Tissue-Specific Metabolic Profiles After Prolonged Cardiac Arrest Reveal Brain Metabolome Dysfunction Predominantly After Resuscitation.

Abstract: Background Cardiac arrest (CA) has been a leading cause of death for many decades. Despite years of research, we still do not understand how each organ responds to the reintroduction of blood flow after prolonged CA. Following changes in metabolites of individual organs after CA and resuscitation gives context to the efficiency and limitations of current resuscitation protocols. Methods and Results Adult male Sprague-Dawley rats were arbitrarily assigned into 3 groups: control, 20 minutes of CA, or 20 minutes of CA followed by 30 minutes of cardiopulmonary bypass resuscitation. The rats were euthanized by decapitation to harvest brain, heart, kidney, and liver tissues. The obtained tissue samples were analyzed by ultra-high-performance liquid chromatography-high-accuracy mass spectrometry for comprehensive metabolomics evaluation. After resuscitation, the brain showed decreased glycolysis metabolites and fatty acids and increased amino acids compared with control. Similarly, the heart displayed alterations mostly in amino acids. The kidney showed decreased amino acid and fatty acid pools with severely increased tricarboxylic acid cycle metabolites following resuscitation, while the liver showed minimal alterations with slight changes in the lipid pool. Each tissue has a distinct pattern of metabolite changes after ischemia/reperfusion. Furthermore, resuscitation worsens the metabolic dysregulation in the brain and kidney, while it normalizes metabolism in the heart. Conclusions Developing metabolic profiles using a global metabolome analysis identifies the variable nature of metabolites in individual organs after CA and reperfusion, establishing a stark contrast between the normalized heart and liver and the exacerbated brain and kidney, only after the reestablishment of blood circulation.

Choi|Jaewoo|J|
Shoaib|Muhammad|M|
Yin|Tai|T|
Nayyar|Gautam|G|
Shinozaki|Koichiro|K|
Stevens|Jan F|JF|
Becker|Lance B|LB|
Kim|Junhwan|J|

D002851:Chromatography, High Pressure Liquid

cardiopulmonary bypass
mass spectrometry
asphyxia
ischemia reperfusion injury


Preparation of optimized lipid-coated calcium phosphate nanoparticles for enhanced in vitro gene delivery to breast cancer cells.

Abstract: Lipid coated calcium phosphate (LCP) nanoparticles (NPs) remain an attractive option for siRNA systemic delivery. Previous research has shown that the stoichiometry of reactants affects the size and morphology of nanostructured calcium phosphate (CaP) particles. However, it is unclear how synthesis parameters such as the Ca/P molar ratio and mixing style influence the siRNA loading and protection by LCP NPs, and subsequent siRNA delivery efficiency. In this research, we found that the Ca/P molar ratio is critical in controlling the size, zeta potential, dispersion state, siRNA loading and protection. Based on the siRNA loading efficiency and capacity as well as siRNA protection effectiveness, we suggested an optimized LCP NPs delivery system. The optimized LCP NPs had a hollow, spherical structure with the average particle size of ~40 nm and were able to maintain their stability in serum containing media and PBS for over 24 h, with a pH-sensitive dissolution property. The superior ability of optimized LCP NPs to maintain the integrity of encapsulated siRNA and the colloidal stability in culture medium allow this formulation to achieve improved cellular accumulation of siRNA and enhanced growth inhibition of human breast cancer cells in vitro, compared with the commercial transfection agent Oligofectamine™.

Tang|Jie|J|
Li|Li|L|
Howard|Christopher B|CB|
Mahler|Stephen M|SM|
Huang|Leaf|L|
Xu|Zhi Ping|ZP|

Calcium phosphate nanoparticle
siRNA delivery
Cellular uptake
Gene loading efficiency
Lipid bilayer coating


Inhibition of cathepsin activity in a cell-based assay by a light-activated ruthenium compound.

Abstract: Light-activated inhibition of cathepsin activity was demonstrated in a cell-based assay. Inhibitors of cathepsin K, Cbz-Leu-NHCH2 CN (2) and Cbz-Leu-Ser(OBn)-CN (3), were caged within the complexes cis-[Ru(bpy)2 (2)2 ]Cl2 (4) and cis-[Ru(bpy)2 (3)2 ](BF4 )2 (5) (bpy=2,2'-bipyridine) as 1:1 mixtures of Δ and Λ stereoisomers. Complexes 4 and 5 were characterized by (1) H NMR, IR, and UV/Vis spectroscopies and electrospray mass spectrometry. Photochemical experiments confirm that 4 releases two molecules of 2 upon exposure to visible light for 15 min, whereas release of 3 by 5 requires longer irradiation times. IC50 determinations against purified cathepsin K under light and dark conditions with 4 and 5 confirm that inhibition is enhanced from 35- to 88-fold, respectively, upon irradiation with visible light. No apparent toxicity was observed for 4 in the absence or presence of irradiation in bone marrow macrophage (BMM) or PC3 cells, as determined by MTT assays, at concentrations up to 10 μM. Compound 5 is well tolerated at lower concentrations (<1 μM), but does show growth-inhibitory effects at higher concentrations. Confocal microscopy experiments show that 4 decreases intracellular cathepsin activity in osteoclasts with light activation. These results support the further development of caged nitrile-based inhibitors as chemical tools for investigating spatial aspects of proteolysis within living systems.

Respondek|Tomasz|T|
Sharma|Rajgopal|R|
Herroon|Mackenzie K|MK|
Garner|Robert N|RN|
Knoll|Jessica D|JD|
Cueny|Eric|E|
Turro|Claudia|C|
Podgorski|Izabela|I|
Kodanko|Jeremy J|JJ|

cathepsins ruthenium inhibitors enzymes photochemistry


Comparison of aqueous levels of inflammatory mediators between toxic anterior segment syndrome and endotoxin-induced uveitis animal models.

Abstract:
PURPOSE
To compare clinical findings and the aqueous levels of inflammatory mediators between toxic anterior segment syndrome (TASS) and endotoxin-induced uveitis (EIU) animal models and to evaluate the efficacy of systemic steroid pretreatment in both animal models.

METHODS
Rats were used in this study. Ortho-phthalaldehyde solution was injected into the anterior chamber to produce TASS (n=30), and lipopolysaccharide was injected into one hind footpad to produce EIU (n=30). Clinical findings were evaluated under slit-lamp examination, and the aqueous levels of prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α) were measured 24 hours after these procedures. Twelve of the rats in each animal model were pretreated with intraperitoneal injection of dexamethasone for 4 days before the development of TASS and EIU.

RESULTS
Corneal haze scores were significantly higher for TASS than EIU, but clinical scores for anterior uveitis were not different between the two animal models. Although aqueous levels of PGE2 were markedly increased in both animal models, PGE2 levels were significantly higher for TASS than for EIU. However, an increase in aqueous levels of TNF-α was observed only in EIU. Dexamethasone pretreatment reduced the corneal haze score and clinical score for anterior uveitis in both animal models and inhibited the increase in aqueous levels of PGE2 and TNF-α.

CONCLUSIONS
Prostaglandin E2 and TNF-α in aqueous humor seem to be regulated differently in animal models of TASS and EIU. However, dexamethasone pretreatment improved the clinical findings and inhibited the increases in PGE2 and TNF-α in both animal models.

Eom|Youngsub|Y|
Lee|Dong Yeol|DY|
Kang|Bo-Ram|BR|
Heo|Jeong-Hwa|JH|
Shin|Kyung-Ho|KH|
Kim|Hyo Myung|HM|
Song|Jong Suk|JS|

toxic anterior segment syndrome
endotoxin-induced uveitis
prostaglandin E2
tumor necrosis factor-alpha


Some limit theorems for weighted negative quadrant dependent random variables with infinite mean.

Abstract: In the present paper, we will investigate weak laws of large numbers for weighted pairwise NQD random variables with infinite mean. The almost sure upper and lower bounds for a particular normalized weighted sum of pairwise NQD nonnegative random variables are established also.

Pairwise negative quadrant dependent sequence


Insights in the Application of Stoichiometric and Non-Stoichiometric Titanium Oxides for the Design of Sensors for the Determination of Gases and VOCs (TiO2-x and TinO2n-1 vs. TiO2).

Abstract: In this review article, attention is paid towards the formation of various nanostructured stoichiometric titanium dioxide (TiO2), non-stoichiometric titanium oxide (TiO2-x) and Magnéli phase (TinO2n-1)-based layers, which are suitable for the application in gas and volatile organic compound (VOC) sensors. Some aspects related to variation of sensitivity and selectivity of titanium oxide-based sensors are critically overviewed and discussed. The most promising titanium oxide-based hetero- and nano-structures are outlined. Recent research and many recently available reviews on TiO2-based sensors and some TiO2 synthesis methods are discussed. Some promising directions for the development of TiO2-based sensors, especially those that are capable to operate at relatively low temperatures, are outlined. The applicability of non-stoichiometric titanium oxides in the development of gas and VOC sensors is foreseen and transitions between various titanium oxide states are discussed. The presence of non-stoichiometric titanium oxide and Magnéli phase (TinO2n-1)-based layers in 'self-heating' sensors is predicted, and the advantages and limitations of 'self-heating' gas and VOC sensors, based on TiO2 and TiO2-x/TiO2 heterostructures, are discussed.

non-stoichiometric titanium oxide (TiOn or TiO2−x)


Contrast-Enhanced Ultrasound Quantification Assessment of Focal Fatty Variations in Liver Parenchyma: Challenging the Traditional Qualitative Paradigm of Uniform Enhancement With Adjacent Parenchyma.

Abstract:
OBJECTIVES
The purpose of this study was to quantify contrast-enhanced ultrasound enhancement of focal fatty sparing (FFS) and focal fatty infiltration (FFI) and compare it with adjacent liver parenchyma.

METHODS
This was a retrospective observational study yielding 42 cases in the last 4 years. Inclusion criteria were a focal liver lesion, adequate video availability, and an established diagnosis of FFS or FFI based on clinical or imaging follow-up or a second modality. Contrast-enhanced ultrasound examinations were performed with a standard low-mechanical index technique. Commercially available software calculated quantitative parameters for a focal liver lesion and a reference area of liver parenchyma, producing relative indices.

RESULTS
In total, 42 patients were analyzed (19 male) with a median age of 18 (interquartile range, 42) years and a median lesion diameter of 30 (interquartile range, 16) mm. The cohort included 26 with FFS and 16 with FFI. Subjectively assessed, 27% of FFS and 25% of FFI were hypoenhancing in the arterial phase, and 73% of FFS and 75% of FFI were isoenhancing. In the venous and delayed phases, all lesions were isoenhancing. The peak enhancement (P = .001), wash-in area under the curve (P < .01), wash-in rate (P = .023), and wash-in perfusion index (P = .001) were significantly lower in FFS compared with adjacent parenchyma but not the mean transit time. In the FFI subgroup, no significant difference was detected. Comparing relative parameters, only the wash-in rate was significantly (P = .049) lower in FFS than FFI. The mean follow-up was 2.8 years.

CONCLUSIONS
Focal fatty sparing shows significantly lower and slower enhancement than the liver parenchyma, whereas FFI enhances identically. Focal fatty sparing had a significantly slower enhancement than FFI.

contrast-enhanced ultrasound
quantification
liver
perfusion
steatosis


Nonarteritic anterior ischaemic optic neuropathy and its association with obstructive sleep apnoea: a health insurance database study.

Abstract:
BACKGROUND
Nonarteritic anterior ischaemic optic neuropathy (NAION) is the most common acute optic neuropathy in old age. Although there are several known risk factors, the influence of obstructive sleep apnoea (OSA) has not been completely elucidated. The aim of this study was to evaluate the association between NAION and OSA.

METHODS
This retrospective, longitudinal cohort study used the national health insurance database of Taiwan covering the period 1996-2013. Patients without NAION at the diagnosis of OSA or who developed NAION 1 year after the diagnosis of OSA were enrolled. The patients were followed until death or the last day of the study. Cox proportional hazard regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) to investigate the association between OSA and NAION.

RESULTS
There were 8488 patients in the OSA group and 33 952 in the control group (without OSA), for a ratio of approximately 1:4. The percentages of NAION were 0.36% and 0.2% in the OSA and control groups, respectively, with a statistically significant difference (p < 0.01; chi-square test), and this significant difference remained in multivariate analysis (p = 0.019) with a significantly higher HR (1.66; 95% CI: 1.08-2.55). There was significant difference in the 30-39 years age group in multivariate analysis (p < 0.01, HR: 6.30; 95% CI: 2.28-17.40).

CONCLUSION
There was a strong association between NAION and OSA, and the patients with OSA had a higher risk of NAION. Further large-scale, prospective studies are warranted to evaluate the effect of OSA on developing NAION.

nonarteritic anterior ischaemic optic neuropathy


Pharmacological inhibition of the NLRP3 inflammasome as a potential target for multiple sclerosis induced central neuropathic pain.

Abstract: The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of multiple diseases including neuroinflammation associated with multiple sclerosis (MS). However, the extent to which NLRP3 has a pathobiological role in MS-associated central neuropathic pain (CNP) is unknown. Hence, the present study was designed to address this issue using an optimised relapsing-remitting experimental encephalomyelitis (RR-EAE)-mouse model of MS-associated neuropathic pain. RR-EAE mice with fully developed mechanical allodynia in the bilateral hindpaws (paw withdrawal thresholds (PWTs) ≤ 1 g) at day 16 post-immunisation (p.i.) were administered single oral bolus doses of MCC950, a selective and potent small-molecule inhibitor of NLRP3, once daily for 21 consecutive days. Following administration of the first dose of MCC950 at 50 mg kg-1, the mean (± SEM) peak anti-allodynic effect was observed at ~ 1 h post-dosing with a duration of action of ~ 2 h. Following chronic dosing with MCC950, mechanical allodynia in the bilateral hindpaws was progressively reversed by oral treatment with MCC950 (50 mg kg-1 day-1), but not vehicle. Specifically, by day 25 p.i. and continuing until study completion on day 36 p.i., bilateral hindpaw PWTs of RR-EAE mice treated with MCC950 (50 mg kg-1 day-1) did not differ significantly (P > 0.05) from the corresponding hindpaw PWTs for the sham (control) group. In addition, MCC950 at 50 mg kg-1 day-1 attenuated disease relapses in RR-EAE mice indicated by tail limpness as well as hindlimb weakness. Together, our findings suggest that inhibition of NLRP3 inflammasome activation may be a potential therapeutic approach to alleviate MS-associated CNP and disease relapses in patients with RR-MS.

Khan|Nemat|N|
Kuo|Andy|A|
Brockman|David A|DA|
Cooper|Matthew A|MA|
Smith|Maree T|MT|

D000071199:NLR Family, Pyrin Domain-Containing 3 Protein

Relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE)


Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation.

Abstract: The exit of a stem cell out of quiescence into an activated state is characterized by major metabolic changes associated with increased biosynthesis of proteins and macromolecules. The regulation of this transition is poorly understood. Using muscle stem cells, or satellite cells (SCs), we found that autophagy, which catabolizes intracellular contents to maintain proteostasis and to produce energy during nutrient deprivation, was induced during SC activation. Inhibition of autophagy suppressed the increase in ATP levels and delayed SC activation, both of which could be partially rescued by exogenous pyruvate as an energy source, suggesting that autophagy may provide nutrients necessary to meet bioenergetic demands during this critical transition from quiescence to activation. We found that SIRT1, a known nutrient sensor, regulates autophagic flux in SC progeny. A deficiency of SIRT1 led to a delay in SC activation that could also be partially rescued by exogenous pyruvate. These studies suggest that autophagy, regulated by SIRT1, may play an important role during SC activation to meet the high bioenergetic demands of the activation process.

D020133:Reverse Transcriptase Polymerase Chain Reaction

autophagy
activation
quiescence
satellite cell
SIRT1


Use of proton therapy for re-irradiation in pediatric intracranial ependymoma.

Abstract:
BACKGROUND AND PURPOSE
To report disease control, survival and treatment-associated toxicity with the use of proton therapy (PRT) for re-irradiation of intracranial ependymoma.

MATERIALS AND METHODS
Twenty patients underwent 33 PRT re-irradiation courses for recurrent or metastatic lesions between June 2004 and February 2015 at Massachusetts General Hospital.

RESULTS
The majority of patients were female (60%), with infratentorial tumors (90%), anaplastic histology (55%), and initially received 55.8 GyRBE (52.2-59.4) involved field (IF) PRT. First failure was local (55%), distant (30%) or both (15%) at a median time of 23.9 months (9.9-98.5) from first treatment. Salvage therapy included re-resection (75%), chemotherapy (60%) and IFPRT (70%) to a median dose 50.4 GyRBE (35-55.8) in the majority of patients. The median follow-up was 37.8 months (5.5-138.0). Three year OS and PFS are 78.6% (95% CI 67.6-89.6) and 28.1% (95% CI 15.6-40.6), respectively. Longer OS was significantly associated with surgical resection of recurrent disease (HR 9.19, 95% CI 1.27-66.44, p=0.028). The pattern of second failure after re-irradiation was directly related to the pattern of first failure (p<0.01). Three of 14 patients (21.4%) locally re-treated experienced grade 2 radiation-associated treatment change.

CONCLUSIONS
Proton therapy appears safe and efficacious for the re-treatment of recurrent intracranial ependymoma.

Eaton|Bree R|BR|
Chowdhry|Varun|V|
Weaver|Kenneth|K|
Liu|Li|L|
Ebb|David|D|
MacDonald|Shannon M|SM|
Tarbell|Nancy J|NJ|
Yock|Torunn I|TI|

Proton Re-irradiation Pediatric Ependymoma Radiotherapy


A prospective study of prepregnancy serum concentrations of perfluorochemicals and the risk of gestational diabetes.

Abstract:
OBJECTIVE
To examine preconception serum concentrations of perfluorooctanoic acid (PFOA) and six other PFCs in relation to gestational diabetes (GDM) risk.

DESIGN
Prospective cohort with longitudinal follow-up.

SETTING
Not applicable.

PATIENT(S)
Among 501 women recruited upon discontinuing contraception for the purpose of becoming pregnant, 258 (51%) became pregnant and were eligible for the study, of which 28 (11%) reported having physician-diagnosed GDM during follow-up.

INTERVENTION(S)
None.

MAIN OUTCOME MEASURE(S)
The odds ratios (ORs) and 95% confidence intervals (CIs) of GDM associated with each standard deviation (SD) increment of preconception serum PFOA concentration (ng/mL, log-transformed) and six other PFCs were estimated with the use of logistic regression after adjusting for age, prepregnancy body mass index, smoking, and parity conditional on gravidity.

RESULT(S)
Preconception geometric mean (95% CI) PFOA concentrations (in ng/mL) were higher for women with than without GDM (3.94 [3.15-4.93] vs. 3.07 [2.83-3.12], respectively). Each SD increment in PFOA was associated with a 1.87-fold increased GDM risk (adjusted OR 1.86 [95% CI 1.14-3.02]). A slightly increased risk associated with each SD increment for the six other PFCs was observed as well (all ORs >1.0, range 1.06-1.27), although the associations were not statistically significant.

CONCLUSION(S)
Our findings suggested that higher environmentally relevant concentrations of PFOA were significantly associated with an increased risk of GDM. If corroborated, these findings may be suggestive of a possible environmental etiology for GDM.

Zhang|Cuilin|C|
Sundaram|Rajeshwari|R|
Maisog|José|J|
Calafat|Antonia M|AM|
Barr|Dana Boyd|DB|
Buck Louis|Germaine M|GM|

gestational diabetes
perfluorooctanoic acid (PFOA)
Perfluorochemicals (PFCs)
pregnancy


Reflections on the meaning of 'resilience' in the Palestinian context.

Abstract: This reflective piece offers an alternative perspective to understanding the components which support the Palestinian capacity to endure and resist 100 years of violation and injustice, in context. It traces the development of the author's understanding over time as part of the Palestinian community living under Israeli military rule in chronic warlike conditions. It combines this lived experience with research results which raise question about what resilience means, the difficulties encountered in its measurement, and the utility of the concept in explaining the Palestinian reality. It emphasizes the need to include the contextual experiences of those who live in wars and conflicts in future research and for knowledge production. It ends by stressing that it is not sufficient to offer humanitarian aid to the victims of wars and conflicts without also advocating for justice not only for Palestinians but also in other contexts of injustice worldwide.

palestinian
war
mental health
public health


Predicting survival in older patients treated for cervical spine fractures: development of a clinical survival score.

Abstract:
BACKGROUND CONTEXT
Emerging literature has identified the importance of pretreatment health and functional status as influential in the prognostication of survival. A comprehensive, accessible, predictive model for survival following cervical spine fracture has yet to be developed.

PURPOSE
To develop an accessible and intuitive predictive model for survival in individuals aged 50 and older treated for cervical spine fractures.

STUDY DESIGN
Retrospective review of records from two tertiary care centers (2009-2016).

PATIENT SAMPLE
Patients age 50 and older who received operative or nonoperative management for cervical fractures.

OUTCOME MEASURES
One-year mortality was the primary outcome with 3-month and 2-year mortality considered secondarily.

METHODS
Multivariable logistic regression was used to identify factors independently associated with mortality. The magnitude and precision of the relationship with 1-year mortality for statistically significant variables determined weighting in the scoring system subsequently developed. Score performance was tested through multivariable regression and bootstrap simulation. In a sensitivity test, the performance of the score developed for 1-year mortality was assessed using figures for the 3-month and 2-year time-points.

RESULTS
We included 1,758 patients. Mortality rates were 12% at 3 months, 17% at 1 year, and 21% at 2 years. Following multivariable testing age, injury severity score and Glasgow coma scale demonstrated the strongest predictive values for a base score, followed by serum albumin and ambulatory status. The resultant composite score ranged from 0 (base score≤4, albumin≤3.5 g/dL, and dependent/nonambulator at presentation) to a maximum of 4 (base score≥5, albumin>3.5 g/dL, and independent ambulator at presentation). Following multivariable analysis, when compared to patients with a score of 4, significantly increased odds of 1-year mortality were appreciated for those with scores of 3 (odds ratio [OR] 7.35; 95% confidence interval [CI] 3.77, 14.32), 2 (OR 8.43; 95% CI 4.66, 15.25), 1 (OR 17.47; 95% CI 9.81, 31.11), and 0 (OR 26.58; 95% CI 13.87, 50.92). Score performance was unchanged in bootstrap testing and sensitivity analyses.

CONCLUSIONS
We have developed a useful prognostic utility capable of informing survival in individuals age 50 and older, following cervical spine fractures. The score can be applied to adjust patient expectations, anticipate outcomes, and as an adjunct to decision-making in the postinjury period.

Cronin|Patrick K|PK|
Ferrone|Marco L|ML|
Marso|Chase C|CC|
Stieler|Evan K|EK|
Beck|Aaron W|AW|
Blucher|Justin A|JA|
Makhni|Melvin C|MC|
Simpson|Andrew K|AK|
Harris|Mitchel B|MB|
Schoenfeld|Andrew J|AJ|

Survival
Cervical spine fracture
Functional status
Albumin
Prognostic models
geriatrics


Development of diagnostic systems for wide range and highly sensitive detection of two waterborne hepatitis viruses from groundwater using the conventional reverse transcription nested PCR assay.

Abstract: Waterborne epidemics of human hepatitis virus A and E (HAV and HEV) have been reported worldwide. Molecular biology techniques, such as reverse transcription polymerase chain reaction (RT-PCR), have been widely used to detect the two hepatitis viruses. However, comparative studies of various types of samples are needed, and different environmental factors, including the low copy pathogens, presence of PCR inhibitors in the sample, unknown non-specific reaction with template, and sequence diversity leading to new variants in viruses, should be considered. In addition, standard positive material is required to determine the accuracy of the PCR and should be able to distinguish between false and real positives. In this study, we developed RT-PCR primer sets and optimised standard templates for HAV and HEV detection to address the above concerns associated with test sensitivity and possible PCR inhibition. Finally, previously reported diagnostic methods of HAV and HEV were compared and an applicability test using groundwater was performed. The nested RT-PCR developed in this study is expected to contribute to assess water safety by monitoring HAV and HEV in non-disinfected water, like groundwater.

Bae|Kyung-Seon|KS|
Lee|Siwon|S|
Lee|Jin-Young|JY|
Kim|Ji-Hye|JH|
Joo|Youn-Lee|YL|
Lee|Soo Hyung|SH|
Chung|Hyen-Mi|HM|
You|Kyung-A|KA|

Groundwater
Hepatitis virus A
HAV
HEV
Standard positive material
Hepatitis virus E


Biochemical, oxidative and histological changes caused by sub-acute oral exposure of some synthetic cyanogens in rats: ameliorative effect of α-ketoglutarate.

Abstract: Time-dependent cyanide generation and acute toxicity of six different cyanogens were reported earlier, out of which malononitrile (MCN), propionitrile (PCN), and sodium nitroprusside (SNP) were found to be very toxic. We report here 14 d sub-acute toxicity of MCN, PCN, and SNP (oral; 1/10 LD50 daily) in female rats, and its amelioration by α-ketoglutarate (α-KG; oral; 5.26 mmol/kg; +5 min), a potential cyanide antidote. Significant decrease in white blood cells (PCN, SNP), platelets count (PCN), and blood glucose levels (MCN, PCN, SNP) was accompanied by elevated levels of alanine aminotransferase, lactate dehydrogenase (MCN, PCN, SNP), and aspartate aminotransferase (PCN, SNP). Oxidative damage was evidenced by diminished total antioxidant status in plasma and enhanced malondialdehyde levels in liver and kidney. This was accompanied by diminished levels of reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase in the brain, liver and kidney. We also observed increased levels of blood cyanide and thiocyanate, together with inhibition of cytochrome c oxidase and thiosulfate-sulfur transferase activities in total brain and liver homogenate, respectively. Cyanogens also produced several histological changes in all the organs studied. Post-treatment with α-KG significantly abrogated the toxicity of cyanogens, indicating its utility as an antidote for long-term cyanogen exposure.

Bhattacharya|Rahul|R|
Rao|Pooja|P|
Singh|Poonam|P|
Yadav|Shiv Kumar|SK|
Upadhyay|Preeti|P|
Malla|Sandhya|S|
Gujar|Niranjan Laxman|NL|
Lomash|Vinay|V|
Pant|Satish Chandra|SC|

Cyanogens
α-Ketoglutarate
Sub-acute toxicity
Oxidative damage
Protection


Influence of architectural style on indoor radon concentration in a radon prone area: A case study.

Abstract: Indoor radon is a major health concern as it is a known carcinogenic. Nowadays there is a trend towards a greater energy conservation in buildings, which is reflected in an increasing number of regulations. But, can this trend increase the indoor radon concentration? In this paper, we selected a radon prone area in Spain and focused on single-family dwellings constructed in a variety of architectural styles. These styles ranged from 1729 up to 2014, with varying construction techniques (from local resources to almost universally standard building materials) and regulations in force (from none to the Spanish regulation in force). The 226Ra concentrations in soil and surface radon exhalation rates were rather similar in this area, mean values ranging 70-126Bq/kg and 49-100mBq/m2·s, respectively. Indoor radon concentration was generally greater than the contribution from soil exhalation (surface exhalation rates), especially in New dwellings (1980-2014). Its concentration in dwellings built in the Traditional style (1729-1940) was significantly lower than in the new houses. This can be consequence of the air tightness of the dwellings as a consequence of the different regulations in force. In the period covered by the Traditional style, there was no regulation in force, and dwelling had loose air tight. Whereas in recent times, there are mandatory regulations assuring a better air tightness of the buildings. Refurbishment of Traditional dwellings also seems to increase the indoor radon concentration, as they must also comply with the regulations in force.

Baeza|A|A| García-Paniagua|J|J| Guillén|J|J| Montalbán|B|B|

Architectural style
Radon
Radon prone area
Building regulation


Particle swarm optimization of partitions and fuzzy order for fuzzy time series forecasting of COVID-19.

Abstract: Major hyperparameters which affect fuzzy time series (FTS) forecasting are the number of partitions, length of partition intervals in the universe of discourse, and the fuzzy order. There are very few studies which have considered an integrated solution to optimize all the hyperparameters. In this paper, we strive to achieve optimum values of all three hyperparameters for fuzzy time series forecasting of the COVID-19 pandemic using the Particle Swarm Optimization (PSO) algorithm. We specifically propose two techniques, namely nested FTS-PSO and exhaustive search FTS-PSO for determining the optimal interval length, as an augmentation to the FTS-PSO model that optimizes the interval length and the fuzzy order. Nested PSO has two PSO loops: (i) the inner PSO optimizes the combination of fuzzy order and boundaries of intervals for a given number of partitions defined by the outer loop, and the resultant cost is fed back to the outer PSO; (ii) the outer PSO optimizes the number of partitions to reduce the cost while meeting the defined constraint. Exhaustive search FTS-PSO also has two loops where the inner loop is similar to nested FTS-PSO while the outer loop iterates over a pre-defined search space of number of partitions. We analyze the effectiveness of the two approaches by comparing with ARIMA, FbProphet, and the state-of-the-art FTS and FTS-PSO models. We adopt COVID-19 highly affected 10 countries worldwide to perform forecasting of coronavirus confirmed cases. We consider two phases of COVID-19 spread, one from the year 2020 and another from 2021. Our study provides an analytical aspect of the COVID-19 pandemic, and aims to achieve optimal number and length of intervals along with fuzzy order for FTS forecasting of COVID-19. The results prove that the exhaustive search FTS-PSO outperformed all the methods whereas nested FTS-PSO performed moderately well.

Particle swarm optimization
Fuzzy time series
Forecasting
COVID-19
Pandemic
Nested PSO
ARIMA
FbProphet


Metabolic profiling of chickpea-Fusarium interaction identifies differential modulation of disease resistance pathways.

Abstract: Chickpea is the third most widely grown legume in the world and mainly used as a vegetarian source of human dietary protein. Fusarium wilt, caused by Fusarium oxysporum f. sp. ciceri (Foc), is one of the major threats to global chickpea production. Host resistance is the best way to protect crops from diseases; however, in spite of using various approaches, the mechanism of Foc resistance in chickpea remains largely obscure. In the present study, non-targeted metabolic profiling at several time points of resistant and susceptible chickpea cultivars using high-resolution liquid chromatography-mass spectrometry was applied to better understand the mechanistic basis of wilt resistance or susceptibility. Multivariate analysis of the data (OPLS-DA) revealed discriminating metabolites in chickpea root tissue after Foc inoculation such as flavonoids, isoflavonoids, alkaloids, amino acids and sugars. Foc inoculated resistant plants had more flavonoids and isoflavonoids along with their malonyl conjugates. Many antifungal metabolites that were induced after Foc infection viz., aurantion-obstine β-glucosides and querecitin were elevated in resistant cultivar. Overall, diverse genetic and biochemical mechanisms were operational in the resistant cultivar for Foc defense as compared to the susceptible plant. The resistant chickpea plants employed the above-mentioned metabolic pathways as potential defense strategy against Foc.

Kumar|Yashwant|Y|
Dholakia|Bhushan B|BB|
Panigrahi|Priyabrata|P|
Kadoo|Narendra Y|NY|
Giri|Ashok P|AP|
Gupta|Vidya S|VS|

D029863:Cicer
D060467:Disease Resistance
D005670:Fusarium
D054884:Host-Pathogen Interactions
D010935:Plant Diseases
D018517:Plant Roots

Chickpea
Fusarium wilt
OPLS-DA
LC–MS
Metabolomics
Phytoalexin


Roles of oxidative stress, apoptosis, and inflammation in metal-induced dysfunction of beta pancreatic cells isolated from CD1 mice.

Abstract: The diabetogenic effects of metals including lead (Pb), mercury (Hg), cadmium (Cd), and molybdenum (Mo) have been reported with poorly identified underlying mechanisms. The current study assessed the effect of metals on the roles of oxidative stress, apoptosis, and inflammation in beta pancreatic cells isolated from CD-1 mice, via different biochemical assays. Data showed that the tested metals were cytotoxic to the isolated cells with impaired glucose stimulated insulin secretion (GSIS). This was associated with increased reactive oxygen species (ROS) production, lipid peroxidation, antioxidant enzymes activities, active proapoptotic caspase-3 (cas-3), inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels in the intoxicated cells. Furthermore, antioxidant-reduced glutathione (GSH-R), cas-3 inhibitor z-VAD-FMK, IL-6 inhibitor bazedoxifene (BZ), and TNF-α inhibitor etanercept (ET) were found to significantly decrease metal-induced cytotoxicity with improved GSIS in metals' intoxicated cells. In conclusion, oxidative stress, apoptosis, and inflammation can play roles in metals-induced diabetogenic effect.

Al Doghaither|Huda|H|
Elmorsy|Ekramy|E|
Al-Ghafari|Ayat|A|
Ghulam|Jihan|J|

Oxidative stress
Inflammation
Lead
Mercury
Cadmium
Molybdenum
Pancreatic beta cells


Lumbar spinal stenosis due to a large calcified mass in the ligamentum flavum.

Abstract: We describe a rare case of lumbar spinal stenosis due to a large calcified mass in the ligamentum flavum. This patient presented with a 12-month history of severe right leg pain and intermittent claudication. A computed tomography scan was performed, revealing a large calcified mass on the ligamentum flavum at the right-hand side of the lumbar spinal canal. We performed a laminotomy at the L4/5 level with resection of the calcified mass from the ligamentum flavum. The findings of various analyses suggested that the calcified mass consisted mostly of Ca3(PO4)2 and calcium phosphate intermixed with protein and water. The calcified mass in the ligamentum flavum was causing lumbar spinal stenosis. Surgical decompression by resection of the mass was effective in this patient. The calcified material was composed mainly of elements derived from calcium phosphate. Degenerative changes in the ligamentum flavum of the lumbar spine may have been involved in the production of this calcified mass.

Seki|Shoji|S| Kawaguchi|Yoshiharu|Y| Ishihara|Hirokazu|H| Oya|Takeshi|T| Kimura|Tomoatsu|T|

Spinal stenosis
Ligamentum flavum
Calcium phosphate
Calcification


Robust Binding between Carbon Nitride Nanosheets and a Binuclear Ruthenium(II) Complex Enabling Durable, Selective CO2 Reduction under Visible Light in Aqueous Solution.

Abstract: Carbon nitride nanosheets (NS-C3 N4 ) were found to undergo robust binding with a binuclear ruthenium(II) complex (RuRu') even in basic aqueous solution. A hybrid material consisting of NS-C3 N4 (further modified with nanoparticulate Ag) and RuRu' promoted the photocatalytic reduction of CO2 to formate in aqueous media, in conjunction with high selectivity (approximately 98 %) and a good turnover number (>2000 with respect to the loaded Ru complex). These represent the highest values yet reported for a powder-based photocatalytic system during CO2 reduction under visible light in an aqueous environment. We also assessed the desorption of RuRu' from the Ag/C3 N4 surface, a factor that can contribute to a loss of activity. It was determined that desorption is not induced by salt additives, pH changes, or photoirradiation, which partly explains the high photocatalytic performance of this material.

Kuriki|Ryo|R| Yamamoto|Muneaki|M| Higuchi|Kimitaka|K| Yamamoto|Yuta|Y| Akatsuka|Masato|M| Lu|Daling|D| Yagi|Shinya|S| Yoshida|Tomoko|T| Ishitani|Osamu|O| Maeda|Kazuhiko|K|0000-0001-7245-8318

carbon nitride
formate
CO2 fixation
artificial photosynthesis
heterogeneous photocatalysis


OCT4 and PAX6 determine the dual function of SOX2 in human ESCs as a key pluripotent or neural factor.

Abstract:
BACKGROUND
Sox2 is a well-established pluripotent transcription factor that plays an essential role in establishing and maintaining pluripotent stem cells (PSCs). It is also thought to be a linage specifier that governs PSC neural lineage specification upon their exiting the pluripotent state. However, the exact role of SOX2 in human PSCs was still not fully understood. In this study, we studied the role of SOX2 in human embryonic stem cells (hESCs) by gain- and loss-of-function approaches and explored the possible underlying mechanisms.

RESULTS
We demonstrate that knockdown of SOX2 induced hESC differentiation to endoderm-like cells, whereas overexpression of SOX2 in hESCs enhanced their pluripotency under self-renewing culture conditions but promoted their neural differentiation upon replacing the culture to non-self-renewal conditions. We show that this culture-dependent dual function of SOX2 was probably attributed to its interaction with different transcription factors predisposed by the culture environments. Whilst SOX2 interacts with OCT4 under self-renewal conditions, we found that, upon neural differentiation, PAX6, a key neural transcription factor, is upregulated and shows interaction with SOX2. The SOX2-PAX6 complex has different gene regulation pattern from that of SOX2-OCT4 complex.

CONCLUSIONS
Our work provides direct evidence that SOX2 is necessarily required for hESC pluripotency; however, it can also function as a neural factor, depending on the environmental input. OCT4 and PAX6 might function as key SOX2-interacting partners that determine the function of SOX2 in hESCs.

Zhang|Shuchen|S|
Bell|Emma|E|
Zhi|Huihan|H|
Brown|Sarah|S|
Imran|Siti A M|SAM|
Azuara|Véronique|V|
Cui|Wei|W|0000-0003-2019-380X

D002454:Cell Differentiation
D002460:Cell Line
D000066449:Human Embryonic Stem Cells
D006801:Humans
D058953:Neural Stem Cells
D050814:Octamer Transcription Factor-3
D000071841:PAX6 Transcription Factor
D055748:SOXB1 Transcription Factors


Case report: The use of three-dimensional biomodels for surgical planning of rib fixation.

Abstract:
Background
Prosthetic titanium plates are frequently used in the stabilization of rib fractures and are typically contoured to the patient's anatomy at the time of implant in the operating room. Smith et al. [17] described the use of a 3D prototype biomodel of his patient's skeletal anatomy for preoperative customization of standard titanium plates for rib fractures. This process facilitated the preoperative planning and provided implants appropriate for a patient's unique anatomy. Further, the approach facilitated repair of complex fractures and may decrease operating time. Besides that, it provides idealized conditions for plate shaping and may facilitate implantation.

Methods
We performed rib fixation combined with 3D biomodels for surgical planning for the first time in Brazil, achieving reduced operating time with a good outcome for our patient.

Results
Surgical planning was conducted one day before the surgery using a 3D printer to make a patient-specific model. The printing time of the model was 16 h. The 3D biomodel was used for simulating the surgical procedure, pre-molding the titanium plates, and measuring the screw sizes that would be used in the procedure. All five fractures were fixed on the 3D biomodel and the total simulation time was 58 min. We used four pre-contoured titanium plates of 1.5 mm thickness and one straight 1.5 mm thickness titanium plate. We used the printed model to measure screw size, as we would do in the surgery. After planning, the material was processed and sterilized according to the hospital standards to be implanted in the patient the following day.

Conclusion
This is the second reported case of surgical stabilization of rib fractures using a 3D model. Both cases demonstrated the advantages of this approach. More studies are needed to validate the safety and benefits for the patient, as well as the impact on cost savings.

Garcia|Diogo de Freitas Valeiro|DFV|
Mesias|Andre Vinicio Cruz|AVC|
Vieites|Luiza|L|
Mendes|Paula Morais Pereira|PMP|
Ripardo|João Paulo Sousa|JPS|

Titanium
Rib fracture fixation
Surgical models


Evaluating the endothelial-microglial interaction and comprehensive inflammatory marker profiles under acute exposure to ultrafine diesel exhaust particles in vitro.

Abstract: Exposure to combustion-derived particulate matter (PM) such as diesel exhaust particles (DEP) is a public health concern because people in urban areas are continuously exposed, and once inhaled, fine and ultrafine DEP may reach the brain. The blood-brain barrier (BBB) endothelial cells (EC) and the perivascular microglia protect the brain from circulating pathogens and neurotoxic molecules like DEP. While the BBB-microglial interaction is critical for maintaining homeostasis, no study has previously evaluated the endothelial-microglial interaction nor comprehensively characterized these cells' inflammatory marker profiles under ultrafine DEP exposures in vitro. Therefore, the goal of this study was to investigate the in vitro rat EC-microglial co-culture under acute (24 h.) exposure to ultrafine DEP (0.002-20 μg/mL), by evaluating key mechanisms associated with PM toxicity: lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) generation, cell metabolic activity (CMA) changes, and production of 27 inflammatory markers. These parameters were also evaluated in rat microglial and endothelial monocultures to determine whether the EC-microglial co-culture responded differently than the cerebrovasculature and microglia alone. While results indicated that ultrafine DEP exposure caused concentration-dependent increases in LDH leakage and ROS production in all groups, as expected, exposure also caused mixed responses in CMA and atypical cytokine/chemokine profiles in all groups, which was not expected. The inflammation assay results further suggested that the microglia were not classically activated under this exposure scenario, despite previous in vitro studies showing microglial activation (priming) at similar concentrations of ultrafine DEP. Additionally, compared to the cerebrovasculature alone, the EC-microglia interaction in the co-culture did not appear to cause changes in any parameter save in pro-inflammatory marker production, where the interaction appeared to cause an overall downregulation in cytokine/chemokine levels after ultrafine DEP exposure. Finally, to our knowledge, this is the first study to evaluate the influence of microglia on the BBB's ultrafine DEP-induced cytotoxic and inflammatory responses, which are heavily implicated in the pathogenesis of PM-related cerebrovascular dysfunction and neurodegeneration.

Aquino|Grace V|GV|
Dabi|Amjad|A|
Odom|Gabriel J|GJ|
Zhang|Fan|F|
Bruce|Erica D|ED|

D000818:Animals
D001812:Blood-Brain Barrier
D002478:Cells, Cultured
D018920:Coculture Techniques
D042783:Endothelial Cells
D007249:Inflammation
D017628:Microglia
D010316:Particle Size
D052638:Particulate Matter
D051381:Rats
D017382:Reactive Oxygen Species
D001335:Vehicle Emissions

Ultrafine diesel exhaust particles
Blood-brain barrier
Endothelial cells
Microglia
Inflammation
Oxidative stress


Safety and efficacy of PLGA(Ag-Fe3O4)-coated dental implants in inhibiting bacteria adherence and osteogenic inducement under a magnetic field.

Abstract:
Introduction
The placement of dental implants is performed in a contaminated surgical field in the oral cavity, which may lead to implant failure. Bacterial adhesion and proliferation (Streptococcus mutans, Porphyromonas gingivalis) often lead to implant infections. Although Ag nanoparticles hold great promise for a broad spectrum of antibacterial activities, their runoff from dental implants compromises their antibacterial efficacy and potentially impairs osteoblast proliferation. Thus, this aspect remains a primary challenge and should be controlled.

Materials and methods
In this study, PLGA(Ag-Fe3O4) was modified on the implanted tooth surface and was characterized by transmission electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The magnetic and antibacterial properties were also determined.

Results
Results showed that Ag successfully bonded with Fe3O4, and Ag-Fe3O4 not only exerted superparamagnetism but also exhibited antibacterial activity almost identical to silver nanoparticles (nano-Ag). The PLGA(Ag-Fe3O4) coating could significantly maintain the antibacterial activity and avoid bacterial adhesion to the implant. Compared with the blank control group, PLGA(Ag-Fe3O4) under magnetic field-coated samples had a significantly lower amount of colonized S. mutans (P<0.01). Osteoblast proliferation results showed that the coated samples did not exhibit cytotoxicity and could promote osteoblast proliferation as shown by MTT, alkaline phosphatase, and the nucleolar organizer region count.

Conclusion
We developed a novel Ag biologically compatible nanoparticle in this study without compromising the nano-Ag antibacterial activity, which provided continuous antibacterial action.

Yang|Yaping|Y| Ren|Shuangshuang|S| Zhang|Xuan|X| Yu|Yijun|Y| Liu|Chao|C| Yang|Jie|J| Miao|Leiying|L|

D000077182:Polylactic Acid-Polyglycolic Acid Copolymer

dental implants
antibacterial property
Ag-Fe3O4
PLGA


Cancer Immunotherapy and the Immune Response in Hodgkin Lymphoma.

Abstract: Patients with classical Hodgkin lymphoma (cHL) have an impaired cellular immune response as indicated by an anergic reaction against standard recall antigens and a diminished rejection reaction of allogeneic skin transplant. This clinical observation can be linked to the histopathological feature of cHL since the typical pattern of a cHL manifestation is characterized by sparse large CD30+ tumor-infiltrating Hodgkin-Reed-Sternberg (HRS) cells that are surrounded by a dense inflammatory immune microenvironment with mixed cellularity. Despite this extensive polymorphous inflammatory infiltrate, there is only a poor antitumor immune response seen to the neoplastic HRS cells. This is primarily mediated by a high expression of PD-L1 and PD-L2 ligands on the HRS cell surface which in turn antagonizes the activity of programmed death-1 (PD-1) antigen-positive T cells. PD-L1/L2 overexpression is caused by gene amplification at the 9p24.1 locus and/or latent Epstein-Barr virus infection present in around 40% of cHL cases. The blockade of the PD-L1/L2-PD-1 pathway by monoclonal antibodies can restore local T cell activity and leads to impressive tumor responses, some of which are long lasting and eventually curative. Another feature of HRS cells is the high CD30 antigen expression. Monoclonal antibody technology allowed for the successful development of CD30-specific immunotoxins, bispecific antibodies, and reprogrammed autologous T cells with the first one already approved for the treatment of high risk or relapsed cHL. Altogether, the discovery of the described pathomechanism of immune suppression and the identification of preferential target antigens has rendered cHL to be a prime subject for the successful development of new immunotherapeutic approaches.

Hodgkin lymphoma
monoclonal antibodies
immunotoxins
bispecific antibodies
check-point blockade inhibitors
chimeric antigen receptors


Antioxidant status in a group of institutionalised elderly people with chronic obstructive pulmonary disease.

Abstract: Chronic obstructive pulmonary disease (COPD) is one of the most important and prevalent diseases suffered by the elderly. Evidence exists that its onset and severity might be conditioned by antioxidant status. The aim of the present study was to investigate the relationship between antioxidant status and COPD in institutionalised elderly people. In all, 183 elderly people aged >65 years (twenty-one had COPD and 160 healthy controls) were studied. The subjects' diets were investigated via the use of precise individual weighing for 7 d. Body weight, height, and biceps and triceps skinfold thickness were measured, and body fat (kg) and BMI (kg/m2) were calculated. Serum retinol, α-tocopherol, β-carotene and vitamin C levels were determined. Subjects with COPD ate less fruits than healthy controls (117 (sd 52) v. 192 (sd 161) g/d), their coverage of the recommended intake of vitamin C was smaller (150 (sd 45) v. 191 (sd 88) %; note that both exceeded 100 %) and their diets had a lower antioxidant capacity (6558 (sd 2381) v. 9328 (sd 5367) mmol trolox equivalent/d). Those with COPD had lower serum vitamin C and α-tocopherol concentrations than healthy controls (32·4 (sd 15·3) v. 41·5 (sd 14·8) µmol/l and 12·1 (sd 3·2) v. 13·9 (sd 2·8) µmol/l, respectively). In addition, subjects with α-tocopherol <14·1µmol/l (50th percentile) were at 6·43 times greater risk of having COPD than those subjects with ≥14·1µmol/l (OR 6·43; 95 % CI 1·17, 35·24; P<0·05), taking sex, age, use of tobacco, body fat and vitamin E intake as covariables. Subjects with COPD had diets of poorer antioxidant quality, especially with respect to vitamins C and E, compared with healthy controls.

D029424:Pulmonary Disease, Chronic Obstructive

COPD chronic obstructive pulmonary disease


The Remarkable Journey of a Weed: Biology and Management of Annual Ryegrass (Lolium rigidum) in Conservation Cropping Systems of Australia.

Abstract: Annual ryegrass (Lolium rigidum Gaud.), traditionally utilised as a pasture species, has become the most problematic and difficult-to-control weed across grain production regions in Australia. Annual ryegrass has been favoured by the adoption of conservation tillage systems due to its genetic diversity, prolific seed production, widespread dispersal, flexible germination requirements and competitive growth habit. The widespread evolution of herbicide resistance in annual ryegrass has made its management within these systems extremely difficult. The negative impacts of this weed on grain production systems result in annual revenue losses exceeding $93 million (AUD) for Australian grain growers. No single method of management provides effective and enduring control hence the need of integrated weed management programs is widely accepted and practiced in Australian cropping. Although annual ryegrass is an extensively researched weed, a comprehensive review of the biology and management of this weed in conservation cropping systems has not been conducted. This review presents an up-to-date account of knowledge on the biology, ecology and management of annual ryegrass in an Australian context. This comprehensive account provides pragmatic information for further research and suitable management of annual ryegrass.

grain production
herbicide resistance
integrated weed management
rigid ryegrass
weed biology


Motivational orientation mediates the association between depression and cardiovascular reactivity to acute psychological stress.

Abstract: Recent theoretical developments in cardiovascular reactivity research suggest the association between depression and blunted reactions to stress is linked to motivational factors. Thus, the present study aimed to test whether the association between depressive symptoms and cardiovascular reactivity to acute stress was mediated by motivation; be it intrinsic or extrinsic motivation. One hundred and eighty-two healthy young adults completed measures of motivation (Global Motivation Scale; GMS), and depression (Hospital Anxiety and Depression Scale; HADS) and had their blood pressure and heart rate monitored throughout a standardised stress testing protocol. Results indicated that depression was negatively associated with both systolic blood pressure (SBP) and heart rate (HR) reactions to the stress task (all ps < .05), such that those who reported higher depressive symptomology displayed a blunted response. Furthermore this relationship was mediated by intrinsic, but not extrinsic motivation; the blunted responses were less pronounced through intrinsic motivation. The present findings add extensively to existing research and confirm that motivation is an underlying mechanism linking depression and cardiovascular reactivity.

motivation
mediation
depression
cardiovascular reactivity
intrinsic
extrinsic


History of pediatric type 1 diabetes in China.

Abstract: The incidence of type 1 diabetes mellitus (T1DM) in children has been increasing worldwide. However, there is not much information about the situation of pediatric T1DM in China. In the past 60 years, the clinical management and research of pediatric T1DM in China have made tremendous progress. We introduced the history of pediatric diabetes in China. In addition to review the current situation of research in pediatric diabetes, we summarized the progress in the treatment and management of pediatric T1DM in China. Finally, we pointed out some shortcomings, which need to be improved in the future.

Liang|Yan|Y| Hou|Ling|L| Wu|Wei|W| Ye|Feng|F| Zhang|Cai|C| Luo|Xiaoping|X|

history
china
pediatric diabets
current situation


Drosophila FANCM helicase prevents spontaneous mitotic crossovers generated by the MUS81 and SLX1 nucleases.

Abstract: Several helicases function during repair of double-strand breaks and handling of blocked or stalled replication forks to promote pathways that prevent formation of crossovers. Among these are the Bloom syndrome helicase BLM and the Fanconi anemia group M (FANCM) helicase. To better understand functions of these helicases, we compared phenotypes of Drosophila melanogaster Blm and Fancm mutants. As previously reported for BLM, FANCM has roles in responding to several types of DNA damage in preventing mitotic and meiotic crossovers and in promoting the synthesis-dependent strand annealing pathway for repair of a double-strand gap. In most assays, the phenotype of Fancm mutants is less severe than that of Blm mutants, and the phenotype of Blm Fancm double mutants is more severe than either single mutant, indicating both overlapping and unique functions. It is thought that mitotic crossovers arise when structure-selective nucleases cleave DNA intermediates that would normally be unwound or disassembled by these helicases. When BLM is absent, three nucleases believed to function as Holliday junction resolvases--MUS81-MMS4, MUS312-SLX1, and GEN--become essential. In contrast, no single resolvase is essential in mutants lacking FANCM, although simultaneous loss of GEN and either of the others is lethal in Fancm mutants. Since Fancm mutants can tolerate loss of a single resolvase, we were able to show that spontaneous mitotic crossovers that occur when FANCM is missing are dependent on MUS312 and either MUS81 or SLX1.

Kuo|H Kenny|HK|
McMahan|Susan|S|
Rota|Christopher M|CM|
Kohl|Kathryn P|KP|
Sekelsky|Jeff|J|

helicase
Fanconi anemia
Holliday junction resolvase
mitotic recombination


Effects of sludge retention times on reactivity of effluent dissolved organic matter for trihalomethane formation in hybrid powdered activated carbon membrane bioreactors.

Abstract: In this study, real municipal wastewater intended for reuse was treated by two identical hybrid PAC/MBRs (membrane bioreactors with powdered activated carbon addition), which were operated at sludge retention times (SRTs) of 30 and 180 days, respectively. In order to investigate the effects of SRT on trihalomethane (THM) formation in chlorinated PAC/MBR effluents, characteristics and THM formation reactivity of effluent dissolved organic matter (EfOM) at different SRTs were examined. PAC/MBR-180 had higher level of EfOM, which contained less simple aromatic proteins and exhibited lower specific UV absorbance. EfOM with molecular weight <5 kDa from PAC/MBR-30 (23%) was lower than PAC/MBR-180 (26%). About 50% of EfOM from PAC/MBR-30 was hydrophobic acids, which was higher than that from PAC/MBR-180 (about 36%). EfOM at SRT 180 days exhibited higher hydrophilicity. Prolonging SRT greatly reduced THM formation reactivity of EfOM, but increased the formation of bromine-containing species during chlorination of PAC/MBR effluents.

Ma|Defang|D| Gao|Baoyu|B| Xia|Chufan|C| Wang|Yan|Y| Yue|Qinyan|Q| Li|Qian|Q|

D057927:Hydrophobic and Hydrophilic Interactions

PAC/MBR THMs Chlorination DOM Fractionation


New methodology for automated SPOT synthesis of peptides on cellulose using 1,3,5-triazine derivatives as linkers and as coupling reagents.

Abstract: Two new rigid bi-aromatic linkers for synthesis of peptide arrays by SPOT methodology were obtained from cellulose treated with 2,4-dichloro-6-methoxy-1,3,5-triazine. Reaction with m-phenylenediamine gave non-cleavable TYPE I linker which enabled attachment of the peptides via resistant to harsh reaction conditions amide, ether, and amine bonds. Reaction with 3-Fmoc-aminobenzoic acid followed by thermal isomerization of the intermediate "superactive" ester producing an amide-like bond gave TYPE II linker that was very stable during peptide synthesis. However, the peptide was cleavable, with fragment of the linker, in the presence of 1 M LiOH solution. The uniform loading of the cellulose and efficient synthesis of the peptide array was achieved by using N-(4,6-dimethoxy-1,3,5-triazin-1-yl)-N-methylmorpholinium 4-toluenesulfonate as the coupling reagent.

peptide array
2,4-dichloro-6-methoxy-1,3,5-triazine
m-phenylenediamine
thermal isomerization
triazine-based coupling reagents


Factors Influencing Nursing Students' Immersive Virtual Reality Media Technology-Based Learning.

Abstract:
BACKGROUND/OBJECTIVES
This study aims to identify the effects of cognitive and emotional variables related to immersive virtual reality media technology on learning for nursing students. Methods/Statistical analysis: The subjects of this study were 121 nursing students from a university in area D. After experiential learning with virtual reality from 6-8 June 2019, data was collected through questionnaires. For virtual reality learning, VIVE's hTC VIVE ECO CE model was used. The collected data was analyzed using the IBM SPSS 26.0 program. Multiple Regression Analysis was used to analyze the factors influencing the subject's virtual reality learning effects.

FINDINGS
The learning effects of the virtual reality medium had a statistically significant positive correlation with the virtual reality technology recognition, sensory immersion, realism, learning satisfaction, learning necessity, and continuous use intention (p < 0.001) scores. In personality traits, only Openness, Extraversion (p < 0.01), and Conscientiousness (p < 0.05) had a statistically significant positive correlation. As a result of regression analysis, the explanatory power of the learning effect of the virtual reality medium was 63.9% (F = 53.61, p < 0.001), with learning satisfaction, sensory immersion, continuous use intention, and Extraversion being significant influencing factors (p < 0.05). Improvements/Applications: This study is meaningful in the sense that it provided strategic implications for the teaching and learning method of virtual reality technology-based learning by considering the insights necessary to develop a learning program using virtual reality technology, according to the characteristics of virtual reality technology, and the learner's cognitive and psychological variables.

students
virtual reality
learning
immersive media technology
teaching method


Career satisfaction and burnout among Ghanaian physicians.

Abstract:
BACKGROUND
Thus far, there has been limited inquiry into the factors associated with physician career satisfaction and burnout in Ghana, although the two have been linked to the brain drain problem. The objective of this study was to assess career satisfaction and burnout among physicians practicing in a developing nation, Ghana.

METHODS
A 21-item instrument was used to assess career satisfaction among actively practicing Ghanaian physicians, using items adapted from the Physician Worklife Study survey. Burnout was assessed using the Abbreviated Maslach's Burnout Inventory. Two hundred physicians participated in the online survey from December 2012 to February 2013.

RESULTS
Generally, physicians in Ghana expressed moderate overall career satisfaction. However, they were least satisfied with the availability of resources, their compensation and work-life balance. Overall, burnout was low in the study population; however physicians exhibited moderate levels of emotional exhaustion. Career satisfaction was negatively associated with the burnout dimensions of depersonalization, emotional exhaustion and low personal accomplishment.

CONCLUSIONS
Health policy-makers in Ghana should address issues relating to resource adequacy, compensation and the work-life balance of physicians in order to improve the overall career satisfaction of an already dwindling physician workforce.

Opoku|Samuel T|ST|
Apenteng|Bettye A|BA|

Career satisfaction
Burnout
Physicians
Ghana
Africa


Cooperative Syngas Production and C-N Bond Formation in One Photoredox Cycle.

Abstract: Solar-driven syngas production by CO2 reduction provides a sustainable strategy to produce renewable feedstocks. However, this promising reaction often suffers from tough CO2 activation, sluggish oxidative half-reaction kinetics and undesired by-products. Herein, we report a function-oriented strategy of deliberately constructing black phosphorus quantum dots-ZnIn2 S4 (BP/ZIS) heterostructures for solar-driven CO2 reduction to syngas, paired with selectively oxidative C-N bond formation, in one redox cycle. The optimal BP/ZIS heterostructure features the enhanced charge-carrier separation and enriched active sites for cooperatively photocatalytic syngas production with a tunable ratio of CO/H2 and efficient oxidation of amines to imines with high conversion and selectivity. This prominent catalytic performance arises from the efficient electronic coupling between black phosphorus quantum dots and ZnIn2 S4 , as well as the optimized adsorption strength for key reaction intermediates, as supported by both experimental and theoretical investigations. We also demonstrate a synergistic interplay between CO2 reduction and amine dehydrogenation oxidation, rather than simply collecting these two single half-reactions in this dual-functional photoredox system.

syngas
CO2 reduction
black phosphorus
heterostructure
benzylamine oxidation


New Bi2MoO6 nano-shapes toward ultrasensitive enzymeless glucose tracing: Synergetic effect of the Bi-Mo association.

Abstract: In a novel approach, an efficient non-enzymatic glucose sensor based on pure phase of aurivillius bismuth molybdate (BM or γ-Bi2MoO6) mixed metal oxides is reported. Three BM samples were synthesized, with/without l-cysteine (Cys) and dodecylamine (DDA) as additives, leading to different shapes: bullet (BM-C), confetti (BM-2Cys) and candy (BM-2DDA). The morphology and purity of the structures were confirmed by FE-SEM images and XRD. In order to investigate the sensor application, the samples were integrated on reduced graphene oxide and incorporated into simple and inexpensive glassy carbon electrode (GCE) without using any polyvinylpyrrolidone (PVP) or Nafion. To perform cyclic voltammetry experiments, all three biosensors were measured in PBS solution (pH = 7) in ±1.5 voltage range and 50 mV s-1 scan rate. Glucose identification by the synthesized composites is an obvious sign of their high efficiency. According to chronoamperomograms, the best sensitivity of 3050 μA L mmol-1 cm-2 with linear range of 0.02-0.14 mmol L-1, low detection limit (LOD) of 0.004 mmol L-1 and the signal/noise equal to 3 was achieved by BM-2DDA/rGO/GCE biosensor and its speedy amperometric response is less than 5 s. This biosensor showed impressive selectivity, repeatability and reproducibility results besides it maintains its stability considerably in great percentage of 98.5% after eight weeks. Also it showed prolonged stability after 50 min.

Khazraei|Avideh|A| Tarlani|Aliakbar|A| Eslami-Moghadam|Mahboube|M| Muzart|Jacques|J|

Glucose
Non-enzymatic
Mixed metal oxides
Semiconductor
γ-Bi(2)MoO(6)


Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production.

Abstract:
BACKGROUND
It is well established that lung pathology and inflammation are more severe during respiratory infections complicated by the presence of both bacteria and viruses. Whilst co-infection can result in invasive pneumococcal disease and systemic inflammation, the neuroinflammatory consequences of co-infection are poorly characterised.

METHODS
In this study, we utilised a mouse co-infection model involving Streptococcus pneumoniae (S. pneumoniae) and influenza A virus (IAV) lung infection, and we also isolated microglia for ex vivo stimulation with pneumococcus or serum amyloid A (SAA).

RESULTS
Co-infection but not S. pneumoniae or IAV alone significantly increased the number of amoeboid-shaped microglia and expression of pro-inflammatory cytokines including tumour necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and C-C motif chemokine ligand-2 (CCL-2) in the hypothalamus. Pneumococcus was only detected in the hypothalamus of co-infected mice. In addition, the systemic inflammatory cytokines TNFα, IL-1β and IL-6 were not elevated in co-infected mice relative to IAV-infected mice, whereas SAA levels were markedly increased in co-infected mice (p < 0.05). SAA and its functional receptor termed formyl peptide receptor 2 (Fpr2) transcript expression were also increased in the hypothalamus. In mouse primary microglia, recombinant SAA but not S. pneumoniae stimulated TNFα, IL-1β, IL-6 and CCL-2 expression, and this response was completely blocked by the pro-resolving Fpr2 agonist aspirin-triggered resolvin D1 (AT-RvD1).

CONCLUSIONS
In summary, lung co-infection increased the number of 'activated' amoeboid-shaped microglia and inflammatory cytokine expression in the hypothalamus. Whilst persistent pneumococcal brain infection was observed, SAA proved to be a much more potent stimulus of microglia than pneumococci, and this response was potently suppressed by the anti-inflammatory AT-RvD1. Targeting Fpr2 with pro-resolving eicosanoids such as AT-RvD1 may restore microglial homeostasis during severe respiratory infections.

Wang|Hao|H|
Blackall|Melissa|M|
Sominsky|Luba|L|
Spencer|Sarah J|SJ|
Vlahos|Ross|R|
Churchill|Melissa|M|
Bozinovski|Steven|S|

Serum amyloid A
Pneumonia
Microglia
Neuroinflammation
Resolvin-D1


Therapeutic Potential of Human Stem Cell Implantation in Alzheimer's Disease.

Abstract: Alzheimer's disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.

Chan|Hau Jun|HJ|
Yanshree|||
Roy|Jaydeep|J|0000-0002-8934-738X
Tipoe|George Lim|GL|
Fung|Man-Lung|ML|
Lim|Lee Wei|LW|0000-0001-6692-6285

D000544:Alzheimer Disease
D000818:Animals
D006801:Humans
D057026:Induced Pluripotent Stem Cells
D059630:Mesenchymal Stem Cells
D019636:Neurodegenerative Diseases
D033581:Stem Cell Transplantation

stem cells
neurodegenerative disease
stem cell therapy
Alzheimer’s disease
Induced pluripotent stem cells
embryonic stem cells
mesenchymal stem cells
neural stem cells
neurogenesis
stem cell transplantation


Time-course transcriptome analysis reveals the mechanisms of Burkholderia sp. adaptation to high phenol concentrations.

Abstract: Microbial tolerance to phenolic pollutants is the key to their efficient biodegradation. However, the metabolic mechanisms that allow some microorganisms to adapt to high phenol concentrations remain unclear. In this study, to reveal the underlying mechanisms of how Burkholderia sp. adapt to high phenol concentrations, the strain's tolerance ability and time-course transcriptome in combination with cell phenotype were evaluated. Surprisingly, Burkholderia sp. still grew normally after a long adaptation to a relatively high phenol concentration (1500 mg/L) and exhibited some time-dependent changes compared to unstressed cells prior to the phenol addition. Time-course transcriptome analysis results revealed that the mechanism of adaptations to phenol was an evolutionary process that transitioned from tolerance to positive degradation through precise gene regulation at appropriate times. Specifically, basal stress gene expression was upregulated and contributed to phenol tolerance, which involved stress, DNA repair, membrane, efflux pump and antioxidant protein-coding genes, while a phenol degradation gene cluster was specifically induced. Interestingly, both the catechol and protocatechuate branches of the β-ketoadipate pathway contributed to the early stage of phenol degradation, but only the catechol branch was used in the late stage. In addition, pathways involving flagella, chemotaxis, ATP-binding cassette transporters and two-component systems were positively associated with strain survival under phenolic stress. This study provides the first insights into the specific response of Burkholderia sp. to high phenol stress and shows potential for application in remediation of polluted environments. KEY POINTS: • Shock, DNA repair and antioxidant-related genes contributed to phenol tolerance. • β-Ketoadipate pathway branches differed at different stages of phenol degradation. • Adaptation mechanisms transitioned from negative tolerance to positive degradation.

D015964:Gene Expression Regulation, Bacterial

Transcriptome
Burkholderia sp.
Phenol
Adaptation mechanisms


Rapid detection of H2S gas driven by the catalysis of flower-like α-Bi2Mo3O12 and its visual performance: A combined experimental and theoretical study.

Abstract: Metal oxide semiconductor (MOSs) are attractive materials for the development of H2S gas sensors. However, detecting H2S with short response and recovery times while also lowering the limit of detection to sub-ppb levels remains a significant challenge. We therefore developed flower-like α-Bi2Mo3O12 microspheres for H2S gas detection that provide fast response and recovery times (3 and 22 s, respectively, for 100 ppm H2S), while also reducing the limit of detection to 1 ppb. The sensor performs well in terms of sensitivity, reproducibility, long-term stability, including humidity stability. X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) calculations revealed that H2S dissociates readily on the reduced α-Bi2Mo3O12 surface and that Mo plays a catalytic role, accelerating the rate of H2S decomposition and enabling a fast response. Moreover, test strips containing α-Bi2Mo3O12 were also prepared, which enabled the naked eye detection of ppm-level H2S gas at room temperature; a light-yellow to orange to brown color change occurs when exposed to H2S, due to its conversion into stable sulfides. This work expands the application of α-Bi2Mo3O12 to H2S gas sensing, and provides a strategy for the use of MOSs as sensor materials for the detection of other gases.

Zhang|Fangdou|F| Zheng|Ming|M| Zhang|Xianfa|X| Cheng|Xiaoli|X| Li|Mingxia|M| Huo|Lihua|L| Zhou|Xin|X| Xu|Yingming|Y|

DFT calculations
Flower-like α-Bi(2)Mo(3)O(12)
H(2)S gas sensing
H(2)S test strip
Short response/recovery time


At the forefront of psychoneuroimmunology in pregnancy: Implications for racial disparities in birth outcomes PART 1: Behavioral risks factors.

Abstract: Birth prior to full term is a substantial public health issue. In the US, ˜400,000 babies per year are born preterm (<37 weeks), while>1 million are early term (37-386/7 weeks). Birth prior to full term confers risk both immediate and long term, including neonatal intensive care, decrements in school performance, and increased mortality risk from infancy through young adulthood. Risk for low birth weight and preterm birth are 1.5-2 times greater among African Americans versus Whites. Psychosocial stress related to being a member of a discriminated racial minority group contributes substantially to these racial disparities. Providing promising targets for intervention, depressed mood, anxiety, and poor sleep are each linked with exposure to chronic stress, including racial discrimination. A rigorous transdisciplinary approach addressing these gaps holds great promise for clinical impact in addressing racial disparities as well as ameliorating effects of stress on perinatal health more broadly. As will be reviewed in a companion paper, the mechanistic roles of physiological sequelae to stress - including neuroendocrine, inflammatory regulation, biological aging, and the microbiome - also require delineation.

Psychoneuroimmunology
Pregnancy
Racial disparities
Birth outcomes
Stress
Depression
Anxiety
Sleep


Confronting the frustrations of negative clinical trials in acute respiratory distress syndrome.

Abstract: Despite robust successes in trials of mechanical ventilation, pharmacologic interventions in acute respiratory distress syndrome have been disappointing. Although ineffective therapy remains the compelling explanation for these negative trials, other possible explanations exist. These negative trials, better termed "statistically negative trials" or "indeterminate trials," cannot prove that a therapy is ineffective. It is important for clinicians and investigators to appreciate the alternative explanations for negative trials of potentially effective therapies because these indicate options for improving clinical trials in acute respiratory distress syndrome. These options can be organized into strategies that increase sample size, increase the signal from the therapy, and reduce the noise or variation in the study. Each of the strategies to improve the likelihood of a positive clinical trial poses a potential tradeoff in generalizability, cost, sample size, signal, or noise.

D002986:Clinical Trials as Topic
D006801:Humans
D012107:Research Design
D012128:Respiratory Distress Syndrome

clinical trials
ARDS
statistical power
study methodology


An Italian individual-level data study investigating on the association between air pollution exposure and Covid-19 severity in primary-care setting.

Abstract:
BACKGROUND
Several studies have been focusing on the potential role of atmospheric pollutants in the diffusion and impact on health of Covid-19. This study's objective was to estimate the association between ≤10 μm diameter particulate matter (PM10) exposure and the likelihood of experiencing pneumonia due to Covid-19 using individual-level data in Italy.

METHODS
Information on Covid-19 patients was retrieved from the Italian IQVIA® Longitudinal Patient Database (LPD), a computerized network of general practitioners (GPs) including anonymous data on patients' consultations and treatments. All patients with a Covid-19 diagnosis during March 18th, 2020 - June 30th, 2020 were included in the study. The date of first Covid-19 registration was the starting point of the 3-month follow-up (Index Date). Patients were classified based on Covid-19-related pneumonia registrations on the Index date and/or during follow-up presence/absence. Each patient was assigned individual exposure by calculating average PM10 during the 30-day period preceding the Index Date, and according to GP's office province. A multiple generalized linear mixed model, mixed-effects logistic regression, was used to assess the association between PM10 exposure tertiles and the likelihood of experiencing pneumonia.

RESULTS
Among 6483 Covid-19 patients included, 1079 (16.6%) had a diagnosis of pneumonia. Pneumonia patients were older, more frequently men, more health-impaired, and had a higher individual-level exposure to PM10 during the month preceding Covid-19 diagnosis. The mixed-effects model showed that patients whose PM10 exposure level fell in the second tertile had a 30% higher likelihood of having pneumonia than that of first tertile patients, and the risk for those who were in the third tertile was almost doubled.

CONCLUSION
The consistent findings toward a positive association between PM10 levels and the likelihood of experiencing pneumonia due to Covid-19 make the implementation of new strategies to reduce air pollution more and more urgent.

Pegoraro|Valeria|V| Heiman|Franca|F| Levante|Antonella|A| Urbinati|Duccio|D| Peduto|Ilaria|I|

Individual-level data
Air pollution
Covid-19
Primary-care
Particulate matter
Pneumonia


Receptor-Targeted Photodynamic Therapy of Glucagon-Like Peptide 1 Receptor-Positive Lesions.

Abstract: Treatment of hyperinsulinemic hypoglycemia is challenging. Surgical treatment of insulinomas and focal lesions in congenital hyperinsulinism is invasive and carries major risks of morbidity. Medication to treat nesidioblastosis and diffuse congenital hyperinsulinism has varying efficacy and causes significant side effects. Here, we describe a novel method for therapy of hyperinsulinemic hyperglycemia, highly selectively killing β-cells by receptor-targeted photodynamic therapy (rtPDT) with exendin-4-IRDye700DX, targeting the glucagon-like peptide 1 receptor (GLP-1R). Methods: A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. The efficacy and specificity of rtPDT with exendin-4-IRDye700DX were examined in vitro in cells with different levels of GLP-1R expression. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. Induction of cellular damage and the effect on tumor growth were analyzed to determine treatment efficacy. Results: Exendin-4-IRDye700DX has a high affinity for the GLP-1R, with a half-maximal inhibitory concentration of 6.3 nM. rtPDT caused significant specific phototoxicity in GLP-1R-positive cells (2.3% ± 0.8% and 2.7% ± 0.3% remaining cell viability in CHL-GLP-1R and INS-1 cells, respectively). The tracer accumulates dose-dependently in GLP-1R-positive tumors. In vivo, rtPDT induces cellular damage in tumors, shown by strong expression of cleaved caspase-3, and leads to a prolonged median survival of the mice (36.5 vs. 22.5 d, respectively; P < 0.05). Conclusion: These data show in vitro as well as in vivo evidence of the potency of rtPDT using exendin-4-IRDye700DX. This approach might in the future provide a new, minimally invasive, highly specific treatment method for hyperinsulinemic hypoglycemia.

Boss|Marti|M|
Bos|Desiree|D|
Frielink|Cathelijne|C|
Sandker|Gerwin|G|
Bronkhorst|Patricia|P|
van Lith|Sanne A M|SAM|
Brom|Maarten|M|
Buitinga|Mijke|M|
Gotthardt|Martin|M|

photodynamic therapy
hyperinsulinemic hypoglycemia
glucagon-like peptide 1 receptor
exendin


Species diversity of fishes in the Dingqu River Basin, tributary of the upper Yangtze River, China.

Abstract:
Background
The Dingqu River Basin, a major tributary of the upper Yangtze River, is located at southeast edge of the Qinghai-Tibet Plateau of China. The fishes of this plateau constitute a major faunal component of this basin, particularly Schizothoracinae (Cypriniformes: Cyprinidae) and Triplophysa (Cypriniformes: Nemacheilidae). Hydropower development is an impact that affects natural habitats and biological resources of the upper Yangtze River and this has led to a decrease in biodiversity. This study investigated the species diversity of fishes of the Dingqu River Basin and accumulated basic data for conservation of biodiversity and assessment of ecological health of the upper Yangtze River.

New information
The upper streams of the Jinshajiang River harbours numerous endemic fish species in China. Most of them belong to the Qianghai-Tibet Plateau fish fauna. However, while the fish species of the Jinshajiang River have been well studied, there is still a gap in the research on fish species diversity of the Dingqu River Basin tributary. This study provides information for 18 native fish species belonging to two orders, four families, three subfamilies and eight genera, and is the first complete record of fishes in the Dingqu River Basin, a primary tributary of the Yangtze River. Supplemental information of species diversity in the Jinshajiang River is also provided. The study includes two datasets, which present taxonomic, distribution, habitat condition, endemism and threat information for each species collected from the Dingqu River Basin and historical literature, respectively. In particular, these fish species all have limited distribution within the south-eastern Qinghai-Tibet Plateau areas of China and could determine the importance of habitat protection for the upper Yangtze River.

Qinghai-Tibet Plateau
hydropower
endemism
distribution
habitat condition
endangered species


Dexamethasone treatment for bilateral lingual nerve injury following orotracheal intubation.

Abstract: Lingual nerve injury is a rare complication of general anesthesia. The causes of lingual nerve injury following general anesthesia are multifactorial; possible mechanisms may include difficult laryngoscopy, prolonged anterior mandibular displacement, improper placement of the oropharyngeal airway, macroglossia and tongue compression. In this report, we have described a case of bilateral lingual nerve injury that was associated with orotracheal intubation for open reduction and internal fixation of the left distal radius fracture in a 61-year-old woman. In this case, early treatment with dexamethasone effectively aided the recovery of the injured lingual nerve.

Dexamethasone
Lingual nerve injuries
Orotracheal intubation
General anesthesia
Steroid


A Transposon Story: From TE Content to TE Dynamic Invasion of Drosophila Genomes Using the Single-Molecule Sequencing Technology from Oxford Nanopore.

Abstract: Transposable elements (TEs) are the main components of genomes. However, due to their repetitive nature, they are very difficult to study using data obtained with short-read sequencing technologies. Here, we describe an efficient pipeline to accurately recover TE insertion (TEI) sites and sequences from long reads obtained by Oxford Nanopore Technology (ONT) sequencing. With this pipeline, we could precisely describe the landscapes of the most recent TEIs in wild-type strains of Drosophila melanogaster and Drosophila simulans. Their comparison suggests that this subset of TE sequences is more similar than previously thought in these two species. The chromosome assemblies obtained using this pipeline also allowed recovering piRNA cluster sequences, which was impossible using short-read sequencing. Finally, we used our pipeline to analyze ONT sequencing data from a D. melanogaster unstable line in which LTR transposition was derepressed for 73 successive generations. We could rely on single reads to identify new insertions with intact target site duplications. Moreover, the detailed analysis of TEIs in the wild-type strains and the unstable line did not support the trap model claiming that piRNA clusters are hotspots of TE insertions.

transposable elements
ONT
Drosophila melanogaster
Drosophila simulans
piRNA


Prediction of the Outcome of Cochlear Implantation in the Patients with Congenital Cytomegalovirus Infection based on Magnetic Resonance Imaging Characteristics.

Abstract: The goal of this study was to elucidate radiologic biomarker that can predict the outcome of cochlear implantation (CI) in congenital cytomegalovirus (cCMV) related deafness. A retrospective survey of speech perception after CI and an evaluation of brain magnetic resonance imaging (MRI) findings were performed in 10 cochlear implantees with cCMV-related prelingual deafness. Specifically, a special attention was paid to the degree of white matter (WM) abnormality shown in brain MRI, which was used to divide our cohort into two groups: The mild and severe pathology groups. Age-matched prelingual deaf patients with idiopathic sensorineural hearing loss were selected as controls. Subjects in mild pathology groups showed higher a Category of Auditory Performance (CAP) score (5.2 ± 0.8) than those with severe pathologies (3.4 ± 1.5) (P = 0.041). Importantly, speech performance from subjects with mild pathology was comparable to that of the control group (mean CAP score of 5.2 ± 0.8 vs. 5.1 ± 1.2) (P = 0.898). Mild pathologies related to the limited WM lesion in MRI not accompanied by severe MRI pathologies, such as diffuse WM abnormality, myelination delay, ventriculomegaly, migration abnormality, and cerebellar hypoplasia, can be tolerated and do not adversely affect the CI outcome in cCMV deafness.

Han|Jae Joon|JJ|0000-0002-5642-107X
Bae|Yun Jung|YJ|
Song|Seul Ki|SK|
Song|Jae-Jin|JJ|
Koo|Ja-Won|JW|
Lee|Jun Ho|JH|
Oh|Seung Ha|SH|
Kim|Bong Jik|BJ|0000-0002-6384-2171
Choi|Byung Yoon|BY|

outcome
cochlear implantation
cytomegalovirus
magnetic resonance imaging
radiologic biomarker
speech perception
white matter
hearing loss


Pulp regeneration in a full-length human tooth root using a hierarchical nanofibrous microsphere system.

Abstract:
UNLABELLED
While pulp regeneration using tissue engineering strategy has been explored for over a decade, successful regeneration of pulp tissues in a full-length human root with a one-end seal that truly simulates clinical endodontic treatment has not been achieved. To address this challenge, we designed and synthesized a unique hierarchical growth factor-loaded nanofibrous microsphere scaffolding system. In this system, vascular endothelial growth factor (VEGF) binds with heparin and is encapsulated in heparin-conjugated gelatin nanospheres, which are further immobilized in the nanofibers of an injectable poly(l-lactic acid) (PLLA) microsphere. This hierarchical microsphere system not only protects the VEGF from denaturation and degradation, but also provides excellent control of its sustained release. In addition, the nanofibrous PLLA microsphere integrates the extracellular matrix-mimicking architecture with a highly porous injectable form, efficiently accommodating dental pulp stem cells (DPSCs) and supporting their proliferation and pulp tissue formation. Our in vivo study showed the successful regeneration of pulp-like tissues that fulfilled the entire apical and middle thirds and reached the coronal third of the full-length root canal. In addition, a large number of blood vessels were regenerated throughout the canal. For the first time, our work demonstrates the success of pulp tissue regeneration in a full-length root canal, making it a significant step toward regenerative endodontics.

STATEMENT OF SIGNIFICANCE
The regeneration of pulp tissues in a full-length tooth root canal has been one of the greatest challenges in the field of regenerative endodontics, and one of the biggest barriers for its clinical application. In this study, we developed a unique approach to tackle this challenge, and for the first time, we successfully regenerated living pulp tissues in a full-length root canal, making it a significant step toward regenerative endodontics. This study will make positive scientific impact and interest the broad and multidisciplinary readership in the dental biomaterials and craniofacial tissue engineering community.

Li|Xiangwei|X| Ma|Chi|C| Xie|Xiaohua|X| Sun|Hongchen|H| Liu|Xiaohua|X|

D061307:Human Umbilical Vein Endothelial Cells

D042461:Vascular Endothelial Growth Factor A

Pulp regeneration
Nanofibrous microspheres
VEGF
Angiogenesis
Human dental pulp stem cell


Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase.

Abstract: The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastase-deficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastase-deficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40- to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.

Jonigk|Danny|D|
Al-Omari|Mariam|M|
Maegel|Lavinia|L|
Müller|Meike|M|
Izykowski|Nicole|N|
Hong|Jaewoo|J|
Hong|Kwangwon|K|
Kim|Soo-Hyun|SH|
Dorsch|Martina|M|
Mahadeva|Ravi|R|
Laenger|Florian|F|
Kreipe|Hans|H|
Braun|Armin|A|
Shahaf|Galit|G|
Lewis|Eli C|EC|
Welte|Tobias|T|
Dinarello|Charles A|CA|
Janciauskiene|Sabina|S|

alpha 1-antitrypsin
immunomodulation
inflammation


The yin and yang faces of the mitochondrial deacetylase sirtuin 3 in age-related disorders.

Abstract: Aging, the most important risk factor for many of the chronic diseases affecting Western society, is associated with a decline in mitochondrial function and dynamics. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that has emerged as a key regulator of fundamental processes which are frequently dysregulated in aging and related disorders. This review highlights recent advances and controversies regarding the yin and yang functions of SIRT3 in metabolic, cardiovascular and neurodegenerative diseases, as well as the use of SIRT3 modulators as a therapeutic strategy against those disorders. Although most studies point to a protective role upon SIRT3 activation, there are conflicting findings that need a better elucidation. The discovery of novel SIRT3 modulators with higher selectivity together with the assessment of the relative importance of different SIRT3 enzymatic activities and the relevance of crosstalk between distinct sirtuin isoforms will be pivotal to validate SIRT3 as a useful drug target for the prevention and treatment of age-related diseases.

Gomes|Pedro|P|
Viana|Sofia D|SD|
Nunes|Sara|S|
Rolo|Anabela P|AP|
Palmeira|Carlos M|CM|
Reis|Flávio|F|

Sirtuins
Age-related diseases
Deacetylation
Genetic manipulations
Mitochondria
Pharmacological modulators


Pancreatic Cystic Neoplasms: An Update.

Abstract: The incidence of pancreatic cystic neoplasms is rising, in part from detection through the increasing use of high-resolution cross-sectional imaging techniques. Initial diagnosis is generally based on imaging characteristics identified on computed tomography and/or MRI. Endoscopic ultrasound provides further imaging characterization and also enables fluid aspiration and analysis to additionally aid differentiation. The general approach to these lesions includes surgical intervention and/or surveillance imaging. Taking into account diverse presentations, varying malignant potential, and the uncertain natural history of some of these lesions, an evidence-based approach is limited. This article discusses recent updates in the diagnosis and management of cystic neoplasms of the pancreas.

Ketwaroo|Gyanprakash A|GA|
Mortele|Koenraad J|KJ|
Sawhney|Mandeep S|MS|

D018297:Neoplasms, Cystic, Mucinous, and Serous


Chromatin Regulator SPEN/SHARP in X Inactivation and Disease.

Abstract: Enzymes, such as histone methyltransferases and demethylases, histone acetyltransferases and deacetylases, and DNA methyltransferases are known as epigenetic modifiers that are often implicated in tumorigenesis and disease. One of the best-studied chromatin-based mechanism is X chromosome inactivation (XCI), a process that establishes facultative heterochromatin on only one X chromosome in females and establishes the right dosage of gene expression. The specificity factor for this process is the long non-coding RNA Xinactivespecifictranscript (Xist), which is upregulated from one X chromosome in female cells. Subsequently, Xist is bound by the corepressor SHARP/SPEN, recruiting and/or activating histone deacetylases (HDACs), leading to the loss of active chromatin marks such as H3K27ac. In addition, polycomb complexes PRC1 and PRC2 establish wide-spread accumulation of H3K27me3 and H2AK119ub1 chromatin marks. The lack of active marks and establishment of repressive marks set the stage for DNA methyltransferases (DNMTs) to stably silence the X chromosome. Here, we will review the recent advances in understanding the molecular mechanisms of how heterochromatin formation is established and put this into the context of carcinogenesis and disease.

Spen
SHARP
XCI
HDAC
polycomb
repression
silencing
DNA methylation
NCoR
transcription


African Americans Demonstrate Significantly Lower Serum Alanine Aminotransferase Compared to Non-African Americans.

Abstract:
BACKGROUND AND AIMS
Normal ranges of serum alanine aminotransferase (ALT) may vary by race. However, results from research studies are contradictory, and many of these studies have included only small numbers of African Americans. We investigated ALT values in patients without evidence of liver disease to determine whether normal ranges differ across race groups. We also evaluated whether a race- and sex-dependent upper limit of normal (ULN) would improve the ability of ALT to predict liver disease compared to the sex-dependent ULN currently in use.

METHODS
We identified ICD9 codes for liver conditions and diabetes in medical records from a sample of 6719 patients. Analysis of variance (ANOVA) was used to assess differences in ALT log-transformed distributions by race. Logistic regression was used to evaluate whether the addition of race to the current sex-dependent ULN improves the ability of ALT to predict liver disease (assessed by area under the receiver operating characteristic curve (AUROC)).

RESULTS
Among 1200 patients with BMI 18.5 < 25 and no evidence of liver disease or type 2 diabetes in their medical record, African Americans demonstrated significantly lower ALT (23.47 IU/L; 95% CL 22.87-24.10) than a combined group of Asian American/White/Other patients (25.71 IU/L; 95% CL 24.69-26.77). This difference remained across BMI categories. The race- and sex-dependent model demonstrated significantly better predictive ability than the sex-dependent model (AUROC = 66.6% versus 59.6%, respectively; p < 0.0001).

CONCLUSIONS
In a large, racially diverse sample, African Americans demonstrated significantly lower ALT compared to non-African Americans; this difference remained as BMI increased. The establishment of race-specific normal ranges for ALT could contribute to better screening and care for African American patients.

Varma|Adarsh|A|
Trudeau|Sheri|S|
Zhou|Yueren|Y|
Jafri|Syed-Mohammed|SM|
Krajenta|Richard|R|
Lamerato|Lois|L|
Brown|Kimberly|K|
Luzzi|Veronica|V|
Lu|Mei|M|
Gordon|Stuart C|SC|

ALT
Race
BMI
Health disparities
Reference range intervals