Metabolic signatures of bisphenol A and genistein in Atlantic salmon liver cells.

Abstract: Screening has revealed that aquafeeds with high inclusion of plant material may contain small amounts of endocrine disrupting agricultural pesticides. In this work, bisphenol A (BPA) and genistein (GEN) were selected as model endocrine disrupting toxicants with impact on DNA methylation in fish. Atlantic salmon hepatocytes were exposed in vitro to four concentrations of BPA and GEN (0.1, 1.0, 10 and 100 μM) for 48 h. Toxicity endpoints included cytotoxicity, global DNA methylation, targeted transcriptomics and metabolomic screening (100 μM). GEN was not cytotoxic in concentrations up to 100 μM, whereas one out of two cell viability assays indicated a cytotoxic response to 100 μM BPA. Compared to the control, significant global DNA hypomethylation was observed at 1.0 μM BPA. Both compounds upregulated cyp1a1 transcription at 100 μM, while estrogenic markers esr1 and vtg1 responded strongest at 10 μM. Dnmt3aa transcription was downregulated by both compounds at 100 μM. Metabolomic screening showed that BPA and GEN resulted in significant changes in numerous biochemical pathways consistent with alterations in carbohydrate metabolism, indicating perturbation in glucose homeostasis and energy generation, and glutamate metabolism. Pathway analysis showed that while the superpathway of methionine degradation was among the most strongly affected pathways by BPA, GEN induced changes to uridine and pyrimidine biosynthesis. In conclusion, this mechanistic study proposes metabolites associated with glucose and glutamate metabolism, glucuronidation detoxification, as well as cyp1a1, vtg1, esr1, ar, dnmt3aa, cdkn1b and insig1 as transcriptional markers for BPA and GEN exposure in fish liver cells.

Olsvik|Pål A|PA|
Skjærven|Kaja H|KH|
Søfteland|Liv|L|

Bisphenol A
Genistein
Atlantic salmon hepatocytes
Global DNA methylation
Metabolomics
Gene expression


Evaluation of butyrylcholinesterase inhibitory activity by chlorogenic acids and coffee extracts assed in ITC and docking simulation models.

Abstract: In patients with Alzheimer's disease (AD), elevated levels of butyrylcholinesterase (BChE) are observed. The enzyme hydrolyses acetylcholine, which shows deficiency in these patients. Therefore, BChE inhibitors are used in the treatment of Alzheimer's disease, especially synthetic ones, showing side effects with long-term intake. The sources of natural BChE inhibitors are constantly being sought. Coffee brews have been shown to reduce the symptoms of AD in epidemiological studies. However, the ability to inhibit BChE activity has not been investigated, depending on the degree of coffee roasting. The study was aimed at determining the interactions between BChE and the bioactive compounds of coffee and their ability to inhibit the activity of BChE. A comparison of individual bioactive compounds of coffee as well as extracts obtained from two main species, Arabica and Robusta, and additionally from different degrees of roasting was made. Two models were used: isothermal titration calorimetry (ITC) and molecular docking simulation. ITC analysis showed strong interactions of ferulic and dihydrocaffeic acids with BChE. These compounds are the metabolites of the chlorogenic acids, including both mono- and diesters of caffeic acid with quinic acid. Docking simulation showed their strong hydrophobic interaction with BChE, stabilized by hydrogen bonds and pi-pi interactions. After introducing acetylcholine into the model system, the strongest ability to inhibit hydrolytic activity of BChE was again observed for ferulic acid and additionally for 3-caffeoylquinic acid, and among coffee brews the most active were light roasted Arabica and green Robusta. The study was based on the physiological concentrations of coffee components, so the potential therapeutic effect of coffee infusions was proved.

Budryn|Grażyna|G|
Grzelczyk|Joanna|J|
Jaśkiewicz|Andrzej|A|
Żyżelewicz|Dorota|D|
Pérez-Sánchez|Horacio|H|
Cerón-Carrasco|José P|JP|

D057927:Hydrophobic and Hydrophilic Interactions

Butyrylcholinesterase
Chlorogenic acids
Coffee
ITC
Docking simulation
Hydroxycinnamic acids


Journey of Hydrocotyle sibthorpioides Lam.: From traditional utilization to modern therapeutics-A review.

Abstract: Hydrocotyle sibthorpioides Lam. (Araliaceae) is a short and edible medicinal herb, which is used in the traditional system of medicines. The review aims to report the current information of H. sibthorpioides on the basis of its botanical and taxonomical description, traditional use, active phytoconstituents, pharmacological use and toxicity. The information on H. sibthorpioides with respect to its journey from traditional uses to scientific validation was gathered based on the online survey. The results from the review signify that the plant is used by the different tribes of the world for the treatment of patients suffering from fever, edema, dysentery, rheumatalgia, whooping cough, jaundice, throat pain, psoriasis, herpes zoster infection, hepatitis-B infection, soothing pain, dysmenorrhoea and carbunculosis. It is also used as a brain tonic, detoxifying agent and hepatoprotective agent. Scientific investigation reported that the plant has a significant pharmacological activity, viz. cognitive agent, anti-cancer, antiviral, antibacterial, anti-fungal and hepatoprotective. Moreover, based on the phytochemical aspects, a total of 50 phytoconstituents was identified and isolated from the plant. In conclusion, the outcome of this review will be useful for (a) developing a comprehensive plant profile; (b) assist investigators for exploring further research; and (c) to fulfil the gaps lacking in terms of clinical studies.

Hydrocotyle sibthorpioides
Araliaceae
Apiaceae
cognitive activity
traditional medicines


Assessing maintenance techniques and in-situ pavement conditions to restore hydraulic function of permeable interlocking concrete pavements.

Abstract: Permeable pavements are increasingly implemented to mitigate the negative hydrologic outcomes associated with impervious surfaces. However, the hydraulic function of permeable pavements is hindered by clogging in their joint openings, and systematic maintenance is needed to ensure hydraulic functionality throughout the design lifespan of these systems. To quantify the effectiveness of various maintenance measures, surface infiltration rates (SIRs) were measured before and after five different maintenance techniques were applied to five permeable interlocking concrete pavements (PICPs) in central Ohio, USA. Three maintenance techniques, the Municipal Cleaning Vehicle (MCV), the Rejuvenater, and a pressure washer and the Rejuvenater performed in series, significantly improved median SIRs from 16 to 26, 5 to 106, and 11 to 37 mm/min, respectively. However, pressure washing alone resulted in no significant difference to PICP SIR (median SIRs increased from 8 to 20 mm/min). Regenerative air street sweeping significantly worsened SIRs when performed during wet weather (median SIRs decreased from 19 to 4 mm/min) but had no significant impact on SIRs during dry weather (median SIRs decreased from 21 to 18 mm/min). This work captured the maintenance effectiveness of two techniques for the first or second time, namely the Rejuvenater and MCV, to investigate their use as a suitable maintenance technique. Further, the maintenance techniques were tested on multiple PICPs, thus the effect of in-situ pavement conditions had on hydraulic improvement via maintenance could be addressed. Differences in general upkeep, traffic, and runoff routed to a PICP affected the depth of clogging below the pavement surface, which forestalled hydraulic improvement. Though shown to improve the SIR of PICP systems, results indicate that the maintenance techniques were not capable of restoring pavement hydraulics to initial conditions. These results demonstrate the need for regular, routine maintenance and topping up of joint aggregate before clogging migrates deeper into the pavement profile.

Simpson|Ian M|IM|
Winston|Ryan J|RJ|
Tirpak|R Andrew|RA|

Maintenance
Restoration
Permeable pavement
Clogging
Surface infiltration rate
Porous pavement


Safety and efficacy of Direct Oral Anticoagulants in cerebral venous thrombosis: A meta-analysis.

Abstract: Cerebral venous thrombosis (CVT) is caused by partial or complete occlusion of the major cerebral venous sinuses or the smaller feeding cortical veins which predispose to the risk of venous infarction and hemorrhage. Current guidelines recommend treating CVT with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) followed by an oral vitamin K antagonist (VKA) for 3-12 months. Direct oral anticoagulants (DOACs) have already established benefit over warfarin as a long-term treatment of symptomatic venous thromboembolic disorder like deep vein thrombosis (DVT), and pulmonary embolism (PE) given its equal efficacy and better safety profile. The benefit of DOACs over warfarin as a long-term anticoagulation for CVT has likewise been extensively studied, yet it has not been approved as first-line therapy in the current practice. We therefore performed a systematic review and meta-analysis of relevant studies to generate robust evidence regarding the safety and efficacy of DOACs in CVT. This meta-analysis demonstrates that the use of DOACs in CVT has similar efficacy and safety compared to VKAs with better recanalization rate.

cerebral venous thrombosis
CVT
DOAC
CVST
NOAC
apixaban
dabigatran
edoxaban
rivaroxaban


Prenatal diagnosis of left-sided aortic arch, right descending aorta and right-sided ductus arteriosus associated with anomalous origin of left pulmonary artery from ascending aorta.

Abstract: Left-sided aortic arch (LAA), right descending aorta (rDAo), and right-sided ductus arteriosus (RDA) constitute a rare aortic arch anomaly. Moreover, anomalous origin of the pulmonary artery from the ascending aorta, especially that of the left pulmonary artery, is also a rare anomaly of the pulmonary artery branches. Because of the presence of the ductus arteriosus, prenatal ultrasound is an optimal diagnostic tool for the LAA with rDAo. Four-dimensional color Doppler can clearly demonstrate the spatial relationship between the LAA, rDAo, and RDA and the anomalous origin of the left pulmonary artery from the ascending aorta.

anomalous origin of pulmonary artery from ascending aorta


Sustainable Antibiotic-Free Broiler Meat Production: Current Trends, Challenges, and Possibilities in a Developing Country Perspective.

Abstract: Antibiotic-free broiler meat production is becoming increasingly popular worldwide due to consumer perception that it is superior to conventional broiler meat. Globally, broiler farming impacts the income generation of low-income households, helping to alleviate poverty and secure food in the countryside and in semi-municipal societies. For decades, antibiotics have been utilized in the poultry industry to prevent and treat diseases and promote growth. This practice contributes to the development of drug-resistant bacteria in livestock, including poultry, and humans through the food chain, posing a global public health threat. Additionally, consumer demand for antibiotic-free broiler meat is increasing. However, there are many challenges that need to be overcome by adopting suitable strategies to produce antibiotic-free broiler meat with regards to food safety and chicken welfare issues. Herein, we focus on the importance and current scenario of antibiotic use, prospects, and challenges in the production of sustainable antibiotic-free broiler meat, emphasizing broiler farming in the context of Bangladesh. Moreover, we also discuss the need for and challenges of antibiotic alternatives and provide a future outlook for antibiotic-free broiler meat production.

antibiotic-free
broiler meat production
antibiotics
antibiotic resistance
sustainable agricultural system


The association of sociodemographic and objectively-assessed disease variables with fatigue in systemic sclerosis: an analysis of 785 Canadian Scleroderma Research Group Registry patients.

Abstract: Fatigue is prevalent among patients with systemic sclerosis (SSc). To date, studies investigating fatigue in SSc have been hampered by the instruments used to measure fatigue in SSc and have included patient-reported rather than objectively-rated measures of disease. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale is a validated measure for assessing fatigue in SSc that, compared to other instruments, provides good coverage of the full range of the fatigue spectrum. The objective of this study was to assess sociodemographic and objectively-rated disease-related associates of fatigue, as measured by the FACIT-F, in a large sample of patients with SSc. Fatigue was assessed using the FACIT-F scale. Disease severity was assessed using Medsger's severity scale. Multivariable linear regression was performed to assess the independent associations between sociodemographic and medical variables and fatigue. Among 785 patients, the mean FACIT-F score was 32.2 (SD = 12.1). Being age 40-49 (reference = 60+; standardized regression coefficient (β) = -0.11), less than post-secondary education (β = 0.07), having more medical comorbidities (β = -0.11) and more severe muscle (β = -0.10), gastrointestinal (β = -0.15), lung (β = -0.13), and general system disease severity (β = -0.13) were independently associated with more fatigue (p < 0.05). Fatigue in SSc was independently associated with more severe disease. These data contribute to a better understanding of fatigue in SSc and help inform patient-centered research in SSc.

Levis|Brooke|B|
Kwakkenbos|Linda|L|
Hudson|Marie|M|
Baron|Murray|M|
Thombs|Brett D|BD|
|||

Fatigue
Systemic sclerosis
FACIT-F
Medsger’s disease severity scale


Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation.

Abstract: Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

Higuchi|Haruka|H|
Kamimura|Daisuke|D|
Jiang|Jing-Jing|JJ|
Atsumi|Toru|T|
Iwami|Daiki|D|
Hotta|Kiyohiko|K|
Harada|Hiroshi|H|
Takada|Yusuke|Y|
Kanno-Okada|Hiromi|H|
Hatanaka|Kanako C|KC|
Tanaka|Yuki|Y|
Shinohara|Nobuo|N|
Murakami|Masaaki|M|


Carbonyl 13C-detect solution-state protein NMR experiments to circumvent amide-solvent exchange broadening: Application to β2-microglobulin.

Abstract: The 15N-1H heteronuclear single-quantum correlation (HSQC) technique in protein NMR spectroscopy suffers from line-broadening effects, such as chemical exchange of labile protons with solvent, and exchange broadening for residues undergoing conformational dynamics. The amide resonance of β2-microglobulin residue S88 is not observed in the HSQC spectrum but can be obtained through 13C-detect experiments that circumvent the problem of amide-solvent exchange broadening. Line broadening of S88 resonance beyond detection in the HSQC spectrum is not attributed to conformational exchange but rather to solvent exchange occurring on the order of ~103 s-1.

D066244:Proton Magnetic Resonance Spectroscopy

(13)C-detect NMR spectroscopy
Hydrogen exchange
NMR relaxation
β(2)-microglobulin


Physicochemical properties improvement and structural changes of bamboo shoots (Phyllostachys praecox f. Prevernalis) dietary fiber modified by subcritical water and high pressure homogenization: a comparative study.

Abstract: In presented study, the effects of subcritical water (SW) and high pressure homogenization (HPH) treatments on the physicochemical and structural characteristics of dietary fibers (DFs) from bamboo shoots (Phyllostachys praecox f. Prevernalis) were investigated. The soluble dietary fiber (SDF) content was dramatically increased in SW and HPH treated DFs. Compared with HPH, SW modification enhanced higher physicochemical properties including water holding capacity (WHC), oil holding capacity (OHC) and swelling capacity (SC) of DFs. The abilities of DFs to absorb cholesterol and nitrite ions were both greatly increased after treatments. The results of Scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), and X-ray diffraction (XRD) showed that the structure of DFs were changed by SW and HPH. In conclusion, SW treatment showed better effects on improvement of physicochemical properties of bamboo shoot DFs than that of HPH, and the modified DFs could be a potential new functional foods or food additives.

Yang|Kai|K| Yang|Zhenhuan|Z| Wu|Weijie|W| Gao|Haiyan|H| Zhou|Cheng|C| Sun|Peilong|P| Wu|Changqing|C| Xia|Qile|Q| Chen|Jianbing|J|0000-0002-1180-9521

Physicochemical properties
Bamboo shoots
Dietary fiber
Subcritical water
High pressure homogenization
Modification


Determining the necessity of phenyl ring π-character in warfarin.

Abstract: Despite the difficulty in administering a safe dose regimen and reports of emerging resistance, warfarin (1) remains the most widely-used oral anticoagulant for the prevention and treatment of thrombosis in humans globally. Systematic substitution of the warfarin phenyl ring with either 1,3,5,7-cyclooctatetraene (COT) (2), cubane (3), cyclohexane (4) or cyclooctane (5) and subsequent evaluation against the target enzyme, vitamin K epoxide reductase (VKOR), facilitated interrogation of both steric and electronic properties of the phenyl pharmacophore. The tolerance of VKOR to further functional group modification (carboxylate 14, PTAD adduct 15) was also investigated. The results demonstrate the importance of both annulene conferred π-interactions and ring size in the activity of warfarin.

Xing|Hui|H|
Houston|Sevan D|SD|
Chen|Xuejie|X|
Jin|Da-Yun|DY|
Savage|G Paul|GP|
Tie|Jian-Ke|JK|
Williams|Craig M|CM|

Warfarin Cyclohexane Cyclooctane VKOR π-Interaction


Adipose tissue complement factor B promotes adipocyte maturation.

Abstract:
OBJECTIVES
It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system-related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism.

METHODS
We investigated the expression level of complement system-related genes in adipocytes. To understand the role of CfB in adipocyte, we performed Cfb overexpression in 3T3-L1 preadipocytes and generated adipocyte-specific Cfb transgenic mice.

RESULTS
Cfb expression was markedly enhanced in 3T3-L1 adipocytes co-cultured with macrophages following endotoxin stimulation. In Cfb-overexpressing cells, the expression of adipocyte differentiation/maturation-related genes encoding peroxisome proliferator-activated receptor γ (Pparγ), adipocyte Protein 2 and perilipin was significantly enhanced. Cfb transgenic mice showed a marked increase in the expression of genes encoding Pparγ, perilipin, sterol regulatory element-binding protein 1 c, and Cd36 in the subcutaneous adipose tissue.

CONCLUSIONS
CfB plays a crucial role in late-phase of adipocyte differentiation and subsequent lipid droplet formation.

Matsunaga|Hiroaki|H| Iwashita|Misaki|M| Shinjo|Takanori|T| Yamashita|Akiko|A| Tsuruta|Mitsudai|M| Nagasaka|Shoichiro|S| Taniguchi|Ataru|A| Fukushima|Mitsuo|M| Watanabe|Naoya|N| Nishimura|Fusanori|F|

Complement factor B
Adipocyte maturation
Obesity


Analysis of the initiation of nuclear pore assembly by ectopically targeting nucleoporins to chromatin.

Abstract: Nuclear pore complexes (NPCs) form the gateway to the nucleus, mediating virtually all nucleocytoplasmic trafficking. Assembly of a nuclear pore complex requires the organization of many soluble sub-complexes into a final massive structure embedded in the nuclear envelope. By use of a LacI/LacO reporter system, we were able to assess nucleoporin (Nup) interactions, show that they occur with a high level of specificity, and identify nucleoporins sufficient for initiation of the complex process of NPC assembly in vivo. Eleven nucleoporins from different sub-complexes were fused to LacI-CFP and transfected separately into a human cell line containing a stably integrated LacO DNA array. The LacI-Nup fusion proteins, which bound to the array, were examined for their ability to recruit endogenous nucleoporins to the intranuclear LacO site. Many could recruit nucleoporins of the same sub-complex and a number could also recruit other sub-complexes. Strikingly, Nup133 and Nup107 of the Nup107/160 subcomplex and Nup153 and Nup50 of the nuclear pore basket recruited a near full complement of nucleoporins to the LacO array. Furthermore, Nup133 and Nup153 efficiently targeted the LacO array to the nuclear periphery. Our data support a hierarchical, seeded assembly pathway and identify Nup133 and Nup153 as effective "seeds" for NPC assembly. In addition, we show that this system can be applied to functional studies of individual nucleoporin domains as well as to specific nucleoporin disease mutations. We find that the R391H cardiac arrhythmia/sudden death mutation of Nup155 prevents both its subcomplex assembly and nuclear rim targeting of the LacO array.

Schwartz|Michal|M|
Travesa|Anna|A|
Martell|Steven W|SW|
Forbes|Douglass J|DJ|

D021581:Active Transport, Cell Nucleus
D001145:Arrhythmias, Cardiac
D045744:Cell Line, Tumor
D002843:Chromatin
D006801:Humans
D056968:Lac Repressors
D009154:Mutation
D009685:Nuclear Envelope
D028861:Nuclear Pore Complex Proteins
D017434:Protein Structure, Tertiary

nuclear pore assembly
LacI
Nup133
Nup153
LacO array
cardiac arrhythmia
ELYS
FG, phenylalanine-glycine
GFP, green fluorescent protein
CFP, cyan fluorescent protein
LacO, Lac operon
LacI, Lac repressor gene
Nup155 R391H
Nup160/107 complex
nuclear rim localization


Outpatient Cardiac Rehabilitation Suppresses Deterioration of Renal Function in Patients ≥75 Years of Age With Heart Disease.

Abstract:
BACKGROUND
This study investigated the effect of outpatient cardiac rehabilitation (OCR) and physical activity on the estimated glomerular filtration rate based on serum cystatin C (eGFRcys) in patients with heart disease (HD) aged ≥75 years.Methods and Results:This non-randomized prospective intervention study involved 136 patients (non-OCR group, n=66; OCR group, n=70), 55 of whom were aged ≥75 years (non-OCR group, n=29; OCR group, n=26). Renal function (eGFRcys) was evaluated at discharge and 3 months thereafter. A linear mixed model (LMM) was used to assess changes in renal function over time. The hospital readmission rate within 3 months after discharge was also evaluated. LMM analysis showed that the change in eGFRcys was -2.27 and +0.48 mL/min/1.73 m2in the non-OCR and OCR groups, respectively (F=2.960, P=0.022). Further, among patients aged ≥75 years in the non-OCR and OCR groups, the change in eGFRcys was -3.83 and -1.08 mL/min/1.73 m2, respectively (F=2.719, P=0.039). The proportion of patients aged ≥75 years who were rehospitalized due to exacerbation of HD was 16.9% (n=10) and 6.7% (n=2) in the non-OCR and OCR groups, respectively.

CONCLUSIONS
Among patients with HD aged ≥75 years, participation in OCR reduces the decline in renal function and hospital readmission rates.

Sasamoto|Yuichiro|Y| Endo|Noriko|N| Kanazawa|Kohko|K| Utsumi|Taeko|T| Takahashi|Tomomi|T| Endo|Yosuke|Y| Nanba|Makoto|M| Takeda|Hiroto|H| Takano|Tomohiro|T| Takahashi|Koki|K| Tanji|Masahiro|M| Kohzuki|Masahiro|M|

Physical activity
Glomerular filtration rate
Cystatin C
Kidney disease
Patient readmission


Splenic switch-off as a novel marker for adenosine response in nitrogen-13 ammonia PET myocardial perfusion imaging: Cross-validation against CMR using a hybrid PET/MR device.

Abstract:
BACKGROUND
No methodology is available to distinguish truly reduced myocardial flow reserve (MFR) in positron emission tomography myocardial perfusion imaging (PET MPI) from seemingly impaired MFR due to inadequate adenosine response. The adenosine-induced splenic switch-off (SSO) sign has been proposed as a potential marker for adequate adenosine response in cardiac magnetic resonance (CMR). We assessed the feasibility of detecting SSO in nitrogen-13 ammonia PET MPI using SSO in CMR as the standard of reference.

METHODS AND RESULTS
Fifty patients underwent simultaneous CMR and PET MPI on a hybrid PET/MR device with co-injection of a gadolinium-based contrast agent and nitrogen-13 ammonia during rest and adenosine-induced stress. In CMR, SSO was assessed visually (positive vs negative SSO) and quantitatively by calculating the ratio of the peak signal intensity of the spleen during stress over rest (SIR). In PET MPI, the splenic signal activity ratio (SAR) was calculated as the maximal standard uptake value of the spleen during stress over rest. The median SIR was significantly lower in patients with positive versus negative SSO in CMR (0.57 [IQR 0.49 to 0.62] vs 0.89 [IQR 0.76 to 0.98]; P < .001). Similarly, median SAR in PET MPI was significantly lower in patients with positive versus negative SSO (0.40 [IQR 0.32 to 0.45] vs 0.80 [IQR 0.47 to 0.98]; P < .001).

CONCLUSION
Similarly to CMR, SSO can be detected in nitrogen-13 ammonia PET MPI. This might help distinguish adenosine non-responders from patients with truly impaired MFR due to microvascular dysfunction or multivessel coronary artery disease.

Bakula|Adam|A|
Patriki|Dimitri|D|
von Felten|Elia|E|
Benetos|Georgios|G|
Sustar|Aleksandra|A|
Benz|Dominik C|DC|
Wiedemann-Buser|Muriel|M|
Treyer|Valerie|V|
Pazhenkottil|Aju P|AP|
Gräni|Christoph|C|
Gebhard|Catherine|C|
Kaufmann|Philipp A|PA|
Buechel|Ronny R|RR|
Fuchs|Tobias A|TA|

PET
MPI
Hybrid imaging
MRI
Myocardial blood flow
Vasodilators


Ginkgolide B ameliorates myocardial ischemia reperfusion injury in rats via inhibiting endoplasmic reticulum stress.

Abstract:
Purpose
Ginkgolide B (GB) is a terpene lactone component found in Ginkgo biloba, which has a protective role on ischemia reperfusion (I/R) injury. This study was aimed at exploring the protective mechanism of GB on the myocardial I/R.

Patients and methods
Myocardial I/R model was established on Sprague Dawley rats. The levels of cardiac troponin I, cardiac troponin T, lactic dehydrogenase, and myoglobin were determined by a 200FR NEO automatic biochemical analyzer. Histological examination was performed through HE and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. The expression levels of p-PERK, p-IRE1α, ATF6, p-AKT, and mTOR were detected by Western blot.

Results
The results exhibited that GB treatment suppressed the high levels of cardiac troponin I, cardiac troponin T, lactic dehydrogenase, and myoglobin and ameliorated the damaged and irregularly arranged myocardial cells induced by I/R injury significantly, indicating that GB could ameliorate myocardial I/R injury. Moreover, the high expression levels of endoplasmic reticulum (ER) stress key proteins caused by I/R injury were suppressed significantly by GB treatment, including p-PERK, p-IRE1α, and ATF6. GB treatment also decreased the number of apoptotic cells compared with I/R group. In addition, activation of ER stress by Tunicamycin treatment could counteract the protective effects of GB on I/R injury, suggesting that GB ameliorated myocardial I/R injury through inhibition of ER stress-induced apoptosis. Finally, the decreased p-AKT and p-mTOR expressions caused by I/R injury were upregulated by GB and inhibition of PI3K/AKT/mTOR pathway by LY294002 abolished the protective effects of GB on I/R injury, indicating that GB activated PI3K/AKT/mTOR pathway during I/R injury.

Conclusion
GB protected against myocardial I/R injury through inhibiting ER stress-induced apoptosis via PI3K/AKT/mTOR signaling pathway.

Guo|Changlei|C| Zhang|Junbiao|J| Zhang|Peiyong|P| Si|Aoyang|A| Zhang|Zhenling|Z| Zhao|Liangping|L| Lv|Fenghua|F| Zhao|Guoan|G|

Ginkgolide B
endoplasmic reticulum stress
apoptosis PI3K/AKT/mTOR pathway
myocardial injury


Time-trend population analysis of the clinical and epidemiologic effect on pediatric infective endocarditis after change of antibiotic prophylaxis guidelines.

Abstract:
PURPOSE
In 2007, antibiotic prophylaxis (AP) guidelines for infective endocarditis (IE) changed, but the possible influence on the annual incidences of pediatric IE is unclear.

METHODS
We studied the clinical and epidemiologic impact of AP change by comparing two time periods before and after change of AP guidelines in a tertiary care center as referral center for a total population of more than 4,500,000 inhabitants.

RESULTS
After change of AP guidelines, twenty-five patients were diagnosed for IE at a median age of 6.9 years (range 0.1-19.4, female 48%). Modified Duke criteria were fulfilled for definite (12/25; 48%), or probable IE (13/25; 52%). The frequency of IE (cases per 1000 hospitalized patients) increased from 0.37% (1995-2005) to 0.59% (2006-2017) [p = 0.152], the annual incidence of IE (cases per 1000 CHD patients, < 20 years of age) increased from 0.195 ‰ to 0.399 ‰ [p = 0.072]. Postoperative IE (13/25; 52%), was associated mostly with prosthetic pulmonary valves (12/13; 92%). Pathogens were staphylococci spp. (8/25; 32%), streptococci spp. (7/25; 28%), HACEK (3/25; 12%), other (4/25; 16%), or culture-negative (3/25; 12%). Treatment included antibiotics (25/25; 100%), and cardiac surgery (16/25; 64%). The clinical findings and complications of pediatric IE including mortality (2/25; 8%) did not differ between the two time periods.

CONCLUSIONS
Pediatric IE remains a severe cardiac disease with a comparable clinical picture. Unless increasing absolute case numbers of IE, the relative case number of IE remains stable despite AP change. The high number of prosthetic pulmonary valve associated IE needs further evaluation and therapeutic alternatives.

Infective endocarditis
Prophylaxis
Child
Heart disease


Comparison of multi-delay FAIR and pCASL labeling approaches for renal perfusion quantification at 3T MRI.

Abstract:
OBJECTIVE
To compare the most commonly used labeling approaches, flow-sensitive alternating inversion recovery (FAIR) and pseudocontinuous arterial spin labeling (pCASL), for renal perfusion measurement using arterial spin labeling (ASL) MRI.

METHODS
Multi-delay FAIR and pCASL were performed in 16 middle-aged healthy volunteers on two different occasions at 3T. Relative perfusion-weighted signal (PWS), temporal SNR (tSNR), renal blood flow (RBF), and arterial transit time (ATT) were calculated for the cortex and medulla in both kidneys. Bland-Altman plots, intra-class correlation coefficient, and within-subject coefficient of variation were used to assess reliability and agreement between measurements.

RESULTS
For the first visit, RBF was 362 ± 57 and 140 ± 47 mL/min/100 g, and ATT was 0.47 ± 0.13 and 0.70 ± 0.10 s in cortex and medulla, respectively, using FAIR; RBF was 201 ± 72 and 84 ± 27 mL/min/100 g, and ATT was 0.71 ± 0.25 and 0.86 ± 0.12 s in cortex and medulla, respectively, using pCASL. For both labeling approaches, RBF and ATT values were not significantly different between visits. Overall, FAIR showed higher PWS and tSNR. Moreover, repeatability of perfusion parameters was better using FAIR.

DISCUSSION
This study showed that compared to (balanced) pCASL, FAIR perfusion values were significantly higher and more comparable between visits.

Arterial spin labeling (ASL)
Renal blood flow
Arterial transit time
Kidney
Magnetic resonance imaging


Comment on Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights by Róna et al. (2013).

Abstract: The authors comment on the article by Róna et al. [(2013), Acta Cryst. D69, 2495-2505].

human dUTPase
letters to the editor
nucleo-cytoplasmic trafficking


Sustainable management of Se-rich silkworm residuals by black soldier flies larvae to produce a high nutritional value and accumulate ω-3 PUFA.

Abstract: Waste disposal and utilisation of its important components are pioneering goals for achieving sustainable development and a clean environment. Silkworm pupae (SWP) are considered a by-product of the sericulture industry and may contain a high concentration of selenium (Se) in some regions, making them a potentially hazardous waste posing health risks. This study examined six treatments of Se-rich SWP (0-100%) as a substrate for black soldier fly (BSF) larvae. Growth performance and protein content of BSF larvae were not affected by increasing SWP content. The total fat, mono-, and poly-unsaturated fatty acids in BSF pre-pupae increased with increasing SWP inclusion in the substrate, from P0 (pre-pupae fed control treatment) through P100 (pre-pupae fed 100% SWP treatment), by 18.83, 61.14, and 62.42%, respectively. The results of significance were: (1) BSF pre-pupae did not accumulate Se, maintaining the same amount of Se in their bodies (~0.18 mg/kg); (2) omega-3 fatty acids represented by linolenic acid in BSF increased by 1,223.35% from P0 to P100, with 70.65% recovered from the SWP; (3) valine percentage increased in BSF compared with the percentage of SWP by 25.30%; and (4) BSF larvae were observed reducing SWP waste by more than one-third. BSF larvae can reduce the waste from sericulture industry and exploit the beneficial properties and components of SWP, converting them into safe and highly nutritious products.

El-Dakar|Marco A|MA|
Ramzy|Remondah R|RR|
Wang|Dun|D|
Ji|Hong|H|

Black soldier fly
Nutritional values
Silkworm pupae
Selenium
Protein
Omega-3 PUFAs


Protective Effect of Octylmethoxycinnamate against UV-Induced Photoaging in Hairless Mouse via the Regulation of Matrix Metalloproteinases.

Abstract: Ultraviolet (UV) irradiation damages skin and produces symptoms of photoaging, such as thickening, rough texture, wrinkles, and pigmentation. However, the cellular and molecular mechanisms underlying photoaging induced by chronic UV irradiation are not yet fully understood. Matrix metalloproteinases (MMPs) have been reported to be involved in the response to UV irradiation. In this study, we examined the effects of the sunscreen agent Octylmethoxycinnamate (OMC) on photoaging of the skin induced by chronic UV exposure in hairless albino Crl:SKH1-Hrhr (SKH-1) mice. We demonstrated that the expression of MMPs was elevated by UV irradiation, whereas the topical application of OMC inhibited the upregulation of MMPs. Furthermore, UV-induced wrinkle formation was decreased by OMC treatment. These results suggest that OMC is a potential agent for the prevention and treatment of skin photoaging.

Kim|So Young|SY|
Lamichhane|Santosh|S|
Ju|Jung-Hun|JH|
Yun|Jaesuk|J|

octylmethoxycinnamate
photoaging
matrix metalloproteinase
UV
sunscreen agent


Lymphoproliferative Disease in CVID: a Report of Types and Frequencies from a US Patient Registry.

Abstract:
PURPOSE
Lymphoproliferative disease in common variable immunodeficiency disease (CVID) is heterogeneous in pathogenesis and ranges from non-malignant lymphoid hyperplasia to lymphoma.

METHODS
The United States Immunodeficiency Network (USIDNET) patient registry was queried for lymphoproliferative diseases reported in CVID patients. Diagnoses included as possible manifestations of lymphoproliferation included lymphadenopathy, lymphoid hyperplasia, lymphocytic inflammation, lymphocytosis, and gammopathy.

RESULTS
Among 1091 CVID patients, lymphoproliferative conditions were reported in 17.2% (N = 188). These conditions included lymphadenopathy (N = 192, 12.3%), lymphoid hyperplasia or lymphocytic inflammation (N = 50, 4.6%), lymphocytosis (N = 3, 0.3%), and gammopathies (N = 3, 0.3%). Of the 188 patients with lymphoproliferative conditions, 15 (8%) also had a diagnosis of lymphoma, while the remaining 173 (92%) did not. Nine (4.8%) had a diagnosis of non-lymphomatous malignancy including basal cell carcinoma (N = 3, 1.6%), thyroid carcinoma (N = 2, 1.1%), gynecologic cancer (N = 2, 1.1%), testicular cancer (N = 1), and vocal cord carcinoma (N = 1). CVID patients with lymphoma were older than patients with lymphoproliferative disease who did not have a diagnosis of lymphoma at the time of analysis (median age 49 vs. 35 years, p = 0.005). CVID patients with lymphoproliferative disease had 2.5 times higher odds of having chronic lung disease compared with those with lymphoma (OR = 0.4, p = 0.049). There were no significant differences in the frequency of autoimmune, gastrointestinal, hepatic, or granulomatous disease between these populations.

CONCLUSIONS
While CVID patients are at increased risk for lymphoma, lymphoproliferation may be observed in the absence of a concurrent hematologic or solid tumor malignancy.

Yakaboski|Elizabeth|E|
Fuleihan|Ramsay L|RL|
Sullivan|Kathleen E|KE|
Cunningham-Rundles|Charlotte|C|
Feuille|Elizabeth|E|

lymphoproliferative disease
CVID
common variable immunodeficiency
lymphoma
lymphoproliferation
lymphoproliferative disorder


Altering the ratio of dietary palmitic and oleic acids affects production responses during the immediate postpartum and carryover periods in dairy cows.

Abstract: The objectives of our study were to determine the effects of altering the dietary ratio of palmitic (C16:0) and oleic (cis-9 C18:1) acids on production and metabolic responses of early-lactation dairy cows during the immediate postpartum period and to evaluate carryover effects of the treatment diets early in lactation. Fifty-six multiparous cows were used in a randomized complete block design and randomly assigned to 1 of 4 treatments (14 cows per treatment) fed from 1 to 24 d in milk (DIM). The treatments were: (1) control (CON) diet not supplemented with fatty acids (FA); (2) diet supplemented with a FA blend containing 80% C16:0 and 10% cis-9 C18:1 (80:10); (3) diet supplemented with a FA blend containing 70% C16:0 and 20% cis-9 C18:1 (70:20); and (4) diet supplemented with a FA blend containing 60% C16:0 and 30% cis-9 C18:1 (60:30). The FA supplement blends were added at 1.5% of diet DM by replacing soyhulls in the CON diet. All cows were offered a common diet from d 25 to 63 postpartum (carryover period) to evaluate carryover effects. Three preplanned contrasts were used to compare treatment differences: CON versus FA-supplemented diets (80:10 + 70:20 + 60:30)/3; the linear effect of cis-9 C18:1 inclusion in diets; and the quadratic effect of cis-9 C18:1 inclusion in diets. During the treatment period, FA-supplemented diets increased milk yield, 3.5% fat-corrected milk (FCM), and energy-corrected milk (ECM) compared with CON. Compared with CON, FA-supplemented diets increased milk fat content, milk fat yield, yield of mixed FA, and tended to increase protein yield and lactose yield. Also, compared with CON, FA-supplemented diets tended to increase body condition score (BCS) change. A treatment by time interaction was observed for body weight (BW), due to 80:10 inducing a greater BW loss over time compared with other treatments. Increasing cis-9 C18:1 in FA treatments tended to linearly increase dry matter intake (DMI) but did not affect milk yield, 3.5% FCM, ECM, and the yields of milk fat, protein and lactose. Increasing cis-9 C18:1 in FA treatments linearly decreased milk fat content and milk lactose content. Also, increasing cis-9 C18:1 in FA treatments linearly decreased BW and BCS losses. During the carryover period, compared with CON, FA-supplemented diets tended to increase milk yield. Also, FA-supplemented diets increased 3.5% FCM, ECM, and milk fat yield, and tended to increase milk protein yield compared with CON. A treatment by time interaction was observed for BW due to 80:10 increasing BW over time compared with CON. Our results indicate that feeding FA supplements containing C16:0 and cis-9 C18:1 during the immediate postpartum period increased milk yield and ECM compared with a nonfat supplemented control diet. Increasing cis-9 C18:1 in the FA supplement increased DMI and reduced BW and BCS losses. Additionally, the fat-supplemented diets fed during the immediate postpartum period had a positive carryover effect during early lactation, when cows were fed a common diet.

oleic acid
carryover
early lactation
palmitic acid


CGRP Receptor Biology: Is There More Than One Receptor?

Abstract: Calcitonin gene-related peptide (CGRP) has many reported pharmacological actions. Can a single receptor explain all of these? This chapter outlines the molecular nature of reported CGRP binding proteins and their pharmacology. Consideration of whether CGRP has only one or has more receptors is important because of the key role that this peptide plays in migraine. It is widely thought that the calcitonin receptor-like receptor together with receptor activity-modifying protein 1 (RAMP1) is the only relevant receptor for CGRP. However, some closely related receptors also have high affinity for CGRP and it is still plausible that these play a role in CGRP biology, and in migraine. The calcitonin receptor/RAMP1 complex, which is currently called the AMY1 receptor, seems to be the most likely candidate but more investigation is needed to determine its role.

D018015:Receptors, Calcitonin Gene-Related Peptide


Development of an indirect ELISA for detection of antibody to wobbly possum disease virus in archival sera of Australian brushtail possums (Trichosurus vulpecula) in New Zealand.

Abstract:
AIMS
To develop an indirect ELISA based on recombinant nucleocapsid (rN) protein of wobbly possum disease (WPD) virus for investigation of the presence of WPD virus in Australian brushtail possums (Trichosurus vulpecula) in New Zealand.

METHODS
Pre- and post-infection sera (n=15 and 16, respectively) obtained from a previous experimental challenge study were used for ELISA development. Sera were characterised as positive or negative for antibody to WPD virus based on western-blot using WPD virus rN protein as antigen. An additional 215 archival serum samples, collected between 2000-2016 from five different regions of New Zealand, were also tested using the ELISA. Bayesian modelling of corrected optical density at 450 nm (OD450) results from the ELISA was used to obtain estimates of receiver operating characteristic (ROC) curves to establish cut-off values for the ELISA, and to estimate the prevalence of antibody to WPD virus.

RESULTS
Western blot analysis showed 5/14 (36%) pre-infection sera and 11/11 (100%) post-infection sera from experimentally infected possums were positive for antibodies to WPD virus. Bayesian estimates of the ROC curves established cut-off values of OD450≥0.41 for samples positive, and OD450<0.28 for samples negative for antibody to WPD virus, for sera diluted 1:100 for the ELISA. Based on the model, the estimated proportion of samples with antibodies to WPD virus was 0.30 (95% probability interval=0.196-0.418). Of the 230 archival serum samples tested using the ELISA, 48 (20.9%) were positive for antibody to WPD virus, 155 (67.4%) were negative and 27 (11.7%) equivocal, using the established cut-off values. The proportion of samples positive for WPD virus antibody differed between geographical regions (p<0.001).

CONCLUSION
The results suggested that WPD virus or a related virus has circulated among possums in New Zealand with differences in the proportion of antibody-positive samples from different geographical regions. Antibodies to WPD virus did not seem to protect possums from disease following experimental infection, as one third of possums from the previous challenge study showed evidence of pre-existing antibody at the time of challenge. These results provide further support for existence of different pathotypes of WPD virus, but the exact determinants of protection against WPD and epidemiology of infection in various regions of New Zealand remain to be established.

CLINICAL RELEVANCE
Availability of the indirect ELISA for detection of WPD virus antibody will facilitate prospective epidemiological investigation of WPD virus circulation in wild possum populations in New Zealand.

Giles|J C|JC|
Johnson|W|W|
Jones|G|G|
Heuer|C|C|
Dunowska|M|M|

ELISA
Wobbly possum disease
brushtail possum
WPD
WPD virus
arterivirus
serology


Inhalable bacteriophage powders: Glass transition temperature and bioactivity stabilization.

Abstract: Recent heightened interest in inhaled bacteriophage (phage) therapy for combating antibacterial resistance in pulmonary infections has led to the development of phage powder formulations. Although phages have been successfully bioengineered into inhalable powders with preserved bioactivity, the stabilization mechanism is yet unknown. This paper reports the first study investigating the stabilization mechanism for phages in these powders. Proteins and other biologics are known to be preserved in dry state within a glassy sugar matrix at storage temperatures (T s) at least ~50°C below the glass transition temperature (T g). This is because at (T g - T s) >50°C, molecules are sufficiently immobilized with reduced reactivity. We hypothesized that this glass stabilization mechanism may also be applicable to phages comprising mostly of proteins. In this study, spray dried powders of Pseudomonas phage PEV20 containing lactose and leucine as excipients were stored at 5, 25 or 50°C and 15 or 33% relative humidity (RH), followed by assessment of bioactivity (PEV20 stability) and physical properties. PEV20 was stable with negligible titer loss after storage at 5°C/15% RH for 250 days, while storage at 33% RH caused increased titer losses of 1 log10 and 3 log10 at 5 and 25°C, respectively. The plasticizing effect of water at 33% RH lowered the T g by 30°C, thus narrowing the gap between T s and T g to 19-28°C, which was insufficient for glass stabilization. In contrast, the (T g - T s) values were higher (range, 46-65°C) under the drier condition of 15% RH, resulting in the improved stability which corroborated with the vitrification hypothesis. Furthermore, phage remained stable (≤1 log10) when the (T g - T s) value lay between 26-48°C, but became inactivated as the value fell below 20°C. In conclusion, this study demonstrated that phage can be sufficiently stabilized in spray dried powders by keeping the (T g - T s) value above 46°C, thus supporting the vitrification hypothesis that phages are stabilized by immobilization inside a rigid glassy sugar matrix. These findings provide a guide to better manufacture and storage practices of inhaled phage powder products using for translational medicines.

powder
bacteriophage (phage) therapy
glass transition temperature (Tg)
stability, inhalation aerosol


Rational Engraftment of Quaternary-Interactive Acidic Loops for Anti-HIV-1 Antibody Improvement.

Abstract: Broadly neutralizing antibodies (bNAbs) are the focus of increasing interest for human immunodeficiency virus type 1 (HIV-1) prevention and treatment. Although several bNAbs are already under clinical evaluation, the development of antibodies with even greater potency and breadth remains a priority. Recently, we reported a novel strategy for improving bNAbs against the CD4-binding site (CD4bs) of gp120 by engraftment of the elongated framework region 3 (FR3) from VRC03, which confers the ability to establish quaternary interactions with a second gp120 protomer. Here, we applied this strategy to a new series of anti-CD4bs bNAbs (N49 lineage) that already possess high potency and breadth. The resultant chimeric antibodies bound the HIV-1 envelope (Env) trimer with a higher affinity than their parental forms. Likewise, their neutralizing capacity against a global panel of HIV-1 Envs was also increased. The introduction of additional modifications further enhanced the neutralization potency. We also tried engrafting the elongated CDR1 of the heavy chain from bNAb 1-18, another highly potent quaternary-binding antibody, onto several VRC01-class bNAbs, but none of them was improved. These findings point to the highly selective requirements for the establishment of quaternary contact with the HIV-1 Env trimer. The improved anti-CD4bs antibodies reported here may provide a helpful complement to current antibody-based protocols for the therapy and prevention of HIV-1 infection.IMPORTANCE Monoclonal antibodies represent one of the most important recent innovations in the fight against infectious diseases. Although potent antibodies can be cloned from infected individuals, various strategies can be employed to improve their activity or pharmacological features. Here, we improved a lineage of very potent antibodies that target the receptor-binding site of HIV-1 by engineering chimeric molecules containing a fragment from a different monoclonal antibody. These engineered antibodies are promising candidates for development of therapeutic or preventive approaches against HIV/AIDS.

Liu|Qingbo|Q|
Zhang|Peng|P|
Miao|Huiyi|H|
Lin|Yin|Y|
Kwon|Young Do|YD|
Kwong|Peter D|PD|0000-0003-3560-232X
Rikhtegaran-Tehrani|Zahra|Z|
Seaman|Michael S|MS|
DeVico|Anthony L|AL|
Sajadi|Mohammad M|MM|
Lusso|Paolo|P|0000-0002-2813-4081

neutralizing antibodies
human immunodeficiency virus
prevention
mutagenesis
protein structure-function
recombinant protein production
retroviral therapy
viral envelope


Phylogeography and Antioxidant Activity of Proso Millet (Panicum miliaceum L.).

Abstract: Proso millet (Panicum miliaceum L.) or broomcorn millet is among the most important food crops to be domesticated by humans; it is widely distributed in America, Europe, and Asia. In this study, we genotyped 578 accessions of P. miliaceum using 37 single-sequence repeat (SSR) markers, to study the genetic diversity and population structure of each accession. We also investigated total phenolic content (TPC) and superoxide dismutase (SOD) activity and performed association analysis using SSR markers. The results showed that genetic diversity and genetic distance were related to geographic location and the fixation index (Fst). Population structure analysis divided the population into three subpopulations. Based on 3 subpopulations, the population is divided into six clusters in consideration of geographical distribution characteristics and agronomic traits. Based on the genetic diversity, population structure, pairwise Fst, and gene flow analyses, we described the topological structure of the six proso millet subpopulations, and the geographic distribution and migration of each cluster. Comparison of the published cluster (cluster 1) with unique germplasms in Japan and South Korea suggested Turkey as a possible secondary center of origin and domestication (cluster 3) for the cluster. We also discovered a cluster domesticated in Nepal (cluster 6) that is adapted to high-latitude and high-altitude cultivation conditions. Differences in phenotypic characteristics, such as TPC, were observed between the clusters. The association analysis showed that TPC was associated with SSR-31, which explained 7.1% of the total variance, respectively. The development of markers associated with TPC and SOD will provide breeders with new tools to improve the quality of proso millet through marker-assisted selection.

genetic diversity
population structure
total phenolic content
association analysis
SSR marker
gene migration


ProtekDuo as a bridge to lung transplant and heart-lung transplant.

Abstract: Recent advances in technology have led to significantly greater use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation with better outcomes. The novel ProtekDuo veno-venous ECMO (CardiacAssist, Inc.) has gained significance as it facilitates effective decompression of the right heart in patients with acute decompensation, while also providing consistent and effective gas exchange by eliminating recirculation. Here, we report two cases of effectively using ProtekDuo veno-venous ECMO: one case as a bridge to lung transplantation and another case as a bridge to heart-lung transplantation.

ProtekDuo
lung transplant
heart-lung transplant
ECMO


Hospital-Based Analysis of Trends and Outcomes for Patients Undergoing Pyelolithotomy.

Abstract:
OBJECTIVE
To determine trends in pyelolithotomy, evaluate risk factors for complications, and evaluate the difference in outcomes and charges between open and minimally invasive (MI) techniques.

PATIENTS AND METHODS
We used the Nationwide Inpatient Sample to identify patients with a diagnosis of having nephrolithiasis undergoing pyelolithotomy from 2008 to 2012. Total charges were inflation-adjusted to U.S. dollars in 2012. Patient demographics, hospital characteristics, and outcomes were reported and compared between open and MI groups after survey weighting.

RESULTS
We included a survey-weighted population of 17,294 patients, of whom 841 (4.9%) had MI pyelolithotomy. The proportion of MI cases increased by 2.57% annually (r2 = 0.921, p = 0.01), although total pyelolithotomy cases remained stable. Simultaneous pyeloplasty occurred in 6.6% of all patients. Patients receiving open surgery experienced longer length of stay (3.9 days vs 2.7 days; p < 0.001), but accrued equivalent inflation-adjusted charges ($49,588 ± 2088 vs $51,716 ± 4893; p = 0.665). On multivariable analysis, higher Elixhauser comorbidity index and presence of any genitourinary anomaly were associated with experiencing a complication, while undergoing surgery at a top quartile hospital and elective admission status were protective against complications. MI technique and simultaneous ureteropelvic junction repair did not alter complication risk.

CONCLUSION
While the annual number of pyelolithotomy cases was stable, there was an increasing trend toward MI technique. Both patient and hospital factors can significantly alter the risk for complications following pyelolithotomy.

Nottingham|Charles U|CU|
Cohen|Andrew J|AJ|
Packiam|Vignesh T|VT|
Pariser|Joseph J|JJ|
Gerber|Glenn S|GS|

trends
pyelolithotomy
nephrolithiasis
pyeloplasty
renal calculus


Two actin-interacting protein 1 isoforms function redundantly in the somatic gonad and are essential for reproduction in Caenorhabditis elegans.

Abstract: The somatic gonad of the nematode Caenorhabditis elegans exhibits highly regulated contractility during ovulation, which is essential for successful reproduction. Nonstriated actin filament networks in the myoepithelial sheath at the proximal ovary provide contractile forces to push a mature oocyte for ovulation, but the mechanism of assembly and regulation of the contractile actin networks is poorly understood. Here, we show that actin-interacting protein 1 (AIP1) is essential for the assembly of the contractile actin networks in the myoepithelial sheath. AIP1 promotes disassembly of actin filaments in the presence of actin depolymerizing factor (ADF)/cofilin. C. elegans has two AIP1 genes, unc-78 and aipl-1. Mutation or RNA interference of a single AIP1 isoform causes only minor impacts on reproduction. However, simultaneous depletion of the two AIP1 isoforms causes sterility. AIP1-depleted animals show very weak contractility of the myoepithelial sheath and fail to ovulate a mature oocyte, which results in accumulation of endomitotic oocytes in the ovary. Depletion of AIP1 prevents assembly of actin networks and causes abnormal aggregation of actin as well as ADF/cofilin in the myoepithelial sheath. These results indicate that two AIP1 isoforms have redundant roles in assembly of the contractile apparatuses necessary for C. elegans reproduction.

ovulation
sterility
actin depolymerizing factor/cofilin
actin dynamics
myoepithelial cells
spermatheca


Activating BRAF mutation in sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid gland: two case reports and review of the literature.

Abstract:
BACKGROUND
Sclerosing mucoepidermoid carcinoma with eosinophilia is a rare form of thyroid carcinoma. The underlying molecular mechanisms of sclerosing mucoepidermoid carcinoma with eosinophilia tumorigenesis remain unknown.

CASE PRESENTATION
We present two cases of sclerosing mucoepidermoid carcinoma with eosinophilia, both with a concurrent papillary thyroid carcinoma. Patient 1, a 70-year-old Caucasian woman, presented with sclerosing mucoepidermoid carcinoma with eosinophilia with distant renal metastasis and coexisting papillary thyroid carcinoma. Patient 2, a 74-year-old Caucasian woman with a remote history of thyroid cancer treated with thyroidectomy, presented with locoregionally invasive sclerosing mucoepidermoid carcinoma with eosinophilia and recurrent papillary thyroid carcinoma in the thyroid bed. BRAF mutation studies were performed on the sclerosing mucoepidermoid carcinoma with eosinophilia tumors. In both cases, sclerosing mucoepidermoid carcinoma with eosinophilia was positive for the BRAF V600E mutation by polymerase chain reaction. Patient 1 is the first reported case of sclerosing mucoepidermoid carcinoma with eosinophilia with renal metastasis, to the best of our knowledge.

CONCLUSIONS
Our findings suggest, for the first time, to our knowledge, involvement of the RAS-RAF-MEK-ERK signaling pathway in the pathogenesis of sclerosing mucoepidermoid carcinoma with eosinophilia. Thus, BRAF inhibitors may prove to be a useful targeted medical therapy in the treatment of a subset of patients with aggressive sclerosing mucoepidermoid carcinoma with eosinophilia tumors who exhibit BRAF activating mutation.

Sukumar|Jasmine S|JS|
Sukumar|Senthil|S|
Purohit|Darshana|D|
Welch|Brian J|BJ|
Balani|Jyoti|J|
Yan|Shirley|S|
Hathiramani|Sumitha S|SS|


An optimal acquisition and post-processing pipeline for hybrid IVIM-DKI in head and neck.

Abstract:
PURPOSE
To optimize the diffusion-weighting b values and postprocessing pipeline for hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region.

METHODS
Optimized diffusion-weighting b value sets ranging between 5 and 30 b values were constructed by optimizing the Cramér-Rao lower bound of the hybrid intravoxel incoherent motion diffusion kurtosis imaging model. With this model, the perfusion fraction, pseudodiffusion coefficient, diffusion coefficient, and kurtosis were estimated. Sixteen volunteers were scanned with a reference b value set and 3 repeats of the optimized sets, of which 1 with volunteers swallowing on purpose. The effects of (1) b value optimization and number of b values, (2) registration type (none vs. intervolume vs. intra- and intervolume registration), and (3) manual swallowing artifact rejection on the parameter precision were assessed.

RESULTS
The SD was higher in the reference set for perfusion fraction, diffusion coefficient, and kurtosis by a factor of 1.7, 1.5, and 2.3 compared to the optimized set, respectively. A smaller SD (factor 0.7) was seen in pseudodiffusion coefficient. The sets containing 15, 20, and 30 b values had comparable repeatability in all parameters, except pseudodiffusion coefficient, for which set size 30 was worse. Equal repeatability for the registration approaches was seen in all parameters of interest. Swallowing artifact rejection removed the bias when present.

CONCLUSION
To achieve optimal hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region, b value optimization and swallowing artifact image rejection are beneficial. The optimized set of 15 b values yielded the optimal protocol efficiency, with a precision comparable to larger b value sets and a 50% reduction in scan time.

D038524:Diffusion Magnetic Resonance Imaging

intravoxel incoherent motion diffusion kurtosis imaging (IVIM-DKI)


Encapsulated follicular variant of papillary thyroid carcinoma/noninvasive follicular thyroid neoplasm with papillary-like nuclear features with Spindle Cell Metaplasia: Case report and review of literature.

Abstract: Spindle cell lesions of the thyroid are rare overall, and span a wide clinical spectrum that ranges from spindle cell metaplasia (SCM1) to anaplastic carcinoma. Their differentiation is only seldom straightforward, and usually requires the integration of the clinical, histological and immunohistochemical data. Only a handful of publications have described cases of SCM in the thyroid and we add to that literature by reporting a unique case of encapsulated follicular variant of papillary thyroid carcinoma/noninvasive follicular thyroid neoplasm with papillary-like nuclear features with SCM. In addition, we review the literature on the relationship between SCM and different thyroid lesions, summarizing the morphological and immunohistochemical features that aid in its differentiation from more aggressive spindle cell proliferations.

Haroon Al Rasheed|Mohamed Rizwan|MR|
Acosta|Andres|A|
Tarjan|Gabor|G|

EFVPTC
Endocrine
Follicular neoplasm
HBME-1
NIFTP
Spindled lesion


Effect of 12 Weeks Core Training on Core Muscle Performance in Rhythmic Gymnastics.

Abstract:
BACKGROUND
Rhythmic gymnastics performance is characterized by technical elements involving flexibility, aerobic capacity and strength. Increased core strength in rhythmic gymnastics could lead to improved sporting performance.

OBJECTIVE
The aim of this study was to analyze the effect of 12 weeks of core muscle training on core muscle performance in rhythmic gymnasts.

METHODS
A randomized controlled study involving 24 rhythmic gymnastics was conducted. Participants were randomly assigned to a control group (CG; n = 12; age 13.50 ± 3.17 years) or a training group (TG; n = 12; age 14.41 ± 2.35 years). Body composition, isometric strength of trunk, core endurance and core muscle electromyographic activity were measured (EMG) after 12 weeks of core training. Independent sample t-tests were carried out to compare baseline values between groups. A two-way repeated-measures analysis of variance (ANOVA) (time × group) was applied.

RESULTS
The TG improved body composition, trunk lean mass (mean differences MD = -0.31; p = 0.040), lean mass (MD = 0.43; p = 0.037) and bone mass (MD = -0.06; p < 0.001) after training. Core training increased isometric strength of trunk, flexion test (MD = -21.53; p = 0.019) and extension test (MD = 22.7; p = 0.049), as well as the prone bridge core endurance test (MD = -11.27; p = 0.040). The EMG values also increased in the TG in prone bridge for front trunk (MD = -58.58; p = 0.026).

CONCLUSIONS
Core strength training leads to improvements in body composition, as well as improvements in trunk strength and increases in muscle electromyographic activity. These improvements could therefore improve performance during competitive rhythmic gymnastics exercises.

strength
core endurance test
electromyography
muscular activity
muscular performance


Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss.

Abstract: Background: PTEN-deficient tumors are dependent on PI3Kβ activity, making PI3Kβ a compelling target. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 on tumors with PTEN loss. Results: In vitro cell viability assay and immunoblotting demonstrated that PTEN loss was significantly correlated with AZD8186 sensitivity in triple negative breast cancer (TNBC) cell lines. Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling in PTEN loss TNBC cells. AZD8186 in combination with paclitaxel, eribulin had synergistic effects on growth inhibition in PTEN loss cells. AZD8186 promoted apoptosis in PTEN loss cells which was synergized by paclitaxel. In vivo, AZD8186 had limited activity as a single agent, but enhanced antitumor activity when combined with paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line xenografts. AZD8186 significantly enhanced antitumor efficacy of anti-PD1 antibodies in the PTEN-deficient BP murine melanoma xenograft model, but not in the PTEN-wild-type CT26 xenograft model. Methods: In vitro, cell proliferation and colony formation assays were performed to determine cell sensitivity to AZD8186. Immunoblotting was performed to assess PTEN expression and PI3K signaling activity. FACS was performed to evaluate apoptosis. In vivo, antitumor efficacy of AZD8186 and its combinations were evaluated. Conclusions: AZD8186 has single agent efficacy in PTEN-deficient TNBC cell lines in vitro, but has limited single agent efficacy in vivo. However, AZD8186 has enhanced efficacy when combined with paclitaxel and anti-PD1 in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors.

Owusu-Brackett|Nicci|N|
Zhao|Ming|M|
Akcakanat|Argun|A|
Evans|Kurt W|KW|
Yuca|Erkan|E|
Dumbrava|Ecaterina Ileana|EI|
Janku|Filip|F|
Meric-Bernstam|Funda|F|


Non-steroidal anti-inflammatory drugs, prostaglandins, and COVID-19.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID-19 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti-inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS-CoV-2 infection and the development and progression of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Robb|Calum T|CT|0000-0002-0249-7212
Goepp|Marie|M|
Rossi|Adriano G|AG|
Yao|Chengcan|C|0000-0003-3754-2842

prostaglandin
COVID-19
SARS-CoV-2
NSAID
inflammation
cytokine storm


Insight into the diagnosis and management of subclinical genital tuberculosis in women with infertility.

Abstract: Genital tuberculosis (GTB) is an important cause of infertility in India. Lack of an accurate diagnostic test has led to an indiscriminate use of antitubercular treatment in infertile women. Apart from concerns of drug toxicity, this may be a contributing factor in the increasing incidence of multidrug-resistant TB reported in India. We conducted a study to analyze whether a combination of tests could help improve diagnostic accuracy. An algorithm for the management of GTB in infertile women based on the use of multiple tests is presented.

Mahajan|Nalini|N|
Naidu|Padmaja|P|
Kaur|Simran Deep|SD|

Genital tuberculosis
infertility
Mycobacterium tuberculosis infection
latent tuberculosis


Aiming for excellence - A simulation-based study on adapting and testing an instrument for developing non-technical skills in Norwegian student nurse anaesthetists.

Abstract: There is increasing focus on building safety into anaesthesia practice, with excellence in anaesthesia as an aspirational goal. Non-technical skills are an important factor in excellence and improved patient safety, though there have been few systematic attempts at integrating them into anaesthesia nursing education. This study aimed to test the reliability of NANTS-no, a specially adapted behavioural marker system for nurse anaesthetists in Norway, and explore the development of non-technical skills in student nurse anaesthetists. The pre-test post-test design incorporated a 10-week simulation-based programme, where non-technical skills in 14 student nurse anaesthetists were rated on three different occasions during high-fidelity simulation, before and after taking part in a training course. NANTS-no demonstrated high overall inter-rater reliability (ICC = 0.91), high test-retest reliability (ICC = 0.94) and good internal consistency (Cronbach's α of 0.85-0.92). A significant improvement was demonstrated across all categories of non-technical skills, with greatest improvements between the first and third and second and third sessions. There was also a significant improvement in two categories between the first and second sessions. NANTS-no is therefore suitable for assessing non-technical skills during simulation training in anaesthesia nursing education. More research is needed to validate its use in clinical practice.

Flynn|Fiona M|FM|
Sandaker|Kjersti|K|
Ballangrud|Randi|R|

D000070856:High Fidelity Simulation Training

Non-technical skills
Patient safety
Education
Nurse anaesthetist/anesthetist


WNT5a in Colorectal Cancer: Research Progress and Challenges.

Abstract: Despite the clinical development of new adjuvant and neoadjuvant chemotherapy drugs, colorectal cancer is still one of the leading causes of cancer-related death in human beings. WNT5a, an autocrine and paracrine β-catenin independent ligand, has been shown to induce tumor inhibition and carcinogenic signals, depending on the type of cancer. In patients with colorectal cancer, WNT5a triggers a variety of downstream signaling pathways, which mainly affect the migration and invasion of tumor cells. This article reviews the mechanism and therapeutic potential of WNT5a in colorectal cancer. In short, an in-depth understanding of the role of WNT5a in colorectal cancer is very helpful to better deal with this disease.

Sun|Guangshun|G| Wu|Liangliang|L| Sun|Guoqiang|G| Shi|Xuesong|X| Cao|Hongyong|H| Tang|Weiwei|W|


The effectiveness of biosecurity interventions in reducing the transmission of bacteria from livestock to humans at the farm level: A systematic literature review.

Abstract: Zoonotic bacterial infections are a health hazard for people who are in regular contact with livestock at the farm level. Improved biosecurity can limit zoonotic pathogen transmission within farms. The aim of this review was to summarize the effectiveness of farm-level biosecurity interventions in reducing bacterial transmission from animals to people who lived, worked in or visited farms. A systematic literature review was conducted using Embase, Ovid Medline and Agris databases, which were searched on 7th of July 2019, limited to English language papers but with no time exclusion criteria. A narrative synthesis was undertaken utilizing the Centre for Reviews and Dissemination approach, reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias within and across the included studies was performed using established checklists. Out of 869 studies retrieved through database searches, 11 studies were selected. In addition, three studies were found through study reference lists. Fourteen studies were therefore included in this review. Biosecurity interventions were grouped into five categories: hand washing, sanitization and hygienic measures (six studies); personal protective equipment (five studies); vaccination (two studies); other interventions (e.g. air ventilation flap) (four studies); and routine farm activities (two studies). Across studies that investigated odds of human colonization or infection (three studies), odds were seen to both be increased and decreased through use of tested biosecurity measures. Large confidence intervals that often crossed the threshold of an odds ratio equal to 1 were found. Most of the studies' overall risk of bias was 'medium risk' (11 studies), with selection bias domains generally being scored 'medium risk.' Biosecurity interventions are potentially beneficial in reducing bacterial transmission from animals to humans. However, more high-quality evidence is needed to increase certainty in which interventions, in which contexts, are most effective from the human health perspective.

effectiveness
biosecurity interventions
livestock
farm level
bacterial infections
occupational risk


A mathematical model for the simulation of the formation and the subsequent regression of hypertrophic scar tissue after dermal wounding.

Abstract: A continuum hypothesis-based model is presented for the simulation of the formation and the subsequent regression of hypertrophic scar tissue after dermal wounding. Solely the dermal layer of the skin is modeled explicitly and it is modeled as a heterogeneous, isotropic and compressible neo-Hookean solid. With respect to the constituents of the dermal layer, the following components are selected as primary model components: fibroblasts, myofibroblasts, a generic signaling molecule and collagen molecules. A good match with respect to the evolution of the thickness of the dermal layer of scars between the outcomes of simulations and clinical measurements on hypertrophic scars at different time points after injury in human subjects is demonstrated. Interestingly, the comparison between the outcomes of the simulations and the clinical measurements demonstrates that a relatively high apoptosis rate of myofibroblasts results in scar tissue that behaves more like normal scar tissue with respect to the evolution of the thickness of the tissue over time, while a relatively low apoptosis rate results in scar tissue that behaves like hypertrophic scar tissue with respect to the evolution of the thickness of the tissue over time. Our ultimate goal is to construct models with which the properties of newly generated tissues that form during wound healing can be predicted with a high degree of certainty. The development of the presented model is considered by us as a step toward their construction.

Koppenol|Daniël C|DC|
Vermolen|Fred J|FJ|
Niessen|Frank B|FB|
van Zuijlen|Paul P M|PPM|
Vuik|Kees|K|

D017439:Cicatrix, Hypertrophic
D003198:Computer Simulation
D006801:Humans
D008954:Models, Biological
D012867:Skin
D014945:Wound Healing

Modeling
Hypertrophic scar tissue
Compressible neo-Hookean solid
Fibroblasts
Biomechanics
Dermal wound healing
Flux-corrected transport (FCT) limiter
Moving boundary
Moving-grid finite-element method


Safety assessment of titanium dioxide (E171) as a food additive.

Abstract: The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO2 nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension < 100 nm. In addition, the Panel noted that constituent particles < 30 nm amounted to less than 1% of particles by number. The Panel therefore considered that studies with TiO2 NPs < 30 nm were of limited relevance to the safety assessment of E 171. The Panel concluded that although gastrointestinal absorption of TiO2 particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E 171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO2 NPs (> 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E 171 and potential neurotoxicity with TiO2 NPs, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO2 particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico-chemical properties of TiO2 particles and the outcome of either in vitro or in vivo genotoxicity assays. A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO2 particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut-off value for TiO2 particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2 NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive.

|||
Younes|Maged|M|
Aquilina|Gabriele|G|
Castle|Laurence|L|
Engel|Karl-Heinz|KH|
Fowler|Paul|P|
Frutos Fernandez|Maria Jose|MJ|
Fürst|Peter|P|
Gundert-Remy|Ursula|U|
Gürtler|Rainer|R|
Husøy|Trine|T|
Manco|Melania|M|
Mennes|Wim|W|
Moldeus|Peter|P|
Passamonti|Sabina|S|
Shah|Romina|R|
Waalkens-Berendsen|Ine|I|
Wölfle|Detlef|D|
Corsini|Emanuela|E|
Cubadda|Francesco|F|
De Groot|Didima|D|
FitzGerald|Rex|R|
Gunnare|Sara|S|
Gutleb|Arno Christian|AC|
Mast|Jan|J|
Mortensen|Alicja|A|
Oomen|Agnes|A|
Piersma|Aldert|A|
Plichta|Veronika|V|
Ulbrich|Beate|B|
Van Loveren|Henk|H|
Benford|Diane|D|
Bignami|Margherita|M|
Bolognesi|Claudia|C|
Crebelli|Riccardo|R|
Dusinska|Maria|M|
Marcon|Francesca|F|
Nielsen|Elsa|E|
Schlatter|Josef|J|
Vleminckx|Christiane|C|
Barmaz|Stefania|S|
Carfí|Maria|M|
Civitella|Consuelo|C|
Giarola|Alessandra|A|
Rincon|Ana Maria|AM|
Serafimova|Rositsa|R|
Smeraldi|Camilla|C|
Tarazona|Jose|J|
Tard|Alexandra|A|
Wright|Matthew|M|

Titanium dioxide
E 171
CAS No 13463‐67-7


Lanostane Triterpenoids with Glucose-Uptake-Stimulatory Activity from Peels of the Cultivated Edible Mushroom Wolfiporia cocos.

Abstract: A chemical study on the peels of the cultivated edible mushroom Wolfiporia cocos led to the isolation and identification of 47 lanostane triterpenoids including 16 new compounds (1-16). The structures of the new compounds were determined by analysis of the NMR, MS, and electronic circular dichroism (ECD) data. Compounds 1 and 2 represent new members of the family of 4,5-secolanostane triterpenes. Compound 3 is a new aromatic lanostane triterpene with an unusual methyl rearrangement from C-10 to C-6. The absolute configurations of 1 and 8 were assigned by ECD spectra calculation. All compounds were evaluated for cytotoxicity (K562, SW480, and HepG2) and glucose-uptake-stimulating effects. Compounds 23, 25, 29, and 31 showed weak inhibition on the K562 cells with IC50 in the range of 25.7 to 68.2 μM, respectively. Compounds 21, 28, and 30 increased the glucose uptake in 3T3-L1 cells by 25%, 14%, and 50% at 5 μM, respectively. In addition, compounds 14, 23, 29, 35, and 43 showed insulin-sensitizing activity by increasing the insulin-stimulated glucose uptake at 2.5 μM in 3T3-L1 adipocytes. A preliminary structure-activity relationship analysis indicates that the 6/6/6/5 ring skeleton and the double bond between C-8 and C-9 are beneficial for the glucose-uptake-stimulating and insulin-sensitizing activities. Furthermore, the alkaline-insoluble fraction mainly containing compounds 22, 24, 28, and 31 were confirmed to have hypoglycemic and hypolipidemic activity on high-fat-diet-induced obese mice. This work confirms the potential of the peels' extracts of W. cocos as a functional food or dietary supplements.

lanostane triterpene
cytotoxicity
insulin-sensitizing activity
glucose-uptake stimulation
structure−activity relationship


Mesenchymal stem cell energy deficit and oxidative stress contribute to osteopenia in the Pahenu2 classical PKU mouse.

Abstract: Osteopenia occurs in a subset of phenylalanine hydroxylase (PAH) deficient phenylketonuria (PKU) patients. While osteopenia is not fully penetrant in patients, the Pahenu2 classical PKU mouse is universally osteopenic, making it an ideal model of the phenotype. Pahenu2 Phe management, with a Phe-fee amino acid defined diet, does not improve bone density as histomorphometry metrics remain indistinguishable from untreated animals. Previously, we demonstrated Pahenu2 mesenchymal stem cells (MSCs) display impaired osteoblast differentiation. Oxidative stress is recognized in PKU patients and PKU animal models. Pahenu2 MSCs experience oxidative stress determined by intracellular superoxide over-representation. The deleterious impact of oxidative stress on mitochondria is recognized. Oximetry applied to Pahenu2 MSCs identified mitochondrial stress by increased basal respiration with concurrently reduced maximal respiration and respiratory reserve. Proton leak secondary to mitochondrial complex 1 dysfunction is a recognized superoxide source. Respirometry applied to Pahenu2 MSCs, in the course of osteoblast differentiation, identified a partial complex 1 deficit. Pahenu2 MSCs treated with the antioxidant resveratrol demonstrated increased mitochondrial mass by MitoTracker green labeling. In hyperphenylalaninemic conditions, resveratrol increased in situ alkaline phosphatase activity suggesting partial recovery of Pahenu2 MSCs osteoblast differentiation. Up-regulation of oxidative energy production is required for osteoblasts differentiation. Our data suggests impaired Pahenu2 MSC developmental competence involves an energy deficit. We posit energy support and oxidative stress reduction will enable Pahenu2 MSC differentiation in the osteoblast lineage to subsequently increase bone density.

Dobrowolski|Steven F|SF|
Sudano|Cayla|C|
Phua|Yu Leng|YL|
Tourkova|Irina L|IL|
Spridik|Kayla|K|
Goetzman|Eric S|ES|
Vockley|Jerry|J|
Blair|Harry C|HC|

Oxidative stress
Osteopenia
Phenylketonuria
Pah(enu2)
Respiratory complex 1


Unsuspected foreign-body aspiration in adult patient with status asthmaticus: Case report.

Abstract:
Introduction
Accidental foreign body aspiration can cause severe damage to the airway and threaten the patient's life. This situation requires multidisciplinary and systematic approach from the medical and surgical team, in order to achieve complete resolution maintaining airway permeability.

Presentation of case
This is a 49 y/o man who presented with a severe asthma attack, in whom an unsuspected foreign body in the inferior airway was diagnosed, which was possibly the result of aspiration during the initial emergency care, causing worsening of the already critical condition.

Discussion
We described the clinical course, radiologic and endoscopic findings, and outcome of the patient, highlighting the importance of considering the possibility of a foreign body in the airway, when there is no improvement in refractory status asthmaticus. This is particularly important in a university hospital. Moreover, the implementation of checklists when invasive procedures are performed can avoid loss of material, preventing iatrogenic aspiration events.

Conclusion
Foreign body aspirations may remain undetected due to lack of suspicion, especially in adults, in whom they can cause chronic symptoms, or worsen chronic respiratory conditions turning them into more complex diseases. This cause must be considered in the differential diagnosis of refractory status asthmaticus.

Fernandez-Trujillo|Liliana|L|
López-Castilla|Valeria|V|
Morales|Eliana I|EI|
Zúñiga-Restrepo|Valeria|V|
Bautista|Diego F|DF|

Case report
Foreign bodies
Asthma
Bronchoscopy
Extracorporeal membrane oxygenation
Respiratory insufficiency


A descriptive study of pain treatment and its follow-up in primary care of elderly patients after orthopaedic care.

Abstract:
Background
Pain treatment post orthopaedic care in the elderly is complicated and requires careful follow-up. Current guidelines state all patients prescribed opioids should have a plan for gradual reduction, with the treatment progressively reduced and ended if any pain remains after more than three months. How this works in primary care remains to be explored.The aim was to describe pain treatment and its follow-up in primary care of elderly patients after orthopaedic care.

Methods
In this descriptive study, medical case histories were collected for patients ≥ 75 years, which were enrolled at two rural primary care units in southern Sweden, and were discharged from orthopaedic care. Pain medication follow-up plans were noted, as well as current pain medication at discharge as well as two, six and twelve weeks later.

Results
We included a total of 49 community-dwelling patients with medication aid from nurses in municipality care and nursing home residents, ≥ 75 years, discharged from orthopaedic care. The proportion of patients prescribed paracetamol increased from 28/49 (57%) prior to admission, to 38/44 (82%) after 12 weeks. The proportion of patients prescribed opioids increased from 5/49 (10%) to 18/44 (41%). Primary care pain medication follow-up plans were noted for 16/49 patients (33%).

Conclusions
Many patients still used pain medication 12 weeks after discharge, and follow-up plans were quite uncommon, which may reflect upon lacking follow-up of these patients in primary care.

Caleres|Gabriella|G|0000-0002-5296-3656 Midlöv|Patrik|P| Bondesson|Åsa|Å| Modig|Sara|S|

Opioids
Acetaminophen
Aged
Analgesics
Pain management
Primary health care


Characterization of Chitosan Film Incorporated with Curcumin Extract.

Abstract: Curcumin is a phenolic compound derived from turmeric roots (Curcuma longa L.). This research studied the effects of curcumin extract on the properties of chitosan films. The film characteristics measured included mechanical properties, visual aspects, color parameters, light transmission, moisture content, water solubility, water vapor permeability, infrared spectroscopy, and antioxidant activity. The results suggest that adding curcumin to chitosan-based films increases yellowness and light barriers. Infrared spectroscopy analysis showed interactions between the phenolic compounds of the extract and the chitosan, which may have improved the mechanical properties and reduced the moisture content, water solubility, and water vapor permeability of the films. The antioxidant activity of the films increased with increasing concentrations of the curcumin extract. This study shows the potential benefits of incorporating curcumin extract into chitosan films used as active packaging.

chitosan film
curcumin
antioxidant
active packaging
bio-based film
biopolymers


Imitation and recognition of facial emotions in autism: a computer vision approach.

Abstract:
BACKGROUND
Imitation of facial expressions plays an important role in social functioning. However, little is known about the quality of facial imitation in individuals with autism and its relationship with defining difficulties in emotion recognition.

METHODS
We investigated imitation and recognition of facial expressions in 37 individuals with autism spectrum conditions and 43 neurotypical controls. Using a novel computer-based face analysis, we measured instructed imitation of facial emotional expressions and related it to emotion recognition abilities.

RESULTS
Individuals with autism imitated facial expressions if instructed to do so, but their imitation was both slower and less precise than that of neurotypical individuals. In both groups, a more precise imitation scaled positively with participants' accuracy of emotion recognition.

LIMITATIONS
Given the study's focus on adults with autism without intellectual impairment, it is unclear whether the results generalize to children with autism or individuals with intellectual disability. Further, the new automated facial analysis, despite being less intrusive than electromyography, might be less sensitive.

CONCLUSIONS
Group differences in emotion recognition, imitation and their interrelationships highlight potential for treatment of social interaction problems in individuals with autism.

Imitation
Autism
Facial expression
Emotion recognition
Automated analysis


Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum.

Abstract: Embryonic stem cells (ESCs) are characterized by the pluripotent capacity to generate all embryonic lineages. Here, we show that ESCs can occupy a spectrum of distinct transcriptional and epigenetic states in response to varied extrinsic conditions. This spectrum broadly corresponds to a developmental continuum of pluripotency and is coupled with a gradient of increasing global DNA methylation. Each pluripotent state is linked with activation of distinct classes of transposable elements (TEs), which in turn influence ESCs through generating chimeric transcripts. Moreover, varied ESC culture parameters differentially license heterogeneous activation of master lineage regulators, including Sox1, Gata4, or Blimp1, and influence differentiation. Activation of Blimp1 is prevalent in 2i (without LIF) conditions, and marks a dynamic primordial germ cell (PGC)-like sub-state that is directly repressed by Klf4 downstream of LIF/STAT3 signaling. Thus, extrinsic cues establish a spectrum of pluripotent states, in part by modulating sub-populations, as well as directing the transcriptome, epigenome, and TE.

Hackett|Jamie A|JA|
Kobayashi|Toshihiro|T|
Dietmann|Sabine|S|
Surani|M Azim|MA|

D000074462:Positive Regulatory Domain I-Binding Factor 1

transposable element
pluripotency
embryonic stem cell
DNA methylation
chimeric transcripts
heterogeneity
KLF4
STAT3
PGC
imprints


cml biology for the clinician in 2011: six impossible things to believe before breakfast on the way to cure.

Abstract: Chronic myeloid leukemia (cml) is a model disease in oncology: it is the first human cancer linked to a distinct chromosomal abnormality, ultimately causing constitutive overactivity of a known oncogenic tyrosine kinase that represents a drug target. The introduction of the tyrosine kinase inhibitor imatinib into clinical practice has far exceeded expectations and resurrected hope that the fundamental insights from the "war on cancer" can lead to significant therapeutic advances. Nevertheless, the current perception among clinicians is that imatinib and its newer more potent cousins offer superb long-term disease control for most patients, but that cure without transplantation has remained elusive. However, several important laboratory-based observations over the last few years have changed those perceptions. Several of those developments are discussed here, including direct manipulation of the apoptosis pathway in cancer cells and prevention of disease progression with the use of antioxidants. Intriguing results from a French study indicate that, if disease progression is halted, a small but significant group of patients may be able to stop imatinib therapy without disease recurrence. And for patients whose disease, because of resistant stem cells, needs a more direct attack than tyrosine kinase inhibitors alone, several approaches investigated in laboratory and animal models seem promising, and some are ripe for clinical testing, including inhibitors of Smoothened and 5-lipoxygenase, and suppression of autophagy. Thus, there is realistic hope that true cure of cml, without transplantation, may be a feasible goal in the near future.

Leukemia
tyrosine kinase inhibitor
apoptosis
stem cells
targeted therapy


Improved osteosarcoma survival with addition of mifamurtide to conventional chemotherapy - Observational prospective single institution analysis.

Abstract:
Purpose
Conventional osteosarcoma is an orphan disease. Current treatment approaches include combining a three drug chemotherapy schedule and surgery. The 3- and 5-year event-free survival (EFS) in localized disease is roughly 65 and 60%, respectively. The registration study of mifamurtide reported survival benefit, but some methodological controversies have been insufficient for FDA market authorization in contrast to EMA.

Methods
prospective single centre survival analysis of a mifamurtide addition to conventional therapy in 23 patients over a 5.5 year enrolment period is reported and compared to a historical control of 26 patient with localized disease. Bias arising from observational methodology was addressed using Landmark analysis and time-dependent Cox models. Blood count dynamics were analysed during the treatment.

Results
The adverse event profile was as expected with no dose limiting toxicities. There were no local relapses observed, one patient died in the first complete remission due to doxorubicin cardiotoxicity, one patient had pulmonary metastatic relapse. The observed 3- and 5-year EFS was 87.4% (CI 72.4-100%) and 87.4% (CI 72.4-100%), progression free survival (PFS) was 92.9% (CI 80.3-100%) and 92.9% (CI 80.3-100%), overall survival was 94.1% (CI 83.6-100) and 80.7% (CI 58.3-100), respectively. Comparison to the historical control showed statistically significant better PFS for mifamurtide patients (Landmark analysis; p = 0.044). Risk of progression was 5-times lower for the mifamurtide group (Cox model; HR 0.21, p = 0.136). Only subtle differences in lymphocyte counts were observed across treatment.

Conclusion
the PFS benefit of mifamurtide is reported herein. The addition of mifamurtide could be considered as a best treatment option for localized osteosarcoma.

Múdry|Peter|P|
Kýr|Michal|M|
Rohleder|Ondřej|O|
Mahdal|Michal|M|
Staniczková Zambo|Iva|I|
Ježová|Marta|M|
Tomáš|Tomáš|T|
Štěrba|Jaroslav|J|

A/AP, adriamycin (doxorubicin)/adriamycin (doxorubicin) and cisplatin

CTCAE, common terminology criteria for adverse events

R0 and R1 resection, free margins and microscopic rest after resection respectively

P P P P M M M M M R R M M M M M M M M M R M M M


Comprehensive Review and Comparison for Anticancer Peptides Identification Models.

Abstract: Anticancer peptides (ACPs) eliminate pathogenic bacteria and kill tumor cells, showing no hemolysis and no damages to normal human cells. This unique ability explores the possibility of ACPs as therapeutic delivery and its potential applications in clinical therapy. Identifying ACPs is one of the most fundamental and central problems in new antitumor drug research. During the past decades, a number of machine learning-based prediction tools have been developed to solve this important task. However, the predictions produced by various tools are difficult to quantify and compare. Therefore, in this article, we provide a comprehensive review of existing machine learning methods for ACPs prediction and fair comparison of the predictors. To evaluate current prediction tools, we conducted a comparative study and analyzed the existing ACPs predictor from 10 public literatures. The comparative results obtained suggest that Support Vector Machine-based model with features combination provided significant improvement in the overall performance, when compared to the other machine learning method-based prediction models.

Song|Xiao|X| Zhuang|Yuanying|Y| Lan|Yihua|Y| Lin|Yinglai|Y| Min|Xiaoping|X|

anticancer peptides
machine learning
feature representation


Implementation of GlycanBuilder to draw a wide variety of ambiguous glycans.

Abstract: GlyTouCan version 1.0 was released in 2015 as the international glycan structure repository, and a new sequence format called WURCS (Web3 Unique Representation of Carbohydrate Structures) was proposed during the early stages of the GlyTouCan project. GlyTouCan uses WURCS as its base representation for glycans because existing formats were insufficient in their flexibility to represent any and all glycans universally. Therefore, in order to obtain WURCS strings for existing or new glycan structures, conversion tools or glycan structure editors that can export WURCS became necessary. GlycanBuilder was an obvious choice to extend due to its wide usage by the community. However, GlycanBuilder was limited because it was originally developed to support mammalian glycans. It also did not support the newly proposed monosaccharide symbol standard called Symbol Nomenclature for Glycans (SNFG). Therefore in this work, we implemented a new version of GlycanBuilder to greatly increase its usability. The glycan rendering system was refactored so that cyclic glycans, nested repeating units, monosaccharide compositions and cross-linked glycan structures can be represented. Both import and export utilities for WURCS were also implemented and SNFG symbols were incorporated to allow glycans to be exported as graphics using the latest glycan symbol nomenclature. This new version of GlycanBuilder called "GlycanBuilder2", is able to support a wide variety of ambiguous glycans, including structures containing monosaccharides from bacteria and plants. These glycans can also be displayed using the new SNFG symbols. This tool can aid researchers in communicating about the complex, diverse, and ambiguous structures of glycans more rapidly. Moreover, the new GlycanBuilder can now easily output WURCS sequences from glycans drawn on the canvas. Most importantly, because GlyTouCan employs WURCS as the basic format for registration and searching of glycan information, a wider variety of glycans can now be readily registered and queried in GlyTouCan.

Tsuchiya|Shinichiro|S|
Aoki|Nobuyuki P|NP|
Shinmachi|Daisuke|D|
Matsubara|Masaaki|M|
Yamada|Issaku|I|
Aoki-Kinoshita|Kiyoko F|KF|
Narimatsu|Hisashi|H|

Glycan sequence format
Glycan visualization
Glyco bioinformatics
Sequence conversion
Symbolic notation