Mutations in KRT10 in epidermolytic acanthoma.

Abstract:
BACKGROUND
Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA.

METHODS
Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis.

RESULTS
DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10.

CONCLUSIONS
Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.

mutations
KRT10
epidermolytic acanthoma
whole-exome sequencing
keratin 10


Superstable Wet Foams and Lightweight Solid Composites from Nanocellulose and Hydrophobic Particles.

Abstract: Colloids are suitable options to replace surfactants in the formation of multiphase systems while simultaneously achieving performance benefits. We introduce synergetic combination of colloids for the interfacial stabilization of complex fluids that can be converted into lightweight materials. The strong interactions between high aspect ratio and hydrophilic fibrillated cellulose (CNF) with low aspect ratio hydrophobic particles afford superstable Pickering foams. The foams were used as a scaffolding precursor of porous, solid materials. Compared to foams stabilized by the hydrophobic particles alone, the introduction of CNF significantly increased the foamability (by up to 350%) and foam lifetime. These effects are ascribed to the fibrillar network formed by CNF. The CNF solid fraction regulated the interparticle interactions in the wet foam, delaying or preventing drainage, coarsening, and bubble coalescence. Upon drying, such a complex fluid was transformed into lightweight and strong architectures, which displayed properties that depended on the surface energy of the CNF precursor. We show that CNF combined with hydrophobic particles universally forms superstable complex fluids that can be used as a processing route to synthesize strong composites and lightweight structures.

nanocellulose
multiphase
stabilization
colloidal foams
interfacial interactions
nanofibril
particle-stabilized foams


Histamine may contribute to vortioxetine's procognitive effects; possibly through an orexigenic mechanism.

Abstract: Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine's effect on cognitive function likely involves the modulation of several neurotransmitter systems. Acute and chronic administration of vortioxetine resulted in changes in histamine concentrations in microdialysates collected from the rat prefrontal cortex and ventral hippocampus. Based on these results and a literature review of the current understanding of the interaction between the histaminergic and serotonergic systems and the role of histamine on cognitive function, we hypothesize that vortioxetine through an activation of the orexinergic system stimulates the tuberomammilary nucleus and enhances histaminergic neurotransmission, which contributes to vortioxetine's positive effects on cognitive function.

Smagin|Gennady N|GN|
Song|Dekun|D|
Budac|David P|DP|
Waller|Jessica A|JA|
Li|Yan|Y|
Pehrson|Alan L|AL|
Sánchez|Connie|C|

Histamine
Antidepressant
Cognition
5-HT receptors


Magnitude of Nonalcoholic Fatty Liver Disease: Eastern Perspective.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide, affecting a quarter of the global adult population. Nonalcoholic steatohepatitis, the more active form of NAFLD with active hepatic necroinflammation and faster fibrosis progression, has become one of the leading indications for liver transplantation and an important cause of hepatocellular carcinoma in Western countries. Epidemiological studies suggest that NAFLD is almost equally prevalent in Asia as in the West, but severe liver complications appear to be less common. In this article, we review the epidemiology, clinical characteristics, risk factors and clinical outcomes of NAFLD in Asia. We highlight the issue of NAFLD in the nonobese population and discuss whether it is a unique phenomenon in Asia. Because of the rapidly changing epidemiology and natural history, future studies should continue to monitor the magnitude of NAFLD in Asia and define the best policy to control this new epidemic.

Ching-Yeung Yu|Becky|B|
Kwok|Deborah|D|
Wong|Vincent Wai-Sun|VW|

HSD17B13, hydroxysteroid 17-beta dehydrogenase 13

PNPLA3, patatin-like phospholipase domain–containing protein 3


Development of bioactive fish gelatin/chitosan nanoparticles composite films with antimicrobial properties.

Abstract: The objective of this work was to develop active bio-based nanocomposite films from fish gelatin (FG) and chitosan nanoparticles (CSNPs) incorporated with Origanum vulgare L. essential oil (OEO). CSNPs were obtained by ionic gelation of chitosan with sodium tripolyphosphate, which presented a spherical morphology with size range of 40-80nm. Remarkable differences in the surface morphology were observed between the control and bioactive nanocomposite films as revealed by SEM and AFM images. FTIR results confirmed that an interaction between polymer matrix and essential oil had occurred, as shown by an increase in the amplitude of peaks at wavenumbers 1242cm(-1) and 1451cm(-1). Meanwhile, XRD peaks of OEO-containing films were more intense, indicating that the introduction of essential oil into the film matrix induces an increase in crystallinity. TGA analysis demonstrated that the addition of OEO had no impact on thermal stability of the films. Inclusion of OEO in the film matrix resulted in less resistant and more flexible films, with a decrease in water vapor permeability (WVP). The FG/CSNPs bioactive films exhibited distinctive antimicrobial activity against four test food pathogens, namely Staphylococcus aureus, Listeria monocytogenes, Salmonella enteritidis and Escherichia coli.

Hosseini|Seyed Fakhreddin|SF|
Rezaei|Masoud|M|
Zandi|Mojgan|M|
Farahmandghavi|Farhid|F|

Fish gelatin
Chitosan nanoparticles
Antimicrobial properties
Origanum vulgare L. essential oil
Bio-nanocomposite
Bioactive packaging


Genome-Wide Association Study Identifies NBS-LRR-Encoding Genes Related with Anthracnose and Common Bacterial Blight in the Common Bean.

Abstract: Nucleotide-binding site and leucine-rich repeat (NBS-LRR) genes represent the largest and most important disease resistance genes in plants. The genome sequence of the common bean (Phaseolus vulgaris L.) provides valuable data for determining the genomic organization of NBS-LRR genes. However, data on the NBS-LRR genes in the common bean are limited. In total, 178 NBS-LRR-type genes and 145 partial genes (with or without a NBS) located on 11 common bean chromosomes were identified from genome sequences database. Furthermore, 30 NBS-LRR genes were classified into Toll/interleukin-1 receptor (TIR)-NBS-LRR (TNL) types, and 148 NBS-LRR genes were classified into coiled-coil (CC)-NBS-LRR (CNL) types. Moreover, the phylogenetic tree supported the division of these PvNBS genes into two obvious groups, TNL types and CNL types. We also built expression profiles of NBS genes in response to anthracnose and common bacterial blight using qRT-PCR. Finally, we detected nine disease resistance loci for anthracnose (ANT) and seven for common bacterial blight (CBB) using the developed NBS-SSR markers. Among these loci, NSSR24, NSSR73, and NSSR265 may be located at new regions for ANT resistance, while NSSR65 and NSSR260 may be located at new regions for CBB resistance. Furthermore, we validated NSSR24, NSSR65, NSSR73, NSSR260, and NSSR265 using a new natural population. Our results provide useful information regarding the function of the NBS-LRR proteins and will accelerate the functional genomics and evolutionary studies of NBS-LRR genes in food legumes. NBS-SSR markers represent a wide-reaching resource for molecular breeding in the common bean and other food legumes. Collectively, our results should be of broad interest to bean scientists and breeders.

Wu|Jing|J| Zhu|Jifeng|J| Wang|Lanfen|L| Wang|Shumin|S|

association study
anthracnose
common bacterial blight
common bean
NBS-LRR
disease resistance genes


Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ(+) thalassemia with IVS1-5(G→C) mutation.

Abstract:
BACKGROUND
Despite compelling evidence that hydroxyurea is safe and effective in sickle cell disease, it is prescribed sparingly due to several barriers like knowledge gaps in certain genotypes, apprehension about its safety and toxicity, and limited resources. We undertook this study to find out the efficacy and safety of HU in patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation.

PROCEDURE
We registered 318 patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation. Of these, 203 were enrolled for hydroxyurea treatment at a low and fixed dose of 10 mg/kg/day. One hundred four patients (Group-I: 37 children and Group-II: 67 adults) with ≥2 years of hydroxyurea treatment were studied.

RESULTS
The rate of vaso-occlusive crises, requirement of blood transfusion and rate of hospitalization reduced from 3 to 0.5, 1 to 0 and 1 to 0 in Group-I and 3 to 0, 1 to 0 and 0.5 to 0 in Group-II respectively after HU therapy (P < 0.0001). %HbF level, hemoglobin, MCV and MCH increased significantly, whereas HbS, WBC, platelet count, serum-bilirubin and LDH levels decreased significantly after HU therapy. It has been observed that along with fairly subtle hematological changes following HU therapy, there was a substantial clinical improvement occurred in these patients. Transient myelotoxicity was observed in 4.8%. There was minimal gonadal toxicity without affecting reproductive function.

CONCLUSION
In view of easy affordability, better acceptability, minimal toxicity, the need of infrequent monitoring and its potential effectiveness, low and fixed dose of hydroxyurea is suitable for treatment of patients with HbSβ(+) -thalassemia in resource poor setting.

Dehury|Snehadhini|S|
Purohit|Prasanta|P|
Patel|Siris|S|
Meher|Satyabrata|S|
Kullu|Bipin Kishore|BK|
Sahoo|Lulup Kumar|LK|
Patel|Nayan Kumar|NK|
Mohapatra|Alok Kumar|AK|
Das|Kishalaya|K|
Patel|Dilip Kumar|DK|

hydroxyurea
HbF
HbSβ+ thalassemia
fertility
low dose
vaso occlusive crisis (VOC)


Operative versus conservative treatment of proximal rectus femoris avulsions: A systematic review with meta-analysis of clinical outcomes, complications and return to sports.

Abstract:
Prospero registration number
CRD42020198333.

Objective
To compare the surgical and conservative treatment of proximal rectus femoris avulsions regarding clinical outcomes, rate of return to sports and incidence of complications.

Design
Systematic review and meta-analysis.

Data sources
Cochrane, Medline, Scopus and SPORTDiscus.

Eligibility criteria for selecting studies
Studies reporting on outcomes of PRFAs or return to sports were included.

Results
Nine studies consisting of a total eighty-two patients met the inclusion criteria. The mean age was 22.2 years and 75.9% of patients were male. Mean follow-up was 28.9 months and 65% avulsions were managed surgically. The overall outcomes were similar in surgical and conservative treatment group (p = 0.72) with similar incidence of complications (14%). The rate of return to sports was 95% in surgical and 92.7% in the conservative management groups (p = 0.93). Overall, the quality of the methodology of included studies was low, with a mean CMS of 45.6.

Conclusion
Both conservative and operative treatment provide excellent outcomes in proximal rectus femoris avulsions, with similar rates of return to sports and incidence of complications. More prospective and good quality studies are needed to compare surgical techniques and time to return to sports. Avulsions with retraction of more than 20 mm and high demand patients may benefit from surgical treatment. Patients should be counselled accordingly.

Proximal Rectus Femoris Avulsions Outcomes Return Sports


Changing character of rainfall in eastern China, 1951-2007.

Abstract: The topography and continental configuration of East Asia favor the year-round existence of storm tracks that extend thousands of kilometers from China into the northwestern Pacific Ocean, producing zonally elongated patterns of rainfall that we call "frontal rain events." In spring and early summer (known as "Meiyu Season"), frontal rainfall intensifies and shifts northward during a series of stages collectively known as the East Asian summer monsoon. Using a technique called the Frontal Rain Event Detection Algorithm, we create a daily catalog of all frontal rain events in east China during 1951-2007, quantify their attributes, and classify all rainfall on each day as either frontal, resulting from large-scale convergence, or nonfrontal, produced by local buoyancy, topography, or typhoons. Our climatology shows that the East Asian summer monsoon consists of a series of coupled changes in frontal rain event frequency, latitude, and daily accumulation. Furthermore, decadal changes in the amount and distribution of rainfall in east China are overwhelmingly due to changes in frontal rainfall. We attribute the "South Flood-North Drought" pattern observed beginning in the 1980s to changes in the frequency of frontal rain events, while the years 1994-2007 witnessed an uptick in event daily accumulation relative to the rest of the study years. This particular signature may reflect the relative impacts of global warming, aerosol loading, and natural variability on regional rainfall, potentially via shifting the East Asian jet stream.

Day|Jesse A|JA|
Fung|Inez|I|
Liu|Weihan|W|

rainfall
monsoons
East Asian monsoon
Meiyu front
new methods


Maturity-Associated Variations in Resistance Exercise-Induced Hormonal Responses in Young Male Athletes.

Abstract:
PURPOSE
To examine differences in resistance exercise-induced hormonal responses among young athletes according to their maturity levels.

MATERIALS AND METHODS
A total of 12 collegiate and 32 junior high school male athletes were enrolled. The junior high school participants were divided into pre-peak height velocity (PHV) and post-PHV groups, according to their PHV ages. The salivary testosterone, cortisol, and human growth hormone levels were analyzed before (pre), immediately after (post), and at 15 minutes after performing body weight resistance exercise.

RESULTS
The testosterone levels were higher in the collegiate than in the junior high school group (P < .01) and increased after 15 minutes of exercise (P < .01). A significant decrease in the cortisol levels postexercise in the junior high school groups (P < .01) and an increase in the human growth hormone levels at 15 minutes after exercise in the post-PHV group were observed (P < .01). In the collegiate and post-PHV groups, the testosterone-to-cortisol ratio increased post and at 15 minutes after exercise (P < .01). The testosterone-to-cortisol ratio values were higher in the collegiate than in the post-PHV (at preexercise and at 15 min after [P < .01]) and pre-PHV groups (at all times [P < .01]).

CONCLUSION
Exercise-induced acute hormonal responses to resistance exercise may depend on individuals' maturity levels, even in those having the same age.

hormone
adolescent
biological maturity
training


Parents' Insights into Pediatric Oncology Phase I Clinical Trials: Experiences from Their Child's Participation.

Abstract:
OBJECTIVES
Phase 1 clinical trials are essential in the development of novel therapies for childhood cancers. Children with cancer can participate in phase 1 clinical trials when no known curative therapy remains. Understanding the experiences of children and their families in these clinical trials can help ensure that participation supports the children's and parents' well-being. This article explores the specific aspects of pediatric oncology phase 1 trials that parents found particularly challenging.

DATA SOURCES
This qualitative, empirical phenomenology study considered 11 parents' experiences during the time their child with cancer participated in a phase 1 clinical trial. The primary study results were previously reported. This article reports parents' insights into the processes and procedures that occurred as part of participation in a pediatric oncology phase 1 trial.

CONCLUSION
Parents' experiences during the phase 1 clinical trials were primarily positive. However, data analysis revealed five aspects of these trials that were challenging for families: learning about clinical trials, being referred to another institution, research-only procedures, adhering to trial requirements, and oral medications.

IMPLICATIONS FOR NURSING PRACTICE
Although experiences during phase 1 clinical trials were positive overall, opportunities to enhance children's and parents' experiences warrant attention. Enhancing the education provided to families during recruitment and minimizing the logistical burdens associated with trial requirements through care coordination may alleviate challenges experienced by children and parents.

Crane|Stacey|S|
Croop|James M|JM|
Lee|Jill|J|
Walski|Jamie|J|
Haase|Joan|J|

Parents
Child
Phase 1 clinical trials
Cancer
Phenomenology
Research participation


Reduced E-Cadherin expression is a prognostic biomarker of non-small cell lung cancer: a meta-analysis based on 2395 subjects.

Abstract:
OBJECTIVE
Previous studies related to the prognostic value of E-Cadherin expression on non-small cell lung cancer (NSCLC) were inconsistent. The present study aimed to evaluate the relation between E-Cadherin expression and the prognosis of NSCLC.

METHODS
We performed a meta-analysis based on 14 studies including 2395 NSCLC patients. Literature retrieval, data extraction, and meta-analyses were performed according to the Revman 5.0 guidelines. We utilized the fixed-effect model to pool the HR according to the test of heterogeneity in the meta-analysis.

RESULTS
A total of 14 eligible studies including 2395 NSCLC patients were analyzed. In total, 51.2% of the patients were considered as having reduced expression of E-Cadherin according to the authors' cutoff. The pooled hazard ratio (HR) of reduced expression of E-Cadherin for overall survival (OS) was 1.19 (95% CI: 1.01 to 1.40, P=0.04), showing a worse survival when E-Cadherin expression is decreased.

CONCLUSION
Patients with reduced expression of E-cadherin have a poorer OS compared with those with normal or high expression of E-cadherin.

Yan|Bo|B| Zhang|Wei|W| Jiang|Li-Yan|LY| Qin|Wen-Xin|WX| Wang|Xin|X|

E-cadherin
non-small cell lung cancer
prognosis


Super-resolution Localization and Defocused Fluorescence Microscopy on Resonantly Coupled Single-Molecule, Single-Nanorod Hybrids.

Abstract: Optical antennas made of metallic nanostructures dramatically enhance single-molecule fluorescence to boost the detection sensitivity. Moreover, emission properties detected at the optical far field are dictated by the antenna. Here we study the emission from molecule-antenna hybrids by means of super-resolution localization and defocused imaging. Whereas gold nanorods make single-crystal violet molecules in the tip's vicinity visible in fluorescence, super-resolution localization on the enhanced molecular fluorescence reveals geometrical centers of the nanorod antenna instead. Furthermore, emission angular distributions of dyes linked to the nanorod surface resemble that of nanorods in defocused imaging. The experimental observations are consistent with numerical calculations using the finite-difference time-domain method.

Su|Liang|L| Yuan|Haifeng|H| Lu|Gang|G| Rocha|Susana|S| Orrit|Michel|M| Hofkens|Johan|J| Uji-i|Hiroshi|H|

super-resolution localization
optical antennas
defocused imaging
gold nanorods
plasmon-enhanced fluorescence
single molecules


Grouped sparse Bayesian learning for voxel selection in multivoxel pattern analysis of fMRI data.

Abstract: Multivoxel pattern analysis (MVPA) methods have been widely applied in recent years to classify human brain states in functional magnetic resonance imaging (fMRI) data analysis. Voxel selection plays an important role in MVPA studies not only because it can improve decoding accuracy but also because it is useful for understanding brain functions. There are many voxel selection methods that have been proposed in fMRI literature. However, most of these methods either overlook the structure information of fMRI data or require additional cross-validation procedures to determine the hyperparameters of the models. In the present work, we proposed a voxel selection method for binary brain decoding called group sparse Bayesian logistic regression (GSBLR). This method utilizes the group sparse property of fMRI data by using a grouped automatic relevance determination (GARD) as a prior for model parameters. All the parameters in the GSBLR can be estimated automatically, thereby avoiding additional cross-validation. Experimental results based on two publicly available fMRI datasets and simulated datasets demonstrate that GSBLR achieved better classification accuracies and yielded more stable solutions than several state-of-the-art methods.

Wen|Zhenfu|Z| Yu|Tianyou|T| Yu|Zhuliang|Z| Li|Yuanqing|Y|

Sparse Bayesian learning
Voxel selection
Multivoxel pattern analysis (MVPA)
Automatic relevance determination (ARD)


Using unmanned aerial vehicle (UAV) surveys and image analysis in the study of large surface-associated marine species: a case study on reef sharks Carcharhinus melanopterus shoaling behaviour.

Abstract: A novel image analysis-based technique applied to unmanned aerial vehicle (UAV) survey data is described to detect and locate individual free-ranging sharks within aggregations. The method allows rapid collection of data and quantification of fine-scale swimming and collective patterns of sharks. We demonstrate the usefulness of this technique in a small-scale case study exploring the shoaling tendencies of blacktip reef sharks Carcharhinus melanopterus in a large lagoon within Moorea, French Polynesia. Using our approach, we found that C. melanopterus displayed increased alignment with shoal companions when distributed over a sandflat where they are regularly fed for ecotourism purposes as compared with when they shoaled in a deeper adjacent channel. Our case study highlights the potential of a relatively low-cost method that combines UAV survey data and image analysis to detect differences in shoaling patterns of free-ranging sharks in shallow habitats. This approach offers an alternative to current techniques commonly used in controlled settings that require time-consuming post-processing effort.

Rieucau|Guillaume|G|
Kiszka|Jeremy J|JJ|
Castillo|Jose Carlos|JC|
Mourier|Johann|J|
Boswell|Kevin M|KM|
Heithaus|Michael R|MR|

UAV
image analysis
Carcharhinus melanopterus
shoaling behaviour
blacktip reef shark


Short communication: Variability in milk urea nitrogen and dairy total mixed ration composition in the northeastern United States.

Abstract: The main objective of this survey was to examine variability in milk urea nitrogen (MUN) for Dairy Herd Improvement Association (DHIA) herds in the northeastern United States (the Northeast), examine trends in dairy cow diet composition, and determine potential relationships for MUN and diet composition. Trends in milk fat and protein concentrations, milk yield, days in milk on test day, and lactation number of the cows were also evaluated. The data set for the survey included 10,839,461 DHIA dairy cow records from 2004 to 2015 for 13 states (CT, DE, MA, MD, ME, NH, NJ, NY, PA, RI, VA, VT, and WV) and was retrieved from Dairy Records Management Systems (Raleigh, NC). Average (across states and years) milk yield, milk fat, and milk protein were 31.6 ± 0.24 kg/d, 3.85 ± 0.021%, and 3.13 ± 0.013%, respectively. No obvious trends were observed for milk fat or protein content, but milk yield steadily increased during the survey period. Milk urea N concentration averaged 13.3 ± 0.13 mg/dL, with no obvious or consistent trends. Examination of variability in dairy feed cost and all milk price for the Northeast indicated that high MUN generally coincided with high feed cost and high milk price. For the diet composition survey, 9,707 records of total mixed ration (TMR) analyses, unrelated to the milk composition data set, from the Cumberland Valley Analytical Service (Maugansville, MD) database were examined. Concentration of TMR crude protein (CP) decreased from 17.1% in 2007 to 16.4% in 2015, but there was not an obvious trend in soluble protein concentration. Concentration of TMR neutral detergent fiber (NDF) and 24-h in vitro NDF degradability declined steadily during the survey period and was accompanied by a steady increase in TMR starch concentration. Examination of these unrelated data sets revealed lack of correlation between MUN and diet chemical composition. Thus, we conclude that individual cow MUN in Northeast dairy herds fluctuated between 2004 and 2015. It appeared that MUN followed variability in feed cost; however, ration feed ingredient data were not available to better define the reasons for the variations in MUN.

Hristov|A N|AN|
Harper|M|M|
Oh|J|J|
Giallongo|F|F|
Lopes|J C|JC|
Cudoc|G|G|
Clay|J|J|
Ward|R|R|
Chase|L E|LE|

D000824:Animal Nutritional Physiological Phenomena

milk urea nitrogen
northeastern United States
dairy cow
diet composition


Investigation of design space for freeze-drying injectable ibuprofen using response surface methodology.

Abstract: This study explores the use of a statistical model to build a design space for freeze-drying two formulations with ibuprofen. A 2 × 3 factorial experimental design was used to evaluate independent variables (filling volume and annealing time) and responses as residual moisture content, specific surface area and reconstitution time. A statistical model and response surface plots were generated to define the interactions among the selected variables. The models constructed for both formulations suggest that 1 mL of filled volume and no annealing should be used to achieve optimal residual moisture content, specific surface area and reconstitution time. The proposed models were validated with additional experiments, in which the responses observed were mainly in close agreement with the predicted ones. Additionally, the established models demonstrate the reliability of the evaluation procedure in predicting the selected responses.

Preskar|Maja|M| Videc|Danijel|D| Vrečer|Franc|F| Gašperlin|Mirjana|M|

design space
ibuprofen
lyophilization
response surface method


Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations.

Abstract:
OBJECTIVE
Approximately 10%-15% patients with epidermal growth factor receptor (EGFR) mutations harbor non-classical mutations. However, the effects of EGFR-tyrosine kinases (TKIs), particularly second-generation EGFR-TKI (afatinib) compared to first-generation EGFR-TKIs (gefitinib/erlotinib), in patients with non-classical EGFR mutations remain unknown.

METHODS
We conducted this retrospective study at the China Medical University Hospital (Taichung, Taiwan) from June 2011 to July 2016. Specimens from 1632 patients were tested for EGFR mutations. We surveyed the effectiveness of afatinib and gefitinib/erlotinib in stage IIIb-IV lung adenocarcinoma patients with non-classical EGFR mutations.

RESULTS
Fifty-six patients with advanced-stage (stage IIIB-IV) lung adenocarcinoma with non-classical mutations and receiving EGFR-TKI treatment had completed follow-up and were further analyzed. Afatinib versus gefitinib/erlotinib showed that the objective response rates were 62.5% versus 50.0% (p=0.35). Median progression-free survival (PFS) of 11.0 versus 3.6 months (p=0.03), respectively, was observed for the 51 non-classical EGFR mutated (excluding 5 patients with exon 20 insertions) lung adenocarcinomas. Subset analysis showed that PFS curves of afatinib were more easily distinguished in non-classical EGFR mutations lacking a combination with a classical mutation (non-classical with classical complex mutations group: median PFS, 11.0 versus 8.2 months, p=0.19; non-classical mutation alone or in combination with other non-classical mutations group: median PFS, 18.3 versus 2.8 months, p=0.07).

CONCLUSIONS
Afatinib may be a first-choice EGFR-TKI for patients with advanced-stage lung adenocarcinomas harboring non-classical mutations.

Shen|Yi-Cheng|YC| Tseng|Guan-Chin|GC| Tu|Chih-Yeh|CY| Chen|Wei-Chun|WC| Liao|Wei-Chih|WC| Chen|Wei-Cheng|WC| Li|Chia-Hsiang|CH| Chen|Hung-Jen|HJ| Hsia|Te-Chun|TC|

D000971:Antineoplastic Combined Chemotherapy Protocols

Afatinib
Gefitinib
Erlotinib
Lung adenocarcinoma
EGFR
Non-classical EGFR mutation


Variable echo time imaging for detecting the short T2* components of the sciatic nerve: a validation study.

Abstract:
OBJECTIVE
The aim of this study was to develop and validate an MRI protocol based on a variable echo time (vTE) sensitive to the short T2* components of the sciatic nerve.

MATERIALS AND METHODS
15 healthy subjects (M/F: 9/6; age: 21-62) were scanned at 3T targeting the sciatic nerve at the thigh bilaterally, using a dual echo variable echo time (vTE) sequence (based on a spoiled gradient echo acquisition) with echo times of 0.98/5.37 ms. Apparent T2* (aT2*) values of the sciatic nerves were calculated with a mono-exponential fit and used for data comparison.

RESULTS
There were no significant differences in aT2* related to side, sex, age, and BMI, even though small differences for side were reported. Good-to-excellent repeatability and reproducibility were found for geometry of ROIs (Dice indices: intra-rater 0.68-0.7; inter-rater 0.70-0.72) and the related aT2* measures (intra-inter reader ICC 0.95-0.97; 0.66-0.85) from two different operators. Side-related signal-to-noise-ratio non-significant differences were reported, while contrast-to-noise-ratio measures were excellent both for side and echo.

DISCUSSION
Our study introduces a novel MR sequence sensitive to the short T2* components of the sciatic nerve and may be used for the study of peripheral nerve disorders.

Validation study
Peripheral nerves
Fibrosis
Magnetic resonance imaging


Sex-specific effects of heme oxygenase-2 deficiency on renovascular hypertension.

Abstract:
BACKGROUND
Heme oxygenase-2 (HO-2) is the main isoform responsible for the breakdown of heme and release of carbon monoxide in the vasculature. Vascular-derived carbon monoxide protects against excessive vasoconstriction due to agents such as angiotensin II (Ang II) and in states of deficiency of nitric oxide. The current study was designed to determine the role of HO-2 in the development of renovascular hypertension using HO-2 knockout mice.

METHODS
Polyurethane cuffs were placed around the left renal artery of male and female HO-2 wild-type (WT), heterozygous (HET), and knockout (KO) mice between 16 and 24 weeks of age to induce renovascular hypertension. After 3 weeks, blood pressure was measured for 5 days, after which time both clipped and unclipped kidneys were harvested.

RESULTS
No differences were observed in the blood pressure of sham mice between the different genotypes of both sexes. Cuffing of the left renal artery resulted in a significant increase in blood pressure in all genotypes of both sexes. In male mice, the increase in blood pressure was significantly greater in HET and KO mice as compared to WT mice (P < .05). This effect was not observed in female mice. Renovascular hypertension resulted in a significant increase (P < .05) in cardiac hypertrophy in male mice, which was not different between the genotypes. In female mice, HET and KO mice exhibited significantly greater (P < .05) cardiac hypertrophy as compared with WT mice.

CONCLUSION
These results demonstrate a sex-specific effect of HO-2 deficiency on the development of renovascular hypertension and its effects on the heart in response to the increase in blood pressure.

Stout|Jacob M|JM|
Gousset|Monette U|MU|
Drummond|Heather A|HA|
Gray|Will|W|
Pruett|Brandon E|BE|
Stec|David E|DE|

carbon monoxide
Angiotensin II
blood pressure
bilirubin
renin


The Effect of Heavy Ion Irradiation on the Forward Dissolution Rate of Borosilicate Glasses Studied in Situ and Real Time by Fluid-Cell Raman Spectroscopy.

Abstract: Borosilicate glasses are the favored material for immobilization of high-level nuclear waste (HLW) from the reprocessing of spent fuel used in nuclear power plants. To assess the long-term stability of nuclear waste glasses, it is crucial to understand how self-irradiation affects the structural state of the glass and influences its dissolution behavior. In this study, we focus on the effect of heavy ion irradiation on the forward dissolution rate of a non-radioactive ternary borosilicate glass. To create extended radiation defects, the glass was subjected to heavy ion irradiation using 197Au ions that penetrated ~50 µm deep into the glass. The structural damage was characterized by Raman spectroscopy, revealing a significant depolymerization of the silicate and borate network in the irradiated glass and a reduction of the average boron coordination number. Real time, in situ fluid-cell Raman spectroscopic corrosion experiments were performed with the irradiated glass in a silica-undersaturated, 0.5 M NaHCO3 solution at temperatures between 80 and 85 °C (initial pH = 7.1). The time- and space-resolved in situ Raman data revealed a 3.7 ± 0.5 times increased forward dissolution rate for the irradiated glass compared to the non-irradiated glass, demonstrating a significant impact of irradiation-induced structural damage on the dissolution kinetics.

Lönartz|Mara Iris|MI|
Dohmen|Lars|L|
Lenting|Christoph|C|
Trautmann|Christina|C|
Lang|Maik|M|
Geisler|Thorsten|T|

heavy ion irradiation
forward dissolution rate
borosilicate glass corrosion
in situ fluid-cell Raman spectroscopy


N staging: the role of the pathologist.

Abstract: Gastric cancer is the second cause of cancer-related mortality worldwide. Metastases, including lymph nodes ones, heavily influence the prognosis of this disease. The pathological detection of positive lymph nodes is pivotal for an optimal prognostication and clinical management of affected individuals. Several factors influence the pathological investigation of surgical specimens, ultimately affecting the number of retrieved lymph nodes and, with it, the reliability of N staging. The pathologist plays a central role in optimizing this process. Factors influencing lymph node retrieval and analysis will be herein reviewed, together with the procedures adopted for an optimal pathological analysis of lymph nodes in gastric cancer.

De Marco|Costanza|C|
Biondi|Alberto|A|
Ricci|Riccardo|R|

Lymph nodes
lymphatic metastasis
neoplasm staging
stomach neoplasms


Glutathione-Priming Nanoreactors Enable Fluorophore Core/Shell Transition for Precision Cancer Imaging.

Abstract: In an attempt to develop an imaging probe with ultra-high sensitivity for a broad range of tumors in vivo and inspired by the concept of chemical synthetic nanoreactors, we designed a type of glutathione-priming fluorescent nanoreactor (GPN) with an albumin-coating shell and hydrophobic polymer core containing disulfide bonds, protonatable blocks, and indocyanine green (ICG), a near-infrared fluorophore. The albumin played multiple roles including biocompatible carriers, hydrophilic stabilizer, "receptor" of the fluorophores, and even targeting molecules. The protonation of the hydrophobic core triggered the outside-to-core transport of acidic glutathione (GSH), as well as the core-to-shell transference of ICGs after the disulfide bond cleavage by GSH, which induced strong binding of fluorophores with albumins on the GPN shell, initiating intensive fluorescence signals. As a result, the GPNs demonstrated extremely high response sensitivity and imaging contrast, proper time window, and broad cancer specificity. In fact, an orthogonal activation pattern was found in vitro with an ON/OFF ratio up to 24.7-fold. Furthermore, the nanoprobes specifically amplified the tumor signals in five cancer-bearing mouse models and actualized tumor margin delineation with a contrast up to 20-fold, demonstrating much better imaging efficacy than the other four commercially available probes. Therefore, the GPNs provide a new paradigm in developing high-performance bioresponsive nanoprobes.

nanoreactors
core/shell transition
glutathione
bioresponsive
precision imaging


Poloxamer 407 Based Gel Formulations for Transungual Delivery of Hydrophobic Drugs: Selection and Optimization of Potential Additives.

Abstract: The current study aimed to develop poloxamer 407 (P407) gel for transungual delivery of antifungal hydrophobic drugs with sufficient gel strength and drug loading. Gel strength and drug loading of P407 gel was improved by use of functional additives. Hydration enhancement effect was used to select optimum nail penetration enhancer. Face-centered central composite design (FCCCD) was used to observe the effect of the selected penetration enhancer (thioglycolic acid (TGA)) and cosolvent (ethanol) on gelation behavior to develop formulation with enough loading of hydrophobic drug, i.e., terbinafine HCl (TBN), and its permeation across the nail plate without compromising on gel strength. It was observed that increasing concentration of P407 and TGA significantly reduced gelation temperature and enhanced the gel strength of P407 gel and can be used to improve P407 gel strength. Under the scanning electron microscope, the significant effect of TGA as an ungual penetration enhancer was observed on the morphology of the nail plate. Optimized P407 gel prepared with modified cold method showed a gelation temperature of 8.7 ± 0.16 °C, gel strength of 122 ± 7.5 s and drug loading of 1.2% w/w, which was four times more than the drug loading in the gels prepared with conventional cold method. Rheological behavior was pseudoplastic with 47.75 ± 3.48% of gel erosion after 12 washings and 67.21 ± 2.16% of drug release after 12 h. A cumulative amount of TBN permeated from P407 gel with and without PE after 24 h was 27.30 ± 4.18 and 16.69 ± 2.31 µg/cm2, respectively. Thioglycolic acid can be used as a nail penetration enhancer without the chemical modification or addition of extra additives while retaining the gel strength. Water miscible cosolvents with moderate evaporability such as ethanol, can be incorporated to P407 gel by minor modification in method of preparation to load the required dose of hydrophobic drugs. Developed P407 gel formulation with sufficient gel strength and drug loading will be a promising carrier for transungual delivery of hydrophobic antifungal agents.

Terbinafine
ungual penetration enhancer
hydrogel
onychomycosis
poloxamer 407 gel
poloxamer 407 polymer
transungual drug delivery


Preparation and characterization of 3D printed PLA microneedle arrays for prolonged transdermal drug delivery of estradiol valerate.

Abstract: Biodegradable polymeric microneedle arrays (BPMNAs) could be explored as potential devices for transdermal drug delivery, which can provide a painless and safe drug delivery method. BPMNAs could also provide high drug-loading capacity and prolonged drug delivery once integrated with a drug reservoir. However, the fabrication of MNAs with a drug reservoir is expensive and requires complicated procedures. The present study was conducted to describe the preparation of a reservoir-based BPMNA containing estradiol valerate using polylactic acid (PLA) with the combination of FDM 3D printing and injection volume filling techniques. The tip size of the 3D printed needles decreased to 173 μm utilizing a chemical etching process. The content of estradiol valerate loaded in the 3D printed PLA MNAs was 29.79 ± 0.03 mg, and the release was in a prolonged manner for up to 7 days. The results of mechanical tests revealed that the force needed for the 3D printed PLA MNAs fracture (900 N) was significantly higher than that needed for their skin penetration (4 N). The successful penetration of 3D printed PLA MNAs through the stratum corneum was confirmed via penetration test, methylene blue staining, and histological examination. The results showed that 3D printed PLA MNAs can penetrate into the skin without reaching to the dermal nerves and puncture of blood vessels. In conclusion, in the current study, we explored the practicability of the preparation of drug loaded reservoir-based BPMNAs using the combination of FDM 3D printing and injection volume filling techniques for painless and prolonged transdermal drug delivery.

Khosraviboroujeni|Afsoun|A|
Mirdamadian|Seyedeh Zahra|SZ|
Minaiyan|Mohsen|M|
Taheri|Azade|A|

Microneedle array
Prolonged drug delivery
FDM 3D printing
Injection volume filling
Etching


Anti-diabetic effects of astaxanthin on an STZ-induced diabetic model in rats.

Abstract: Type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance and relative insulin insufficiency, has become the most common chronic metabolic disease threatening global health. The preferred therapies for T2DM include lifestyle interventions and the use of anti-diabetic drugs. However, considering their adverse reactions, it is important to find a low-toxicity and effective functional food or drug for diabetes prevention and treatment. Astaxanthin is a potent antioxidant carotenoid found in marine organisms has been reported to prevent diet-induced insulin resistance and hepatic steatosis. To investigate the anti-diabetic effects of astaxanthin, male Wistar rats were fed a high-energy diet for 4 weeks, followed by a low dose streptozotocin (STZ) injection to induce the diabetes model, and the rats were then fed an astaxanthin-containing diet for another 3 weeks. Astaxanthin significantly decreased blood glucose and total cholesterol (TC) levels, and increased blood levels of high density lipoprotein cholesterol (HDL-C) in STZ-induced diabetic rats in a dose dependent manner. These results were associated with increased expression of insulin sensitivity related genes (adiponectin, adipoR1, and adipoR2) in vivo, thereby attenuating STZ-induced diabetes. In addition, we also compared the anti-diabetic effects of astaxanthin and monacolin K, which has been reported to downregulate hyperlipidemia and hyperglycemia. The results revealed that astaxanthin and monacolin K showed similar anti-diabetic effects in STZ-induced diabetic rats. Therefore, astaxanthin may be developed as an anti-diabetic agent in the future.

Zhuge|Fen|F| Ni|Yinhua|Y| Wan|Chunyan|C| Liu|Fen|F| Fu|Zhengwei|Z|

Astaxanthin
Diabetes
Insulin sensitivity


Effect of Kayak Ergometer Elastic Tension on Upper Limb EMG Activity and 3D Kinematics.

Abstract: Despite the prevalence of shoulder injury in kayakers, limited published research examining associated upper limb kinematics and recruitment patterns exists. Altered muscle recruitment patterns on-ergometer vs. on-water kayaking were recently reported, however, mechanisms underlying changes remain to be elucidated. The current study assessed the effect of ergometer recoil tension on upper limb recruitment and kinematics during the kayak stroke. Male kayakers (n = 10) performed 4 by 1 min on-ergometer exercise bouts at 85%VO2max at varying elastic recoil tension; EMG, stroke force and three-dimensional 3D kinematic data were recorded. While stationary recoil forces significantly increased across investigated tensions (125% increase, p < 0.001), no significant differences were detected in assessed force variables during the stroke cycle. In contrast, increasing tension induced significantly higher Anterior Deltoid (AD) activity in the latter stages (70 to 90%) of the cycle (p < 0.05). No significant differences were observed across tension levels for Triceps Brachii or Latissimus Dorsi. Kinematic analysis revealed that overhead arm movements accounted for 39 ± 16% of the cycle. Elbow angle at stroke cycle onset was 144 ± 10°; maximal elbow angle (151 ± 7°) occurred at 78 ± 10% into the cycle. All kinematic markers moved to a more anterior position as tension increased. No significant change in wrist marker elevation was observed, while elbow and shoulder marker elevations significantly increased across tension levels (p < 0.05). In conclusion, data suggested that kayakers maintained normal upper limb kinematics via additional AD recruitment despite ergometer induced recoil forces. Key pointsKayak ergometer elastic tension significantly alters Anterior Deltoid recruitment patterns.Kayakers maintain optimal arm kinematics despite changing external forces via altered shoulder muscle recruitment.Overhead arm movements account for a high proportion of the kayak stroke cycle.

Kayaking
3D joint kinematics
electromyography
ergometry
shoulder.


Nanometer scale insight on the analysis of limpets mineralized teeth: Special focus on the silica-containing regions.

Abstract: We report the electron microscopy-based analysis of the major lateral tooth of the limpet Colisella subrugosa during early and intermediate stages of development. We aimed to analyze the structural relationship among the needle-like crystals of the iron oxide goethite, the amorphous silica phase that forms the tooth base and occupy inter-crystalline spaces in the cusp, and the chitin fibers of the matrix. Goethite crystals followed the three dimensional organization pattern of the chitin fibers in the cusp. In the tooth base, spherical individual silica granules were found in regions where the chitin fibers cross. The spherical granules near the interface between the tooth base and the cusp (junction zone) formed an almost continuous medium that could easily be ultrathin-sectioned for further analysis. By contrast, the nearby silica-rich region localized on the other side of the junction zone contained needle-like goethite crystals immersed in the matrix and presented a conchoidal fracture. The chitin fibers from the silica granules of the tooth base were dotted or undulating in projection with a periodicity of about 6 nm when observed by high magnification transmission electron microscopy. Very thin goethite crystals were present in the base of the cusp near the junction zone surrounded by silica. On several occasions, crystals presented internal thin straight white lines parallel to the major axis, indicating a possible growth around fibers. We propose that silica and iron oxide phases mineralization may occur simultaneously at least for some period and that silica moderates the dimensions of the iron oxide crystals.

Farina|Marcos|M|
Werckmann|Jacques|J|
Campos|Andrea P C|APC|
Mendoza|Martin E|ME|
Wendt|Camila|C|
Almeida|Fernando P|FP|
Rougerie|Pablo|P|
Rossi|André|A|
Bouillet|Corinne|C|
Ersen|Ovidiu|O|

Goethite
Silica
Analytical electron microscopy
Biominerals
Limpet tooth
Mineralized tissue
Radular teeth


Salivary proteome of a Neotropical primate: potential roles in host defense and oral food perception.

Abstract:
Background
Saliva contains a very complex mixture of proteins for defense against microbiological pathogens and for oral food perception. Howler monkeys are Neotropical primates that can consume a mostly leaf diet. They are well known to thrive in highly disturbed habitats where they may cope with a diversity of dietary challenges and infection risks. We aimed to describe the salivary proteome of howlers to contribute to better understanding of their physiology.

Methods
We analyzed the salivary proteins of wild black howler monkeys (Alouatta pigra), by SDS-PAGE-1-D and Nano LC-MS/MS and categorized them by their function involved in host defense and oral food perception.

Results
Our proteomic analysis identified 156 proteins in howler saliva including a number of host defense peptides that are the first line of defense in mammals, such as defensin, cathelicidin, dermcidin, and lactotransferrin, and proteins with anti-bacterial, anti-fungal, and anti-viral capacity, such as IgA, IgG, IgM, BPI, salivary heat shock 70 kDa protein, beta-2-microbulin, and protein S-100. We also identified key proteins necessary for taste perception, including salivary carbonic anhydrase VI, cystatin D, IgA, and fatty acid-binding protein. Proteins to detect astringent foods were identifying, including four members of cystatins (A, B, C and D), lactoperoxidase, and histidine-rich proteins. No chitinase and amylase were identified as would be expected because howlers do not eat insects and little starch. These findings provide basic information to future studies in oral biology, ingestive physiology, and physiological ecology of mammals and non-human primates.

Espinosa-Gómez|Fabiola Carolina|FC|
Ruíz-May|Eliel|E|
Serio-Silva|Juan Carlos|JC|
Chapman|Colin A|CA|

Salivary proteome
Primates
Saliva
Howler monkeys
Host-defense


Features of complement activation-related pseudoallergy to liposomes with different surface charge and PEGylation: comparison of the porcine and rat responses.

Abstract: Pigs are known to provide a sensitive model for studying complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction to liposomal and many other nanomedicines that limits their clinical use. The utility of rats as a CARPA model has, however, not been analyzed to date in detail. The present study compared the two models by inducing CARPA with i.v. bolus injections of two reactogenic liposomes that differed from each other in surface properties: one was AmBisome, a strong anionic, free-surface small unilamellar liposome (SUV), while the other was neutral, polyethylene glycol (PEG)-grafted SUV wherein the 2 kDa-PEG was anchored to the membrane via cholesterol (Chol-PEG). Both in pigs and rats AmBisome caused significant consumption of C3, indicating C activation, along with paralleling massive changes in blood pressure, white blood cell, platelet counts and in plasma thromboxane B2 levels, indicating CARPA. These processes were similar in the two species in terms of kinetics, but significantly differed in the doses that caused major hemodynamic changes (~0.01 and ~22 mg phospholipid (PL)/kg in pigs and rats, respectively). Pigs responded to AmBisome with pulmonary hypertension and systemic hypotension, and the reaction was not tachyphylactic. The major response of rats was systemic hypotension, leukopenia followed by leukocytosis, and thrombocytopenia. Chol-PEG liposomes caused severe reaction in pigs at 0.1 mg/kg, while the reaction they caused in rats was mild even at 300 mg PL/kg. Importantly, the reaction to Chol-PEG in pigs was partly tachyphylactic. These observations highlight fundamental differences in the immune mechanisms of porcine and rat CARPA, and also show a major impact of liposome surface characteristics, determining the presence or absence of tachyphylaxis. The data suggest that rats are 2-3 orders of magnitude less sensitive to liposomal CARPA than pigs; however, the causes of these differences, the PEG-dependent tachyphylaxis and the massive reactivity of Chol-PEG liposomes remain unclear.

Dézsi|László|L|
Fülöp|Tamás|T|
Mészáros|Tamás|T|
Szénási|Gábor|G|
Urbanics|Rudolf|R|
Vázsonyi|Csenge|C|
Őrfi|Erik|E|
Rosivall|László|L|
Nemes|Réka|R|
Kok|Robbert Jan|RJ|
Metselaar|Josbert M|JM|
Storm|Gert|G|
Szebeni|János|J|

Pseudoallergy
CARPA
Nanomedicines
Adverse drug effects
Anaphylatoxins
Anaphylaxis


Quaternization of Vinyl/Alkynyl Pyridine Enables Ultrafast Cysteine-Selective Protein Modification and Charge Modulation.

Abstract: Quaternized vinyl- and alkynyl-pyridine reagents were shown to react in an ultrafast and selective manner with several cysteine-tagged proteins at near-stoichiometric quantities. We have demonstrated that this method can effectively create a homogenous antibody-drug conjugate that features a precise drug-to-antibody ratio of 2, which was stable in human plasma and retained its specificity towards Her2+ cells. Finally, the developed warhead introduces a +1 charge to the overall net charge of the protein, which enabled us to show that the electrophoretic mobility of the protein may be tuned through the simple attachment of a quaternized vinyl pyridinium reagent at the cysteine residues. We anticipate the generalized use of quaternized vinyl- and alkynyl-pyridine reagents not only for bioconjugation, but also as warheads for covalent inhibition and as tools to profile cysteine reactivity.

protein modification
antibody-drug conjugates
cysteine
bioconjugation
microfluidics


Nanostructured carbon black for simultaneous electrochemical determination of trace lead and cadmium by differential pulse stripping voltammetry.

Abstract: Nanostructured carbon black (CB) was first employed directly in this paper for the simultaneous electrochemical determination of trace Pb(II) and Cd(II) using differential pulse anodic stripping voltammetry. The morphology and surface properties of conductive CB were characterized by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, ultraviolet-visible spectroscopy and Raman spectroscopy. Special pore structures, as well as surface chemical functional groups, endow CB with excellent catalytic and adsorption properties. Some parameters affecting electrical analysis performance were investigated systematically including deposition time and potential, pH value of solution, volume of suspension, amount of Bi(III) and Nafion solution. CB-Nafion-glassy carbon electrode sensor linear response ranges from 6 to 1000 nM for selective and simultaneous determination. The detection limits were calculated to be 8 nM (0.9 µg l-1) for Cd(II) and 5 nM (1.0 µg l-1) for Pb(II) (S/N = 3) for the electrocatalytic determination under optimized conditions. The method was successfully used to the determination of actual samples and good recovery was achieved from different spiked samples. Low detection limits and good stability of the modified electrode demonstrated a promising perspective for the detection of trace metal ions in practical application.

Xie|Ruigang|R|0000-0001-5848-7892 Zhou|Lingli|L| Lan|Cuiling|C| Fan|Fangfang|F| Xie|Ruifeng|R| Tan|Hongyu|H| Xie|Tiansheng|T| Zhao|Lingmin|L|

electrochemical determination
stripping voltammetry
carbon nanomaterials


Synthesis and antiprotozoal activity of nitazoxanide-N-methylbenzimidazole hybrids.

Abstract: A series of a novel hybrid compounds between nitazoxanide and N-methylbenzimidazole were synthesized starting from the corresponding N-methyl-2-nitroanilines. The new hybrid compounds (1-13) were evaluated in vitro against Giardia intestinalis, Entamoeba histolytica, Trichomonas vaginalis. NTZ, MTZ and ABZ were used as drug standards. Experimental evaluations revealed all of the new compounds (1-13) were active and showed strong activity against the three protozoa, particularly with E. histolytica where the IC50 values ranged between 3 and 69 nM. Overall, compounds 2, 5, 7, 8, 9, 11 and 12 stood out with values lower than 87 nM for all three protozoa, comparatively better than the reference drugs.

Soria-Arteche|Olivia|O|
Hernández-Campos|Alicia|A|
Yépez-Mulia|Lilián|L|
Trejo-Soto|Pedro Josué|PJ|
Hernández-Luis|Francisco|F|
Gres-Molina|Jorge|J|
Maldonado|Luis A|LA|
Castillo|Rafael|R|

D000981:Antiprotozoal Agents
D001562:Benzimidazoles
D015195:Drug Design
D004748:Entamoeba histolytica
D056890:Eukaryota
D016829:Giardia lamblia
D009574:Nitro Compounds
D013844:Thiazoles
D014246:Trichomonas vaginalis

Hybrid compounds
Nitazoxanide
Giardia intestinalis
Entamoeba histolytica
Trichomonas vaginalis
Benzimidazole


Importance of microRNAs in Skin Oncogenesis and Their Suitability as Agents and Targets for Topical Therapy.

Abstract: Skin cancer is the most common cancer worldwide, with rapidly increasing incidence and consistent mortality. Skin cancer encompasses melanoma and non-melanoma skin cancer, which in turn is mainly divided into cutaneous squamous cell carcinoma and basal cell carcinoma. Small noncoding micro-RNAs (miRNAs) regulate protein expression after transcription and play a role in the development and progression of skin cancer. Deregulated expression of miRNAs in skin cancer is associated with cell proliferation, angiogenesis, metastasis, apoptosis, immune response, and drug resistance. Specific patterns of miRNAs in specific skin cancer types can be used as diagnostic markers. For therapeutic purposes, both miRNA and chemically modified variants thereof as well as miRNA antagonists (antagomiRs) or RNA inhibitors may be applied topically. Due to their specific physicochemical properties, physical or chemical diffusion promoters are used with varying degrees of success. There is no question by now that such preparations have a high potential for the treatment of epithelial skin tumors in particular.

MicroRNA
Topical therapy
Skin cancer
Therapeutic target


Synthesis and antiviral evaluation of fluorinated acyclo-nucleosides and their phosphoramidates.

Abstract: A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3-tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed.

Mahmoud|Sawsan|S|
Li|Hao|H|
McBrayer|Tamara R|TR|
Bassit|Leda|L|
Hammad|Sherif F|SF|
Coats|Steven J|SJ|
Amblard|Franck|F|
Schinazi|Raymond F|RF|

D000577:Amides
D000818:Animals
D019380:Anti-HIV Agents
D000998:Antiviral Agents
D060326:Chemistry Techniques, Synthetic
D004353:Drug Evaluation, Preclinical
D005461:Fluorine
D056945:Hep G2 Cells
D006515:Hepatitis B virus
D018259:Herpesvirus 1, Human
D006801:Humans
D015394:Molecular Structure
D009705:Nucleosides
D010756:Phosphoric Acids
D014709:Vero Cells
D014779:Virus Replication

Fluorine
phosphoramidates
acyclonucleoside
antiviral agent


NADPH oxidase-generated reactive oxygen species in mature follicles are essential for Drosophila ovulation.

Abstract: Ovarian reactive oxygen species (ROS) are believed to regulate ovulation in mammals, but the details of ROS production in follicles and the role of ROS in ovulation in other species remain underexplored. In Drosophila ovulation, matrix metalloproteinase 2 (MMP2) is required for follicle rupture by degradation of posterior follicle cells surrounding a mature oocyte. We recently demonstrated that MMP2 activation and follicle rupture are regulated by the neuronal hormone octopamine (OA) and the octopamine receptor in mushroom body (OAMB). In the current study, we investigated the role of the superoxide-generating enzyme NADPH oxidase (NOX) in Drosophila ovulation. We report that Nox is highly enriched in mature follicle cells and that Nox knockdown in these cells leads to a reduction in superoxide and to defective ovulation. Similar to MMP2 activation, NOX enzymatic activity is also controlled by the OA/OAMB-Ca2+ signaling pathway. In addition, we report that extracellular superoxide dismutase 3 (SOD3) is required to convert superoxide to hydrogen peroxide, which acts as the key signaling molecule for follicle rupture, independent of MMP2 activation. Given that Nox homologs are expressed in mammalian follicles, the NOX-dependent hydrogen peroxide signaling pathway that we describe could play a conserved role in regulating ovulation in other species.

Li|Wei|W|
Young|Jessica F|JF|
Sun|Jianjun|J|0000-0002-6015-738X

D000818:Animals
D029721:Drosophila Proteins
D004331:Drosophila melanogaster
D005260:Female
D006861:Hydrogen Peroxide
D020778:Matrix Metalloproteinase 2
D019255:NADPH Oxidases
D006080:Ovarian Follicle
D010060:Ovulation
D015398:Signal Transduction
D013482:Superoxide Dismutase

ovulation
octopamine
NADPH oxidase
superoxide dismutase
hydrogen peroxide


Enteric parasitic infection among HIV-infected patients visiting Tribhuvan University Teaching Hospital, Nepal.

Abstract:
BACKGROUND
Enteric parasitic infection among human immunodeficiency virus (HIV) patients has been a significant health problem in developing countries like Nepal. This study was undertaken to access the burden of enteric parasites among HIV patients and its association with their immune status.

METHODS
A cross-sectional study, involving 112 HIV sero-positive patients was conducted in Tribhuvan University Teaching Hospital, Public Health Research Laboratory, Kathmandu, Nepal from July 2011 to June 2012. The fecal samples were processed by direct-smear technique, in both normal saline solution and 1% iodine solution as well as modified acid fast staining (Kinyoun's method) after formalin ether concentration and Sheather's sucrose flotation for the identification of enteric parasites.

RESULTS
Infection with one or more parasite was seen in 33.9% (n = 38) of the cases enrolled in the study, with the parasite prevalence rate of 41.1% (n = 46). Literacy (OR = 1.9, 95% CI 0.9-4.3) and CD4 T-cell count <200 (OR = 2.5, 95% CI 1.1-5.7) were found to be associated with enteric parasite infection. Similarly, CD4 T-cell count <200 was found to be associated with opportunistic parasitic infection (OR = 3.2, 95% CI 1.2-7.8). Among opportunistic parasites, Giardia duodenalis was the most common (28.3%, n = 13) one. Multi-parasitism was observed in six patients (15.8%).

CONCLUSION
Enteric parasitic infections are common in HIV-infected people. The poor immune status as indicated by low CD4 T-cell count may account for higher risk of both opportunistic and non-opportunistic enteric parasitic infection.

Ghimire|Ananda|A|
Bhandari|Shiva|S|
Tandukar|Sarmila|S|
Amatya|Jyoti|J|
Bhandari|Dinesh|D|
Sherchand|Jeevan Bahadur|JB|

Enteric parasites
HIV
CD4 T-cell
Multi-parasitism
Diarrhea


A survey on clinical practice of interstitial cystitis in Japan.

Abstract:
BACKGROUND
To explore the real-life practice of clinical management of interstitial cystitis (IC) in Japan.

METHODS
A questionnaire on the number of IC patients, cystoscopic findings, diagnostic methods, and the treatment modalities was sent via e-mail to 114 medical institutions belonging to the Society of Interstitial Cystitis of Japan (SICJ).

RESULTS
Completed questionnaires were returned from 62 institutions (20 university hospitals, 26 general hospitals and 16 clinics), with a response rate of 54%. The median of patient number per institution was 20 and the national number of IC patients was counted as 4,531 in Japan. The number of new patients in 2013 was 7 (median) per institution and calculated as 1,214 in total. The case volume per institution distributed broadly and skewed to a lower volume. The patients were categorized according to cystoscopic findings as either Hunner type IC with Hunner lesions (n=2,066, 45%), non-Hunner type IC with glomerulations on hydrodistension (n=1,720, 38%) or hypersensitive bladder without endoscopic abnormalities (n=304, 7%), excluding unknown (n=441, 10%). The proportion of Hunner type IC was highly variable among the institutions, ranging from 0% to 100% with a median of 29%. As for evaluation, symptom and quality of life (QOL) assessment by questionnaires, frequency volume chart, urinalysis, urine cytology, urine culture, post-void residual measurement, uroflowmetry, ultrasound and cystoscopy were widely adapted. Administration of oral medicines and intravesical instillation therapy were undertaken at 98% and 63% of institutions, respectively. Hydrodistension was commonly performed, totaling in 812 procedures at 53 institutions, while only five cystectomies were reported from four institutions.

CONCLUSIONS
The survey estimated about 4,500 IC patients and 2,000 Hunner type IC patients in Japan. It also revealed a wide range of case volume, acceptable adherence to clinical guidelines, and high variability in the proportion of Hunner type IC. The variable proportions of Hunner type IC despite a high performing rate of endoscopy suggest inconsistency in diagnostic criteria for the Hunner lesion.

Yamada|Yukio|Y| Nomiya|Akira|A| Niimi|Aya|A| Igawa|Yasuhiko|Y| Ito|Takaaki|T| Tomoe|Hikaru|H| Takei|Mineo|M| Ueda|Tomohiro|T| Homma|Yukio|Y|

Interstitial cystitis (IC)
questionnaires
Hunner lesion


Efficacy of anti-SARS-CoV-2 mRNA vaccine in systemic autoimmune disorders: induction of high avidity and neutralising anti-RBD antibodies.

Abstract:
OBJECTIVES
In patients with systemic autoimmune rheumatic disorders (SARDs), vaccination with SARS-CoV-2 mRNA vaccines has been proposed. The aim of this study is to evaluate the immune response elicited by vaccination with mRNA vaccine, testing IgM, IgA and IgG antibodies to SARS-CoV-2 receptor-binding domain (RBD) and measuring neutralising antibodies.

METHODS
IgG, IgM and IgA anti-RBD antibodies were measured in 101 patients with SARDs. Antibodies inhibiting the interaction between RBD and ACE2 were evaluated. Antibody avidity was tested in a chaotropic ELISA using urea. Twenty-one healthcare workers vaccinated with mRNA vaccine served as control group.

RESULTS
Anti-RBD IgG and IgA were produced after the first dose (69% and 64% of the patients) and after the boost (93% and 83%). Antibodies inhibiting the interaction of RBD with ACE2 were detectable in 40% of the patients after the first dose and 87% after boost, compared with 100% in healthy controls (p<0.01). Abatacept and mycophenolate had an impact on the titre of IgG anti-RBD antibodies (p<0.05 and p<0.005, respectively) and on the amount of neutralising antibodies. No effect of other therapies was observed. Vaccinated patients produce high avidity antibodies, as healthy controls.

CONCLUSIONS
These data show that double-dose vaccination induced in patients with SARDs anti-RBD IgG and IgA antibodies in amounts not significantly different from controls, and, most interestingly, characterised by high avidity and endowed with neutralising activity.

Tani|Chiara|C|0000-0002-0870-8738
Pratesi|Federico|F|0000-0002-7226-0907
Talarico|Rosaria|R|0000-0003-4268-9611
Cardelli|Chiara|C|
Caruso|Teresita|T|
Di Cianni|Federica|F|
Laurino|Elenia|E|
Italiano|Nazzareno|N|
Moretti|Michele|M|
Manca|Maria Laura|ML|
Migliorini|Paola|P|
Mosca|Marta|M|

vaccination
COVID-19
autoimmune diseases


Serum erythropoietin levels, breast cancer and breast cancer-initiating cells.

Abstract:
BACKGROUND
Cancer is frequently associated with tumor-related anemia, and many chemotherapeutic agents impair hematopoiesis, leading to impaired quality of life for affected patients. The use of erythropoiesis-stimulating agents has come under scrutiny after prospective clinical trials using recombinant erythropoietin to correct anemia reported increased incidence of thromboembolic events and cancer-related deaths. Furthermore, previous preclinical reports indicated expansion of the pool of breast cancer-initiating cells when erythropoietin was combined with ionizing radiation.

METHODS
Using four established breast cancer cell lines, we test the effects of recombinant human erythropoietin and the number of breast cancer-initiating cells in vitro and in vivo and study if recombinant human erythropoietin promotes the phenotype conversion of non-tumorigenic breast cancer cells into breast cancer-initiating cells. In a prospective study, we evaluate whether elevated endogenous serum erythropoietin levels correlate with increased numbers of tumor-initiating cells in a cohort of breast cancer patients who were scheduled to undergo radiation treatment.

RESULTS
Our results indicate that recombinant erythropoietin increased the number of tumor-initiating cells in established breast cancer lines in vitro. Irradiation of breast cancer xenografts caused a phenotype conversion of non-stem breast cancer cells into induced breast cancer-initiating cells. This effect coincided with re-expression of the pluripotency factors c-Myc, Sox2, and Oct4 and was enhanced by recombinant erythropoietin. Hemoglobin levels were inversely correlated with serum erythropoietin levels, and the latter were correlated with disease stage. However, tumor sections revealed a negative correlation between serum erythropoietin levels and the number of ALDH1A3-positive cells, a marker for breast cancer-initiating cells.

CONCLUSIONS
We conclude that physiologically slow-rising serum erythropoietin levels in response to tumor-related or chemotherapy-induced anemia, as opposed to large doses of recombinant erythropoietin, do not increase the pool of breast cancer-initiating cells.

Bhat|Kruttika|K|
Sandler|Kiri|K|
Duhachek-Muggy|Sara|S|
Alli|Claudia|C|
Cheng|Fei|F|
Moatamed|Neda A|NA|
Magyar|Clara E|CE|
Du|Lin|L|
Li|Gang|G|
McCloskey|Susan|S|
Vlashi|Erina|E|
Pajonk|Frank|F|

D023041:Xenograft Model Antitumor Assays

Erythropoietin
Breast cancer-initiating cells
Radiation therapy


Assisted conception as a potential prognostic factor predicting insulin therapy in pregnancies complicated by gestational diabetes mellitus.

Abstract:
BACKGROUND
Advanced maternal age, family history of diabetes, pre-gestational obesity, increased level of HbA1c, history of gestational diabetes mellitus (GDM), and poor pregnancy consequences are considered risk factors for antenatal insulin requirement in women with GDM. However, the role of assisted reproductive technology (ART) in increasing the risk of insulin therapy in pregnancies complicated with GDM remained elusive. The current study aimed to determine the role of ART in predicting insulin therapy in GDM women and investigate the clinical and biochemical factors predicting the need for insulin therapy in pregnancies complicated with GDM.

METHODS
In this prospective cohort study, 236 Iranian women with GDM were diagnosed by one-step oral glucose tolerance test (OGTT) between October 2014 and June 2017. They were mainly assigned to two groups; the first group (n = 100) was designated as ART which was further subdivided into two subgroups as follows: 60 participants who received medical nutrition therapy (MNT) and 40 participants who received MNT plus insulin therapy (MNT-IT). The second group (n = 136) was labeled as the spontaneous conception (SC), consisting of 102 participants receiving MNT and 34 participants receiving MNT in combination with IT (MNT-IT). The demographic, clinical, and biochemical data were compared between groups. Multivariate logistic regression was performed to estimate prognostic factors for insulin therapy.

RESULTS
A higher rate of insulin therapy was observed in the ART group as compared with the SC group (40% vs. 25%; P < 0.001). Multivariate logistic regression demonstrated that maternal age ≥ 35 years [OR: 2.91, 95% CI: (1.28-6.62)], high serum FBS [1.10: (1.04-1.16)], HbA1c [1.91 (1.09-3.34)], and ART treatment [2.94: (1.24-6.96)] were independent risk factors for insulin therapy in GDM women.

CONCLUSIONS
Apart from risk factors mentioned earlier, ART may be a possible prognostic factor for insulin therapy in pregnancies complicated with GDM.

Prognostic factors
Insulin
Pregnancy
Gestational diabetes mellitus
Assisted reproductive technology


Inhibition of Endoplasmic Reticulum Stress Alleviates Lung Injury Induced by Brain Death.

Abstract: Brain death (BD) can induce inflammation and injury of organs. Endoplasmic reticulum (ER) stress is associated with a variety of diseases. However, little is known about how ER stress is implicated in brain death (BD)-induced lung injury. In this study, a stable BD rat model was constructed to investigate the role of ER stress on BD-induced lung injury. H&E staining demonstrated that BD can induce lung injury in rats. The results of Western blot and immunohistochemistry showed that apoptosis was observed in the lung tissues of BD rats. And the level of GRP78, p-PERK, p-eIF2α, CHOP, and Caspase-12 was highly expressed in BD rats compared with the control group. Inhibition of ER stress with salubrinal reduced the BD-induced lung inflammation. Moreover, BD-induced increase of NF-κB activity was lowered by inhibition of ER stress. These results suggested that inhibition of ER stress alleviates BD-induced lung inflammation by regulating NF-κB signaling pathway.

Tang|Hongwei|H| Zhang|Jiakai|J| Cao|Shengli|S| Yan|Bing|B| Fang|Hongbo|H| Zhang|Huapeng|H| Guo|Wenzhi|W| Zhang|Shuijun|S|

endoplasmic reticulum stress
lung injury
brain death
inflammation


Whole-genome sequencing to investigate a non-clonal melioidosis cluster on a remote Australian island.

Abstract: Melioidosis is a tropical disease caused by the bacterium Burkholderia pseudomallei. Outbreaks are uncommon and can generally be attributed to a single point source and strain. We used whole-genome sequencing to analyse B. pseudomallei isolates collected from an historical 2-year long case cluster that occurred in a remote northern Australian indigenous island community, where infections were previously linked to a contaminated communal water supply. We analysed the genome-wide relatedness of the two most common multilocus sequence types (STs) involved in the outbreak, STs 125 and 126. This analysis showed that although these STs were closely related on a whole-genome level, they demonstrated evidence of multiple recombination events that were unlikely to have occurred over the timeframe of the outbreak. Based on epidemiological and genetic data, we also identified two additional patients not previously associated with this outbreak. Our results confirm the previous hypothesis that a single unchlorinated water source harbouring multiple B. pseudomallei strains was linked to the outbreak, and that increased melioidosis risk in this community was associated with Piper methysticum root (kava) consumption.

Sarovich|Derek S|DS|
Chapple|Stephanie N J|SNJ|
Price|Erin P|EP|
Mayo|Mark|M|
Holden|Matthew T G|MTG|
Peacock|Sharon J|SJ|
Currie|Bart J|BJ|

melioidosis
Burkholderia pseudomallei
outbreak
recombination
population genetics
source tracing


Efficacy of Pulpal Anesthesia Using a Needle-less Syringe.

Abstract: The purpose of this study was to investigate the manufacturer's claims regarding a novel needleless intraligamentary local anesthesia injection device (Numbee, BioDent) to provide effective single tooth anesthesia. Investigators compared the Numbee with a traditional inferior alveolar nerve block (IANB) during a restorative procedure on mandibular teeth. A randomized, split-mouth design was conducted with 15 adult subjects receiving an IANB on one side and a Numbee injection on the same tooth type on the contralateral side. Subjects recorded injection pain using the Visual Analog Scale (VAS) and their preferred injection technique. Anesthesia was considered profound with 2 consecutive electric pulp tester readings of 80. If subjects became symptomatic during the restorative procedure, rescue anesthesia was administered. The difference in VAS scores for injection pain between the Numbee and the IANB was not significant (p = .078). For the IANB, the incidence of profound anesthesia was 46%, and required rescue anesthesia was 20%. For the Numbee, the incidence of profound anesthesia was 0%, and required rescue anesthesia was 60%. Subject preference was evenly split (50/50%) between the 2 techniques. The IANB outperformed the Numbee device for achieving profound anesthesia and requiring less rescue anesthesia.

Christensen|Coleman|C|
Arnason|Stephen C|SC|
Oates|Ross|R|
Crabtree|Michael|M|
Kersey|John W|JW|
Vandewalle|Kraig S|KS|


Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure.

Abstract: Although numerous studies have raised public concerns regarding the safety of anesthetics including sevoflurane in children, the biochemical mechanisms leading to anesthetics-induced neurotoxicity remain elusive. Moreover, potential biomarker(s) for early detection of general anesthetics-induced brain injury are urgent for public health. We employed an enabling technology of shotgun lipidomics and analyzed nearly 20 classes and subclasses of lipids present in the blood serum of postnatal day (PND) 5 or 6 rhesus monkeys temporally collected after exposure to sevoflurane at a clinically relevant concentration or room-air as control. Lipidomics analysis revealed numerous significant anesthetic-induced changes of serum lipids and their metabolites as well as short chain acylcarnitines in the brain and cerebrospinal fluid after anesthetic exposure. These include decreased carnitine and acylcarnitines, unchanged triacylglycerol mass but accumulation of 16:0 and 18:1 fatty acyl chains in the triacylglycerol pool, losses of polyunsaturated fatty acids in both non-esterified fatty acid and phospholipid pools, and increased 4-hydroxynonenal content as early as 2 h after sevoflurane exposure. Importantly, the amounts of short chain acylcarnitines in the brain and cerebrospinal fluid were also significantly reduced after anesthetic exposure. We propose that this serum lipidomic profile can serve as indicative of neuronal damage. Our results reveal that sevoflurane exposure induces an energy deficient state in the brain evidenced by reduced free and acyl carnitine contents, as well as the presence of a pro-inflammatory state in the exposed animals, providing deep insights into the underlying mechanisms responsible for anesthetic-induced neurotoxicity.

Wang|Chunyan|C|
Liu|Fang|F|
Frisch-Daiello|Jessica L|JL|
Martin|Shannon|S|
Patterson|Tucker A|TA|
Gu|Qiang|Q|
Liu|Shuliang|S|
Paule|Merle G|MG|
Hanig|Joseph P|JP|
Slikker|William|W|
Crawford|Peter A|PA|
Wang|Cheng|C|
Han|Xianlin|X|

Lipidomics
Energy deficiency
Neurotoxicity
Sevoflurane
Lipid metabolism
Metabolomics


Identifying victims of the largest Second World War family massacre in Slovenia.

Abstract: The killings during the Second World War, with nearly one hundred thousand victims, is one of the greatest losses of life in Slovenia's modern history. This article presents the genetic identification of the victims of the largest family massacre that occurred in Slovenia, in which 10 members of the same family were killed. Seven of them were buried in a hidden mass grave and only two children survived. In 2015 and 2016, two graves were found and three incomplete female skeletons and at least three incomplete male skeletons were exhumed. A total of 12 bones and teeth were analysed and compared to two living relatives. Extracted DNA was quantified using the PowerQuant kit, and various autosomal and Y-STR kits were used for STR typing. Up to 2.7 ng DNA/g of powder was acquired from the samples analysed. We managed to obtain nuclear DNA for successful STR typing from seven bones and one molar. From the female grave, autosomal profiles were obtained only from one skeleton, and from the male grave from five out of six femurs. The relationships between the males were additionally confirmed by analyses of Y-STRs. STR profiles made possible the identification of four family members; one of the aunts from the female grave, and two uncles and the father of the surviving children, who were used as family references, from the male grave. The product rule was used to calculate a combined likelihood ratio for autosomal and Y-STRs, and statistical analyses showed high confidence of correct identification with posterior probability (PP) greater than 99.9 % for three out of four victims identified. For identifying the aunt, the PP obtained after ESI-17 and NGM STR typing was too low. To increase the PP, the next-generation sequencing Precision ID GlobalFiler NGS STR Panel was used and, after the analysis of additional STR loci, the statistical analysis showed a PP greater than 99.9 %, indicating that a sufficient number of genetic markers had been investigated in identifying the skeletal remains of the aunt. An elimination database containing the genetic profiles of all individuals that had been in contact with the bones was created to ensure traceability in case of contamination, and no matches were found. After more than 70 years, the skeletal remains were returned to the surviving children, who buried their relatives in a family grave.

Zupanič Pajnič|Irena|I|
Obal|Marcel|M|
Zupanc|Tomaž|T|

Second World War
Bones
Teeth
STR typing
Skeletal remains
Missing person identification


Reducing Nitrogen Dosage in Triticum durum Plants with Urea-Doped Nanofertilizers.

Abstract: Nanotechnology is emerging as a very promising tool towards more efficient and sustainable practices in agriculture. In this work, we propose the use of non-toxic calcium phosphate nanoparticles doped with urea (U-ACP) for the fertilization of Triticum durum plants. U-ACP nanoparticles present very similar morphology, structure, and composition than the amorphous precursor of bone mineral, but contain a considerable amount of nitrogen as adsorbed urea (up to ca. 6 wt % urea). Tests on Triticum durum plants indicated that yields and quality of the crops treated with the nanoparticles at reduced nitrogen dosages (by 40%) were unaltered in comparison to positive control plants, which were given the minimum N dosages to obtain the highest values of yield and quality in fields. In addition, optical microscopy inspections showed that Alizarin Red S stained nanoparticles were able to penetrate through the epidermis of the roots or the stomata of the leaves. We observed that the uptake through the roots occurs much faster than through the leaves (1 h vs. 2 days, respectively). Our results highlight the potential of engineering nanoparticles to provide a considerable efficiency of nitrogen uptake by durum wheat and open the door to design more sustainable practices for the fertilization of wheat in fields.

Ramírez-Rodríguez|Gloria B|GB|
Miguel-Rojas|Cristina|C|
Montanha|Gabriel S|GS|
Carmona|Francisco J|FJ|
Sasso|Gregorio Dal|GD|
Sillero|Josefina C|JC|
Pedersen|Jan Skov|JS|
Masciocchi|Norberto|N|
Guagliardi|Antonietta|A|
Pérez-de-Luque|Alejandro|A|
Delgado-López|José M|JM|

nanofertilizer
agriculture
calcium phosphate
urea
quality
wheat


An Experimental and Theoretical Investigation on Pentacoordinated Cobalt(III) Complexes with an Intermediate S=1 Spin State: How Halide Ligands Affect their Magnetic Anisotropy.

Abstract: Understanding the factors that control the magnitude and symmetry of magnetic anisotropy should facilitate the rational design of mononuclear metal complexes in the quest for single-molecule magnets (SMMs), based on a single metal ion, with high blocking temperatures and large energy barriers. The best strategy is to define magnetostructural correlations through the investigation of a series of metal complexes. It has been demonstrated that the main contribution to the magnetic anisotropy arises from the spin-orbit coupling (SOC) effect in metal-ion-based systems, so current studies focus particularly on the use of both ligands and metal ions possessing a large SOC. In this context, we report a unique series of halide Co(III) complexes, [CoL(X)], with X=Cl, Br, I (CoX) and L=2,2'-(2,2'-bipyridine-6,6'-diyl)bis(1,1-diphenylethanethiolate), which possess a rare intermediate S=1 spin ground state. The S=1 Co(III) complexes are attractive species because they possess a remarkably large axial zero-field splitting (defined by D from the following Hamiltonian: H=DSz (2) ), as well as the halide ligands inducing large SOC constants. The single-crystal X-ray structures reveal that the CoBr and CoI complexes are isostructural with the previously described CoCl complex. Their coordination sphere displays a distorted pentacoordinated square pyramidal geometry, with the halide located in the Co(III) axial position. Large positive D values of 35, 26, and 18 cm(-1) are found for CoCl, CoBr, and CoI, respectively, through analysis of the magnetic susceptibility data as a function of temperature. To rationalize this trend, theoretical calculations based on both density functional theory (DFT) and complete active space self-consistent field (CASSCF) methods are performed successfully. Both the sign and magnitude of D are predicted remarkably well by these theoretical approaches. The DFT calculations also show that the resulting D values originate from a balance of several contributions, and that many factors, including differences in their structural properties and in the contribution of the halide, should be taken into account to explain the trend of D in this series of complexes.

Brazzolotto|Deborah|D| Gennari|Marcello|M| Yu|Shengying|S| Pécaut|Jacques|J| Rouzières|Mathieu|M| Clérac|Rodolphe|R| Orio|Maylis|M| Duboc|Carole|C|

halides
magnetic anisotropy
single-molecule magnets
magnetic properties
quantum chemistry


Direct suppression of a rice bacterial blight (Xanthomonas oryzae pv. oryzae) by monoterpene (S)-limonene.

Abstract: Rice bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo), is a severe disease of rice plants. Upon pathogen infection, rice biosynthesizes phytoalexins, including diterpenoids such as momilactones, phytocassanes, and oryzalexins. However, information on headspace volatiles in response to Xoo infection is limited. We have examined headspace volatile terpenes, induced by the infection of Xoo, and investigated their biological roles in the rice plant. Monoterpenes α-thujene, α-pinene, sabinene, myrcene, α-terpene, and (S)-limonene and sesquiterpenes cyclosativene, α-copaene, and β-elemene were detected from 1-week-old Xoo-infected rice seedlings, by solid-phase microextraction-gas chromatography-mass spectrometry. All monoterpenes were constitutively released from rice seedlings before Xoo infection. However, (S)-limonene emission was further elicited after exposure of the seedlings to Xoo in coincidence with upregulation of limonene synthase gene (OsTPS20) transcripts. Only the stereospecific (S)-limonene [and not (R)-limonene or other monoterpenes] severely inhibited Xoo growth, as confirmed by disc diffusion and liquid culture assays. Rice seedlings showed suppressed pathogenic symptoms suggestive of resistance to Xoo infection after foliar treatment with (S)-limonene. Collectively, our findings suggest that (S)-limonene is a volatile phytoanticipin, which plays a significant role in suppressing Xoo growth in rice seedlings.

Lee|Gun Woong|GW|
Chung|Moon-Soo|MS|
Kang|Mihyung|M|
Chung|Byung Yeoup|BY|
Lee|Sungbeom|S|

D018506:Gene Expression Regulation, Plant

Xanthomonas oryzae pv. oryzae
(S)-Limonene
Volatile terpene
A disc diffusion assay
Antibacterial activity


Bone marrow-derived mesenchymal stem/stromal cells reverse the sensorial diabetic neuropathy via modulation of spinal neuroinflammatory cascades.

Abstract:
BACKGROUND
Diabetic neuropathy (DN) is a frequent and debilitating manifestation of diabetes mellitus, to which there are no effective therapeutic approaches. Mesenchymal stem/stromal cells (MSC) have a great potential for the treatment of this syndrome, possibly through regenerative actions on peripheral nerves. Here, we evaluated the therapeutic effects of MSC on spinal neuroinflammation, as well as on ultrastructural aspects of the peripheral nerve in DN-associated sensorial dysfunction.

METHODS
C57Bl/6 mice were treated with bone marrow-derived MSC (1 × 106), conditioned medium from MSC cultures (CM-MSC) or vehicle by endovenous route following the onset of streptozotocin (STZ)-induced diabetes. Paw mechanical and thermal nociceptive thresholds were evaluated by using von Frey filaments and Hargreaves test, respectively. Morphological and morphometric analysis of the sciatic nerve was performed by light microscopy and transmission electron microscopy. Mediators and markers of neuroinflammation in the spinal cord were measured by radioimmunoassay, real-time PCR, and immunofluorescence analyses.

RESULTS
Diabetic mice presented behavioral signs of sensory neuropathy, mechanical allodynia, and heat hypoalgesia, which were completely reversed by a single administration of MSC or CM-MSC. The ultrastructural analysis of the sciatic nerve showed that diabetic mice exhibited morphological and morphometric alterations, considered hallmarks of DN, such as degenerative changes in axons and myelin sheath, and reduced area and density of unmyelinated fibers. In MSC-treated mice, these structural alterations were markedly less commonly observed and/or less pronounced. Moreover, MSC transplantation inhibited multiple parameters of spinal neuroinflammation found in diabetic mice, causing the reduction of activated astrocytes and microglia, oxidative stress signals, galectin-3, IL-1β, and TNF-α production. Conversely, MSC increased the levels of anti-inflammatory cytokines, IL-10, and TGF-β.

CONCLUSIONS
The present study described the modulatory effects of MSC on spinal cord neuroinflammation in diabetic mice, suggesting new mechanisms by which MSC can improve DN.

Evangelista|Afrânio Ferreira|AF|
Vannier-Santos|Marcos André|MA|
de Assis Silva|Gessica Sabrina|GS|
Silva|Daniela Nascimento|DN|
Juiz|Paulo José Lima|PJL|
Nonaka|Carolina Kymie Vasques|CKV|
Dos Santos|Ricardo Ribeiro|RR|
Soares|Milena Botelho Pereira|MBP|
Villarreal|Cristiane Flora|CF|

D000818:Animals
D016026:Bone Marrow Transplantation
D002135:Calcium-Binding Proteins
D017077:Culture Media, Conditioned
D016207:Cytokines
D003929:Diabetic Neuropathies
D004195:Disease Models, Animal
D049452:Green Fluorescent Proteins
D006930:Hyperalgesia
D015227:Lipid Peroxidation
D008297:Male
D059630:Mesenchymal Stem Cells
D051379:Mice
D008810:Mice, Inbred C57BL
D008822:Mice, Transgenic
D008840:Microfilament Proteins
D009043:Motor Activity
D009573:Nitrites
D012584:Sciatic Nerve
D013116:Spinal Cord
D013311:Streptozocin

Diabetes
Neuroinflammation
Spinal cord
Sensory neuropathy
Galectin-3
Stem cells


Cathepsin B is an executioner of ferroptosis.

Abstract: Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death.

Nagakannan|Pandian|P|
Islam|Md Imamul|MI|
Conrad|Marcus|M|
Eftekharpour|Eftekhar|E|

Glutathione
Lipid peroxidation
Lysosomes
Histone H3
Autophagy
GPX4


Identification of Active Compounds and Mechanism of Huangtu Decoction for the Treatment of Ulcerative Colitis by Network Pharmacology Combined with Experimental Verification.

Abstract:
Introduction
Huangtu decoction (HTD) has been widely used in the treatment of gastrointestinal bleeding, ulcerative colitis (UC) and gastrointestinal tumors in China, but its active compounds and mechanism are still not clear yet. The present research aimed to identify the active compounds and mechanism of HTD for the treatment of UC.

Methods
Firstly, the chemical compounds of HTD were qualitatively identified based on Q Exactive Orbitrap LC-MS/MS, and their potential targets were predicted through SwissTargetPrediction. Secondly, the differential expressed genes (DEGs) in colon tissues of UC patients and normal controls were retrieved from the GEO database. Thirdly, the overlapping targets of DEGs and the predicted targets were obtained and subjected to GO and KEGG analysis. Finally, the key targets in the most significantly enriched pathway were verified by in vivo experiment, and the protein and mRNA expressions of matrix metalloproteinase-1 (MMP1), MMP3, MMP7, MMP9 and MMP12 were determined by immunohistochemistry (IHC), Western blotting (WB) and quantitative real-time-PCR (qRT-PCR).

Results
A total of 47 compounds were identified and 29 overlapping targets were obtained from HTD extract. The most significantly enriched pathway of overlapping targets involved was MMP. HTD improved the pathological damage in colon tissues of DSS-induced UC model and significantly decreased the serum levels of IL-1β and IL-6. The protein and mRNA expressions of MMP1, MMP3 and MMP9 in colon tissues were significantly decreased after HTD treatment.

Conclusion
HTD treatment can alleviate the colonic inflammation via inhibiting MMPs including MMP1, MMP3 and MMP9.

Chen|Wenwen|W|0000-0001-9175-3937 He|Lin|L| Zhong|Lian|L| Sun|Jiayi|J| Zhang|Lilin|L| Wei|Daneng|D| Wu|Chunjie|C|0000-0001-7496-8469

Huangtu decoction
ulcerative colitis
bioinformatic analysis
matrix metalloproteinases


Bone marrow mesenchymal stem cells offer an immune-privileged niche to Cutibacterium acnes in case of implant-associated osteomyelitis.

Abstract: Considered as some of the most devastating complications, Cutibacterium acnes (C. acnes)-related osteomyelitis are among the hardest infections to diagnose and treat. Mesenchymal stem cells (MSCs) secrete number of immunomodulatory and antimicrobial soluble factors, making them an attractive treatment for bacterial infection. In this study, we examined MSCs/C. acnes interaction and analyzed the subsequent MSCs and bacteria's behaviors. Human bone marrow-derived MSCs were infected by C. acnes clinical strain harvested from non-infected bone site. Following 3 h of interaction, around 4% of bacteria were found in the intracellular compartment. Infected MSCs increased the secretion of prostaglandin E2 and indolamine 2,3 dioxygenase immunomodulatory mediators. Viable intracellular bacteria analyzed by infrared spectroscopy and atomic force microscopy revealed deep modifications in the wall features. In comparison with unchallenged bacteria, the viable intracellular bacteria showed (i) an increase in biofilm formation on orthopaedical-based materials, (ii) an increase in the invasiveness of osteoblasts and (iii) persistence in macrophage, suggesting the acquisition of virulence factors. Overall, these results showed a direct impact of C. acnes on bone marrow-derived MSCs, suggesting that blocking the C. acnes/MSCs interactions may represent an important new approach to manage chronic osteomyelitis infections. STATEMENT OF SIGNIFICANCE: The interaction of bone commensal C. acnes with bone marrow mesenchymal stem cells induces modifications in C. acnes wall characteristics. These bacteria increased (i) the biofilm formation on orthopaedical-based materials, (ii) the invasiveness of bone forming cells and (iii) the resistance to macrophage clearance through the modification of the wall nano-features and/or the increase in catalase production.

Dubus|M|M|
Varin|J|J|
Papa|S|S|
Chevrier|J|J|
Quilès|F|F|
Francius|G|G|
Audonnet|S|S|
Mauprivez|C|C|
Gangloff|S C|SC|
Siboni|R|R|
Ohl|X|X|
Reffuveille|F|F|
Kerdjoudj|H|H|

Mesenchymal stem cells
Cutibacterium acnes
Bacteria/ stem cells interactions
Bone repair
Implant-associated infection


Non-oncotic properties of albumin. A multidisciplinary vision about the implications for critically ill patients.

Abstract: Effective resuscitation with human albumin solutions is achieved with less fluid than with crystalloid solutions. However, the role of albumin in today's critical care unit is also linked to its multiple pharmacological effects. Areas covered: The potential clinical benefits of albumin in select populations of critically ill patients like sepsis seem related to immunomodulatory and anti-inflammatory effects, antibiotic transportation and endothelial stabilization. Albumin transports many drugs used in critically ill patients. Such binding to albumin is frequently lessened in critically ill patients with hypoalbuminemia. These changes could result in sub-optimal treatment. Albumin has immunomodulatory capacity by binding several bacterial products. Albumin also influences vascular integrity, contributing to the maintenance of the normal capillary permeability. Moreover, the albumin molecule encompasses several antioxidant properties, thereby significantly reducing re-oxygenation injury, which is especially important in sepsis. In fact, most studies of albumin administration are a combination of a degree of resuscitation with a degree of maintenance or supplementation of albumin. Expert commentary: The potential clinical benefits of the use of albumin in selected critically ill patients such as sepsis seem related to its immunomodulatory and anti-inflammatory effects, antioxidant properties, antibiotic transportation and endothelial stabilization. Additional studies are warranted to further elucidate the underlying physiologic and molecular rationale.

Ferrer|Ricard|R|
Mateu|Xavier|X|
Maseda|Emilio|E|
Yébenes|Juan Carlos|JC|
Aldecoa|César|C|
De Haro|Candelaria|C|
Ruiz-Rodriguez|Juan Carlos|JC|
Garnacho-Montero|José|J|

Albumin
critical care
sepsis
antioxidation
drug transportation
endothelium
immunomodulation