bluuebunny/crossref_metadata_2025 huggingface dataset:
The Virtues of Military Politics
Authors: Coletta Damon , Crosbie Thomas
Published: September 2019

Sociologists and political scientists have long fretted over the dangers that a politicized military poses to democracy. In recent times, however, civil–military relations experts in the United States accepted retired or indeed still serving generals and admirals in high-ranking political posts. Despite customary revulsion from scholars, the sudden waivers are an indicator that military participation in momentous national security decisions is inherently political without necessarily being partisan, including when civilian authority defers to a largely autonomous sphere for objective military expertise. Military politics is actually critical for healthy civil–military collaboration, when done prudently and moderately. Janowitz and Huntington, founders of the modern study of civil–military relations, understood the U.S. military’s inevitable invitation to political influence. Here, we elaborate on two neglected dimensions, implicit in their projects, of military politics under objective civilian control based on classical virtues of civic republicanism: Aristotle’s practical wisdom and Machiavelli’s virtú.
Hypoactivity in the Paraterminal Gyrus Following Bilateral Anterior Capsulotomy
Authors: Hurwitz Trevor A. , Honey Christopher R. , McLeod Kevin R. , Poologaindran Anujan , Kuan Annie J.
Published: September 2019

Objective:

Bilateral anterior capsulotomy (BAC) is one of the ablative neurosurgical procedures used to treat major depressive disorder or obsessive-compulsive disorder when all other therapies fail. Tristolysis, a reduction in sadness, is the most striking clinical effect of BAC and is seen in the first 1 to 2 weeks after surgery. This retrospective study measured regional cerebral blood flow (rCBF) following surgery to identify which cortical regions were impacted and could account for this clinical effect.

Methods:

All patients had their capsulotomies done in Vancouver by the same team. Pre- and postoperative single-photon emission computed tomography perfusion scans were analyzed for 10 patients with major depressive disorder and 3 with obsessive-compulsive disorder. rCBF was measured semiquantitatively by calculating the ratio between an identified region of interest and a whole brain reference area.

Results:

Decreased rCBF was found in the paraterminal gyri. Increased rCBF was found in the dorsolateral prefrontal cortices and in the left lateral temporal lobe.

Conclusions:

BAC causes hypoactivity in the paraterminal gyri and is the most likely explanation for its tristolytic effect, suggesting that the paraterminal gyrus is the limbic cortical locus for the emotion of sadness. Increased activity in the dorsolateral prefrontal cortices may be occurring via connectional diaschisis, and suppression by overactive paraterminal gyri during depression may account for some of the neurocognitive deficits observed during depressive episodes.
Engaging in Global Nursing Education
Authors: Baumann Steven L.
Published: September 2019

The nursing profession in the Sultanate of Oman in the past 50 years has undergone considerable growth and development. Its modernization was assisted by visiting professors from outside the country and by sending some nurses to study abroad. Visiting nurses and nurse educators who go to work in countries like Oman should consider implementing the ethic behind the mission statement of Partners in Health, which holds a preferential option for the poor, rather than just considering global health as another international business or job opportunity.
Managing multilingual collections: Insights from data analytics research
Authors: Musgrave Simon , Wright Steve , Denison Tom , Willoughby Louisa
Published: September 2019

Libraries, through their catalogues and borrowing records are well-placed to use data analytics to enhance their collection management (and of course do this already, for example by directing orders to genres/areas that are heavily borrowed). In this article, we explore some of the insights for the management of multilingual collections offered by a novel research method that fuses analysis of a large data set of borrowing records with data from interviews with library staff. Such a method, we argue, helps to untangle the Gordian knot around why materials in some languages are widely popular while materials for other equally widely-spoken languages sit unused on the shelves. It also draws our attention to the ways in which different demographics of speakers are engaging with library materials across the various languages, and gives a suite of tools local libraries might use to better assess the likely demand for materials in languages other than English.
Modeling Emergent Properties in the Brain Using Tissue Models to Investigate Neurodegenerative Disease
Authors: Harris Alexander R. , McGivern Patrick , Ooi Lezanne
Published: September 2019

Here we describe emergent properties of the brain and the key challenges associated with modelling them in vitro. Modeling emergent properties of the brain will provide insights into brain function, development, and disease.
Nationwide Results on Chronic Pain After Bilateral Transabdominal Preperitoneal Inguinal Hernia Repair
Authors: Johansen N. , Vyrdal C. D. , Bisgaard T.
Published: September 2019

Background:

Majority of studies on chronic postoperative inguinal pain has described the occurrence after unilateral inguinal hernia repair. Endo-laparoscopic repair, for example, laparoscopic transabdominal preperitoneal inguinal hernia repair, has been recommended for primary bilateral symptomatic inguinal hernias, although the literature on chronic postoperative inguinal pain among this type of patients is limited. The present study analyzed chronic postoperative inguinal pain following bilateral transabdominal preperitoneal inguinal hernia repair.

Methods:

Nationwide consecutive patients who underwent bilateral transabdominal preperitoneal inguinal hernia repair (July 2012–June 2013) were recruited from the Danish Inguinal Hernia Database and cross-checked with hospital files and the National Patient Registry. A prospective follow-up was performed with a standardized postal questionnaire including questions on functional performance status assessed by a modified version of the Activity Assessment Scale. The primary outcome was incidence of chronic postoperative inguinal pain defined as moderate to severe pain-related impairment of everyday activities. Pain was registered according to the two individual groin areas. Furthermore, the overall incidence of chronic postoperative inguinal pain per operated inguinal hernia was calculated. Intensity of experienced pain (Activity Assessment Scale score) was compared between patients reporting pain from one versus both groin areas.

Results:

In total, 209 patients (418 hernia repairs) were analyzed (questionnaire response rate 83%). The median follow-up time was 27 months (22–34 months). In total, 27 of 209 patients (13%) complained of chronic postoperative inguinal pain from either one ( n = 17) or both ( n = 10) groin areas after bilateral transabdominal preperitoneal inguinal hernia repair. The incidence of chronic inguinal pain per operated hernia was 9%. The intensity of impairment due to pain (Activity Assessment Scale score) did not differ significantly between patients with chronic postoperative inguinal pain in one (19%) versus both sides (30%), p = 0.056.

Conclusion:

Bilateral transabdominal preperitoneal inguinal hernia repair for symptomatic inguinal hernias was related to a high incidence (13%) of chronic postoperative inguinal pain and decreased functional performance status.
Mediated effects of insomnia, psychological distress and medication adherence in the association of eHealth literacy and cardiac events among Iranian older patients with heart failure: a longitudinal study
Authors: Lin Chung-Ying , Ganji Maryam , Griffiths Mark D , Bravell Marie Ernsth , Broström Anders , Pakpour Amir H
Published: September 2019

Background:

Given the importance of improving health for patients with heart failure, the present study examined the temporal associations between eHealth literacy, insomnia, psychological distress, medication adherence, quality of life and cardiac events among older patients with heart failure.

Methods:

With a longitudinal design older patients with echocardiography verified heart failure ( N=468; 50.4% New York Heart Association class II, mean age 69.3±7.3 years; 238 men) in need of cardiac care at seven Iranian university outpatient clinics went through clinical examinations and completed the following questionnaires at baseline: eHealth literacy scale (eHEALS, assessing eHealth literacy); 5-item medication adherence report scale (MARS-5, assessing medication adherence); Minnesota living with heart failure questionnaire (MLHFQ, assessing quality of life); insomnia severity index (ISI, assessing insomnia); and hospital anxiety and depression scale (HADS, assessing psychological distress). All the patients completed the ISI and HADS again 3 months later; and the MARS-5 6 months later. Also, their cardiac events were collected 18 months later. Three mediation models were then conducted.

Results:

eHealth literacy had direct and indirect effects (through insomnia and psychological distress) on medication adherence and quality of life. Moreover, eHealth literacy had protecting effects on cardiac events (hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.37, 0.65) through the mediators of insomnia (HR 0.19; 95% CI 0.15, 0.26), psychological distress (HR 0.08; 95% CI 0.05, 0.12) and medication adherence (HR 0.05; 95% CI 0.04, 0.08).

Conclusion:

As eHealth literacy was a protector for patients with heart failure, healthcare providers may plan effective programmes to improve eHealth literacy for the population. Additional benefits of improving eHealth literacy in heart failure may be decreased insomnia and psychological distress, improved quality of life, as well as decreased cardiovascular events.
Head-Mounted Display Use in Surgery: A Systematic Review
Authors: Rahman Rafa , Wood Matthew E. , Qian Long , Price Carrie L. , Johnson Alex A. , Osgood Greg M.
Published: September 2019

Purpose. We analyzed the literature to determine (1) the surgically relevant applications for which head-mounted display (HMD) use is reported; (2) the types of HMD most commonly reported; and (3) the surgical specialties in which HMD use is reported. Methods. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched through August 27, 2017, for publications describing HMD use during surgically relevant applications. We identified 120 relevant English-language, non-opinion publications for inclusion. HMD types were categorized as “heads-up” (nontransparent HMD display and direct visualization of the real environment), “see-through” (visualization of the HMD display overlaid on the real environment), or “non–see-through” (visualization of only the nontransparent HMD display). Results. HMDs were used for image guidance and augmented reality (70 publications), data display (63 publications), communication (34 publications), and education/training (18 publications). See-through HMDs were described in 55 publications, heads-up HMDs in 41 publications, and non–see-through HMDs in 27 publications. Google Glass, a see-through HMD, was the most frequently used model, reported in 32 publications. The specialties with the highest frequency of published HMD use were urology (20 publications), neurosurgery (17 publications), and unspecified surgical specialty (20 publications). Conclusion. Image guidance and augmented reality were the most commonly reported applications for which HMDs were used. See-through HMDs were the most commonly reported type used in surgically relevant applications. Urology and neurosurgery were the specialties with greatest published HMD use.
Impact of intravenous thrombolysis on functional outcome in patients with mild ischemic stroke without large vessel occlusion or rapidly improving symptoms
Authors: Haeberlin Marcellina Isabelle , Held Ulrike , Baumgartner Ralf W , Georgiadis Dimitrios , Valko Philipp O
Published: September 2019

Background

Optimal treatment strategy in patients with mild ischemic stroke remains uncertain. While functional dependency or death has been reported in up to one-third of non-thrombolyzed mild ischemic stroke patients, intravenous thrombolysis is currently not recommended in this patient group. Emerging evidence suggests two risk factors—rapid early improvement and large vessel occlusion—as main associates of unfavorable outcome in mild ischemic stroke patients not undergoing intravenous thrombolysis.

Aims

To analyze natural course as well as safety and three-month outcome of intravenous thrombolysis in mild ischemic stroke without rapid early improvement or large vessel occlusion.

Methods

Mild ischemic stroke was defined by a National Institute of Health Stroke Scale score ≤6. We used the modified Rankin Scale (mRS) to compare three-month functional outcome in 370 consecutive mild ischemic stroke patients without early rapid improvement and without large vessel occlusion, who either underwent intravenous thrombolysis (n = 108) or received best medical treatment (n = 262).

Results

Favorable outcome (mRS ≤ 1) was common in both groups (intravenous thrombolysis: 91%; no intravenous thrombolysis: 90%). Although intravenous thrombolysis use was independently associated with a higher risk of asymptomatic hemorrhagic transformation (OR = 4.62, p = 0.002), intravenous thrombolysis appeared as an independent predictor of mRS = 0 at three months (OR = 3.33, p < 0.0001).

Conclusions

Mild ischemic stroke patients without rapidly improving symptoms and without large vessel occlusion have a high chance of favorable three-month outcome, irrespective of treatment type. Patients receiving intravenous thrombolysis, however, more often achieved complete remission of symptoms, which particularly in mild ischemic stroke may constitute a meaningful endpoint.
Rheumatoid arthritis and systemic lupus erythematosus: Pathophysiological mechanisms related to innate immune system
Authors: Pabón-Porras Maria Angélica , Molina-Ríos Sebastian , Flórez-Suárez Jorge Bruce , Coral-Alvarado Paola Ximena , Méndez-Patarroyo Paul , Quintana-López Gerardo
Published: September 2019

Rheumatoid arthritis and systemic lupus erythematosus are two highly prevalent autoimmune diseases that generate disability and low quality of life. The innate immune system, a long-forgotten issue in autoimmune diseases, is becoming increasingly important and represents a new focus for the treatment of these entities. This review highlights the role that innate immune system plays in the pathophysiology of rheumatoid arthritis and systemic lupus erythematosus. The role of the innate immune system in rheumatoid arthritis and systemic lupus erythematosus pathophysiology is not only important in early stages but is essential to maintain the immune response and to allow disease progression. In rheumatoid arthritis, genetic and environmental factors are involved in the initial stimulation of the innate immune response in which macrophages are the main participants, as well as fibroblast-like synoviocytes. In systemic lupus erythematosus, all the cells contribute to the inflammatory response, but the complement system is the major effector of the inflammatory process. Detecting alterations in the normal function of these cells, besides its contribution to the understanding of the pathophysiology of autoimmune diseases, could help to establish new treatment strategies for these diseases.
Trends in Alveolar Bone Grafting and the Use of Recombinant Bone Morphogenetic Protein (RhBMP) in the United States
Authors: Kanack Melissa , Krasnoff Chloe , Daly Lauren , Laurence Vincent , Jaffurs Daniel
Published: September 2019

Objectives:

To gather information about current practices and assess the opinions, preferences, and clinical knowledge of surgeons who perform alveolar bone grafts. In addition, surgical training differences in correlation to techniques and outcomes are evaluated.

Methods:

A survey with both multiple choice and narrative answers regarding surgeons’ practices for alveolar bone grafting was designed and sent via email to members of the American Cleft Palate/Craniofacial Association (ACPA) identified as general craniofacial or oral maxillofacial surgeons. Responses were collected via an anonymous online survey tool.

Participants:

Members (336) of ACPA identified as craniofacial or oral-maxillofacial surgeons were contacted, and 62 responses were recorded.

Results:

The majority of survey respondents were oral-maxillofacial surgeons in practice for more than 15 years. 98.4% of respondents had used iliac crest and at least one additional source for grafting, while only 52.7% had performed grafting using recombinant bone morphogenetic protein (RhBMP). 82% used cone beam CT as their evaluation of choice for graft assessment and the majority (62.9%) waited more than 8 weeks postoperatively to image. Chi-square analysis demonstrated significantly longer time in practice for practitioners without craniofacial fellowship training.

Conclusions:

The results of this study demonstrate that there remains significant variation in alveolar bone grafting practices among surgeons. While some consensus exists, new innovations and technologies will require continued evaluation of surgical practices and outcomes. Long-term follow-up studies are needed especially with regard to the use of RhBMP in alveolar clefts.
A KLF4-DYRK2–mediated pathway regulating self-renewal in CML stem cells
Authors: Park Chun Shik , Lewis Andrew H. , Chen Taylor J. , Bridges Cory S. , Shen Ye , Suppipat Koramit , Puppi Monica , Tomolonis Julie A. , Pang Paul D. , Mistretta Toni-Ann , Ma Leyuan , Green Michael R. , Rau Rachel , Lacorazza H. Daniel
Published: September 2019

Park et al describe a novel KLF4-mediated pathway that promotes chromic myeloid leukemia (CML) stem cell (LSC) survival. Deletion of KLF4 in a mouse model of CML decreases LSC survival through repression of Dyrk2, resulting in c-Myc depletion and increased p53 activity.
Synergistically Enhanced Inhibitory Effects of Pullulan Nanoparticle-Mediated Co-Delivery of Lovastatin and Doxorubicin to Triple-Negative Breast Cancer Cells
Authors: Wu Di , Chen Yao , Wen Shun , Wen Yi , Wang Rong , Zhang Qiuting , Qin Ge , Yi Huimei , Wu Mi , Lu Lu , Tao Xiaojun , Deng Xiyun
Published: September 2019

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is prone to drug resistance and difficult to treat. In this study, we grafted water-soluble pullulan with lovastatin (LV) to develop a novel amphiphilic conjugate, pullulan-encapsulated LV (PLV). The PLV conjugate was synthesized with three different ratios of pullulan to LV and characterized by Fourier transform infrared (FTIR). The degree of substitution (DS) of LV in terms of molar ratio was 7.87%, 3.58%, and 3.06% for PLV (1/2), PLV (1/3), and PLV (1/4), respectively, by proton NMR analysis. We selected the PLV (1/2) conjugate to prepare doxorubicin (DXR)-loaded PLV nanoparticles (PLV/DXR NPs) because of its superior properties. The average size and zeta potential for PLV (1/2) NPs were 177.6 nm and − 11.66 mV, respectively, determined by dynamic light scattering, and those for PLV/DXR NPs were 225.6 nm and − 10.51 mV, respectively. In vitro drug release profiling showed that PLV/DXR NPs sustainably released DXR within 72 h, which was more robust at pH 5.4 (97.90%) than pH 7.4 (76.15%). In the cytotoxicity study, PLV/DXR NPs showed greater inhibition of proliferation of TNBC MDA-MB-231 than non-TNBC MDA-MB-453 cells (IC50 0.60 vs 11.05 μM). FITC-loaded PLV/DXR NPs were prepared to investigate cellular uptake: both cell lines showed a time-dependent uptake of NPs, but the number of NPs entering MDA-MB-231 cells was greater than that entering the MDA-MB-453 cells. Pullulan-based NP co-delivery of LV and DXR could efficiently inhibit TNBC cells, which may help in designing a powerful drug delivery system for treating TNBC.
Within-task variability on standardized language tests predicts autism spectrum disorder: a pilot study of the Response Dispersion Index
Authors: Hare-Harris Abby E. , Mitchel Marissa W. , Myers Scott M. , Mitchel Aaron D. , King Brian R. , Ruocco Brittany G. , Martin Christa Lese , Flax Judy F. , Brzustowicz Linda M.
Published: September 2019

Background

Qualitatively atypical language development characterized by non-sequential skill acquisition within a developmental domain, which has been called developmental deviance or difference, is a common characteristic of autism spectrum disorder (ASD). We developed the Response Dispersion Index (RDI), a measure of this phenomenon based on intra-subtest scatter of item responses on standardized psychometric assessments, to assess the within-task variability among individuals with language impairment (LI) and/or ASD.

Methods

Standard clinical assessments of language were administered to 502 individuals from the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Participants were divided into four diagnostic groups: unaffected, ASD-only, LI-only, and ASD + LI. For each language measure, RDI was defined as the product of the total number of test items and the sum of the weight (based on item difficulty) of test items missed. Group differences in RDI were assessed, and the relationship between RDI and ASD diagnosis among individuals with LI was investigated for each language assessment.

Results

Although standard scores were unable to distinguish the LI-only and ASD/ASD + LI groups, the ASD/ASD + LI groups had higher RDI scores compared to LI-only group across all measures of expressive, pragmatic, and metalinguistic language. RDI was positively correlated with quantitative ASD traits across all subgroups and was an effective predictor of ASD diagnosis among individuals with LI.

Conclusions

The RDI is an effective quantitative metric of developmental deviance/difference that correlates with ASD traits, supporting previous associations between ASD and non-sequential skill acquisition. The RDI can be adapted to other clinical measures to investigate the degree of difference that is not captured by standard performance summary scores.
Polymorphism of MHC class IIB in an acheilognathid species, Rhodeus sinensis shaped by historical selection and recombination
Authors: Jeon Hyung-Bae , Won Hari , Suk Ho Young
Published: September 2019

Background

Rhodeus sinensis is a bitterling species occurring throughout the numerous freshwater systems on the East Asia. Here, we analyzed the diversity of the MHC class IIB (DAB) genes from this species, which may offer meaningful insights into evolutionary processes in this species as well as other bitterlings.

Results

Using cDNA and gDNA samples from 50 individuals, we discovered classical 140 allelic sequences that could be allocated into either DAB1 (Rhsi-DAB1) or DAB3 (Rhsi-DAB3). DAB sequences completely lacking the intron, but identical or similar to Rhsi-DAB1, were also discovered from our gDNA samples, and this intron loss likely originated from the retrotransposition events of processed mDNA. The β1 domain was the most polymorphic in both Rhsi-DAB1 and -DAB3. Putative peptide biding residues (PBRs) in Rhsi-DAB1, but not in Rhsi-DAB3, exhibited a significant dN/dS, presumably indicating that different selection pressures have acted on those two DABs. Recombination between different alleles seemed to have contributed to the increase of diversity in Rhsi-DABs. Upon phylogenetic analysis, Rhsi-DAB1 and -DAB3 formed independent clusters. Several alleles from other species of Cypriniformes were embedded in the clade of Rhsi-DAB1, whereas Rhsi-DAB3 clustered with alleles from the wider range of taxa (Cyprinodontiformes), indicating that these two Rhsi-DABs have taken different historical paths.

Conclusions

A great deal of MHC class IIB allelic diversity was found in R. sinensis, and gene duplication, selection and recombination may have contributed to this diversity. Based on our data, it is presumed that such historical processes have commonly or differently acted on the polymorphism of Rhsi-DAB1 and -DAB3.
Environmental factors affecting childhood diarrheal disease among under-five children in Jamma district, South Wello zone, Northeast Ethiopia
Authors: Workie Getachew Yismaw , Akalu Temesgen Yihunie , Baraki Adhanom Gebreegziabher
Published: September 2019

Background

Globally, diarrhea is the leading cause of morbidity and mortality among less than 5 years old children and it contributes to the deaths of approximately one million children every year. In Ethiopia, diarrhea is the second cause of under-five mortality and morbidity. However, in the study area, studies were limited. Therefore, this study has assessed the prevalence of diarrhea and associated factors among < 5 years of age in Jamma district, Northeast Ethiopia.

Methods

A community-based cross-sectional study was conducted from August 15 to September 15, 2017, in Jamma district, South Wello zone, northeast Ethiopia. A Systematic random sampling technique was used to select 614 households and a pretested structured questionnaire was used to collect the data. A multivariable logistic regression analysis was used to investigate factors associated with diarrheal disease. Adjusted Odds Ratio (AOR) with the corresponding 95% Confidence Interval (CI) for variables withP-value < 0.05 was used to show statistically significant association.

Results

In this study, the prevalence of diarrhea among under-five children was 23.1% (95% CI: (19.4, 26.5). Child’s age 6 to 23 months [AOR: 2.46, 95% CI: (1.49, 4.05)], Living in rural area [AOR: 2.75, 95% CI: (1.33,5.66)], absence of latrine [AOR: 4.80, 95% CI: (2.39,9.60)], absence of handwashing facility [AOR: 2.45, 95% CI: (1.53,3.93], unprotected drinking water source [AOR:2.68, 95% CI: (1.54,4.68)], and Improper waste disposal practices [AOR:3.86, 95% CI: (2.38,6.26)] were associated with diarrhea disease.

Conclusion

There was a high prevalence of diarrheal disease among children in the study area. Child age, rural residence, availability of latrine and handwashing facility, source of drinking water, and improper waste disposal were notably associated with childhood diarrheal disease. Therefore, improving handwashing practices and pure water supply, proper waste disposal including the availability of latrines would minimize the burden of diarrheal disease.
TRPP2 dysfunction decreases ATP-evoked calcium, induces cell aggregation and stimulates proliferation in T lymphocytes
Authors: Magistroni Riccardo , Mangolini Alessandra , Guzzo Sonia , Testa Francesca , Rapanà Mario R. , Mignani Renzo , Russo Giorgia , di Virgilio Francesco , Aguiari Gianluca
Published: September 2019

Background

Autosomal dominant polycystic kidney disease (ADPKD) is mainly characterised by the development and enlargement of renal cysts that lead to end-stage renal disease (ESRD) in adult patients. Other clinical manifestations of this pathology include hypertension, haematuria, abdominal pain, cardiovascular system alterations and intracranial aneurysms. ADPKD is linked to mutations in either PKD1 or PKD2 that codifies polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. PC1 and TRPP2 are membrane proteins that function as receptor-channel elements able to regulate calcium homeostasis. The function of polycystins has been mainly studied in kidney cells; but the role of these proteins in T lymphocytes is not well defined.

Methods

T lymphocytes were produced from ADPKD1 and ADPKD2 patients as well as from non-ADPKD subjects undergoing renal replacement therapy (RRT) and healthy controls. Protein expression and phosphorylation levels were analysed by western blotting, cell proliferation was calculated by direct counting using trypan blue assay and intracellular calcium concentration was measured by Fura-2 method.

Results

PKD2 mutations lead to the significant reduction of TRPP2 expression in T lymphocytes derived from ADPKD patients. Furthermore, a smaller TRPP2 truncated protein in T lymphocytes of patients carrying the mutation R872X in PKD2 was also observed, suggesting that TRPP2 mutated proteins may be stably expressed. The silencing or mutation of PKD2 causes a strong reduction of ATP-evoked calcium in Jurkat cells and ADPKD2 T lymphocytes, respectively. Moreover, T lymphocytes derived from both ADPKD1 and ADPKD2 patients show increased cell proliferation, basal chemotaxis and cell aggregation compared with T lymphocytes from non-ADPKD subjects. Similarly to observations made in kidney cells, mutations in PKD1 and PKD2 dysregulate ERK, mTOR, NFkB and MIF pathways in T lymphocytes.

Conclusions

Because the alteration of ERK, mTOR, NFkB and MIF signalling found in T lymphocytes of ADPKD patients may contribute to the development of interstitial inflammation promoting cyst growth and kidney failure (ESRD), the targeting of inflammasome proteins could be an intriguing option to delay the progression of ADPKD.
Preclinical efficacy of dual mTORC1/2 inhibitor AZD8055 in renal cell carcinoma harboring a TFE3 gene fusion
Authors: Kauffman Eric C. , Lang Martin , Rais-Bahrami Soroush , Gupta Gopal N. , Wei Darmood , Yang Youfeng , Sourbier Carole , Srinivasan Ramaprasad
Published: September 2019

Background

Renal cell carcinomas (RCC) harboring aTFE3gene fusion (TfRCC) represent an aggressive subset of kidney tumors. Key signaling pathways of TfRCC are unknown and preclinical in vivo data are lacking. We investigated Akt/mTOR pathway activation and the preclinical efficacy of dual mTORC1/2 versus selective mTORC1 inhibition in TfRCC.

Methods

Levels of phosphorylated Akt/mTOR pathway proteins were compared by immunoblot in TfRCC and clear cell RCC (ccRCC) cell lines. Effects of the mTORC1 inhibitor, sirolimus, and the dual mTORC1/2 inhibitor, AZD8055, on Akt/mTOR activation, cell cycle progression, cell viability and cytotoxicity were compared in TfRCC cells. TfRCC xenograft tumor growth in mice was evaluated after 3-week treatment with oral AZD8055, intraperitoneal sirolimus and respective vehicle controls.

Results

The Akt/mTOR pathway was activated to a similar or greater degree in TfRCC than ccRCC cell lines and persisted partly during growth factor starvation, suggesting constitutive activation. Dual mTORC1/2 inhibition with AZD8055 potently inhibited TfRCC viability (IC50 = 20-50 nM) due at least in part to cell cycle arrest, while benign renal epithelial cells were relatively resistant (IC50 = 400 nM). Maximal viability reduction was greater with AZD8055 than sirolimus (80–90% versus 30–50%), as was the extent of Akt/mTOR pathway inhibition, based on significantly greater suppression of P-Akt (Ser473), P-4EBP1, P-mTOR and HIF1α. In mouse xenograft models, AZD8055 achieved significantly better tumor growth inhibition and prolonged mouse survival compared to sirolimus or vehicle controls.

Conclusions

Akt/mTOR activation is common in TfRCC and a promising therapeutic target. Dual mTORC1/2 inhibition suppresses Akt/mTOR signaling more effectively than selective mTORC1 inhibition and demonstrates in vivo preclinical efficacy against TFE3-fusion renal cell carcinoma.
Diosgenin ameliorates palmitic acid-induced lipid accumulation via AMPK/ACC/CPT-1A and SREBP-1c/FAS signaling pathways in LO2 cells
Authors: Fang Ke , Wu Fan , Chen Guang , Dong Hui , Li Jingbin , Zhao Yan , Xu Lijun , Zou Xin , Lu Fuer
Published: September 2019

Background

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is characterized by excessive hepatic lipid accumulation. Many studies have suggested that lipid overload is the key initial factor that contributes to hepatic steatosis. Our previous study indicated that diosgenin (DSG) has a beneficial effect on energy metabolism, but the underlying mechanism remains unclear.

Methods

Human normal hepatocytes (LO2 cells) were incubated with palmitic acid to establish the cell model of nonalcoholic fatty liver. The effects of DSG on lipid metabolism, glucose uptake and mitochondrial function were evaluated. Furthermore, the mechanism of DSG on oxidative stress, lipid consumption and lipid synthesis in LO2 cells was investigated.

Results

The results indicated that palmitic acid induced obvious lipid accumulation in LO2 cells and that DSG treatment significantly reduced the intracellular lipid content. DSG treatment upregulated expression of lipolysis proteins, including phospho-AMP activated protein kinase (p-AMPK), phospho-acetyl-coA carboxylase (p-ACC) and carnitine acyl transferase 1A (CPT-1A), and inhibited expression of lipid synthesis-related proteins, including sterol regulatory element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS). Additionally, DSG-treated cells displayed a marked improvement in mitochondrial function, with less production of reactive oxygen species and a higher mitochondrial membrane potential compared with the model group.

Conclusion

This study suggests that DSG can reduce intracellular lipid accumulation in LO2 cells and that the underlying mechanism may be related to the improving oxidative stress, increasing fatty acid β-oxidation and decreasing lipid synthesis. The above changes might be mediated by the activation of the AMPK/ACC/CPT-1A pathway and inhibition of the SREBP-1c/FAS pathway.
Influence of supplemented coated-cysteamine on morphology, apoptosis and oxidative stress status of gastrointestinal tract
Authors: Liu Hongnan , Bai Miaomiao , Tan Bie , Xu Kang , Yu Rong , Huang Ruilin , Yin Yulong
Published: September 2019

Background

Cysteamine was coated to cover its odor and maintain the stability. However, coated cysteamine (CC) has not been clearly evaluated for its effects on the gastrointestinal mucosa status. We hypothesize that the appropriate CC supplementation in diet impacts the stomach and intestinal mucosa variously through regulating the morphology, apoptosis, and oxidative stress status in model of pigs.

Results

The results showed that villus height increased (P < 0.05), and crypt depth decreased (P < 0.05) in the ileum when pigs were fed the diet with low cysteamine (LCS) compared with the control diet. The ileal lesion score in the LCS group was significantly (P < 0.01) lower than that in the control group, while the gastric lesion score in the CC group was significantly (P < 0.01) higher compared with that of the control group. It also showed that the activities of total superoxide dismutase (T-SOD) and diamine oxidase (DAO) were upregulated (P < 0.05) in the LCS group. In addition, Bax and caspase 3 immunore-activity increased (P < 0.01), and Bcl-2 immunoreactivity decreased (P < 0.01) in the gastric mucosa of pigs fed the diet with high cysteamine (HCS). The Bax and caspase 3 immunoreactivity decreased (P < 0.01), and Bcl-2 immunoreactivity increased (P < 0.01) in ileum mucosa of pigs fed the HCS diet.

Conclusions

Although moderate dietary coated cysteamine showed positive effects on GI mucosal morphology, apoptosis, and oxidative stress status, the excess coated cysteamine may cause apoptosis leading to GI damage in pigs.
Host genetic variability and pneumococcal disease: a systematic review and meta-analysis
Authors: Kloek Anne T. , Brouwer Matthijs C. , van de Beek Diederik
Published: September 2019

Background

Pneumonia, sepsis, meningitis, and empyema due to Streptococcus pneumoniae is a major cause of morbidity and mortality. We provide a systemic overview of genetic variants associated with susceptibility, phenotype and outcome of community acquired pneumococcal pneumonia (CAP) and invasive pneumococcal disease (IPD).

Methods

We searched PubMed for studies on the influence of host genetics on susceptibility, phenotype, and outcome of CAP and IPD between Jan 1, 1983 and Jul 4, 2018. We listed methodological characteristics and when genetic data was available we calculated effect sizes. We used fixed or random effect models to calculate pooled effect sizes in the meta-analysis.

Results

We identified 1219 studies of which 60 studies involving 15,358 patients were included. Twenty-five studies (42%) focused on susceptibility, 8 (13%) on outcome, 1 (2%) on disease phenotype, and 26 (43%) on multiple categories. We identified five studies with a hypothesis free approach of which one resulted in one genome wide significant association in a gene coding for lincRNA with pneumococcal disease susceptibility. We performed 17 meta-analyses of which two susceptibility polymorphisms had a significant overall effect size: variant alleles of MBL2 (odds ratio [OR] 1·67, 95% confidence interval [CI] 1·04–2·69) and a variant in CD14 (OR 1·77, 95% CI 1·18–2·66) and none of the outcome polymorphisms.

Conclusions

Studies have identified several host genetics factors influencing risk of pneumococcal disease, but many result in non-reproducible findings due to methodological limitations. Uniform case definitions and pooling of data is necessary to obtain more robust findings.
Biogenesis, functions and clinical significance of circRNAs in gastric cancer
Authors: Shan Chan , Zhang Yinfeng , Hao Xiaodan , Gao Jinning , Chen Xinzhe , Wang Kun
Published: September 2019

Gastric cancer (GC) is one of the most common malignant tumours in the world and has high morbidity and mortality. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently linked circular structures. In recent years, plentiful circRNAs have been discovered that participate in many biological processes, including the initiation and development of tumours. Increasing evidences suggest important biological functions of circRNAs, implying that circRNAs may serve as vital new biomarkers and targets for disease diagnosis and prognosis. Among these, circRNAs are tend to aberrantly expressed and are regarded as potential biomarkers in the carcinogenesis and progression of GC. This review systematically summarised the biogenesis, biological properties and functions of circRNAs, with a focus on their relationship with GC, as well as their probable clinical implications on GC. As our cognition of the relation between circRNAs and GC deepens, more molecular mechanisms of GC progression will be discovered, and new therapeutic strategies will be used for the prevention and treatment of GC.
cAMP- and cGMP-elevating agents inhibit GPIbα-mediated aggregation but not GPIbα-stimulated Syk activation in human platelets
Authors: Makhoul Stephanie , Trabold Katharina , Gambaryan Stepan , Tenzer Stefan , Pillitteri Daniele , Walter Ulrich , Jurk Kerstin
Published: September 2019

Background

The glycoprotein (GP) Ib-IX-V complex is a unique platelet plasma membrane receptor, which is essential for platelet adhesion and thrombus formation. GPIbα, part of the GPIb-IX-V complex, has several physiological ligands such as von Willebrand factor (vWF), thrombospondin and distinct coagulation factors, which trigger platelet activation. Despite having an important role, intracellular GPIb-IX-V signaling and its regulation by other pathways are not well defined. Our aim was to establish the intracellular signaling response of selective GPIbα activation in human platelets, in particular the role of the tyrosine kinase Syk and its regulation by cAMP/PKA and cGMP/PKG pathways, respectively. We addressed this using echicetin beads (EB), which selectively bind to GPIbα and induce platelet aggregation.

Methods

Purified echicetin from snakeEchis carinatusvenom was validated by mass spectrometry. Washed human platelets were incubated with EB, in the presence or absence of echicetin monomers (EM), Src family kinase (SFK) inhibitors, Syk inhibitors and the cAMP- and cGMP-elevating agents iloprost and riociguat, respectively. Platelet aggregation was analyzed by light transmission aggregometry, protein phosphorylation by immunoblotting. Intracellular messengers inositolmonophosphate (InsP1) and Ca2+iwere measured by ELISA and Fluo-3 AM/FACS, respectively.

Results

EB-induced platelet aggregation was dependent on integrin αIIbβ3and secondary mediators ADP and TxA2, and was antagonized by EM. EB stimulated Syk tyrosine phosphorylation at Y352, which was SFK-dependent and Syk-independent, whereas Y525/526 phosphorylation was SFK-dependent and partially Syk-dependent. Furthermore, phosphorylation of both Syk Y352 and Y525/526 was completely integrin αIIbβ3-independent but, in the case of Y525/526, was partially ADP/TxA2-dependent. Syk activation, observed as Y352/ Y525/Y526 phosphorylation, led to the phosphorylation of direct substrates (LAT Y191, PLCγ2 Y759) and additional targets (Akt S473). PKA/PKG pathways inhibited EB-induced platelet aggregation and Akt phosphorylation but, surprisingly, enhanced Syk and LAT/PLCγ2 tyrosine phosphorylation. A similar PKA/PKG effect was confirmed with convulxin−/GPVI-stimulated platelets. EB-induced InsP1 accumulation/InsP3 production and Ca2+-release were Syk-dependent, but only partially inhibited by PKA/PKG pathways.

Conclusion

EB and EM are specific agonists and antagonists, respectively, of GPIbα-mediated Syk activation leading to platelet aggregation. The cAMP/PKA and cGMP/PKG pathways do not inhibit but enhance GPIbα−/GPVI-initiated, SFK-dependent Syk activation, but strongly inhibit further downstream responses including aggregation. These data establish an important intracellular regulatory network induced by GPIbα.

Graphical abstract
The endotoxin hypothesis of neurodegeneration
Authors: Brown Guy C.
Published: September 2019

The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer’s disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer’s disease. Intestinal permeability increases early in Parkinson’s disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson’s disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.
Long-term use of interferon-β in multiple sclerosis increases Vδ1−Vδ2−Vγ9− γδ T cells that are associated with a better outcome
Authors: Maimaitijiang Guzailiayi , Watanabe Mitsuru , Shinoda Koji , Isobe Noriko , Nakamura Yuri , Masaki Katsuhisa , Matsushita Takuya , Yoshikai Yasunobu , Kira Jun-ichi
Published: September 2019

Background

We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients.

Methods

Comprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs).

Results

The percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = − 0.369, p = 0.005), and the percentages of Vδ1−Vδ2−Vγ9− cells in Vδ1−Vδ2− γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = − 0.976, p < 0.001).

Conclusions

The present study suggests that long-term usage of IFN-β increases Vδ1−Vδ2−Vγ9− γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1−Vδ2−Vγ9− cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.