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Introduction Xerostomia is a symptom of self-consciousness, not an independent disease (Tanasiewicz et al. 2016). The prevalence of xerostomia in the population is about 10%-46% and increases with age (Sreebny [...], Xerostomia is a self-conscious symptom. High-mobility group box 1 (HMGB1) promotes pro-inflammatory effects in many diseases. This study aimed to clarify the role of HMGB1 in Sjogren syndrome (SS)-triggered xerostomia. Nonobese diabetic (NOD)/Ltj mice were used to establish an SS-triggered xerostomia model. The results showed that saliva production was decreased and anti-Sjogren syndrome B (anti-SSB) level was increased in SS. PCR, Western blot, and immunohistochemistry experiments indicated that the HMGB1 and aquaporin 5 (AQP5) levels were enhanced and diminished in SS compared with those in the control, respectively. While the mice were treated with anti-HMGB1, xerostomia was reversed due to the elevated saliva production and reduced anti-SSB level. In addition, it was found that the inhibition of HMGB1 restrained the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-[kappa]B) axis activation. The TLR4 and p-I[kappa]B levels were alleviated, while the I[kappa]B[alpha] and NF-[kappa]B p65 levels were augmented. The NF-[kappa]B p65 binding activity was attenuated via the electrophoretic mobility shift assay (EMSA) after anti-HMGB1 treatment. Moreover, the repression of HMGB1 facilitated the expression of AQP5. These findings demonstrate that suppression of HMGB1 ameliorates SS-triggered xerostomia via suppressing the HMGB1/TLR4/NF-[kappa]B signaling pathway and upregulating AQP5 expression. Key words: high-mobility group box 1, AQP5, xerostomia, TLR4, NF-[kappa]B. La xerostomie est un symptome embarrassant. Le HMGB1 (pour << high-mobility group box 1 >>) favorise des effets pro-inflammatoires dans bien des maladies. Cette etude visait a clarifier le role du HMGB1 dans la xerostomie entrainee par le syndrome de Sjogren (SS). Nous avons obtenu un modele de xerostomie entrainee par le SS a l'aide de la souris diabetique non obese (NOD)/Ltj. Les resultats ont montre une diminution de la production de salive avec une augmentation des taux d'anti-SSB (pour << anti- Sjogren syndrome B >>) dans le groupe SS. Les experiences de PCR, d'immunobuvardage de Western et d'immunohistochimie ont montre une augmentation des taux de HMGB1 et une diminution des taux d'aquaporine 5 (AQP5) plus marquees dans le groupe SS que chez les temoins. Avec l'administration d'anti-HMGB1 aux souris, nous avons observe une inversion de la xerostomie par une augmentation de la production de salive et une diminution des taux d'anti-SSB. De plus, nous avons observe que l'inhibition du HMGB1 permettait d'inhiber l'axe d'activation TLR4 (pour << toll-like receptor 4 >>)/facteur nucleaire kappa B (NF-[kappa]B). Les taux de TLR4 et de p-I[kappa]B diminuaient tandis que les taux d'lKB[alpha] et de NF-[kappa]B p65 augmentaient. Le retard sur gel (ou EMSA pour << electrophoretic mobility shift assay >>) montrait que l'activite de liaison du NF-[kappa]B p65 s'attenuait apres l'administration d'anti-HMGB1. De plus, l'inhibition du HMGB1 permettait de faciliter l'expression de l'AQP5. Ces resultats montrent que l'inhibition du HMGB1 permet d'attenuer la xerostomie entrainee par le SS par l'intermediaire de l'inhibition de la voie de signalisation HMGB1/TLR4/NF-[kappa]B et de la regulation a la hausse de l'expression de l'AQP5. [Traduit par la Redaction] Mots-cles: high-mobility group box 1, AQP5, xerostomie, TLR4, NF-[kappa]B.

Author(s): Kavin G. Shah [sup.1], Rongqian Wu [sup.1] [sup.2], Asha Jacob [sup.1] [sup.2], Ernesto P. Molmenti [sup.1], Jeffrey Nicastro [sup.1], Gene F. Coppa [sup.1], Ping Wang [sup.1] [sup.2] Author Affiliations: [...], Purpose Animal milk fat globule-EGF factor 8 (MFG-E8) has been shown to be beneficial in attenuating the inflammatory response in sepsis. In this study, we examined the effect of recombinant human MFG-E8 (rhMFG-E8) in an animal model of sepsis in an effort to develop it as a potential therapy against sepsis in humans. Methods Rats were subjected to sepsis by cecal ligation and puncture (CLP), and at 5 h post-CLP, they were given different doses of rhMFG-E8 (20, 40, 80, 160 [mu]g/kg BW) in normal saline. At 20 h post-CLP, samples were collected for further analysis. A 10-day survival study was also performed. Results At 20 h after CLP, organ injury indicators, serum IL-6 and TNF-[alpha], and plasma HMGB-1 levels were significantly increased as compared to sham-operated animals. Treatment with 20 [mu]g/kg rhMFG-E8 significantly reduced these levels. With higher doses, further reductions in AST and ALT (59-62%), creatinine (65-68%), and lactate (46-57%), and serum IL-6 and TNF-[alpha] were obtained. The 160 [mu]g/kg dose produced the greatest reduction in serum TNF-[alpha]. With treatment with 20 [mu]g/kg rhMFG-E8, HMGB-1 levels decreased by 80%, returning back to sham values. In a 10-day survival study, vehicle-treated animals produced a 36% survival rate, while rhMFG-E8 significantly improved the survival rate to 68-72%. Treatment with increasing doses of rhMFG-E8 significantly reduced the number of apoptotic cells detected and markedly attenuated the tissue damages observed in the lungs. Conclusions These data suggest that recombinant human MFG-E8 is beneficial in ameliorating sepsis in an animal model of sepsis.

Author(s): Tatenobu Goto [sup.1], Mohamed Hamed Hussein [sup.3] [sup.5], Shin Kato [sup.1], Ghada Abdel-Hamid Daoud [sup.4], Takenori Kato [sup.1], Hiroki Kakita [sup.1], Haruo Mizuno [sup.1], Masaki Imai [sup.2], Tetsuya Ito [...], Purpose To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model. Method Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR-P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-[alpha], and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP. Results Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-[alpha], NOx, and HMGB1. ETR-P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-[alpha], NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 ± 2.3 h vs. 9.0 ± 0.8 h, p < 0.01). Conclusions ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-[alpha], and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.07.047 Byline: Shinya Ohta (1), Jimi-Carlo Bukowski-Wills (1)(2), Luis Sanchez-Pulido (4), Flavia de Lima Alves (1), Laura Wood (1), Zhuo A. Chen (1), Melpi Platani (1), Lutz Fischer (1), Damien F. Hudson (1), Chris P. Ponting (4), Tatsuo Fukagawa (3), William C. Earnshaw (1), Juri Rappsilber (1) Keywords: CELLBIO; PROTEINS; SYSBIO Abstract: Despite many decades of study, mitotic chromosome structure and composition remain poorly characterized. Here, we have integrated quantitative proteomics with bioinformatic analysis to generate a series of independent classifiers that describe the [approximately equal to]4,000 proteins identified in isolated mitotic chromosomes. Integrating these classifiers by machine learning uncovers functional relationships between protein complexes in the context of intact chromosomes and reveals which of the [approximately equal to]560 uncharacterized proteins identified here merits further study. Indeed, of 34 GFP-tagged predicted chromosomal proteins, 30 were chromosomal, including 13 with centromere-association. Of 16 GFP-tagged predicted nonchromosomal proteins, 14 were confirmed to be nonchromosomal. An unbiased analysis of the whole chromosome proteome from genetic knockouts of kinetochore protein Ska3/Rama1 revealed that the APC/C and RanBP2/RanGAP1 complexes depend on the Ska complex for stable association with chromosomes. Our integrated analysis predicts that up to 97 new centromere-associated proteins remain to be discovered in our data set. Author Affiliation: (1) Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK (2) Centre for Systems Biology at Edinburgh, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JR, UK (3) Department of Molecular Genetics, National Institute of Genetics and The Graduate University for Advanced Studies, Mishima, Shizuoka 411-8540, Japan (4) MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK Article History: Received 7 December 2009; Revised 20 May 2010; Accepted 14 July 2010 Article Note: (miscellaneous) Published: September 2, 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.06.027 Byline: Yanbin Zhang (1), Fenghua Yuan (1), Steven R. Presnell (2), Keli Tian (1), Yin Gao (2), Alan E. Tomkinson (4), Liya Gu (1)(2), Guo-Min Li (1)(2)(3) Abstract: This paper reports reconstitution of 5'-nick-directed mismatch repair using purified human proteins. The reconstituted system includes MutS[alpha] or MutS[beta], MutL[alpha], RPA, EXO1, HMGB1, PCNA, RFC, polymerase [delta], and ligase I. In this system, MutS[beta] plays a limited role in repair of base-base mismatches, but it processes insertion/deletion mispairs much more efficiently than MutS[alpha], which efficiently corrects both types of heteroduplexes. MutL[alpha] reduces the processivity of EXO1 and terminates EXO1-catalyzed excision upon mismatch removal. In the absence of MutL[alpha], mismatch-provoked excision by EXO1 occurs extensively. RPA and HMGB1 play similar but complementary roles in stimulating MutS[alpha]-activated, EXO1-catalyzed excision in the presence of a mismatch, but RPA has a distinct role in facilitating MutL[alpha]-mediated excision termination past mismatch. Evidence is provided that efficient repair of a single mismatch requires multiple molecules of MutS[alpha]-MutL[alpha] complex. These data suggest a model for human mismatch repair involving coordinated initiation and termination of mismatch-provoked excision. Author Affiliation: (1) Graduate Center for Toxicology and Markey Cancer Center, University of Kentucky Medical Center, Lexington, Kentucky 40536 (2) Department of Pathology, University of Kentucky Medical Center, Lexington, Kentucky 40536 (3) Department of Molecular and Cellular Biochemistry, University of Kentucky Medical Center, Lexington, Kentucky 40536 (4) Department of Radiation Oncology and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201 Article History: Received 4 February 2005; Revised 13 May 2005; Accepted 16 June 2005 Article Note: (miscellaneous) Published: September 8, 2005

The refined model of the self-assembled bacteriochlorphyll c from Chlorobium tepidum exhibits chlorophyll stacks in either anti- or syn-configuration analogous to the aggregation shifts of the chlorophyll in the bacterial chromosome. Data predict a bilayer model for the tubular supra-structure sheets of bacteriochlorophyll c.

Results show that a 46.5-kDA protein, encoded by the chromosomal determinant eep (enhanced expression of pheromone), has a role in the production of the octapeptide sex pheromone cADI and other pheromones.

The binding of the scaffold/matrix attachment region binding protein hnRNP-U (SAF-A) with chromosomal DNA in vivo was probed through utilization of chemical cross-linking studies. Formaldehyde treated DNA/protein complexes were purified over two cesium chloride gradients and were analyzed for their protein components following cross-link reversal. The observed protein peak evident in the fractions of with DNA/protein complexes confirmed that the proteins were components of cross-linked chromatin.

An immunoaffinity approach utilizing antibodies against XCAP-C and XCAP-E was utilized for the purification and analysis of the chromosome condensation protein complexes. Analysis of the XCAP-C and XCAP-E multiprotein complexes indicated the presence of two major forms of condesins that were homologous to the Xenopus SMC family of proteins. Furthermore, the condesin complexes were characterized as components of the chromosome assembly machinery.

The variable lipoprotein system in Mycoplasma hyorhinis was studied and found capable of generating tremendously diverse surface proteins by using a different vlp genes. The vlp repertoire in the GDL-1 strain of the bacterium has the sequence 5'-vlpD-vlpE-vlpF-IS1221-vlpA-IS1221-vlpB- vlpC-3'. vlpD, vlpE, and vlpF contain alternative reading frames and code for repetitive regions with variable sizes.

Analysis of the factors essential for reassembled yeast kinetochore binding to microtubules in Saccharomyces cerevisiae shows that CBF3 protein is vital for the binding. Cellular factors also react with CBF3 to develop functional microtubule-binding complexes with the CDEIII region of centromeric DNA mediating the interaction. All factors mediating the binding of kinetochores to microtubules reside on the core complex that contains DNA-bound CBF3.

Molecular studies of the human centromere protein-A (CENP-A) using a human cDNA clone encoding a 17-kDa histone-like centromere antigen reveal that CENP-A consists of a histone H3-related histone fold domain which mediates the centromere targeting. CENP-A polypeptide contains a 93-amino acid COOH-terminal domain and a NH2-terminal domain, with the COOH terminal domain having 62% identity with histone H3. Introduction of the novel core histone into the centromeric chromatin stimulates the centromere assembly.

A DNA structure in polytene chromosomes of Chironomus thummi thummi, when treated with a pH of 3.6, did not aid protein extraction while a treatment incorporating 45% acetic acid facilitated the extraction of 50% of chromosomal proteins. Raman microspectroscopy was used to study the influence of low pH-treatment on the polytene chromosome's DNA structure.

DNA repair protein Ref-1 reduces the cysteine residue in the DNA-binding domain of Fos and Jun and induces DNA-repair activities of Fos-Jun dimers. A series of synthetically prepared deletion mutants facilitates the analysis of redox and repair functions of Ref-1. C-terminal sequences of Ref-1 protein determines DNA-repair activity.