A strategy to boost xanthine oxidase and angiotensin converting enzyme inhibitory activities of peptides via molecular docking and module substitution.

Molecular docking and activity evaluation screened the dipeptide module GP with low xanthine oxidase (XOD) inhibitory activity and modules KE and KN with high activity, and identified them as low- and high-contribution modules, respectively. We hypothesized the substitution of low-contribution modules in peptides with high contributions would boost their XOD inhibitory activity. In the XOD inhibitory peptide GPAGPR, substitution of GP with both KE and KN led to enhanced affinity between the peptides and XOD. They also increased XOD inhibitory activity (26.4% and 10.3%) and decreased cellular uric acid concentrations (28.0% and 10.4%). RNA sequencing indicated that these improvements were attributable to the inhibition of uric acid biosynthesis. In addition, module substitution increased the angiotensin-converting enzyme inhibitory activity of GILRP and GAAGGAF by 84.8% and 76.5%. This study revealed that module substitution is a feasible strategy to boost peptide activity, and provided information for the optimization of hydrolysate preparation conditions.

Advanced progress of spatial metabolomics in head and neck cancer research.

Head and neck cancer ranks as the sixth most prevalent malignancy, constituting 5 % of all cancer cases. Its inconspicuous onset often leads to advanced stage diagnoses, prompting the need for early detection to enhance patient prognosis. Currently, research into early diagnostic markers relies predominantly on genomics, proteomics, transcriptomics, and other methods, which, unfortunately, necessitate tumor tissue homogenization, resulting in the loss of temporal and spatial information. Emerging as a recent addition to the omics toolkit, spatial metabolomics stands out. This method conducts in situ mass spectrometry analyses on fresh tissue specimens while effectively preserving their spatiotemporal information. The utilization of spatial metabolomics in life science research offers distinct advantages. This article comprehensively reviews the progress of spatial metabolomics in head and neck cancer research, encompassing insights into cancer cell metabolic reprogramming. Various mass spectrometry imaging techniques, such as secondary ion mass spectrometry, stroma-assisted laser desorption/ionization, and desorption electrospray ionization, enable in situ metabolite analysis for head and neck cancer. Finally, significant emphasis is placed on the application of presently available techniques for early diagnosis, margin assessment, and prognosis of head and neck cancer.

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Epithelial-mesenchymal transition (EMT) is closely associated with tumor invasion and metastasis. However, key regulators of EMT in pancreatic ductal adenocarcinoma (PDAC) need to be further studied. Bioinformatics analyses of pancreatic cancer public datasets showed that glycogen phosphorylase L (PYGL) expression is elevated in quasimesenchymal PDAC (QM-PDAC) and positively associated with EMT. In vitro cellular experiments further confirm PYGL as a crucial EMT regulator in PDAC cells. Functionally, PYGL overexpression promotes cell migration and invasion in vitro and facilitates liver metastasis in vivo, while PYGL knockdown has opposite effects. Mechanically, hypoxia induces PYGL expression in a hypoxia inducible factor 1α (HIF1α)-dependent manner and promotes glycogen accumulation. Elevated PYGL mobilizes accumulated glycogen to fuel glycolysis via its activity as a glycogen phosphorylase, thus inducing the EMT process, which could be suppressed by the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). Clinically, PYGL expression is upregulated in PDAC and correlates with its malignant features and poor prognosis. Collectively, the data from our study reveal that the hypoxia/PYGL/glycolysis-induced EMT promotes PDAC metastasis, which establishes the rational for targeting hypoxia/PYGL/glycolysis/EMT signaling pathway against PDAC.

DHA inhibits invasion and metastasis in NSCLC cells by interfering with CCL18/STAT3 signaling pathway.

Omega-3 has been proposed as an antitumor substance that suppresses the growth and metastasis of multiple types of tumor cells, including lung cancer, but the specific mechanisms involved remain obscure. Our previous studies showed that the expression of chemokine ligand 18 was related to the migration and metastasis of non-small cell lung cancer. Here, we aim to explore whether omega-3 inhibits invasion and metastasis of NSCLC by regulating the expression of CCL18. The expression of CCL18, metastasis- and epithelial-mesenchymal transition (EMT)-related genes at mRNA and protein levels in NSCLC cell lines were detected by RT-qPCR and Western blot, respectively. The metastatic and invasive capability of NSCLC cells were evaluated by scratch wound healing and Transwell assays, respectively. Our results showed that the level of CCL18 is positively associated with metastatic ability of NSCLC cells. Docosahexaenoic acid, an important long-chain, polyunsaturated omega-3 (n-3) fatty acid, significantly inhibited invasion and metastasis of NSCLC cells, and concomitantly downregulated the expression of metastasis- and EMT-related genes and p-STAT3 signaling pathway. Additionally, we found that DHA inhibited CCL18 expression in lung cancer cells, while overexpression of CCL18 effectively reversed DHA-mediated downregulation in the expression of metastasis- and EMT-related genes and p-STAT3 signaling as well as DHA-mediated inhibitory effect on metastasis and invasion of NSCLC cells. DHA inhibits NSCLC cell invasion and metastasis possibly through targeted inhibition of CCL18/ STAT3 signaling pathway and EMT process.

Enhancing the effect of biochar ageing on reducing cadmium accumulation in Medicago sativa L.

Biochar (BC) application to farmland soil can reduce the mobility and bioavailability of Cd. Nevertheless, BC is prone to natural ageing in soil, which alters its structure, physicochemical properties, thereby affecting the immobilisation of Cd. We used dry-wet and freeze-thaw cycles to mimic the natural ageing of BC, and used adsorption experiments to explore the changes of Cd adsorption capacity of BC and aged BC (ABC). We conducted a pot experiment to investigate the effects of BC and ABC on soil biotic and abiotic factors, alfalfa growth, and Cd accumulation in agricultural soils with high and low Cd concentrations. The increase of specific surface area, pore size, oxygen containing functional groups and mineral composition leads to better adsorption capacity of ABC. The adsorption of Cd(II) by BC and ABC is mainly by monolayer adsorption and chemical adsorption. Applying BC and ABC to Cd-contaminated soil significantly increased the aboveground biomass and decreased the Cd accumulation by reducing the Cd bioconcentration factor in alfalfa. At high Cd levels, adding BC and ABC reduced the Cd content in alfalfa shoots by 32.8 % and 35.1 %, respectively; the fixing effect of ABC was better than that of BC. Adding BC and ABC significantly increased the microbial biomass and geometric mean of enzymes. BC addition increased soil pH by 0.32-0.36 units and cation exchange capacity (CEC) by 15.5 %. Adding BC and ABC significantly increased soil organic matter (SOM) by 5.7 % and 6.2 %, respectively. Random forest analysis showed that SOM, total organic carbon, and fluorescein diacetate hydrolase were important variables for Cd content in alfalfa shoots. Structural equation modelling showed that BC indirectly affected the Cd content in alfalfa shoots by affecting soil pH, CEC, SOM, microbial biomass, and microbial metabolic activity. BC has a long-term effect on alleviating Cd pollution in farmland.

Altering Brain Amyloidosis by Intra-Lingual and Extra-Nasal Exposure of Aß Aggregates.

Extensive experimental and human-derived evidence suggest that misfolded Aß particles spread similarly to infectious prions. Moreover, peripheral administration of Aß seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aß from the periphery to the brain are not fully understood, although circulation and retrograde axonal transport have been proposed. Here, we demonstrate that injection of Aß seeds in the tongue, a highly innervated organ, substantially accelerates the appearance of plaques in Tg2576 mice. In addition, the extra-nasal exposure of Aß aggregates increased amyloid pathology in the olfactory bulb. Our results show that exposing highly innervated tissues to Aß seeds accelerates AD-like pathological features, and suggest that Aß seeds can be transported from peripheral compartments to the brain by retrograde axonal transport. Research in this direction may be relevant on different fronts, including disease mechanisms, diagnosis, and risk-evaluation of potential iatrogenic transmission of Aß misfolding.

Prognostic value of receptor tyrosine kinases in malignant melanoma patients: A systematic review and meta-analysis of immunohistochemistry.

Background: Substantial evidence suggests that receptor tyrosine kinases (RTKs) are overexpressed in tumors; however, few studies have focused on the prognostic value of RTKs in melanoma. Objectives: The objective of this study is to evaluate the association between overexpression of RTKs and survival in melanoma patients based on immunohistochemistry (IHC) analysis. Methods: Our review is registered on PROSPERO (http://www.crd.york.ac.uk/PROSPERO), registration number CRD42021261460. Seven databases were searched, and data were extracted. We used IHC to measure the association between overexpression of RTKs and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and clinicopathology in melanoma patients. Pooled analysis was conducted to assess the differences between Hazard Ratios along with 95% confidence intervals. Results: Of 5,508 publications examined following the database search, 23 publications were included in this study, which included data from a total of 2,072 patients. Vascular endothelial growth factor receptor 2 (VEGF-R2) overexpression was associated with worse OS and DFS in melanoma. Furthermore, there was an association between OS and the expression of several RTKs, including epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition factor (MET), vascular endothelial growth factor receptor 1 (VEGF-R1), and insulin-like growth factor 1 receptor (IGF-1R). There were no significant correlations between EGFR overexpression and worse DFS or PFS. EGFR overexpression was associated with worse OS cutaneous and nasal melanoma, but not uveal melanoma. However, MET overexpression was related to worse OS in both cutaneous and uveal melanoma. Furthermore, EGFR overexpression was associated with a worse OS in Europe compared to other geographic areas. Moreover, EGFR and MET overexpression showed significant prognostic value in patients with the cut-off "≥10% staining". Conclusions: Our findings build concrete evidence that overexpression of RTKs is associated with poor prognosis and clinicopathology in melanoma, highlighting RTK expression has the potential to inform individualized combination therapies and accurate prognostic evaluation.

Higher than predicted resting energy expenditure and lower physical activity in healthy underweight Chinese adults.

Contrary to popular opinion that lean individuals "eat what they want" and exercise more, Hu et al. study a cohort of healthy underweight volunteers and reveal them to have reduced physical activity relative to normal BMI controls and lower food intake. This cohort is also shown to have higher than expected resting energy expenditure, which is associated with elevations in thyroid hormones.

ACSL4 is essential for radiation-induced intestinal injury by initiating ferroptosis.

Lipid peroxidation-induced ferroptosis is a newly recognized type of programmed cell death. With the method of RNA sequencing, we found that irradiation (IR) markedly increased the expression of ferroptosis promotive genes, whereas reduced the expression of ferroptosis suppressive genes in murine intestine tissues, when compared with those of liver and lung tissues. By using ferroptosis inducer RSL-3 and inhibitor liproxstatin-1, we found that ferroptosis is essential for IR-induced intestinal injury. Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) is an important component for ferroptosis execution, and we found that ACSL4 expression was significantly upregulated in irradiated intestine tissues, but not in liver or lung tissues. Antibacterial and antifungal regents reduced the expression of ASCL4 and protected against tissue injury in irradiated intestine tissues. Further studies showed that troglitazone, a ACSL4 inhibitor, succeeded to suppresses intestine lipid peroxidation and tissue damage after IR.

Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus.

X-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of Ile324Met (I324M) mutation identified in a pedigree showing as typical recessive X-linked NDI. We demonstrated that I324M mutation interfered with the conformation of complex glycosylation of V2R. Moreover, almost all of the I324M-V2R failed to express on the cell surface due to being captured by the endoplasmic reticulum control system. We further examined the signaling activity of DDAVP-medicated cAMP and ERK1/2 pathways and the results revealed that the mutant receptor lost the ability in response to DDAVP stimulation contributed to the failure of accumulation of cAMP and phosphorylated ERK1/2. Based on the characteristics of molecular defects of I324M mutant, we selected two reagents (SR49059 and alvespimycin) to determine whether the functions of I324M-V2R can be restored and we found that both compounds can significantly "rescue" I324M mutation. Our findings may provide further insights for understanding the pathogenic mechanism of AVPR2 gene mutations and may offer some implications on development of promising treatments for patients with X-linked NDI.

Deficient endoplasmic reticulum translocon-associated protein complex limits the biosynthesis of proinsulin and insulin.

The conserved endoplasmic reticulum (ER) membrane protein TRAPα (translocon-associated protein, also known as signal sequence receptor 1, SSR1) has been reported to play a critical but unclear role in insulin biosynthesis. TRAPα/SSR1 is one component of a four-protein complex including TRAPß/SSR2, TRAPγ/SSR3, and TRAPδ/SSR4. The TRAP complex topologically has a small exposure on the cytosolic side of the ER via its TRAPγ/SSR3 subunit, whereas TRAPß/SSR2 and TRAPδ/SSR4 function along with TRAPα/SSR1 largely on the luminal side of the ER membrane. Here, we have examined pancreatic ß-cells with deficient expression of either TRAPß/SSR2 or TRAPδ/SSR4, which does not perturb mRNA expression levels of other TRAP subunits, or insulin mRNA. However, deficient protein expression of TRAPß/SSR2 and, to a lesser degree, TRAPδ/SSR4, diminishes the protein levels of other TRAP subunits, concomitant with deficient steady-state levels of proinsulin and insulin. Deficient TRAPß/SSR2 or TRAPδ/SSR4 is not associated with any apparent defect of exocytotic mechanism but rather by a decreased abundance of the proinsulin and insulin that accompanies glucose-stimulated secretion. Amino acid pulse labeling directly establishes that much of the steady-state deficiency of intracellular proinsulin can be accounted for by diminished proinsulin biosynthesis, observed in a pulse-labeling as short as 5 minutes. The proinsulin and insulin levels in TRAPß/SSR2 or TRAPδ/SSR4 null mutant ß-cells are notably recovered upon re-expression of the missing TRAP subunit, accompanying a rebound of proinsulin biosynthesis. Remarkably, overexpression of TRAPα/SSR1 can also suppress defects in ß-cells with diminished expression of TRAPß/SSR2, strongly suggesting that TRAPß/SSR2 is needed to support TRAPα/SSR1 function.

The Prevalence and Risk Factors of Cerebral Microbleeds: A Community-Based Study in China.

INTRODUCTION: Cerebral microbleeds (CMBs) are frequently found in the healthy elderly. However, data on the prevalence and risk factors of CMBs in the general population of China are lacking. METHODS: A cross-sectional study focusing on the prevalence and risk factors of CMBs was conducted in stroke-free elderly from Shanghai Wuliqiao community. MRI was performed at 3Tesla and cardiovascular risk factors (eg, age, smoking history, and hypertension), cerebral small vessel disease (CSVD) markers (eg, white matter hyperintensities, lacunar infarction, and enlarged perivascular space) and genetic information (eg, APOE, CR1) were recorded. Poisson regression was used to analyze the risk factors of the presence and location of microbleeds. RESULTS: A total of 199 participants (70.8±7.2 years old; male 31.2%) were finally included in our analysis. The overall prevalence of CMBs was 12.6% (25/199) and increased with age from 7.5% (55-64 years old) to 19.3% (over 75 years old). Of those with CMBs, most of them (16/25) located in the deep/mixed region and had 1-2 CMBs (18/25). Poisson regression analysis showed that white matter hyperintensities (OR=1.22, 95% CI: 1.16-1.29), APOE ε4+ carrier (OR=2.16, 95% CI: 1.18-3.96) and CR1 non-F/F isoform (OR=7.78, 95% CI: 4.34-13.96) were associated with CMBs. Further analysis found that in addition to the above three risk factors, hypertension (OR=2.98, 95% CI: 1.16-7.64), lacunar infarction (OR=2.39, 95% CI: 1.19-4.81) also increased the risk of deep/mixed CMBs. CONCLUSION: The prevalence of cerebral microbleeds is similar to other countries. Cardiovascular risk factors, CSVD markers, and genetic factors (APOE ε4, CR1 non-F/F isoform) were associated with CMBs, suggesting an interaction of multiple pathogenesis in Chinese stroke-free community population.

Association of BST1 polymorphism with idiopathic restless legs syndrome in Chinese population.

BACKGROUND: Parkinson's disease (PD) and restless legs syndrome/Willis-Ekbom disease (RLS/WED) are both common movement disorders. Based on their clinical overlap, association studies of PD and RLS/WED have been conducted for many years. OBJECTIVE: To investigate whether or not the genetic risk factor of PD was also associated with RLS/WED. SUBJECTS AND METHODS: We included 102 idiopathic RLS/WED patients and 189 matched controls from southeast China. The clinical data included the International Restless Legs Syndrome Study Group Rating Scale, the subtypes of RLS/WED symptoms (painful or other discomfort), the comorbidities, the pregnancy history of female patients, the Hamilton Depression Scale (HAMD), and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Risk gene analysis between RLS/WED and control groups including 21 SNPs (single nucleotide polymorphisms) was conducted. Genotyping was done by Sanger sequencing. RESULTS: We found that rs4273468 polymorphism of BST1 gene increased the risk of idiopathic RLS/WED patients in southeastern Chinese population (P = <0.001, OR = 2.85, p = 0.019 after Bonferroni correction). Moreover, the haplotype of G-G (rs4698412-rs4273468) was significantly associated with Chinese RLS/WED patients (p = <0.001). CONCLUSION: BST1 may contribute to the development of RLS/WED. Further studies on larger cohorts are needed to confirm these findings.

Activated Platelets Autocrine 5-Hydroxytryptophan Aggravates Sepsis-Induced Acute Lung Injury by Promoting Neutrophils Extracellular Traps Formation.

Excessive neutrophil extracellular trap (NET) formation is an important contributor to sepsis-induced acute lung injury (ALI). Recent reports indicate that platelets can induce neutrophil extracellular trap formation. However, the specific mechanism remains unclear. Tph1 gene, which encodes the rate-limiting enzyme for peripheral 5-hydroxytryptophan (5-HT) synthesis, was knocked out in mice to simulate peripheral 5-HT deficiency. Cecal ligation and puncture (CLP) surgery was performed to induce sepsis. We found that peripheral 5-HT deficiency reduced NET formation in lung tissues, alleviated sepsis-induced lung inflammatory injury, and reduced the mortality rate of CLP mice. In addition, peripheral 5-HT deficiency was shown to reduce the accumulation of platelets and NETs in the lung of septic mice. We found that platelets from wild-type (WT), but not Tph1 knockout (Tph1 -/- ), mice promote lipopolysaccharide (LPS)-induced NET formation. Exogenous 5-HT intervention increased LPS-induced NET formation when Tph1 -/- platelets were co-cultured with WT neutrophils. Therefore, our study uncovers a mechanism by which peripheral 5-HT aggravated sepsis-induced ALI by promoting NET formation in the lung of septic mice.

[Peripheral 5-hydroxytryptophan aggravates lung injury in septic mice by inducing the formation of neutrophils extracellular trap].

OBJECTIVE: To observe the effect of peripheral 5-hydroxytryptophan (5-HT)-induced neutrophil extracellular trap (NET) on lung injury in septic mice. METHODS: Wild-type (WT type) and Tph1 knockout (KO) C57 mice (6-8 weeks) were selected and divided into WT mice sham group, WT mice sepsis group, Tph1KO mice sham group and Tph1KO mice sepsis group according to the random number table method. Mice in the sham group received sham surgery (only open the abdominal cavity to flip the cecum without ligation and puncture, and then close the abdominal cavity); the mice in the sepsis group received cecal ligation and perforature (CLP) to establish sepsis model. The mice were sacrificed 12 hours after the operation, and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in bronchialalveolar lavage fluid (BALF) were detected by enzyme linked immunoadsordent assay (ELISA); at the same time, the lung tissues were collected, and the pathological changes of lung tissues were observed under light microscope, and the production of NET in lung tissues was observed by immunofluorescence microscope. RESULTS: The pathological results suggested that the lung tissue structure in sham groups was intact without exudation, while the alveolar structures of mice in the sepsis groups were damaged, with obvious exudation in the alveolar cavity and thickened alveolar walls accompanied by a large number of inflammatory cell infiltration, and the degree of lung injury in the sepsis group of WT mice was more severe than that of the sepsis group of Tph1KO mice. ELISA results showed that there was no statistically significant difference in the contents of TNF-α and IL-6 in mice BALF from different strains of the sham group; while the contents of TNF-α and IL-6 in BALF of septic mice group were significantly higher than those in sham group [WT mice: TNF-α (µg/L) was 158.20±28.46 vs. 14.00±3.28, IL-6 (µg/L) was 304.98±21.78 vs. 57.70±12.30; Tph1KO mice: TNF-α (µg/L) was 85.88±20.13 vs. 14.95±1.53, IL-6 (µg/L) was 169.50±45.61 vs. 55.05±12.68, all P < 0.01], and the above index levels in the sepsis group of WT mice were significantly higher than the sepsis group of Tph1KO mice [TNF-α (µg/L): 158.20±28.46 vs. 85.88±20.13, IL-6 (µg/L): 304.98±21.78 vs. 169.50±45.61, both P < 0.01]. Immunofluorescence staining showed that a very small amount of NET formation was detected in the mice lungs from the sham group; a large amount of NET formation was detected in the lung tissues in the sepsis group, which were significantly higher than those in sham group [WT mice: (34.75±7.27)% vs. (1.75±0.96)%, Tph1KO mice: (14.25±5.74)% vs. (2.50±1.29)%, both P < 0.01], and the amount of NET produced in the lung tissues of the WT mice sepsis group was significantly higher than that of the Tph1KO mice sepsis group [(34.75±7.27)% vs. (14.25±5.74)%, P < 0.01]. CONCLUSIONS: In sepsis, the increased production of inflammatory factors in the mice lung tissues induces to lung injury. The mechanism may relate to the increased production of NET in the lung tissues mediated by peripheral 5-HT synthesized by enterochromaffin cells and released into the blood; inhibiting the production of 5-HT in the peripheral blood can effectively reduce the production of NET in the lung tissues, thereby reducing lung injury.

Endocrine Manifestations in POEMS Syndrome: a case report and literature review.

BACKGROUND: POEMS syndrome, a rare systemic disease, is characterized by 5 components: Peripheral neuropathy, Organomegaly, Endocrinopathy, M protein elevation, and Skin changes. It usually presents with multiplex endocrine manifestations and is easily misdiagnosed and incorrectly treated. CASE PRESENTATION: We report herein a case of POEMS syndrome that initially presented as hyperpigmentation and severe pitting edema of the lower extremities. Throughout the patient's multiple hospitalizations for more than one year, he was treated erroneously for Addison's disease and primary hypothyroidism due to the presence of limb numbness and weight loss. In addition, he was misdiagnosed with diabetic peripheral neuropathy due to a history of type 2 diabetes mellitus. CONCLUSION: Endocrinopathy is a critical feature of POEMS syndrome but its mechanisms are still poorly understood. The most common endocrine abnormality is hypogonadism, and the second is adrenal insufficiency, followed by hypothyroidism and subclinical hypothyroidism, then diabetes or glucose intolerance. In cases of the coexistence of endocrinopathy and unexplained peripheral neuropathy, especially in multisystem disorders, POEMS syndrome should be considered. Endocrine evaluation including thyrotropin, free thyroxine, fasting glucose, gonadal hormones, prolactin, cortisol, ACTH, and calcium should be assessed. The purpose of the current report was to provide increased awareness of POEMS syndrome.

The Genital Tract Virulence Factor pGP3 Is Essential for Chlamydia muridarum Colonization in the Gastrointestinal Tract.

The cryptic plasmid is essential for Chlamydia muridarum dissemination from the genital tract to the gastrointestinal (GI) tract. Following intravaginal inoculation, a C. muridarum strain deficient in plasmid-encoded pGP3 or pGP4 but not pGP5, pGP7, or pGP8 failed to spread to the mouse gastrointestinal tract, although mice infected with these strains developed productive genital tract infections. pGP3- or pGP4-deficient strains also failed to colonize the gastrointestinal tract when delivered intragastrically. pGP4 regulates pGP3, while pGP3 does not affect pGP4 expression, indicating that pGP3 is critical for C. muridarum colonization of the gastrointestinal tract. Mutants deficient in GlgA, a chromosome-encoded protein regulated by pGP4, also consistently colonized the mouse gastrointestinal tract. Interestingly, C. muridarum colonization of the gastrointestinal tract positively correlated with pathogenicity in the upper genital tract. pGP3-deficient C. muridarum strains did not induce hydrosalpinx or spread to the GI tract even when delivered to the oviduct by intrabursal inoculation. Thus, the current study not only has revealed that pGP3 is a novel chlamydial colonization factor in the gastrointestinal tract but also has laid a foundation for investigating the significance of gastrointestinal Chlamydia.

Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins.

Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP). Eliminating the positive charge of the n-region blocked post-translational translocation of newly synthesized preproteins and selectively impaired translocation efficiency of small secretory preproteins. The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY). Remarkably, we have found that slowing the polypeptide elongation rate of small secretory preproteins could alleviate the translocation defect caused by loss of the n-region positive charge of the signal peptide. Together, these data reveal not only a previously unrecognized role of the n-region's positive charge in ensuring efficient post-translational translocation of small secretory preproteins, but they also highlight the molecular contribution of defects in this process to the pathogenesis of genetic disorders such as MODY.

Critical role of environmental factors in the pathogenesis of psoriasis.

Psoriasis is a common cutaneous disease with multifactorial etiology including genetic and non-genetic factors, such as drugs, smoking, drinking, diet, infection and mental stress. Now, the role of the interaction between environmental factors and genetics are considered to be a main factor in the pathogenesis of psoriasis. However, it is a challenge to explore the mechanisms how the environmental factors break the body balance to affect the onset and development of psoriasis. In this article, we review the pathogenesis of psoriasis and summarize numerous clinical data to reveal the association between environmental factors and psoriasis. In addition, we focus on the mechanisms of environmental risk factors impact on psoriasis and provide a series of potential treatments against environmental risk factors.