment and its relationship with clinical variables and cognitive status.

BACKGROUND: HIV is a neurotropic virus, and it can bring about neurodegeneration and may even result in cognitive impairments. The precise mechanism of HIV-associated white matter (WM) injury is unknown. The effects of multiple clinical contributors on WM impairments and the relationship between the WM alterations and cognitive performance merit further investigation. METHODS: Diffusion tensor imaging (DTI) was performed in 20 antiretroviral-naïve HIV-positive asymptomatic neurocognitive impairment (ANI) adults and 20 healthy volunteers. Whole-brain analysis of DTI metrics between groups was conducted by employing tract-based spatial statistics (TBSS), including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). DTI parameters were correlated with clinical variables (age, CD4+ cell count, CD4+/CD8+ ratio, plasma viral load and duration of HIV infection) and multiple cognitive tests by using multilinear regression analyses. RESULTS: DTI quantified diffusion alterations in the corpus callosum and corona radiata (MD increased significantly, P < 0.05) and chronic axonal injury in the corpus callosum, corona radiata, internal capsule, external capsule, posterior thalamic radiation, sagittal stratum, and superior longitudinal fasciculus (AD increased significantly, P < 0.05). The impairments in the corona radiata had significant correlations with the current CD4+/CD8+ ratios. Increased MD or AD values in multiple white matter structures showed significant associations with many cognitive domain tests. CONCLUSIONS: WM impairments are present in neurologically asymptomatic HIV+ adults, periventricular WM (corpus callosum and corona radiata) are preferential occult injuries, which is associated with axonal chronic damage rather than demyelination. Axonopathy may exist before myelin injury. DTI-TBSS is helpful to explore the WM microstructure abnormalities and provide a new perspective for the investigation of the pathomechanism of HIV-associated WM injury.

Sperm-Associated Antigen 5 Expression Is Increased in Hepatocellular Carcinoma and Indicates Poor Prognosis.

BACKGROUND Sperm-associated antigen 5 (SPAG5), a gene that encodes a mitotic spindle-associated protein, is closely related to tumor development and is involved in cell migration and proliferation. The objective of this research was to explore the clinical significance of SPAG5 expression in hepatocellular carcinoma (HCC) and the relationship between SPAG5 expression and HCC prognosis. MATERIAL AND METHODS Twenty pairs of fresh-frozen HCC samples and samples from 95 HCC patients in a tissue microarray were subjected to quantitative real-time reverse-transcription (qRT)-PCR and immunohistochemistry (IHC), respectively, to investigate the relationship between the expression of SPAG5 and the clinicopathological features of HCC patients. RESULTS PCR data showed that the messenger RNA (mRNA) expression level of SPAG5 in HCC tissue specimens was higher than that in adjacent non-tumor tissue specimens (p<0.05). IHC analyses demonstrated that SPAG5 expression was significantly correlated with tumor grade (p=0.003), tumor number (p=0.009), vascular invasion (p=0.001), and TNM stage (p=0.001). Survival analysis and Kaplan-Meier curves showed that SPAG5 expression is an independent prognostic indicator for disease-free survival (p=0.017) and overall survival (p=0.016) in HCC patients. CONCLUSIONS Our results indicate that SPAG5 expression may be considered as an oncogenic biomarker and a novel predictor for HCC prognosis.

TMEM110 regulates the maintenance and remodeling of mammalian ER-plasma membrane junctions competent for STIM-ORAI signaling.

The stromal interaction molecule (STIM)-ORAI calcium release-activated calcium modulator (ORAI) pathway controls store-dependent calcium entry, a major mechanism of physiological calcium signaling in mammalian cells. The core elements of the pathway are the regulatory protein STIM1, located in the endoplasmic reticulum (ER) membrane, the calcium channel ORAI1 in the plasma membrane, and sites of close contact between the ER and the plasma membrane that permit the two proteins to interact. Research on calcium signaling has centered on STIM1, ORAI1, and a few proteins that directly modulate STIM-ORAI function. However, little is known about proteins that organize ER-plasma membrane junctions for STIM-ORAI-dependent calcium signaling. Here, we report that an ER-resident membrane protein identified in a previous genome-wide RNAi screen, transmembrane protein 110 (TMEM110), regulates the long-term maintenance of ER-plasma membrane junctions and the short-term physiological remodeling of the junctions during store-dependent calcium signaling.

SH479, a Betulinic Acid Derivative, Ameliorates Experimental Autoimmune Encephalomyelitis by Regulating the T Helper 17/Regulatory T Cell Balance.

CD4+ T helper cells, especially T helper 17 (TH17) cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on proinflammatory cytokine interleukin 17 (IL-17) and interferon-γ (IFN-γ) production. In this study, we screened BA derivatives and found a BA derivative, SH479, that had a greater inhibitory effect on TH17 differentiation. Our further analysis showed that SH479 had a greater inhibitory effect on TH17 and TH1, and a more stimulatory effect on regulatory T (Treg) cells. To evaluate the effects of SH479 on autoimmune diseases in vivo, we employed the extensively used MS mouse model experimental autoimmune encephalomyelitis (EAE). Our results showed that SH479 ameliorated clinical and histologic signs of EAE in both prevention and therapeutic protocols by regulating the TH17/Treg balance. SH479 dose-dependently reduced splenic lymphocyte proinflammatory factors and increased anti-inflammatory factors. Moreover, SH479 specifically inhibited splenic lymphocyte viability from EAE mice but not normal splenic lymphocyte viability. At the molecular level, SH479 inhibited TH17 differentiation by regulating signal transducer and activator of transcription-3 (STAT3) phosphorylation, DNA binding activity, and recruitment to the Il-17a promoter in CD4+ T cells. Furthermore, SH479 promoted the STAT5 signaling pathway and inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Together, our data demonstrated that SH479 ameliorated EAE by regulating the TH17/Treg balance through inhibiting the STAT3 and NF-κB pathways while activating the STAT5 pathway, suggesting that SH479 is a potential novel drug candidate for autoimmune diseases including MS.

The Value of GPC3 and GP73 in Clinical Diagnosis of Hepatocellular Carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has increased over the past decades in China. Current screening methods of HCC such as detection of α-fetoprotein (AFP) combined with liver ultrasonography remain unsatisfactory. Many HCC patients have already missed the optimal treatment period when diagnosed. Our study aimed to evaluate the value of Glypican 3 (GPC3) and Golgi protein 73 (GP73) in the detection of HCC. METHODS: Thirty-nine patients with HCC and 31 patients with liver cirrhosis were enrolled. The level of serum GPC3 and GP73 were determined by ELISA. The expression of GPC3 mRNA and GP73 mRNA in peripheral blood mononuclear cell (PBMC) and liver tissues were also measured with qRT-PCR. Then, receiving operating characteristic (ROC) curves were plotted to detect the sensitivity and specificity of serum GPC3 and GP73 in the diagnosis of HCC. RESULTS: The levels of serum GPC3 and GP73 in the HCC group were significantly higher than in the cirrhosis group (p < 0.0001). Patients with GPC3 > 9.3 µg/L and GP73 > 77.68 ng/mL had a risk of HCC of 92.31%. The HCC diagnosis ROC curve analysis indicated that when setting the GPC3 cutoff value > 9.3 µg/L, AUC = 0.956. The sensitivity and specificity of GPC3 were 89.74% and 96.77%, respectively, with a positive predictive value of 97.2%, negative predictive value of 88.2%, + LR of 27.82 and - LR of 0.11. When setting GP73 cutoff value > 77.68 ng/mL, AUC = 0.937. The sensitivity and specificity of GP73 were 92.31% and 83.87%, respectively, with positive predictive value of 87.8%, negative predictive value of 89.7%, + LR of 5.72 and - LR of 0.092. No significant difference (p > 0.05) was found between GPC3 and GP73 AUC in ROC curves, indicating that these two biomarkers were equivalent in the prediction of HCC. CONCLUSIONS: The expression of serum GPC3 and GP73 was significantly higher in the HCC patients compared with the cirrhosis patients. GPC3 and GP73 might be effective non-invasive diagnostic indicators of HCC.

Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study.

OBJECTIVE: To explore the risk factors for atopic dermatitis (AD) and disclose the relationship between immune inflammatory factors (Immunoglobulin E (IgE), interleukin (IL)-4, IL-18) and the prevalence of AD in a Chinese population. METHODS: To evaluate the risk factors for infant AD, a total of 921 mother-newborn pairs were recruited through a questionnaire survey conducted during 2009-2011. Venous blood was collected from the mothers during birth hospitalization and umbilical cord blood was collected during delivery. Thirty-five infants with AD paired with their mothers served as the patient group. Thirty-five non-AD pairs were selected randomly and were used as the control group. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the levels of IgE, IL-4, and IL-18. The relationship between the prevalence of AD and the levels of IgE, IL-4, and IL-18 was analyzed. The risk factors for allergy were assessed in IgE positive cases. RESULTS: Family income, parental history of atopy, age of menarche, performing housing renovation before pregnancy, instance of a virus infection during pregnancy, and calcium supplementation during pregnancy were potential factors determining the incidence rate of infant AD. Compared with the control group, the AD patient group showed higher levels of IgE and IL-4 in both the maternal serum and umbilical cord blood (P < 0.01). In the cases with AD, IL-8 was increased only in the maternal serum (P < 0.01). In addition, the allergens dust mite, mugwort pollen, and mycete spores were risk factors for the incidence of IgE-positive AD. CONCLUSION: IgE and IL-4 levels in the maternal serum and umbilical cord blood as well as IL-18 level in the maternal serum are related to the occurrence of childhood AD. Potential factors for infant AD include family income, parental history of atopy, age of menarche, housing renovation before pregnancy, virus infection, and calcium supplementation during pregnancy.

[The Diagnostic Value of Double Contrast Enhanced Ultrasound in Colorectal Neoplasms].

OBJECTIVES: To determine the value of double contrast enhanced ultrasound (DCEUS) in detecting colorectal neoplasms. METHODS: The conventional abdominal ultrasound and DCEUS (hydrocolonal ultrasound+intravenous contrast-enhanced ultrasonography) were performed in 77 patients with 79 colorectal tumors. The clinical, ultrasonic and pathological data of the patients were reviewed. RESULTS: The conventional abdominal ultrasound detected 32 colorectal tumors (32/79, with a sensitivity of 40.1%), compared with 68 tumors found in DCEUS (68/79, with a sensitivity of 86.1%). The tumors were located accurately in 21.9%(7/32) and 88.2%(60/68) cases for the conventional abdominal ultrasound and DCEUS, respectively ( P<0.05). DCEUS accurately located 94.4%(51/54)cased with colon neoplasm. Two types of enhancing modes were found with colorectal neoplasm: entirely homogeneous enhancing and heterogeneous enhancing perpendicularly from the serosal part to the mucosal part. The enhancing modes were associated with the morphology of neoplasm. Thirty-nine segmented-thickened tumors were found with perpendicularly enhancing from the serosal surface to the mucosal surface, while 29 protruding tumors were found with enhancing from their pedicles or fund. CONCLUSIONS: DCEUS has higher detection sensitivity and location accuracy than conventional ultrasound.

The Configuration of GRB2 in Protein Interaction and Signal Transduction.

Growth-factor-receptor-binding protein 2 (GRB2) is a non-enzymatic adaptor protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses, including signaling transduction and gene expression. GRB2 binds to numerous target molecules, thereby modulating a complex cell signaling network with diverse functions. The structural characteristics of GRB2 are essential for its functionality, as its multiple domains and interaction mechanisms underpin its role in cellular biology. The typical signaling pathway involving GRB2 is initiated by the ligand stimulation to its receptor tyrosine kinases (RTKs). The activation of RTKs leads to the recruitment of GRB2 through its SH2 domain to the phosphorylated tyrosine residues on the receptor. GRB2, in turn, binds to the Son of Sevenless (SOS) protein through its SH3 domain. This binding facilitates the activation of Ras, a small GTPase, which triggers a cascade of downstream signaling events, ultimately leading to cell proliferation, survival, and differentiation. Further research and exploration into the structure and function of GRB2 hold great potential for providing novel insights and strategies to enhance medical approaches for related diseases. In this review, we provide an outline of the proteins that engage with domains of GRB2, along with the function of different GRB2 domains in governing cellular signaling pathways. This furnishes essential points of current studies for the forthcoming advancement of therapeutic medications aimed at GRB2.

Climate warming impacts chewing Spodoptera litura negatively but sucking Corythucha marmorata positively on native Solidago canadensis.

Insect-plant interactions are among importantly ecological processes, and rapid environmental changes such as temperature and resource fluctuations can disrupt long-standing insect-plant interactions. While individual impacts of climate warming, atmospheric nitrogen (N) deposition, and plant provenance on insect-plant interactions are well studied, their joint effects on insect-plant interactions are less explored in ecologically realistic settings. To this end, we performed five experiments with native and invasive Solidago canadensis populations from home and introduced ranges and two insect herbivores (leaf-chewing Spodoptera litura and sap-sucking Corythucha marmorata) in the context of climate warming and N deposition. We determined leaf defensive traits, feeding preference, and insect growth and development, and quantified the possible associations among climate change, host-plant traits, and insect performance with structural equation modeling. First, native S. canadensis populations experienced higher damage by S. litura but lower damage by C. marmorata than invasive S. canadensis populations in the ambient environment. Second, warming decreased the leaf consumption, growth, and survival of S. litura on native S. canadensis populations, but did not affect these traits on invasive S. canadensis populations; warming increased the number of C. marmorata on native S. canadensis populations via direct facilitation, but decreased that on invasive S. canadensis populations via indirect suppression. Third, N addition enhanced the survival of S. litura on native S. canadensis populations, and its feeding preference and leaf consumption on invasive S. canadensis populations. Finally, warming plus N addition exhibited non-additive effects on insect-plant interactions. Based on these results, we tentatively conclude that climate warming could have contrasting effects on insect-plant interactions depending on host-plant provenance and that the effects of atmospheric N deposition on insects might be relatively weak compared to climate warming. Future studies should focus on the molecular mechanisms underlying these different patterns.