Effect of the Synthetic Bile Salt Analog CamSA on the Hamster Model of Clostridium difficile Infection

Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and has gained worldwide notoriety due to emerging hypervirulent strains and the high incidence of recurrence. We previously reported protection of mice from CDI using the antigerminant bile salt analog CamSA. Here we describe the effects of CamSA in the hamster model of CDI. CamSA treatment of hamsters showed no toxicity and did not affect the richness or diversity of gut microbiota; however, minor changes in community composition were observed. Treatment of C. difficile-challenged hamsters with CamSA doubled the mean time to death, compared to control hamsters. However, CamSA alone was insufficient to prevent CDI in hamsters. CamSA in conjunction with suboptimal concentrations of vancomycin led to complete protection from CDI in 70% of animals. Protected animals remained disease-free at least 30 days postchallenge and showed no signs of colonic tissue damage. In a delayed-treatment model of hamster CDI, CamSA was unable to prevent infection signs and death. These data support a putative model in which CamSA reduces the number of germinating C. difficile spores but does not keep all of the spores from germinating. Vancomycin halts division of any vegetative cells that are able to grow from spores that escape CamSA

Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family

Background: Familial papillary thyroid cancer (fPTC) is recognized as a distinct entity only recently and no fPTC predisposing genes have been identified. Several potential regions and susceptibility loci for sporadic PTC have been reported. We aimed to evaluate the role of the reported susceptibility loci and potential risk genomic region in a Chinese familial multinodular goiter (fMNG) with PTC family. Methods: We sequenced the related risk genomic regions and analyzed the known PTC susceptibility loci in the Chinese family members who consented to join the study. These loci included (1) the point mutations of the BRAF and RET; (2) the possible susceptibility loci to sporadic PTC; and (3) the suggested potential fMNG syndrome with PTC risk region. Results: The members showed no mutations in the common susceptible BRAF and RET genomic region, although contained several different heterozygous alleles in the RET introns. All the members were homozygous for PTC risk alleles of rs966423 (C) at chromosome 2q35, rs2910164 (C) at chromosome 5q24 and rs2439302 (G) at chromosome 8p12; while carried no risk allele of rs4733616 (T) at chromosome 8q24, rs965513 (A) or rs1867277 (A) at chromosome 9q22 which were associated with radiation-related PTC. The frequency of the risk allele of rs944289 (T) but not that of rs116909374 (T) at chromosome 14q13 was increased in the MNG or PTC family members. Conclusions: Our work provided additional evidence to the genetic predisposition to a Chinese familial form of MNG with PTC. The family members carried quite a few risk alleles found in sporadic PTC; particularly, homozygous rs944289 (T) at chromosome 14q13 which was previously shown to be linked to a form of fMNG with PTC. Moreover, the genetic determinants of radiation-related PTC were not presented in this family

Global Proteomic Analysis of the Resuscitation State of Vibrio parahaemolyticus Compared With the Normal and Viable but Non-culturable State

Vibrio parahaemolyticus is a common pathogen which has become a major concern of seafood products. The bacteria in the viable but non-culturable (VBNC) state are unable to form colonies on growth media, but under appropriate conditions they can regain culturability. In this study, V. parahaemolyticus was induced into VBNC state at low temperature and oligotrophic condition, and was resuscitated to culturable state. The aim of this study is to explore the comparative proteomic profiles of the resuscitation state compared with the VBNC state and the exponential phase of V. parahaemolyticus using isobaric tags for relative and absolute quantitation (iTRAQ) technique. The differentially expressed proteins (DEPs) were subjected to GO functional annotations and KEGG pathway analysis. The results indicated that a total of 429 proteins were identified as the significant DEPs in the resuscitation cells compared with the VBNC cells, including 330 up-regulated and 99 down-regulated DEPs. Meanwhile, the resuscitation cells displayed 25 up-regulated and 36 down-regulated DEPs (total of 61 DEPs) in comparison with the exponential phase cells. The remarkable DEPs including ribosomal proteins, ABC transporters, outer membrane proteins and flagellar proteins. GO annotation showed that the 429 DEPs were classified into 37 GO terms, of which 17 biological process (BP) terms, 9 cellular component (CC) terms and 11 molecular function (MF) terms. The up-regulated proteins presented in all GO terms except two terms of developmental process and reproduction. The 61 DEPs were assigned to 23 GO terms, the up- and down-regulated DEPs were both mainly involved in cellular process, establishment of localization, metabolic process and so on. KEGG pathway analysis revealed that the 429 DEPs were assigned to 35 KEGG pathways, and the pathways of ribosome, glyoxylate and dicarboxylate metabolism were significantly enriched. Moreover, the 61 DEPs located in 26 KEGG pathways, including the significantly enriched KEGG pathways of ABC transporters and two-component system. This study would contribute to a better understanding of the molecular mechanism underlying the resuscitation of the VBNC state of V. parahaemolyticus

Comparative analysis of aroma components and quality of Geotrichum candidum after space mutation breeding

AimThe aroma-producing strain of Geotrichum candidum GDMCC60675 was taken as the research object, the composition of aroma-producing substances of G. candidum was studied, and the target strains of G. candidum suitable for food additives were screened out by mutagenesis.MethodsMutants were obtained by space breeding. The colony morphology and cell morphology of the mutant strain were identified, the phylogenetic tree of the two strains was constructed, and the whole-genome sequences of the wild strain and the mutant strain were compared. The aroma components and key odor compounds of the two strains were analyzed and compared by HS-SPME-GC-MS and E-nose detection, and the data were processed by using the relative odor activity value (ROAV) analysis method.ResultsA mutant strain of G. candidum was found with different characteristics of aroma production compared with wild-type G. candidum. It was found that its colony morphology and cell morphology were similar. However, it was found that the aroma-producing substances produced by the two strains were different, and the key difference compound was phenyl ethyl alcohol, which also proved that the two strains were different, and the main aroma note was different

Prevalence of Vitamin D Inadequacy Among Chinese Postmenopausal Women: A Nationwide, Multicenter, Cross-Sectional Study

Purpose: We aimed to investigate the status of serum 25-hydroxyvitamin D [25(OH)D] among Chinese postmenopausal women in a multicenter cross-sectional study.Methods: Non-institutionalized postmenopausal women aged ≥55 years were recruited from urban and rural areas in 7 geographically different regions in China. Subject enrollment was executed during the summer and the winter. Vitamin D insufficiency and deficiency were defined as 25(OH)D < 30 and< 20 ng/ml, and was measured by liquid chromatography-tandem mass spectrometry. Women were referred to a dual-energy x-ray absorptiometry (DXA) if they had a medium-to-high fracture risk suggested by Osteoporosis Self-Assessment Tool for Asians (OSTA).Results: Among all subjects, 91.2% (1,535/1,684, 95%CI: 89.7, 92.5) had vitamin D insufficiency and 61.3% had vitamin D deficiency (1,033/1,684, 95%CI: 59.0, 63.7). The prevalence of vitamin D deficiency was significantly higher in urban dwellers (64.9 vs. 57.7% in rural, P = 0.002) and in winter-enrolled subjects (84.7 vs. 41.3% in summer, P < 0.0001). The prevalence of vitamin D inadequacy did not increase in trend by latitude and was numerically lower in women who had high fracture risk and osteoporosis. A non-curvilinear change of intact parathyroid hormone (iPTH) levels was observed at 25(OH)D >16.78 ng/mL.Conclusions: The prevalence of vitamin D inadequacy was remarkable among Chinese postmenopausal women and independent of fracture risk assessed by OSTA or osteoporosis suggested by DXA. Winter season, urban residence, however not latitude, were significantly associated with a higher likelihood of vitamin D deficiency. Optimal vitamin D status for iPTH and bone-related outcomes merits further investigation in this population

Open source board based acoustofluidic transwells for reversible disruption of the blood–brain barrier for therapeutic delivery

Background: Blood–brain barrier (BBB) is a crucial but dynamic structure that functions as a gatekeeper for the central nervous system (CNS). Managing sufficient substances across the BBB is a major challenge, especially in the development of therapeutics for CNS disorders. Methods: To achieve an efficient, fast and safe strategy for BBB opening, an acoustofluidic transwell (AFT) was developed for reversible disruption of the BBB. The proposed AFT was consisted of a transwell insert where the BBB model was established, and a surface acoustic wave (SAW) transducer realized using open-source electronics based on printed circuit board techniques. Results: In the AFT device, the SAW produced acousto-mechanical stimulations to the BBB model resulting in decreased transendothelial electrical resistance in a dose dependent manner, indicating the disruption of the BBB. Moreover, SAW stimulation enhanced transendothelial permeability to sodium fluorescein and FITC-dextran with various molecular weight in the AFT device. Further study indicated BBB opening was mainly attributed to the apparent stretching of intercellular spaces. An in vivo study using a zebrafish model demonstrated SAW exposure promoted penetration of sodium fluorescein to the CNS. Conclusions: In summary, AFT effectively disrupts the BBB under the SAW stimulation, which is promising as a new drug delivery methodology for neurodegenerative diseases. Graphical Abstract

The Oxygen Paradox, the French Paradox, and age-related diseases

open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

The Influence of Social Norms and Environmental Regulations on Rural Households’ Pesticide Packaging Waste Disposal Behavior

The agricultural ecological environment provides an important resource guarantee for social development. The extensive management mode of agriculture in China has not fundamentally changed; the contradiction between production and governance is still prominent, and the management of agricultural surface pollution has a long way to go. Based on the data from 572 rural households in Jiangxi province, this paper uses the Ordered Logit, 2SLS, and the moderation effect model to analyze the mechanism between social norms (SNs) and rural households’ (RHs) disposal of pesticide packaging waste (PPW) and to test the moderation effect of environmental regulation (ER) in the influence path of SN to RHs’ disposal of PPW. The results show that (1) descriptive norms and directive norms promote RHs not littering PPW; the probability of RHs not littering PPW increases by 4.0% for each unit decrease in descriptive norms, and the probability of RHs not littering PPW increases by 12.1% when there are directive norms, but the directive norms are more significant than the descriptive norms. Consistent conclusions were obtained after the robustness test and endogeneity treatment. (2) Reputational incentives strengthen the promotional effect of directive norms on RHs’ behavior of not littering PPW; punitive regulations hinder the promotional effect of descriptive norms on RHs’ behavior of not littering PPW. Based on the findings of the study, the following policy recommendations are put forward: Actively cultivate SNs and give full play to their role in promoting RHs’ choice of the disposal behavior of PPW; improve the role of ER in regulating RHs’ choice of the disposal behavior of PPW; guide the ER and SNs to work in coordination

To Explore the Low-dose CT and QCT “One-stop-shop”Scan Technology for Physical Examination Crowd

Objective: To explore the application of noise index combined with automatic tube current regulation technology in the one-stop scanning of chest and lumbar QCT physical examination. Method: 100 patients who unferwent thoracic CT and lumbar QCT scan in our medical examination were prospectively collected and randomly divided into two groups( conventional dose group and ow dose group). There were 50 patients in the conventianl group (noise index set to NI=8.5) and 50 patients in the low dose group (noise index set to NI=14). Their height, weight and BMI were recorded, as well as the mean BMD of L1, L2 in both radiation and low dose groups, and L1, L2 in the conventional dose group. The differences of radiation dose and mean bone mineral density between the two groups were compared. Results: The average scanning dose was 387.65 mGy in the conventional dose group and 73.18 mGy in the low dose group. There was statistical differences in radiation dose between the two groups. The mean bone mineral density (BMD) of L1 and L2 was 119.71 in the conventional dose group, and that of L1 and L2 was 123.65 in the low dose group. There was no statistical difference between the two groups. Conclusion: Low dose CT scan of thoracic and lumbar spine can not only meet the needs of lung screening and bone mineral density assessment but also greatly reduce radiation dose. It can be widely used in physical examination