bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute phase protein expressions in secretory and cistern lining epithelium tissues of the dairy cattle mammary gland during chronic mastitis caused by staphylococci
Authors: Zalewska M. , Kawecka-Grochocka E. , Słoniewska D. , Kościuczuk E. , Marczak S. , Jarmuż W. , Zwierzchowski L. , Bagnicka E.
Published: August 2020

Background

Mastitis is the most common disease in dairy cattle and the costliest for the dairy farming industry, as it lowers milk yield and quality. Mastitis occurs as a result of interactions between microorganisms and the individual genetic predispositions of each animal. Thus, it is important to fully understand the mechanisms underlying these interactions. Elucidating the immune response mechanisms can determine which genetic background makes an animal highly resistant to mastitis. We analyzed the innate immune responses of dairy cows naturally infected with coagulase-positive staphylococci (CoPS; N = 8) or coagulase-negative staphylococci (CoNS; N = 7), causing persistent mastitis (after several failed treatments) vs. infection-free (i.e., healthy [H]; N = 8) dairy cows. The expressions of the acute phase protein genes serum amyloid A3 (SAA3), haptoglobin (HP), ceruloplasmin (CP) genes in the tissues most exposed to pathogens— mammary gland cistern lining epithelial cells (CLECs) and mammary epithelial cells (MECs)—were analyzed.

Results

We found constitutive and extrahepatic expressions of the studied genes in both tissue types. HP expression in the MECs of the CoPS-infected group was higher than in the H group (p ≤ 0.05). Moreover, higher SAA3 expression in the CoPS and CoNS groups than in the H group (p = 0.06 and 0.08, respectively) was found. No differences between SAA3 and HP in CLECs were revealed, regardless of the pathogen type. However, higher expression of CP (p ≤ 0.05) in the CoPS group than in the H group was noted.

Conclusions

The expressions of selected acute phase proteins were similar between CLECs and MECs, which means that CLECs are not only a mechanical barrier but are also responsible for the biological immune response. Our findings agree with the results of other authors describing the immunological response of MECs during chronic mastitis, but the results for CLECs are novel.
Epstein–Barr virus infection and genome polymorphisms on gastric remnant carcinoma: a meta-analysis
Authors: Lu Chao , Zhang Hongtao , Zhou Weihua , Wan Xingyong , Li Lan , Yu Chaohui
Published: August 2020

Background

Previous studies reported that Epstein–Barr virus (EBV) may play a causal role in the pathogenesis of gastric remnant carcinoma (GRC). However, there was still some controversy.

Methods

Articles published until July 15, 2020, in PubMed, MEDLINE, Embase and CNKI databases were selected. According to the inclusion criteria, corresponding data of included articles were abstracted and used for statistical analysis.

Results

Thirteen papers were finally enrolled, nine of which showed the result that the risk of EBV infection rate in the GRC was higher than conventional gastric carcinoma (OR = 5.22, 95% CI 3.89–7.00). In addition, we found that EBV associated GRC (EBVaGRC) had higher rate of Billroth-II (OR = 3.80, 95% CI 1.90–7.57), carcinoma in anastomotic site (OR = 2.41, 95% CI 1.27–4.56) and diffuse type (Lauren classification) (OR = 1.97, 95% CI 1.04–3.73),while sex, initial diagnosis and lymphocytic infiltration were calculated no statistical difference. By genetic polymorphism analysis, “V-val” subtype of EBNA1 (OR = 21.84, 95% CI 11.92–31.76) and “C” subtype of BamHI-W1/I1 (OR = 7.07, 95% CI 1.47–34.03) were observed to be highly expressed in EBVaGRC.

Conclusion

EBV infection rate in the GRC was higher. Further analysis showed that Billroth-II, carcinoma in anastomotic site and diffuse type (Lauren classification) were associated to EBVaGRC. Through analysis of EBV genome polymorphisms, we thought that “V-val” subtype of EBNA1 and “C” subtype of BamHI-W1/I1 may become predictor of EBVaGRC.
Correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds
Authors: Tam Dao Ngoc Hien , Tawfik Gehad Mohamed , El-Qushayri Amr Ehab , Mehyar Ghaleb Muhammad , Istanbuly Sedralmontaha , Karimzadeh Sedighe , Tu Vo Linh , Tiwari Ranjit , Van Dat Truong , Nguyen Phuong Thuy Viet , Hirayama Kenji , Huy Nguyen Tien
Published: August 2020

Background

Despite noticeable improvement in anti-malarial treatment, rapid growth of resistant malaria strains points out the need for continuous development of novel anti-malarials to fight the disastrous infection. Haemozoin is considered as a novel inhibitory pathway for new anti-malarial drugs, therefore, this study aimed to systematically review all articles investigating the correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds.

Methods

A literature search was conducted on 22 October 2017 in eight databases for relevant in vitro articles reporting the correlation between anti-malarial and anti-haemozoin of anti-malarial compounds, based on the constructed search terms and inclusion criteria. ToxRtool was used to assess quality of each study.

Results

A total of ten articles were included in the review. In vitro anti-malarial and anti-haemozoin activity had a good correlation for quinolines for sensitive strains (R2 ranging from 0.66 to 0.95) and xanthones (Spearman ρ = 0.886). However, these correlations were reached after removing some compounds which had non-detectable anti-malarial or anti-haemozoin effects. Other structures (acridines, pyrolidines) showed negligible correlation with Spearman ρ ranging from 0.095 to 0.381 for acridines, and r varying from 0.54 to 0.62 for pyrolidines. Some good correlations were only shown in a logarithmic manner or when the anti-malarial activity was normalized.

Conclusion

The results raised a relative relationship between anti-haemozoin and in vitro anti-malarial activities. Some studies reported compounds that were effective in the inhibition of haemozoin formation, but failed to inhibit the parasite survival and vice versa. The correlation results in these studies were calculated after these compounds were removed from their analysis. The ability of anti-malarial compounds to accumulate inside the reaction site might strengthen their anti-malarial activity.
Quantification of Plasmodium knowlesi versus Plasmodium falciparum in the rhesus liver: implications for malaria vaccine studies in rhesus models
Authors: Shears Melanie J. , Seilie Annette M. , Kim Lee Sim B. , Hoffman Stephen L. , Murphy Sean C.
Published: August 2020

Background

Rhesus macaques are valuable pre-clinical models for malaria vaccine development. ThePlasmodium knowlesi/rhesus andPlasmodium falciparum/rhesus models are two established platforms for malaria vaccine testing, and both have previously been used to assess live-attenuated sporozoite vaccines. However, there is evidence that the susceptibility of the rhesus liver toP. knowlesiversusP. falciparumsporozoites likely differs, potentially complicating comparisons between these two platforms.

Methods

To quantify the differing susceptibility of rhesus toP. knowlesiandP. falciparumsporozoites, animals were infected by direct venous inoculation of purified, cryopreserved wild-typeP. knowlesisporozoites (PkSPZ) orP. falciparumsporozoites (PfSPZ). The entire liver was collected 5 days post-infection, and parasite burden in each liver lobe was quantified using an ultrasensitivePlasmodium18S rRNA RT-PCR biomarker assay. The potential of using 18S rRNA copy number in the rhesus liver to directly measure the efficacy of vaccines targetingP. falciparumsporozoites and liver stages was also theoretically evaluated.

Results

Infection of rhesus with a high dose of PkSPZ led to consistently high burden liver stage infections (range 9.5–10.1 log10copies 18S rRNA/g of liver), with similar amounts of parasite 18S rRNA detected in every liver lobe. Inoculation of rhesus with high doses of PfSPZ led to more variable, lower liver burdens (range 4.9–6.6 log10copies 18S rRNA/g of liver in infected lobes), with parasite 18S rRNA below the limit of detection in some liver lobes. The low signal and heterogeneity of liver burden in the PfSPZ-infected animals indicates that even this extremely sensitive molecular assay cannot be used to assess reliably vaccine efficacy in theP. falciparum/rhesus platform.

Conclusions

Detection of 18S rRNA in the liver following high dose intravenous PfSPZ confirmed that rhesus are modestly susceptible to wild-typeP. falciparumsporozoites. However, comparison of 18S rRNA RT-PCR biomarker signal indicates that theP. falciparumliver burden was 3–5 logs lower than in PkSPZ-infected animals. Quantification of this difference in liver stage burden will help guide and interpret data from pre-clinical studies of live-attenuated sporozoite vaccines in rhesus models.
Insecticide resistance in indoor and outdoor-resting Anopheles gambiae in Northern Ghana
Authors: Hamid-Adiamoh Majidah , Amambua-Ngwa Alfred , Nwakanma Davis , D’Alessandro Umberto , Awandare Gordon A. , Afrane Yaw A.
Published: August 2020

Background

Selection pressure from continued exposure to insecticides drives development of insecticide resistance and changes in resting behaviour of malaria vectors. There is need to understand how resistance drives changes in resting behaviour within vector species. The association between insecticide resistance and resting behaviour of Anopheles gambiae sensu lato (s.l.) in Northern Ghana was examined.

Methods

F1 progenies from adult mosquitoes collected indoors and outdoors were exposed to DDT, deltamethrin, malathion and bendiocarb using WHO insecticide susceptibility tests. Insecticide resistance markers including voltage-gated sodium channel (Vgsc)-1014F, Vgsc-1014S, Vgsc-1575Y, glutathione-S-transferase epsilon 2 (GSTe2)-114T and acetylcholinesterase (Ace1)-119S, as well as blood meal sources were investigated using PCR methods. Activities of metabolic enzymes, acetylcholine esterase (AChE), non-specific β-esterases, glutathione-S-transferase (GST) and monooxygenases were measured from unexposed F1 progenies using microplate assays.

Results

Susceptibility of Anopheles coluzzii to deltamethrin 24 h post-exposure was significantly higher in indoor (mortality = 5%) than outdoor (mortality = 2.5%) populations (P = 0.02). Mosquitoes were fully susceptible to malathion (mortality: indoor = 98%, outdoor = 100%). Susceptibility to DDT was significantly higher in outdoor (mortality = 9%) than indoor (mortality = 0%) mosquitoes (P = 0.006). Mosquitoes were also found with suspected resistance to bendiocarb but mortality was not statistically different (mortality: indoor = 90%, outdoor = 95%. P = 0.30). Frequencies of all resistance alleles were higher in F1 outdoor (0.11–0.85) than indoor (0.04–0.65) mosquito populations, while Vgsc-1014F in F0An. gambiae sensu stricto (s.s) was significantly associated with outdoor-resting behaviour (P = 0.01). Activities of non-specific β-esterase enzymes were significantly higher in outdoor than indoor mosquitoes (Mean enzyme activity: Outdoor = : 1.70/mg protein; Indoor = 1.35/mg protein. P < 0.0001). AChE activity was also more elevated in outdoor (0.62/mg protein) than indoor (0.57/mg protein) mosquitoes but this was not significant (P = 0.08). Human blood index (HBI) was predominantly detected in indoor (18%) than outdoor mosquito populations (3%).

Conclusions

The overall results did not establish that there was a significant preference of resistant malaria vectors to solely rest indoors or outdoors, but varied depending on the resistant alleles present. Phenotypic resistance was higher in indoor than outdoor-resting mosquitoes, but genotypic and metabolic resistance levels were higher in outdoor than the indoor populations. Continued monitoring of changes in resting behaviour within An. gambiae s.l. populations is recommended.
Potential drug–drug interactions associated with adverse clinical outcomes and abnormal laboratory findings in patients with malaria
Authors: Noor Sidra , Ismail Mohammad , Khadim Faiza
Published: August 2020

Background

Hospitalized patients with malaria often present with comorbidities or associated complications for which a variety of drugs are prescribed. Multiple drug therapy often leads to drug–drug interactions (DDIs). Therefore, the current study investigated the prevalence, levels, risk factors, clinical relevance, and monitoring parameters/management guidelines of potential DDIs (pDDIs) among inpatients with malaria.

Methods

A retrospective cohort study was carried out at two tertiary care hospitals. A total of 398 patients’ profiles were evaluated for pDDIs using the Micromedex Drug-Reax®. Odds ratios were calculated to identify the strength of association between presence of DDIs and potential risk factors via logistic regression analysis. Further, the clinical relevance of frequent pDDIs was investigated.

Results

Of 398 patients, pDDIs were observed in 37.2% patients, while major-pDDIs in 19.3% patients. A total of 325 interactions were found, of which 45.5% were of major- and 34.5% moderate-severity. Patients with the most common pDDIs were found with signs/symptoms and abnormalities in laboratory findings representing nephrotoxicity, hepatotoxicity, QT interval prolongation, and reduced therapeutic efficacy. The following drug pairs reported the highest frequency of adverse events associated with the interactions; calcium containing products-ceftriaxone, isoniazid–rifampin, pyrazinamide–rifampin, isoniazid–acetaminophen, and ciprofloxacin–metronidazole. The adverse events were more common in patients prescribed with the higher doses of interacting drugs. Multivariate regression analysis showed statistically significant association of pDDIs with 5–6 prescribed medicines (p = 0.01), > 6 prescribed medicines (p < 0.001), > 5 days of hospital stay (p = 0.03), and diabetes mellitus (p = 0.04).

Conclusions

PDDIs are commonly observed in patients with malaria. Healthcare professional’s knowledge about the most common pDDIs could help in preventing pDDIs and their associated negative effects. Pertinent clinical parameters, such as laboratory findings and signs/symptoms need to be checked, particularly in patients with polypharmacy, longer hospital stay, and diabetes mellitus.
Modeling the neuro-mechanics of human balance when recovering from a fall: a continuous-time approach
Authors: Cerda-Lugo Angel , González Alejandro , Cardenas Antonio , Piovesan Davide
Published: August 2020

Background

Balance control deteriorates with age and nearly 30% of the elderly population in the United States reports stability problems. Postural stability is an integral task to daily living reliant upon the control of the ankle and hip. To this end, the estimation of joint parameters can be a useful tool when analyzing compensatory actions aimed at maintaining postural stability.

Methods

Using an analytical approach, this study expands on previous work and analyzes a two degrees of freedom human model. The first two modes of vibration of the system are represented by the neuro-mechanical parameters of a second-order, time-varying Kelvin–Voigt model actuated at the ankle and hip. The model is tested using a custom double inverted pendulum and healthy volunteers who were subjected to a positional step-like perturbation during quiet standing. An in silico sensitivity analysis of the influence of inertial parameters was also performed.

Results

The proposed method is able to correctly identify the time-varying visco-elastic parameters of of a double inverted pendulum. We show that that the parameter estimation method can be applied to standing humans. These results appear to identify a subject-independent strategy to control quiet standing that combines both the modulation of stiffness, and the use of an intermittent control.

Conclusions

This paper presents the analysis of the non-linear system of differential equations representing the control of lumped muscle–tendon units. It utilizes motion capture measurements to obtain the estimates of the system’s control parameters by constructing a simple time-dependent regressor for estimating the time-varying parameters of the control with a single perturbation. This work is a step forward into the understanding of the neuro-mechanical control parameters of human recovering from a fall. In previous literature, the analysis is either restricted to the first vibrational mode of an inverted-pendulum model or assumed to be time-invariant. The proposed method allows for the analysis of hip related movement for stability control and highlights the importance of core training.
Perinatal oral exposure to low doses of bisphenol A, S or F impairs immune functions at intestinal and systemic levels in female offspring mice
Authors: Malaisé Yann , Lencina Corinne , Cartier Christel , Olier Maïwenn , Ménard Sandrine , Guzylack-Piriou Laurence
Published: August 2020

Background

Bisphenol A (BPA), one of the highest-volume chemicals produced worldwide, has been identified as an endocrine disruptor. Many peer-reviewing studies have reported adverse effects of low dose BPA exposure, particularly during perinatal period (gestation and/or lactation). We previously demonstrated that perinatal oral exposure to BPA (via gavage of mothers during gestation and lactation) has long-term consequences on immune response and intestinal barrier functions. Due to its adverse effects on several developmental and physiological processes, BPA was removed from consumer products and replaced by chemical substitutes such as BPS or BPF, that are structurally similar and not well studied compare to BPA. Here, we aimed to compare perinatal oral exposure to these bisphenols (BPs) at two doses (5 and 50 μg/kg of body weight (BW)/day (d)) on immune response at intestinal and systemic levels in female offspring mice at adulthood (Post Natal Day PND70).

Methods

Pregnant female mice were orally exposed to BPA, BPS or BPF at 5 or 50 μg/kg BW/d from 15th day of gravidity to weaning of pups at Post-Natal Day (PND) 21. Humoral and cellular immune responses of adult offspring (PND70) were analysed at intestinal and systemic levels.

Results

In female offspring, perinatal oral BP exposure led to adverse effects on intestinal and systemic immune response that were dependant of the BP nature (A, S or F) and dose of exposure. Stronger impacts were observed with BPS at the dose of 5 μg/kg BW/d on inflammatory markers in feces associated with an increase of anti-E. coli IgG in plasma. BPA and BPF exposure induced prominent changes at low dose in offspring mice, in term of intestinal and systemic immune responses, provoking an intestinal and systemic Th1/Th17 inflammation.

Conclusion

These findings provide, for the first time, results of long-time consequences of BPA, S and F perinatal exposure by oral route on immune response in offspring mice. This work warns that it is mandatory to consider immune markers and dose exposure in risk assessment associated to new BPA’s alternatives.
Concentrations of perfluoroalkyl and polyfluoroalkyl substances and blood glucose in pregnant women
Authors: Ren Yanfeng , Jin Longmei , Yang Fen , Liang Hong , Zhang Zhaofeng , Du Jing , Song Xiuxia , Miao Maohua , Yuan Wei
Published: August 2020

Background

Evidence on the association between exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) and blood glucose concentrations in pregnant women is inconsistent. This study aimed to examine the association between PFAS exposure and the concentrations of fasting plasma glucose (FPG) and one-hour plasma glucose (1 h-PG) after a 50-g oral glucose tolerance test in pregnant women.

Methods

The study was based on the Shanghai-Minhang Birth Cohort, in which 1292 pregnant women were recruited. Among them, 981 women provided blood samples (at 12–16 gestational weeks) for PFAS measurement. FPG data collected from 856 women at 12–20 GW and 1 h-PG data collected from 705 women at 20–28 GW were obtained through medical records from the routine prenatal care system. High FPG or 1 h-PG was defined as ≥90th percentile of FPG or 1 h-PG. The analysis of eight PFASs was conducted in this study: perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUdA), perfluorododecanoic acid (PFDoA), and perfluorotridecanoic acid (PFTrDA). The odds ratios (ORs) and associated 95% confidence intervals (CIs) were estimated to determine the associations of each PFAS compound with high FPG and 1 h-PG from a logistic regression model.

Results

After adjustment for potential confounders, most PFASs were positively associated with high 1 h-PG concentrations. The OR for high 1 h-PG concentrations was 1.87 (95% CI: 1.15–3.05) with a one log unit increase of PFOS; similar associations were observed for PFNA (OR: 2.15, 95% CI: 1.24–3.74), PFDA (OR: 1.61, 95% CI: 1.10–2.44), PFUdA (OR: 1.71, 95% CI: 1.12–2.62), and PFDoA (OR: 1.34, 95% CI: 1.00–1.81). When the PFAS concentrations were categorized into three groups by tertiles, the highest tertiles of PFOS, PFOA, PFNA, PFDA, PFDoA, and PFTrDA had a statistically significant increase in the risk of high 1 h-PG concentrations compared with the lowest tertiles. No statistically significant association was observed between PFAS exposure and high FPG.

Conclusion

PFAS exposure was associated with an increased risk of high 1 h-PG among pregnant women, but no such association was observed for FPG.
Synergistic co-delivery of diacid metabolite of norcantharidin and ABT-737 based on folate-modified lipid bilayer-coated mesoporous silica nanoparticle against hepatic carcinoma
Authors: Liu Minchen , Tu Jue , Feng Yi , Zhang Jiquan , Wu Jing
Published: August 2020

Diacid metabolite as the stable form of norcantharidin (DM-NCTD) derived from Chinese blister beetle (Mylabris spp.). The previous studies reported that DM-NCTD could enhance ABT-737-triggered cell viability inhibition and apoptosis in hepatocellular carcinoma (HCC) cell lines. To translate this synergistic therapy into in vivo anticancer treatment, a folate receptor-targeted lipid bilayer-supported chlorodimethyloctadecylsilane-modified mesoporous silica nanoparticle (FA-LB-CHMSN) with DM-NCTD loaded in CHMSN and ABT-737 in lipid bilayer was prepared, which could promote the cancer cell uptake of the drugs through folate receptor-mediated endocytosis. The structure and the properties of the nanoparticle were evaluated. FA-LB-CHMSN with DM-NCTD/ABT-737 loaded induced apparent tumor cell apoptosis and showed remarkably tumor inhibition in H22 tumor-bearing mice model, with significant cellular apoptosis in the tumor and no obvious toxicity to the tissues. We expect that this nanoparticle could be of interest in both biomaterial investigations for HCC treatment and the combination of chemotherapeutic drugs for synergistic therapies.
Effects of oral contraceptives on the quality of life of women with polycystic ovary syndrome: a crossover randomized controlled trial
Authors: Amiri Mina , Nahidi Fatemeh , Yarandi Razieh Bidhendi , Khalili Davood , Tohidi Maryam , Tehrani Fahimeh Ramezani
Published: August 2020

Background and objective

A limited number of studies have evaluated the effects of oral contraceptives (OCs) on the quality of life (QOL) of polycystic ovary syndrome (PCOS) patients. This study aimed to compare the effects of using OCs containing levonorgestrel (LNG) and those containing desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP) for 6 months on the QOL with PCOS.

Methods

In this crossover randomized controlled 6-arm trial, 200 eligible patients with PCOS scheduled for OC therapy were randomly assigned to one of the 6 study arms. All 6 arms include two 6-month treatment periods, one period with OCs containing LNG, and the other with each of the 3 OCs containing DSG, CPA, or DRSP. Outcomes of interest were the total score of QOL and its domains, which were assessed using a specific and valid health-related quality of life questionnaire for PCOS, which is consisted of six domains, including psychosocial–emotional, self-image, fertility, sexual function, hirsutism, and obesity– menstrual disorders.

Results

Finally, a total of 88 patients were analyzed for this study. The results showed that use of OCs containing DSG, CPA, and DRSP for 3 months was not associated with significant differences in the total scores of QOL compared to those OCs containing LNG, whereas, after 6 months of treatment, patients treated with OCs containing CPA had more improvements in their total scores of QOL, in comparison to OCs containing LNG (P < 0.042). We found no significant differences in QoL domains, including psychosocial–emotional, self-image, fertility, sexual function, hirsutism, and obesity-menstrual disorders after 3–6 months of treatment with DSG, CPA, or DRSP, compared to LNG. The sequence and period effects were not significant in any of the analyses at 3 and 6 months of treatment. The carry-over effect was not significant for most outcomes assessed.

Conclusions

This crossover study demonstrated non-inferiority of OCs with newer generation progestins on different domains of QOL, in comparison with older compounds, although usage of products containing CPA was significantly associated with more improvement in total QOL of PCOS patients, compared to those containing LNG after 6-month of treatment.

Trial registration

IRCT201702071281N2.
Early gastric cancer with three gastric gastrointestinal stromal tumors combined with synchronous colon cancer: a case report
Authors: Lee Sung Chul , Nam Kwangwoo , Nam Dajeong , Kwon Min A , Kim Dong-Wook
Published: August 2020

Background

There have been very few reports of patients with early gastric cancer (EGC) and colorectal cancer combined with gastric gastrointestinal stromal tumors (GISTs).

Case presentation

We report the case of a patient with multiple tumors that were found at the same time in the abdomen. The patient was a 77-year-old man who was referred for a gastric GIST. Esophagogastroduodenoscopy showed the known lesion (a gastric GIST) on the lesser curvature of the upper body and a new lesion on the lesser curvature of the lower body of the stomach with suspicion of EGC. Computed tomography findings confirmed the presence of a GIST in the stomach and revealed two new lesions. One of these lesions was suspected to be a 4-cm submucosal tumor on the anterior wall of the upper body of the stomach. The other was a wall thickening of the descending colon that demonstrated the possibility of malignancy. Synchronous colon cancer was confirmed on colonoscopy. Laparoscopic near-total gastrectomy with D1+ lymph node dissection and left hemicolectomy were performed sequentially without significant events. The patient was discharged without any postoperative complications.

Conclusions

We reported a rare case of EGC with multiple gastric GISTs combined with synchronous colon cancer.
TRPP2 and STIM1 form a microdomain to regulate store-operated Ca2+ entry and blood vessel tone
Authors: Guo Jizheng , Zhao Ren , Zhou Muyao , Li Jie , Yao Xiaoqiang , Du Juan , Chen Jiexia , Shen Bing
Published: August 2020

Background

Polycystin-2 (TRPP2) is a Ca2+ permeable nonselective cationic channel essential for maintaining physiological function in live cells. Stromal interaction molecule 1 (STIM1) is an important Ca2+ sensor in store-operated Ca2+ entry (SOCE). Both TRPP2 and STIM1 are expressed in endoplasmic reticular membrane and participate in Ca2+ signaling, suggesting a physical interaction and functional synergism.

Methods

We performed co-localization, co-immunoprecipitation, and fluorescence resonance energy transfer assay to identify the interactions of TRPP2 and STIM1 in transfected HEK293 cells and native vascular smooth muscle cells (VSMCs). The function of the TRPP2-STIM1 complex in thapsigargin (TG) or adenosine triphosphate (ATP)-induced SOCE was explored using specific small interfering RNA (siRNA). Further, we created TRPP2 conditional knockout (CKO) mouse to investigate the functional role of TRPP2 in agonist-induced vessel contraction.

Results

TRPP2 and STIM1 form a complex in transfected HEK293 cells and native VSMCs. Genetic manipulations with TRPP2 siRNA, dominant negative TRPP2 or STIM1 siRNA significantly suppressed ATP and TG-induced intracellular Ca2+ release and SOCE in HEK293 cells. Inositol triphosphate receptor inhibitor 2-aminoethyl diphenylborinate (2APB) abolished ATP-induced Ca2+ release and SOCE in HEK293 cells. In addition, TRPP2 and STIM1 knockdown significantly inhibited ATP- and TG-induced STIM1 puncta formation and SOCE in VSMCs. Importantly, knockdown of TRPP2 and STIM1 or conditional knockout TRPP2 markedly suppressed agonist-induced mouse aorta contraction.

Conclusions

Our data indicate that TRPP2 and STIM1 are physically associated and form a functional complex to regulate agonist-induced intracellular Ca2+ mobilization, SOCE and blood vessel tone.
FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages
Authors: Wang Dongxue , Liu Fei , Zhu Liyun , Lin Ping , Han Fanyi , Wang Xue , Tan Xianxi , Lin Li , Xiong Ye
Published: August 2020

Background

Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) presents anti-inflammatory properties by modulating microglia and macrophages; however, our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages.

Methods

C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 days after MCAO, and the gene expression levels of inflammatory cytokines were analyzed via qRT-PCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages.

Results

rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment inhibited M1 polarization of microglia and pro-inflammatory cytokine expression through its actions on FGF receptor 1 (FGFR1) by suppressing nuclear factor-kappa B (NF-κB) and upregulating peroxisome proliferator-activated receptor-γ (PPAR-γ).

Conclusions

rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.
Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice
Authors: Liu Dan , Zhao Yujia , Qi Yuze , Gao Yun , Tu Dezhen , Wang Yinxi , Gao Hui-Ming , Zhou Hui
Published: August 2020

Background

Exposure to benzo(a)pyrene (BaP) was associated with cognitive impairments and some Alzheimer’s disease (AD)-like pathological changes. However, it is largely unknown whether BaP exposure participates in the disease progression of AD.

Objectives

To investigate the effect of BaP exposure on AD progression and its underlying mechanisms.

Methods

BaP or vehicle was administered to 4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and wildtype (WT) mice for 2 months. Learning and memory ability and exploratory behaviors were evaluated 1 month after the initiation/termination of BaP exposure. AD-like pathological and biochemical alterations were examined 1 month after 2-month BaP exposure. Levels of soluble beta-amyloid (Aβ) oligomers and the number of Aβ plaques in the cortex and the hippocampus were quantified. Gene expression profiling was used to evaluate alternation of genes/pathways associated with AD onset and progression. Immunohistochemistry and Western blot were used to demonstrate neuronal loss and neuroinflammation in the cortex and the hippocampus. Treatment of primary neuron-glia cultures with aged Aβ (a mixture of monomers, oligomers, and fibrils) and/or BaP was used to investigate mechanisms by which BaP enhanced Aβ-induced neurodegeneration.

Results

BaP exposure induced progressive decline in spatial learning/memory and exploratory behaviors in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer behavioral deficits than WT mice. Moreover, BaP exposure promoted neuronal loss, Aβ burden and Aβ plaque formation in APP/PS1 mice, but not in WT mice. Gene expression profiling showed most robust alteration in genes and pathways related to inflammation and immunoregulatory process, Aβ secretion and degradation, and synaptic formation in WT and APP/PS1 mice after BaP exposure. Consistently, the cortex and the hippocampus of WT and APP/PS1 mice displayed activation of microglia and astroglia and upregulation of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), and NADPH oxidase (three widely used neuroinflammatory markers) after BaP exposure. Furthermore, BaP exposure aggravated neurodegeneration induced by aged Aβ peptide in primary neuron-glia cultures through enhancing NADPH oxidase-derived oxidative stress.

Conclusion

Our study showed that chronic exposure to environmental pollutant BaP induced, accelerated, and exacerbated the progression of AD, in which elevated neuroinflammation and NADPH oxidase-derived oxidative insults were key pathogenic events.
MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation
Authors: Jiang Maorong , Li Ran , Lyu Jingjun , Li Xuan , Wang Wei , Wang Zhuoran , Sheng Huaxin , Zhang Weiguo , Karhausen Jörn , Yang Wei
Published: August 2020

Background

Cardiac arrest (CA) is associated with high morbidity and mortality, even after spontaneous circulation is re-established. This dire situation is partly due to post-CA syndrome for which no specific and effective intervention is available. One key component of post-CA syndrome is sterile inflammation, which affects various organs including the brain. A major effector of sterile inflammation is activated NLRP3 inflammasome, which leads to increased release of interleukin (IL)-1β. However, how NLRP3 inflammasome impacts neuroinflammation and neurologic outcome after CA is largely undefined.

Methods

Mice were subjected to a potassium-based murine CA and cardiopulmonary resuscitation (CPR) model. MCC950 was used to suppress activation of NLRP3 inflammasome after CA/CPR. Levels of protein and mRNA were examined by Western blotting and quantitative PCR, respectively. Immunologic changes were assessed by measuring cytokine expression and immune cell compositions. CA outcomes, including neurologic deficits, bacterial load in the lung, and survival rate, were evaluated.

Results

Using our CA/CPR model, we found that NLRP3 inflammasome was activated in the post-CA brain, and that pro-inflammatory cytokine levels, including IL-1β, were increased. After treatment with MCC950, a potent and selective NLRP3 inflammasome inhibitor, mice exhibited improved functional recovery and survival rate during the 14-day observational period after CA/CPR. In line with these findings, IL-1β mRNA levels in the post-CA brain were significantly suppressed after MCC950 treatment. Interestingly, we also found that in MCC950- vs. vehicle-treated CA mice, immune homeostasis in the spleen was better preserved and bacterial load in the lung was significantly reduced.

Conclusions

Our data demonstrate that activation of NLRP3 inflammasome could be a key event shaping the post-CA immuno- and neuro-pathology, and identify this pathway as a unique and promising therapeutic target to improve outcomes after CA/CPR.
Influence of the amino-terminal sequence on the structure and function of HIV integrase
Authors: Eilers Grant , Gupta Kushol , Allen Audrey , Zhou Jeffrey , Hwang Young , Cory Michael B. , Bushman Frederic D. , Van Duyne Gregory
Published: August 2020

Background

Antiretroviral therapy (ART) can mitigate the morbidity and mortality caused by the human immunodeficiency virus (HIV). Successful development of ART can be accelerated by accurate structural and biochemical data on targets and their responses to inhibitors. One important ART target, HIV integrase (IN), has historically been studied in vitro in a modified form adapted to bacterial overexpression, with a methionine or a longer fusion protein sequence at the N-terminus. In contrast, IN present in viral particles is produced by proteolytic cleavage of the Pol polyprotein, which leaves a phenylalanine at the N-terminus (IN 1F). Inspection of available structures suggested that added residues on the N-terminus might disrupt proper protein folding and formation of multimeric complexes.

Results

We purified HIV-1 IN 1F1–212 and solved its structure at 2.4 Å resolution, which showed extension of an N-terminal helix compared to the published structure of IN1–212. Full-length IN 1F showed increased in vitro catalytic activity in assays of coupled joining of the two viral DNA ends compared to two IN variants containing additional N-terminal residues. IN 1F was also altered in its sensitivity to inhibitors, showing decreased sensitivity to the strand-transfer inhibitor raltegravir and increased sensitivity to allosteric integrase inhibitors. In solution, IN 1F exists as monomers and dimers, in contrast to other IN preparations which exist as higher-order oligomers.

Conclusions

The structural, biochemical, and biophysical characterization of IN 1F reveals the conformation of the native HIV-1 IN N-terminus and accompanying unique biochemical and biophysical properties. IN 1F thus represents an improved reagent for use in integration reactions in vitro and the development of antiretroviral agents.
What can be done to reduce the prevalence of teen pregnancy in rural Eastern Uganda?: multi-stakeholder perceptions
Authors: Nabugoomu Josephine , Seruwagi Gloria K. , Hanning Rhona
Published: August 2020

Introduction

The teenage pregnancy rate of 25% in Uganda is worrying though it may seem low compared to 28% in Sub-Saharan countries and West and Central Africa. Young mothers in Uganda risk poor maternal and child health, being isolated, attempting unsafe abortions, failure to continue with school, and poverty. This paper describes perceptions and recommendations of young mothers, family and community members on why the high rate of teenage pregnancies in Uganda and how these can be reduced.

Methods

This qualitative research was conducted from March to May 2016 in six communities within Budondo sub-county (Jinja district), Eastern Uganda. In-depth oral interviews were conducted with 101 purposively sampled adolescent mothers, family members, and workers of government and non-government organizations. Thematic analysis framed around levels of influence within a social cognitive framework was conducted using Atlas-ti (version 7.5.4).

Results

Perceived determinants of teenage pregnancies include: lack of life and social survival skills, lack of knowledge on how to avoid pregnancy, low acceptance/use of contraceptives, neglect by parents, sexual abuse, pressure to contribute to family welfare through early marriage or sexual transactions, lack of community responsibility, media influence, peer pressure, cultural beliefs that promote early marriage/childbearing and lack of role models. Other contributing factors include drug use among boys, poverty, late work hours, long travel distances, e.g., to school, and unsupervised locations like sugarcane plantation thickets. Recommendations participants offered include: sensitization seminars and counselling for parents and girls, closing pornography outlets that accept entrance of minors, using the law to punish rapists, involvement of the President to campaign against early pregnancies, school dismissal before dark, locally accessible schools and job creation for parents to earn money to support the girls financially. Areas for capacity building are: training teachers and community members in transferring empowerment and vocational skills to girls, and construction of homes with separate rooms to support parents’ privacy.

Conclusion

The factors associated with adolescent pregnancy in Uganda fall under individual, economic, social and physical environmental determinants. Recommendations spanning family, community and government involvement can ultimately empower girls, their families and community members, and support collective action to reduce teenage pregnancies.
Home-field advantage: native gecko exhibits improved exertion capacity and locomotor ability in structurally complex environments relative to its invasive counterpart
Authors: Garner Austin M. , Pamfilie Alexandra M. , Hamad E. J. , Kindig Rachael , Taylor Joshua T. , Unsworth Colleen K. , Niewiarowski Peter H.
Published: August 2020

Background

Invasive species are of substantial concern because they may threaten ecosystem stability and biodiversity worldwide. Not surprisingly, studies examining the drivers of biological invasion have increased in number over the past few decades in an effort to curtail invasive species success by way of informing management decisions. The common house gecko, Hemidactylus frenatus, has successfully invaded the Pacific islands where it appears to thrive in and dominate non-natural habitats offering high food availability (i.e., well-lit human dwellings) compared to native geckos. Previous work demonstrated that H. frenatus can outperform the native gecko, Lepidodactylus lugubris, in terms of maximal sprint speed on relatively simple planar surfaces (e.g., building walls). Lepidodactylus lugubris and other native geckos, however, may have superior locomotor performance in three-dimensional, structurally complex habitats.

Results

Here we compared the locomotor behaviour and exertion capacity of the native gecko, Gehyra oceanica, and the invasive gecko, Hemidactylus frenatus, on the island of Mo’orea, French Polynesia, on fabricated structures simulating structurally complex substrates. We found that the native gecko exhibits improved locomotor performance compared to the invasive gecko on structurally complex substrates. We also completed encounter surveys to document free-ranging habitat use and behaviour of these two species. We discovered that H. frenatus were more common in natural habitats than previously observed and used similar substrates as G. oceanica, although G. oceanica appeared to use substrates with greater perch heights (i.e., trees).

Conclusions

Our findings revealed that locomotor performance in complex environments may contribute to the previously observed habitat segregation between native and invasive Pacific island geckos. Furthermore, our locomotor and habitat use data are consistent with the hypothesis that G. oceanica may be resistant to invasion of H. frenatus in natural environments. Our study calls for more detailed ecophysiological and ecomorphological studies of both native and invasive Pacific gecko species.
Metastatic colon cancer of the small intestine diagnosed using genetic analysis: a case report
Authors: Matsuo Mikiko , Hatano Yuichiro , Imaizumi Yuko , Kuroda Takahiro , Arai Toshinori , Tomita Hiroyuki , Matsuhashi Nobuhisa , Yoshida Kazuhiro , Hara Akira
Published: August 2020

Background

Intestinal-type adenocarcinoma is widely detected in the gastrointestinal tract, head and neck, lower respiratory and urinary systems. Determining the nature (monoclonal or multicentric) of the intestinal adenocarcinoma is sometimes a diagnostic challenge owing to its occurrence at various locations of the body, especially in the lower gastrointestinal tract. Herein, we successfully diagnosed metastatic colon cancer in the small intestine using tumor protein 53 gene (TP53) mutation analysis.

Case presentation

An 83-year-old woman presented with severe abdominal pain and nausea at the emergency department of the hospital. Her history included surgery and adjuvant chemotherapy for colon and breast cancers. Abdominal computed tomography revealed small intestinal dilation, which was associated with the mural nodule detected on fluorodeoxyglucose positron emission tomography. Laparoscopy-assisted small bowel resection was performed based on the diagnosis of small bowel obstruction, probably due to recurrence of the colon or breast cancer. Macroscopically, an ulcerated tumor was present in the resected small intestine. Histologically, the cancer cells showed infiltrative growth of colonic dysplastic glands, whose non-specific finding made it difficult to determine the relationship with past colon cancers. Retrospective pathological examination confirmed that the previous breast and colon carcinomas were primary cancers. Immunohistochemical analysis revealed that the small intestinal and colon cancer cells showed diffuse positive tumor protein 53 (p53) expression. However, the breast cancer cells showed only weakly positive p53 expression. In addition, TP53 mutational analysis detected an identical missense mutation (p.T211I) between the two intestinal cancers. Moreover, further molecular genetic work-up revealed that both small intestinal and colon adenocarcinomas harbored an identical missense mutation (p.G12D) of KRAS gene. In conclusion, the small intestinal cancer in this case was identified as a metastatic adenocarcinoma arising from a past colon cancer.

Conclusions

Genetic analyses help in clarifying the identity of the cells in multiple cancer cases. In morphologically indeterminate cases, molecular analysis of common cancer-related genes can be useful for a precise and reproducible diagnosis.
Some notes on the use, concept and socio-political framing of ‘stigma’ focusing on an opioid-related public health crisis
Authors: Fischer Benedikt
Published: August 2020

Canada has been home to a longstanding public health crisis related to opioids, including an extensive mortality and morbidity toll in the face of substantive intervention gaps. Recently (2019), two extensive reports from preeminent federal authorities – the Chief Public Health Officer and the Mental Health Commission of Canada – have been tabled with detailed, core focus on the phenomenon of ‘stigma’ and its impacts on substance/opioid use and harms. The reports present extensive descriptions of the nature and effects, as well as a multitude of prescriptions for remedial measures and actions to “stop the cycle of stigma”. Closer reading of the documents, however, suggests substantial conceptual and empirical limitations in the characterization of the – multi-faceted and challenging – nature and workings of ‘stigma’ as a socio-political, structural or individual process or force, specifically as it applies to and negatively affects substance use and related outcomes, primarily the wellbeing of substance users. Concretely, it is unclear how the remedial actions proposed will materially alleviate stigma process and impacts, especially given apparent gaps in the issues examined, including essential strategies – for example, reform of drug user criminalization as a fundamental element and driver of structural stigma - for action that directly relate to the jurisdictions and privileged mandates of the report sources themselves as health and policy leaders. The commentary provides some concrete while subjective notes and observations on the dynamics of stigma as applies to and framed for substance/opioid use, as well as strategies and measures necessary to both tangibly address the material health and wellbeing of substance users, and related forces of stigma, in the distinct context of the opioid crisis in Canada.