Does the time from symptom onset to surgery affect the outcomes of patients with acute appendicitis? A prospective cohort study of 255 patients.

Abstract:
INTRODUCTION
The objective of this study was to evaluate the impact of operative timing on outcomes of acute appendicitis.

METHODS
This study examined adult patients who had presented to the hospital with acute appendicitis and had undergone appendectomy from December 2017 to February 2019. Time delay and outcomes of perforated and non-perforated appendicitis were compared. Patients were classified into five groups based on the period from symptom onset to operation: group 1, <24 hours; group 2, ≥24 and <48 hours; group 3, ≥48 and <72 hours; group 4, ≥72 and <96 hours; and group 5, ≥96 hours. The five groups were compared, with risk of perforation assessed in particular.

RESULTS
A total of 255 patients were included in the analysis. Symptom duration, operative time, and length of postoperative hospital stay (P < .001) were significantly longer in the perforated group (n = 49) than in the non-perforated group (n = 206). The perforated group also had a higher conversion rate to open procedures (P = .002) and a higher rate of wound infection (P = .034). Group 1 had 53 patients, group 2 had 95 patients, group 3 had 57 patients, group 4 had 32 patients, and group 5 had 18 patients. The incidence of appendiceal perforation and median operative time progressively increased along with symptom duration in the five groups. In multivariate analyses, independent risk factors for appendiceal perforation were male gender (odds ratio = 2.33, 95% confidence interval [CI]: 1.07-5.08) and symptom duration ≥48 hours (relative to ≥24 and <48 hours) (odds ratio = 4.64, 95%CI: 1.76-12.27). Patients with symptom duration ≥72 hours had a significantly longer operative time than those with symptom duration ≥48 and <72 hours (β = 21.38, 95%CI: 5.66-37.11, P = .008).

CONCLUSION
The risk of perforation increased significantly 48 hours after the onset of appendicitis. Symptoms duration ≥72 hours was associated with a longer operative time.

acute appendicitis
operative timing
perforation


Reduction mechanism of Cd accumulation in rice grain by Chinese milk vetch residue: Insight into microbial community.

Abstract: Chinese milk vetch is an efficient approach to reduce Cd accumulation in rice, nevertheless, its reduction mechanism is not well understood. In this study, we investigated the rice grain Cd, soil properties and microbial community in a Cd-polluted paddy field amended with milk vetch residue (MV) or without (CK) during rice growth period. We found that milk vetch residue averagely decreased the Cd content in rice grain by 45%. Decrease of Cd in rice mainly attributed to the inhibition of Cd activation by milk vetch residue at heading stage probably by the formation of HA-Cd (Humic Acid) and CdS. Increased pH and organic matter (OM) promoted the reduction of available Cd. In addition, nonmetric multidimensional scaling (NMDS) analysis revealed that microbial community structure was significantly different between MV and CK treatment (r = 0.187, p = 0.002), and the core functions of differentially abundant genera were mainly associated with N-cycling, organic matter degradation and sulfate-reducing. The application of milk vetch residue increased the abundance of sulfate-reducing bacteria (SRB) by 8-112% during the rice growth period, which may involve in promoting the transformation of Cd to a more stably residual Cd (CdS). Canonical correspondence analysis (CCA) and mantel test analysis indicated that available K (p = 0.004) and available N (p = 0.005) were the key environmental factors of shaping the SRB. Altogether, changes in soil properties affected microbial structure and functional characteristics, especially the response of SRB in MV treatment would provide valuable insights into reducing the bioavailability of Cd in soil.

Zhang|Siyuan|S| Deng|Yan|Y| Fu|Shaodong|S| Xu|Menglong|M| Zhu|Ping|P| Liang|Yili|Y| Yin|Huaqun|H| Jiang|Luhua|L| Bai|Lianyang|L| Liu|Xueduan|X| Jiang|Huidan|H| Liu|Hongwei|H|

Milk vetch
Bioavailable Cd
Cadmium
Rice Cd
Sulfate reducing bacteria


Enhanced Macroanion Recognition of Superchaotropic Keggin Clusters Achieved by Synergy of Anion-π and Anion-Cation Interactions.

Abstract: Keggin clusters are the most widely used polyoxometalate building blocks for the construction advanced materials, but effective methods for precisely recognizing the isostructural analogues of Keggins are still limited. In this study we employed the zwitterionic molecule 4,4'-dipyridyl N,N'-dioxide as a recognition receptor to specifically bind to the three Keggin analogues PW12 O40 3- , PMo12 O40 3- , and SiW12 O40 4- , which separately co-assembled into three different types of spherical charged colloids of different sizes. The recognition phenomena were confirmed by electrochemical methods and their crystallization behavior. Compared with solely anion-cation interaction-driven systems, the synergism with the anion-π interactions between the superchaotropic Keggins and the electron-deficient pyridine rings is believed to enhance the recognition. This observation is intriguing as the long-range solution assembly of Keggins is mainly driven by short-range anion-π interactions. Our results show that the little-noticed hydration shell of Keggins is significantly influenced by the superchaotropic effect, leading to differentiated binding affinity to the receptors and more obvious recognition phenomena between tungsten/molybdenum Keggin analogues.

polyoxometalates
Keggin salts
chaotropic effect
electrostatic interactions
self-assembly


Efficacy of chitinase-3-like protein 1 as an in vivo bone formation predictable marker of maxillary/mandibular bone marrow stromal cells.

Abstract:
Introduction
Maxillary/mandibular bone marrow stromal cells (MBMSCs) are a useful cell source for bone regeneration in the oral and maxillofacial region. To further ensure the clinical application of MBMSCs in bone regenerative therapy, it is important to determine the bone formation capacity of MBMSCs before transplantation. The aim of this study is to identify the molecular marker that determines the in vivo bone formation capacity of MBMSCs.

Methods
The cell growth, cell surface antigens, in vitro and in vivo bone formation capacity of MBMSCs were examined. The amount of chitinase-3-like protein 1 (CHI3L1) secreted into the conditioned medium was quantified. The effects of CHI3L1 on the cell growth and osteogenic differentiation potential of MBMSCs and on the cell growth and migration of vascular endothelial cells and fibroblasts were examined.

Results
The cell growth, and in vitro and in vivo bone formation capacity of the cells treated with different conditions were observed. MBMSCs that secreted a large amount of CHI3L1 into the conditioned medium tended to have low in vivo bone formation capacity, whereas MBMSCs that secreted a small amount of CHI3L1 had greater in vivo bone formation capacity. CHI3L1 promoted the migration of vascular endothelial cells, and the cell growth and migration of fibroblasts.

Conclusion
Our study indicates that the in vitro osteogenic differentiation capacity of MBMSCs and the in vivo bone formation capacities of MBMSCs were not necessarily correlated. The transplantation of high CHI3L1 secretory MBMSCs may suppress bone formation by inducing fibrosis at the site. These results suggest that the CHI3L1 secretion levels from MBMSCs may be used as a predictable marker of bone formation capacity in vivo.

Komabashiri|Naohiro|N| Suehiro|Fumio|F| Ishii|Masakazu|M| Nishimura|Masahiro|M|

HUVEC, human umbilical vein endothelial cells

MBMSC, maxillary/mandibular bone marrow stromal cells

α-MEM, alpha modified Eagle's minimum essential medium


Affective Influences on Older Adults' Attention to Self-Relevant Negative Information.

Abstract:
OBJECTIVES
Some research suggests that older adults have a tendency to be biased toward positive information, but may be more willing to attend to potentially beneficial negative information in certain situations. Following the mood-as-resource framework, one possibility is that older adults may be more willing to consider negative information when in a positive mood, with positive affect serving as a buffer to the adverse emotional consequences that may follow.

METHOD
Young (n = 62) and older (n = 65) adults completed a difficult cognitive task before completing either a positive or negative experience recall task, depending upon assigned condition. Afterwards, they rated their interest in viewing their strengths and weaknesses on the previously completed task, and then selected and viewed different types of feedback (i.e., strengths or weaknesses).

RESULTS
Older adults in the positive condition selected more weaknesses to view and spent more time viewing weaknesses than older adults in the negative condition. There were no differences across conditions in behavioral results for young adults. Ratings of interest in viewing different types of feedback did not correspond with actual feedback viewing behavior.

DISCUSSION
Results highlight the importance of considering older adults' pre-existing mood before addressing self-relevant information that may be negative but important.

Positivity
Mood-as-resource
Emotion
Decision making


Biogenic Fabrication, Characterization and Drug Loaded Antimicrobial Assay of Silver Nanoparticles Using Centratherum anthalminticum (L.) Kuntze.

Abstract: Bionanotechnology is considered a safe and ecofriendly route for the biosynthesis of metal nanoparticles from plant extracts, microorganisms, and biomaterials. The present study was focused on the fabrication of silver nanoparticles (<50 nm) biogenically from the novel Centratherum anthelmminticum's aqueous seed extract. The obtained nanoproduct was evaluated by X-ray diffraction analysis (XRD), Scanning electron microscopy (SEM), UV-Visible spectroscopy, FTIR and Raman spectroscopy. The particle size and surface charge were estimated by Dynamic light scattering (DLS) and Zeta potential measurements. The nanoparticles showed cubic close packed (ccp) morphology with miller indices (111), (200), (220), (311) and (222). The λmax for synthesized silver nanoparticles was measured in the range of 436 nm, 464 nm and 467 nm for 1 mM, 5 mM and 10 mM samples, respectively. The bioreduction of silver ions exhibited a gradual color change which confirms the formation of silver nanoparticles under UV-visible spectrum. Ag-O and Ag-N stretching vibrations corresponding to the bond formation between silver and oxygen of the carboxylate group and nitrogen of amine was corroborated by the presence of a sharp peak in Raman spectra at 245 cm-1. Antimicrobial activity was assessed against eight bacterial and three fungal strains. The silver nanoparticles fabricated from 10 mM AgNO3 solution showed significant results against all Gram-negative bacteria, with the further restriction in growth of C. albicans and A. niger. From in-vitro antimicrobial assay, it was observed that drug-loaded silver nanoparticles (Ciprofloxacin +10 mM) displayed a stronger potential than the synthesized silver nanoparticles and ciprofloxacin alone to restrain the development of E. coli, and E. aerogenes.

Sadiqa|Ayesha|A|
Gilani|Syeda Rubina|SR|
Anwar|Aneela|A|
Mehboob|Adil|A|
Saleem|Aimon|A|
Rubab|Saima|S|

D017550:Spectroscopy, Fourier Transform Infrared

Biogenic fabrication
Antimicrobial activity
C. anthelminticum
CA-AgNPs loaded drug
Multidrug resistant bacteria


A Symmetric Recognition Motif between Vicinal Diols: The Fourfold Grip in Ethylene Glycol Dimer.

Abstract: Ethylene glycol has a transiently chiral, asymmetric global minimum structure, but it favors a highly symmetric, achiral dimer arrangement which has not been considered or found in previous quantum-chemical studies. Complementary FTIR and Raman spectroscopy in supersonic jets allows for the detection and straightforward assignment of this four-fold hydrogen-bonded dimer, which introduces an interesting supramolecular binding motif for vicinal diols and provides a strong case for transient chirality synchronization.

dimers
hydrogen bonds
molecular recognition
racemization
vibrational spectroscopy


Healthcare Priority-Setting: Chat-Ting Is Not Enough Comment on "Swiss-CHAT: Citizens Discuss Priorities for Swiss Health Insurance Coverage".

Abstract: CHAT has its limits. It is a three-hour exercise. However, the real world problems of healthcare rationing and priority-setting are too complex for a three-hour exercise. What is needed, as a supplement, are sustained processes of rational democratic deliberation that can address the challenges to healthcare justice posed by costly emerging medical technologies, such as these targeted cancer therapies.

D019587:Dietary Supplements
D015276:Health Care Rationing
D006801:Humans
D019458:Insurance Coverage
D012935:Social Justice
D014047:Tolnaftate

Priority-Setting
Rationing
Rational Democratic Deliberation
Healthcare Justice
Cost-Effectiveness


Response of ammonia-oxidizing archaea and bacteria to sulfadiazine and copper and their interaction in black soils.

Abstract: The large-scale development of animal husbandry and the wide agricultural application of livestock manure lead to more and more serious co-pollution of heavy metals and antibiotics in soil. In this study, two common feed additives, copper (Cu) and sulfadiazine (SDZ), were selected as target pollutants to evaluate the toxicity and interaction of antibiotics and heavy metals on ammonia oxidizers diversity, potential nitrification rate (PNR), and enzymatic activity in black soils. The results showed that soil enzyme activity was significantly inhibited by single Cu pollution, but the toxicity could be reduced by introducing low-concentration SDZ (5 mg · kg-1), which showed an antagonistic effect between Cu and SDZ (5 mg · kg-1), while the combined toxicity of high-concentration SDZ (10 mg · kg-1) and Cu were strengthened compared with the single Cu contamination on soil enzymes. In contrast, soil PNR was more sensitive to single Cu pollution and its combined pollution with SDZ than the enzyme activity. Real-time fluorescence quota PCR and Illumina Hiseq/Miseq sequencing results showed that ammonia-oxidizing archaea (AOA) was decreased in C2 (200 mg · kg-1 Cu treatment) and ammonia-oxidizing bacteria (AOB) was obviously stimulated in soil contaminated in C2, while in S5 (5 mg · kg-1 SDZ treatment), AOB was decreased; both AOA and AOB were significantly decreased at gene level in soils with combined pollutants (C2S5, 200 mg · kg-1 Cu combined with 5 mg · kg-1 SDZ). So, it can be concluded that combined pollution can cause more serious toxicity on the enzymatic activity, PNR, and ammonia-oxidizing microorganisms in soil through the synergistic effect between heavy metals and antibiotics pollutants.

Cu
SDZ
Enzyme activity
AOA
AOB
Combined contamination


mRNA expression of transient receptor potential melastatin (TRPM) channels 2 and 7 in perinatal brain development.

Abstract: TRPM7 and TRPM2 are non-specific cation channels of the Transient Receptor Potential channel superfamily. Each channel has gained attention for their potential to mediate oxidative and anoxic cell death (Rama and García, 2016; Nazıroğlu, 2011a; Abiria et al., 2017; Sun, 2017), however their physiological expression and roles in the developing brain remain poorly defined. We employed real-time reverse transcription PCR to examine mRNA expression of TRPM7 and TRPM2 in the developing rat brain and brain-specific cell types. We determined the temporal and spatial expression patterns at four developmental time points (postnatal day 7, 14, 21, and 90) in four critical regions of the brain (cortex, hippocampus, striatum, and cerebellum) and examined gene expression in neuronal, astrocytic, and microglial primary cell cultures. Our results revealed that TRPM7 mRNA expression peaks in the cortex at 2-weeks after birth, and thus correlates most closely with a period of rat brain development associated with neurite outgrowth, which is heightened at 2-weeks after birth. Our cell-specific gene expression assays revealed that TRPM7 was expressed at equivalent levels in neurons, astrocytes, and microglia. Conversely, TRPM2 was most highly expressed in microglia with little expression in neurons and astrocytes. In the hippocampus and striatum, the expression profile of TRPM2 parallels the perinatal expression timeline for microglial infiltration and maturation in the rat brain. Microglial maturation is highest from the time of birth, up to 7-days, but subsequently declines. The latter developmental expression profiles indicate a role for TRPM2 in microglial activation.

Ratnam|Melanie|M|
Chan|Jonathan|J|
Lesani|Naghmeh|N|
Sidorova-Darmos|Elena|E|
Eubanks|James H|JH|
Aarts|Michelle M|MM|

D060888:Real-Time Polymerase Chain Reaction

mRNA expression
Brain
Development
Neuron
Astrocyte
Microglia
Real-time PCR


A biotin-streptavidin-biotin bridge dramatically enhances cell fusion.

Abstract: Although the generation of hybrid cells by cell fusion plays a significant role in biotechnology and biomedicine, the low cell-fusion rates and the limitation of large-scale cell fusion for clinical applications of the two widely used approaches, polyethylene-glycol (PEG)-mediated cell fusion and electrofusion, hinder the application of this critical technology in certain key areas, including cancer immunotherapy. In the present study, a simple procedure that can not only significantly increase the heterologous cell fusion but is also capable of producing fused cells on a large scale is reported. A biotin-streptavidin-biotin (BSB) bridge was created by coating one to-be-fused cell with biotin and the other with biotin-streptavidin. The BSB bridge enhances cell-fusion rates induced with PEG fusion or electrofusion by 10-30% depending on the cell types when compared with cell fusions without the bridge. The procedure described increases heterologous cell pairing and eliminates the alignment step required for the majority of electrofusions. Notably, it can be used to make large-scale cell fusions for clinical applications.

Li|Jinhua|J|
Yu|Xianzhong|X|
Wagner|Thomas E|TE|
Wei|Yanzhang|Y|

cell fusion
polyethylene-glycol
biotin
electroporation
streptavidin


Investigating a novel multiplex proteomics technology for detection of changes in serum protein concentrations that may correlate to tumor burden.

Abstract: Background: To account for cancer heterogeneity, we previously introduced the concept of "personalized" tumor markers, which are biomarkers that are informative in subsets of patients or even a single patient. Recent developments in various multiplex protein technologies create excitement for the discovery of markers of tumor burden in individual patients, but the reliability of the technologies remains to be tested for this purpose. Here, we sought to explore the potential of a novel proteomics platform, which utilizes a multiplexed antibody microarray, to detect changes in serum protein concentration that may correlate to tumor burden in pancreatic cancer. Methods: We applied the Quantibody® Human Kiloplex Array to simultaneously measure 1,000 proteins in sera obtained pre- and post-surgically from five pancreatic cancer patients. We expected that proteins which decreased post-surgery may correlate to tumor burden. Sera from two healthy individuals, split into two aliquots each, were used as controls. To validate the multiplexed results, we used single-target ELISA assays to measure the proteins with the largest serum concentration changes after surgery in sera collected pre- and post-surgically from the previous five patients and 10 additional patients. Results: The multiplexed array revealed nine proteins with more than two-fold post-surgical decrease in at least two of five patients. However, validation using single ELISAs showed that only two proteins tested displayed more than two-fold post-surgical decrease in one of the five original patients. In the independent cohort, six of the proteins tested showed at least a two-fold decrease post-surgery in at least one patient. Conclusions: Our study found that the Quantibody® Human Kiloplex Array results could not be reliably replicated with individual ELISA assays and most hits would likely represent false positives if applied to biomarker discovery. These findings suggest that data from novel, high-throughput proteomic platforms need stringent validation to avoid false discoveries.

multiplex
proteomics
protein technologies
pancreatic cancer
ELISA
immunoassay


Isometrically Resolved Photoacoustic Microscopy Based on Broadband Surface Plasmon Resonance Ultrasound Sensing.

Abstract: Photoacoustic microscopy (PAM) can measure optical absorption-based molecular specificities within tissues. Despite the diffraction-limited lateral resolution in optical-resolution photoacoustic microscopy (OR-PAM), the ongoing challenge is poor axial resolution because of an insufficient ultrasound detection bandwidth, which hampers PAM volumetric imaging. We propose polarization-differential surface plasmon resonance (SPR) sensing for broadband and high-sensitivity photoacoustic (PA) detection, allowing OR-PAM with comparable resolution along lateral and axial directions. This sensor possesses an estimated noise-equivalent-pressure sensitivity of ∼477 Pa over an approximately linear pressure response up to 107 kPa. Moreover, an improved PA detection bandwidth of ∼173 MHz permits an axial resolution (∼7.6 μm) that approaches the lateral resolution (∼4.5 μm) of our OR-PAM system. The capability in spatially isometric micrometer-scale resolution enables in vivo volumetric label-free imaging of the microvasculature of a mouse ear. The SPR sensing technology promises broader applications of PAM in biomedical studies such as microcirculation.

photoacoustic microscopy
surface plasmon resonance
sensitivity
broad bandwidth
in vivo imaging
spatial resolution


Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer.

Abstract: Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allele-specific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.

Lee|Donghyun D|DD|
Komosa|Martin|M|
Sudhaman|Sumedha|S|
Leão|Ricardo|R|
Zhang|Cindy H|CH|
Apolonio|Joana D|JD|
Hermanns|Thomas|T|
Wild|Peter J|PJ|
Klocker|Helmut|H|
Nassiri|Farshad|F|
Zadeh|Gelareh|G|
Diplas|Bill H|BH|
Yan|Hai|H|
Gallinger|Steven|S|
Pugh|Trevor J|TJ|
Ramaswamy|Vijay|V|
Taylor|Michael D|MD|
Castelo-Branco|Pedro|P|
Nunes|Nuno Miguel|NM|
Tabori|Uri|U|

Cancer Oncology Epigenetics Genetics Telomeres


Targeting of the purine biosynthesis host cell pathway enhances the activity of tenofovir against sensitive and drug-resistant HIV-1.

Abstract:
BACKGROUND
Targeting host-cell pathways to increase the potency of nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) is an important strategy for clinical investigation. Resveratrol is a natural product that inhibits cellular ribonucleotide reductase, prolonging the S phase of the cell cycle and preferentially lowering dATP levels.

METHODS
We performed in vitro evaluation of resveratrol on the antiviral activity of adenosine analog tenofovir (TFV) against sensitive and drug-resistant human immunodeficiency virus type 1 (HIV-1), from subtypes B and C, in primary cells.

RESULTS
Resveratrol enhanced the antiviral activity of TFV by up to 10-fold and restored susceptibility of TFV-resistant viruses. Resveratrol prevented wild-type HIV-1 from developing phenotypic resistance to TFV. Notably, resveratrol enhanced TFV activity against sensitive and resistant HIV-1 from both subtypes B and C.

CONCLUSIONS
Prolonged wide-scale use of thymidine analogs in the setting of viral failure has limited the efficacy of second-line NRTI-based regimens in Africa. Moreover, the extensive use of ddI and d4T has led to high frequencies of the K65R mutation, further compromising TFV efficacy. In light of increasing resistance to commonly used NRTIs in global HIV treatment programs, targeting nucleoside biosynthesis with resveratrol, or derivatives with improved bioavailabilities, is a potential strategy to maintain, enhance, and restore susceptibility of commonly used NRTIs.

Heredia|Alonso|A|
Davis|Charles E|CE|
Reitz|Marvin S|MS|
Le|Nhut M|NM|
Wainberg|Mark A|MA|
Foulke|James S|JS|
Wang|Lai-Xi|LX|
Redfield|Robert R|RR|

tenofovir
HIV-1
NRTI
resveratrol
antiretrovirals
drug resistance
subtype C


Modified Method of rRNA Structure Analysis Reveals Novel Characteristics of Box C/D RNA Analogues.

Abstract: Ribosomal RNA (rRNA) maturation is a complex process that involves chemical modifications of the bases or sugar residues of specific nucleotides. One of the most abundant types of rRNA modifications, ribose 2'-O-methylation, is guided by ribonucleoprotein complexes containing small nucleolar box C/D RNAs. Since the majority of 2'-O-methylated nucleotides are located in the most conserved regions of rRNA that comprise functionally important centers of the ribosome, an alteration in a 2'-O-methylation profile can affect ribosome assembly and function. One of the key approaches for localization of 2'-O-methylated nucleotides in long RNAs is a method based on the termination of reverse transcription. The current study presents an adaptation of this method for the use of fluorescently labeled primers and analysis of termination products by capillary gel electrophoresis on an automated genetic analyzer. The developed approach allowed us to analyze the influence of the synthetic analogues of box C/D RNAs on post-transcriptional modifications of human 28S rRNA in MCF-7 cells. It has been established that the transfection of MCF-7 cells with a box C/D RNA analogue leads to an enhanced modification level of certain native sites of 2'-O-methylation in the target rRNA. The observed effect of synthetic RNAs on the 2'-O-methylation of rRNA in human cells demonstrates a path towards targeted regulation of rRNA post-transcriptional maturation. The described approach can be applied in the development of novel diagnostic methods for detecting diseases in humans.

Filippova|J A|JA|
Stepanov|G A|GA|
Semenov|D V|DV|
Koval|O A|OA|
Kuligina|E V|EV|
Rabinov|I V|IV|
Richter|V A|VA|

small nucleolar box C/D RNAs
RNA 2’-O-methylation
RNA post-transcriptional modifications
reverse transcription termination


Experimental design for TBT quantification by isotope dilution SPE-GC-ICP-MS under the European water framework directive.

Abstract: In Europe the maximum allowable concentration for tributyltin (TBT) compounds in surface water has been regulated by the water framework directive (WFD) and daughter directive that impose a limit of 0.2 ng L(-1) in whole water (as tributyltin cation). Despite the large number of different methodologies for the quantification of organotin species developed in the last two decades, standardised analytical methods at required concentration level do not exist. TBT quantification at picogram level requires efficient and accurate sample preparation and preconcentration, and maximum care to avoid blank contamination. To meet the WFD requirement, a method for the quantification of TBT in mineral water at environmental quality standard (EQS) level, based on solid phase extraction (SPE), was developed and optimised. The quantification was done using species-specific isotope dilution (SSID) followed by gas chromatography (GC) coupled to inductively coupled plasma mass spectrometry (ICP-MS). The analytical process was optimised using a design of experiment (DOE) based on a factorial fractionary plan. The DOE allowed to evaluate 3 qualitative factors (type of stationary phase and eluent, phase mass and eluent volume, pH and analyte ethylation procedure) for a total of 13 levels studied, and a sample volume in the range of 250-1000 mL. Four different models fitting the results were defined and evaluated with statistic tools: one of them was selected and optimised to find the best procedural conditions. C18 phase was found to be the best stationary phase for SPE experiments. The 4 solvents tested with C18, the pH and ethylation conditions, the mass of the phases, the volume of the eluents and the sample volume can all be optimal, but depending on their respective combination. For that reason, the equation of the model conceived in this work is a useful decisional tool for the planning of experiments, because it can be applied to predict the TBT mass fraction recovery when the experimental conditions are drawn. This work shows that SPE is a convenient technique for TBT pre-concentration at pico-trace levels and a robust approach: in fact (i) number of different experimental conditions led to satisfactory results and (ii) the participation of two institutes to the experimental work did not impact the developed model.

Alasonati|Enrica|E|
Fabbri|Barbara|B|
Fettig|Ina|I|
Yardin|Catherine|C|
Del Castillo Busto|Maria Estela|ME|
Richter|Janine|J|
Philipp|Rosemarie|R|
Fisicaro|Paola|P|

Experimental design
Isotope dilution
Water framework directive
Tributyltin
Organotin compounds
Solid-phase extraction


Associations of depressive symptoms with outcomes in patients implanted with left ventricular assist devices.

Abstract:
OBJECTIVE
We examined characteristics of depressive symptoms in patients who received left ventricular assist devices (LVAD) to assess their effects on negative outcomes post-implantation.

METHODS
We retrospectively identified 203 adults with pre-operative PHQ-9 scores who underwent LVAD placement as bridge to transplant (BTT) or destination therapy (DT). We analyzed effects of PHQ-9 total, somatic, and cognitive/affective scores and proportion of patients with clinical depression on all-cause mortality, rehospitalization, major bleeding, and neurologic events post-implantation, controlling for demographics and other medical comorbidities.

RESULTS
Mean total PHQ-9 scores did not differ between 81 BTT and 122 DT patients (BTT 6.4 vs. DT 7.5, p = 0.12). A higher proportion of DT patients had clinical depression (BTT 22% vs. DT 39%, p = 0.015). Somatic symptoms accounted for three-quarters of total scores in both groups. PHQ-9 domains were not associated with negative outcomes post-implantation.

CONCLUSION
Depression severity did not differ based on implant strategy, but more DT patients had clinical depression. Somatic symptoms were the biggest contributor to depressive symptoms. Pre-implantation PHQ-9 scores were not associated with outcomes, possibly because depression was mild in both groups. Additional work is needed in LVAD patients to better characterize depressive symptoms and their unique effects on clinical course and well-being.

Suarez|Laura|L|
Dunlay|Shannon M|SM|
Schettle|Sarah D|SD|
Stulak|John M|JM|
Staab|Jeffrey P|JP|

Depression
Left ventricular assist device (LVAD)
Somatic
Cognitive/affective
End-stage heart failure
Patient health questionnaire (PHQ-9)


Sin1 (Stress-Activated Protein Kinase-Interacting Protein) Regulates Ischemia-Induced Microthrombosis Through Integrin αIIbβ3-Mediated Outside-In Signaling and Hypoxia Responses in Platelets.

Abstract: Objective- Microthrombosis as a serious consequence of myocardial infarction, impairs the microvascular environment and increases the occurrences of heart failure, arrhythmia, and death. Sin1 (stress-activated protein kinase-interacting protein) as an essential component of mTORC2 (mammalian target of rapamycin complex 2) is required for cell proliferation and metabolism in response to nutrients, stress, and reactive oxygen species and activates Akt and PKC (protein kinase C). However, the activation and function of Sin1/mTORC2 in ischemia-induced microthrombosis remain poorly understood. Approach and Results- The phosphorylation of the mTORC2 target Akt at S473 (serine 473) was significantly elevated in platelets from the distal end of left anterior descending obstructions from patients who underwent off-pump coronary artery bypass grafting compared with platelets from healthy subjects. Consistent with this finding, phosphorylation of T86 in Sin1 was also dramatically increased. Importantly, the augmented levels of phosphorylated Sin1 and Akt in platelets from 61 preoperative patients with ST-segment-elevation myocardial infarction correlated well with the no-reflow phenomena observed after revascularization. Platelet-specific Sin1 deficiency mice and Sin1 T86 phosphorylation deficiency mice were established to explore the underlying mechanisms in platelet activation. Mechanistically, Sin1 T86 phosphorylation amplifies mTORC2-mediated downstream signals; it is also required for αIIbβ3-mediated outside-in signaling and plays a role in generating hypoxia/reactive oxygen species through NAD+/Sirt3 (sirtuin 3)/SOD2 (superoxide dismutase 2) pathway. Importantly, Sin1 deletion in platelets protected mice from ischemia-induced microvascular embolization and subsequent heart dysfunction in a mouse model of myocardial infarction. Conclusions- Together, the results of our study reveal a novel role for Sin1 in platelet activation. Thus, Sin1 may be a valuable therapeutic target for interventions for ischemia-induced myocardial infarction deterioration.

Xu|Yanyan|Y| Ouyang|Xinxing|X| Yan|Lichong|L| Zhang|Mingliang|M| Hu|Zhenlei|Z| Gu|Jianmin|J| Fan|Xuemei|X| Zhang|Lin|L| Zhang|Junfeng|J| Xue|Song|S| Chen|Guoqiang|G| Su|Bing|B| Liu|Junling|J|

D048868:Adaptor Proteins, Signal Transducing

D000076225:Mechanistic Target of Rapamycin Complex 2

D019039:Platelet Glycoprotein GPIIb-IIIa Complex

hypoxia
myocardial infarction
cell proliferation
protein kinase C
serine


Dauricine upregulates the chemosensitivity of hepatocellular carcinoma cells: Role of repressing glycolysis via miR-199a:HK2/PKM2 modulation.

Abstract: Dauricine (Dau) is a natural alkaloid exhibiting anti-proliferative activity against several different types of malignant cell. However, effects of Dau on hepatocellular carcinoma (HCC) cells and the underlying molecular mechanisms have remained to be fully elucidated. In this study, we found that Dau elevated the sensitivities of HCC cells to chemotherapeutic reagents, including cisplatin, sorafenib, and isoliensinine. Moreover, Dau promoted apoptosis of HCC cells triggered by these chemotherapeutic reagents. Consistently, in a xenograft mouse model, Dau sensitized HCC cells to sorafenib. In HCC cells, Dau dose-dependently inhibited glucose glycolysis and increased oxidative phosphorylation. Mechanistically, Dau downregulated the expression of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). HK2 and PKM2 can be directly targeted by miR-199a. Dau dose-dependently increased miR-199a expression in HCC cells. Transfection of anti-miR-199a abrogated Dau-mediated suppression of HK2 and PKM2. Dau-induced metabolic shift was thereby severely crippled by anti-miR-199a. In addition, the incremental activity of Dau on sorafenib sensitivity of HCC cells was diminished in response to the transfection of anti-miR-199a. Taken together, our findings provided novel insights into the impact of Dau on HCC cells and supported considering Dau as an adjuvant reagent in the clinical treatment of HCC.

Li|Wei|W| Qiu|Yunhan|Y| Hao|Ji|J| Zhao|Chi|C| Deng|Xukun|X| Shu|Guangwen|G|

Dauricine
Chemosensitivity
Hepatocellular carcinoma
Glycolysis
MiR-199a


CoQ10 promotes resolution of necrosis and liver regeneration after acetaminophen-induced liver injury.

Abstract: Coenzyme Q10 (CoQ10) which acts as an electron transporter in the mitochondrial respiratory chain has many beneficial effects on liver diseases. In our previous research, CoQ10 has been found to attenuate acetaminophen (APAP) induced acute liver injury (ALI). However, whether CoQ10 administration is still effective at the late stage of APAP overdose is still unknown. In this study, we aimed to test CoQ10 efficacy at the late stage of APAP overdose. C57BL/6J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 16 hours after APAP treatment. The results showed that while CoQ10 treatment at 16 hours post-APAP overdose had no effects on the expression of ROS generated genes or scavenged genes, it still significantly decreased necrosis of hepatocytes following APAP-induced ALI. Moreover, CoQ10 increased MerTK+ macrophages accumulation in the APAP-overdose liver and inhibition of MerTK signaling partly abrogated the protective role of CoQ10 treatment on the hepatic necrosis. CoQ10 treatment also significantly enhanced hepatocytes proliferation as shown in the increased BrdU incorporation in the APAP-intoxicated mice liver section. In addition, CoQ10 treatment increased hepatic PCNA and Cyclin D1 expression and promoted activation of the β-catenin signaling in APAP-overdose mice. To conclude, these data provide evidence that CoQ10 treatment is still effective at the late stage of APAP-induced ALI and promotes resolution of necrosis and liver regeneration following ALI.

Chen|Shen|S| Tang|Yi|Y| Fang|Wanjun|W| He|Taiping|T| Chen|Xu|X| Zhang|Peiwen|P|

liver regeneration
Coenzyme Q10
acetaminophen
β-catenin


Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition.

Abstract: One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age-dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is an upstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent with this, blocking BTK impairs p53-induced senescence. This suggests that sustained BTK inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of BTK, prolonged the maximum lifespan of a Zmpste24-/- progeroid mice, which also showed a reduction in general age-related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety-like behaviour and better long-term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower accumulation of senescent cells after BTK inhibition. Our data show that blocking BTK has a modest increase in lifespan in Zmpste24-/- mice and protects them from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age-related degeneration of organs such as the brain.

Ekpenyong-Akiba|Akang E|AE|
Poblocka|Marta|M|
Althubiti|Mohammad|M|
Rada|Miran|M|
Jurk|Diana|D|
Germano|Sandra|S|
Kocsis-Fodor|Gabriella|G|
Shi|Yu|Y|
Canales|Juan J|JJ|
Macip|Salvador|S|0000-0003-1963-8840

BTK
p53
cellular senescence
healthspan
progeria


Providing Context for Ambient Particulate Matter and Estimates of Attributable Mortality.

Abstract: Four papers on fine particulate matter (PM2.5 ) by Anenberg et al., Fann et al., Shin et al., and Smith contribute to a growing body of literature on estimated epidemiological associations between ambient PM2.5 concentrations and increases in health responses relative to baseline notes. This article provides context for the four articles, including a historical review of provisions of the U.S. Clean Air Act as amended in 1970, requiring the setting of National Ambient Air Quality Standards (NAAQS) for criteria pollutants such as particulate matter (PM). The substantial improvements in both air quality for PM and population health as measured by decreased mortality rates are illustrated. The most recent revision of the NAAQS for PM2.5 in 2013 by the Environmental Protection Agency distinguished between (1) uncertainties in characterizing PM2.5 as having a causal association with various health endpoints, and as all-cause mortality, and (2) uncertainties in concentration--excess health response relationships at low ambient PM2.5 concentrations below the majority of annual concentrations studied in the United States in the past. In future reviews, and potential revisions, of the NAAQS for PM2.5 , it will be even more important to distinguish between uncertainties in (1) characterizing the causal associations between ambient PM2.5 concentrations and specific health outcomes, such as all-source mortality, irrespective of the concentrations, (2) characterizing the potency of major constituents of PM2.5 , and (3) uncertainties in the association between ambient PM2.5 concentrations and specific health outcomes at various ambient PM2.5 concentrations. The latter uncertainties are of special concern as ambient PM2.5 concentrations and health morbidity and mortality rates approach background or baseline rates.

D014484:United States Environmental Protection Agency

particulate matter
PM2.5
Clean Air Act
National Ambient Air Quality Standards
criteria pollutants


In Vitro Skin Retention and Drug Permeation through Intact and Microneedle Pretreated Skin after Application of Propranolol Loaded Microemulsions.

Abstract:
PURPOSE
Topical beta-blockers are efficacious for treating infantile hemangiomas, but no formulations have been specifically optimized for skin delivery. Our objective was to quantify skin concentrations and drug permeation of propranolol (a nonselective beta-blocker) after application of microemulsions to intact and microneedle pretreated skin.

METHODS
Four propranolol-loaded microemulsions were characterized for droplet size, surface charge, conductivity, pH, drug solubility, and drug release. Skin concentrations and drug permeation through skin were quantified using LC-MS. Skin-to-receiver ratios were used to compare the microemulsion formulations to a drug-in-PBS solution.

RESULTS
Propranolol solubility was significantly greater in microemulsions vs PBS. Cumulative drug release from the microemulsions over 24 h ranged from 13 to 26%. Skin concentrations and drug permeation through intact skin was significantly higher from PBS; however, the skin-to-receiver ratios were significantly higher for water-rich microemulsions compared to PBS or surfactant-rich microemulsions. Microneedle pretreatment significantly increased skin concentrations for all formulations. Skin-to-receiver ratios significantly increased after microneedle pretreatment for surfactant-rich microemulsions.

CONCLUSIONS
Microemulsion formulation can be altered to elicit different drug delivery profiles through MN-treated skin. This could be advantageous for maximizing local skin drug concentrations and improving dosing schedules for infantile hemangioma treatment.

skin
microneedle
propranolol
microemulsion
infantile hemangioma


Lipid profile and metabolic syndrome status in patients with oral lichen planus, oral lichenoid reaction and healthy individuals attending a dental college in northern India - a descriptive study.

Abstract:
BACKGROUND
Chronic inflammation causes disturbances in the lipid metabolism. When this dyslipidemia becomes prolonged it increases the risk of cardiovascular disease. Recent literature reveals similar dyslipidemia in patients with lichen planus. However, the results were not compared with lichenoid reactions.

OBJECTIVE
The aim of this study was to profile the lipid levels and metabolic syndrome status in patients with oral lichen planus (OLP), oral lichenoid reactions (OLR) and healthy individuals in order to evaluate their respective cardiovascular risk.

MATERIALS AND METHODS
This case-control descriptive study included 32 adults from the OPD visiting the Department of Oral Medicine, 18 with either oral lichen planus or oral lichenoid reactions and 14 age and sex matched healthy controls. Ethical clearance and informed consent were obtained. Their lipid levels, body mass index and metabolic syndrome status were evaluated. Statistical analyses were performed with the SPSS version 16.0 software.P≥0.05 was considered significant.

RESULTS
The key findings of this study were a) increased levels of S.cholesterol and LDL-C in OLP and OLR patients when compared to normal healthy individuals b) significantly higher S.triglyceride and VLDL in OLP when compared to OLR and c) lower HDL-C levels in OLP when compared to OLR. 2(18%) patients with OLP and 3(50%) with OLR were found to have high BMI suggestive of obesity whereas none of the normal individuals were obese.

CONCLUSION
There may be an association between chronic inflammation and dyslipidemia that increases the risk for cardiovascular disease. OLP and OLR patients have increased serum cholesterol and LDL-C when compared to normal adults. Further research on lipid levels in OLR are required to establish the findings of this study.

Krishnamoorthy|Bhuvana|B|
Gn|Suma|S|
N S|Mamatha|M|
M B|Sowbhagya|S|
Garlapati|Komali|K|

Lipid profile
Metabolic syndrome status
Oral lichen planus
Oral lichenoid reaction
Dyslipidemia


Impact of meniscal coverage on subchondral bone mineral density of the proximal tibia in female subjects - A cross-sectional in vivo study using QCT.

Abstract:
OBJECTIVE
To verify earlier data in cadavers that in female subjects with OA meniscal coverage is associated with lowered bone mineral density of the underlying subchondral bone in the proximal tibia by investigating the local bone mineral density (BMD) distribution within the epiphysis.

METHODS
BMD of the subchondral bone of the tibia was measured by QCT in 67 elderly females diagnosed with OA (Kellgren-Lawrence grades 2-3). The epiphysis was subdivided along the axis of the tibia into a subchondral-epiphyseal VOI covering the first 5-6 mm below the subchondral bone plate, a mid-epiphyseal VOI covering the adjacent 7-8 and a juxtaphyseal VOI of another 7-8 mm that bordered the growth plate. These VIOs were further divided into lateral and medial and then into anterior, mid and posterior sub-VOIs. Finally, all subVOIs were divided in one subVOI covered by the menisci (CM) and another not covered by the menisci (nCM). BMD ratios of these two subVOIs were compared.

RESULTS
In the subchondral epiphysis BMD was significantly lower (Medial: mean BMDdiff = 125 mg/cm3, p<0.001; Lateral: mean BMDdiff = 56 mg/cm3p < 0.001) in subVOIs covered by the meniscus compared to subVOIs not covered by the meniscus. The BMD difference was no longer significant in the mid epiphysis (Medial: mean BMDdiff = 10 mg/cm3, p>0.82; Lateral: mean BMDdiff = 7 mg/cm3, p=0.99) and was reversed in the juxtaphysis. With a few exceptions these BMD differences were independent of the lateral-medial and the anterior-mid-posterior position. BMD significantly (p<0.05) decreased with age independent on whether the location was covered or uncovered by the meniscus, however the BMD ratio of the corresponding nCM and CM subVOIs did not significantly (p>0.1) change with age.

CONCLUSION
In-vivo QCT measurements of the BMD distribution in the proximal tibia indicate a protective effect of the menisci in the subchondral bone close to the joint. This protective effect is age independent despite the overall age-related decrease of BMD.

Sannmann|Frederike|F| Laredo|Jean-Denis|JD| Chappard|Christine|C| Engelke|Klaus|K|

Subchondral bone
Tibia
QCT
BMD
Meniscus
Knee
Osteoarthritis


Diametric measurement of foveal avascular zone in healthy young adults using optical coherence tomography angiography.

Abstract:
BACKGROUND
The objective of this study is to measure the diameter size of foveal avascular zone (FAZ) in both eyes of healthy young adults using optical coherence tomography (OCT) angiography.

METHODS
A cross sectional study to measure the foveal avascular zone in healthy young adults. Subjects underwent OCT angiography using Zeiss AngioPlex OCT angiography in both eyes.

RESULTS
30 eyes of 15 healthy young adults were evaluated. The mean horizontal FAZ diameter of superficial vascular plexus was 661.166 ± 119.99 microns and mean vertical FAZ diameter was 660.033 ± 96.169 microns (P = 0.9442). The mean horizontal FAZ diameter of deep vascular plexus was 1011.2 ± 154.526 microns and the mean vertical FAZ diameter of deep vascular plexus was 818.033 ± 102.108 microns. There was no difference between the contralateral eyes of subjects in FAZ diameter of both superficial and deep capillary plexuses.

CONCLUSION
The mean diametric size of FAZ in superficial capillary plexus is 660.599 ± 0.801 microns and deep capillary plexus is 914.616 ± 136.589 microns. There was no significant difference with the contralateral eyes.

Optical coherence tomography angiography


Investigations on characteristics of polyurethane foam impregnated with nanochitosan and nanosilver/silver oxide and its effectiveness in phosphate removal.

Abstract: A novel potential adsorbent, produced with chitosan nanoparticles and silver/silver oxide nanoparticles impregnated on polyurethane foam (PFCA), is developed for phosphate removal in aqueous solutions. The ultraviolet-visible (UV-Vis) spectroscopy uncovered the emergence of nanoparticles. The field emission scanning electron microscopy (FESEM) provided the mean size of chitosan nanoparticles between 56 and 112 nm and that of silver-silver oxide nanoparticles between 44 and 75 nm. Energy dispersive X-ray (EDX) spectroscopy determined the presence of specific elements (C, O, P and Ag) in the adsorbent before and after treatment. Fourier transform infrared (FTIR) spectroscopy revealed the interplay between the N-H bond of amino group in PFCA and phosphate ions during adsorption. X-ray diffraction (XRD) analysis of PFCA showed nearly the same pattern before and after treatment, indicating the stability of PFCA. The silver ion concentration in the effluent from inductively coupled plasma optical emission spectroscopy (ICP-OES) analysis was found to be very less and below the drinking water limits. The surface area estimated by Brunauer-Emmett-Teller (BET) studies was found to be 2.17 m2/g. The experimental studies showed that PFCA can remove 61.24% of phosphate from an influent phosphate phosphorus concentration of 50 mg P/L, at its propitious condition. Even after 7 cycles of reuse, PFCA proved to be effective in removing 20.58% of phosphate. Hence, PFCA can be considered to be a potential sorbent for removing phosphate from surface water. Graphical abstract.

Sasidharan|Anjali P|AP|
Meera|V|V|
Raphael|Vinod P|VP|

Polyurethane foam
Impregnation
Phosphate
Chitosan nanoparticles
Silver/silver oxide nanoparticles


Nine years' trend of dental caries and severe early childhood caries among 3-6-year-old children in Babol, Northern Iran.

Abstract:
BACKGROUND AND OBJECTIVE
Malnutrition, pain, and insomnia are common adverse effects of early dental caries among 3-6-year-old children. To increase our understanding of the dental caries status which will help in the control and prevention of it, this study aimed to assess the trend of dental caries, Severe Early Childhood Caries (S-ECC) and its related factors among 3-6-year-old children during a 9-year period in Babol, Northern Iran.

METHODS
This was a cross-sectional study among 2,080 children aged 3-6 years old in Babol, Northern Iran. The studied samples were examined from May 2007 to June 2015. Oral examinations were performed with visual-touch technique. S-ECC was measured as number of decayed, missing, and filled teeth surface (dmfs). Data were evaluated by SPSS software for Windows version 23 and were analyzed using the one-way ANOVA, chi-square test and independent-samples t-test. Level of significance was set at ≤ 0.05.

RESULTS
The trend of dental caries and S-ECC rose among 3-6-year-old children over a 9-year period. Of the children, 26.3% were caries free. The mean dmft was increased significantly among boys (p<0.001), among 3-4-year-old children (p=0.01), and those children with both employed parents (p=0.01) and low educated parents (p<0.001) from 2007 to 2015.

CONCLUSION
Dental caries status showed an increasing trend over the study period in Babol preschool children, therefore effective preventive strategies are required to decrease the prevalence of dental caries in children.

Sistani|Mohammad Mehdi Naghibi|MMN|
Hataminia|Zohreh|Z|
Hajiahmadi|Mahmoud|M|
Khodadadi|Effat|E|

Trend
Dental caries
Iran
Preschool children


Structural insights into acyl-ACP selective recognition by the Aeromonas hydrophila AHL synthase AhyI.

Abstract:
BACKGROUND
Aeromonas hydrophila is a gram-negative bacterium and the major causative agent of the fish disease motile aeromonad septicemia (MAS). It uses N-acyl-homoserine lactone (AHL) quorum sensing signals to coordinate biofilm formation, motility, and virulence gene expression. The AHL signaling pathway is therefore considered to be a therapeutic target against pathogenic A. hydrophila infection. In A. hydrophila, AHL autoinducers biosynthesis are specifically catalyzed by an ACP-dependent AHL synthase AhyI using the precursors SAM and acyl-ACP. Our previously reported AhyI was heterologously expressed in E. coli, which showed the production characteristics of medium-long chain AHLs. This contradicted the prevailing understanding that AhyI was only a short-chain C4/C6-HSL synthase.

RESULTS
In this study, six linear acyl-ACP proteins with C-terminal his-tags were synthesized in Vibrio harveyi AasS using fatty acids and E. coli produced active holo-ACP proteins, and in vitro biosynthetic assays of six AHL molecules and kinetic studies of recombinant AhyI with a panel of four linear acyl-ACPs were performed. UPLC-MS/MS analyses indicated that AhyI can synthesize short-, medium- and long-chain AHLs from SAM and corresponding linear acyl-ACP substrates. Kinetic parameters measured using a DCPIP colorimetric assay, showed that there was a notable decrease in catalytic efficiency with acyl-chain lengths above C6, and hyperbolic or sigmoidal responses in rate curves were observed for varying acyl-donor substrates. Primary sequence alignment of the six representative AHL synthases offers insights into the structural basis for their specific acyl substrate preference. To further understand the acyl chain length preference of AhyI for linear acyl-ACP, we performed a structural comparison of three ACP-dependent LuxI homologs (TofI, BmaI1 and AhyI) and identified three key hydrophobic residues (I67, F125 and L157) which confer AhyI to selectively recognize native C4/C6-ACP substrates. These predictions were further supported by a computational Ala mutation assay.

CONCLUSIONS
In this study, we have redefined AhyI as a multiple short- to long-chain AHL synthase which uses C4/C6-ACP as native acyl substrates and longer acyl-ACPs (C8 ~ C14) as non-native ones. We also theorized that the key residues in AhyI would likely drive acyl-ACP selective recognition.

Jin|Lei|L| Bao|Jingjiao|J| Chen|Yu|Y| Yang|Wenge|W| Du|Wenyi|W|

Selective recognition
Aeromonas hydrophila
N-acyl-homoserine lactone
Biosynthesis
AhyI
Structural basis
Native acyl substrates


Taking Another Look: Thoughts on Behavioral Symptoms in Dementia and Their Measurement.

Abstract: This article proposes taking another look at behavioral symptoms of dementia (BSDs) both from a theoretical perspective that informs research and practice and from a measurement perspective. We discuss why this rethinking of behaviors impacts current models of care and our ability to better detect outcomes from interventions. We propose that BSDs be viewed from a pattern perspective and provide some suggestions for how to identify and measure these patterns that can influence the timing and type of intervention. Evidence suggests that BSDs are complex, sequential, patterned clusters of behavior recurring repeatedly in the same individual and escalate significantly without timely intervention. However, BSDs are frequently viewed as separate behaviors rather than patterns or clusters of behaviors, a view that affects current research questions as well as the choice, timing, and outcomes of interventions. These symptoms cause immense distress to persons with the disease and their caregivers, trigger hospitalizations and nursing home placement, and are associated with increased care costs. Despite their universality and that symptoms manifest across disease etiologies and stages, behaviors tend to be underrecognized, undertreated, and overmanaged by pharmacological treatments that may pose more harm than benefit.

behavioral symptoms
measurement
clustering
reconceptualization


Liquid biopsy in central nervous system tumors: the potential roles of circulating miRNA and exosomes.

Abstract: The Central nervous system (CNS) tumor still remains the most lethal cancer, and It is hard to diagnose at an earlier stage on most occasions. It is found that recurrent disease is finally observed in patients who occurred chemo-resistance after completely primary treatment. It is a challenge that monitoring treatment efficacy and tumor recurrence of CNS tumors are full of risks and difficulties by brain biopsies. However, the brain biopsies are considered as an invasive technique with low specificity and low sensitivity. In contrast, the liquid biopsy is based on blood and cerebrospinal fluid (CSF) test, which is going to acceptable among the patients through it's minimally invasive and serial bodily fluids. The advantages of liquid biopsy are to follow the development of tumors, provide new insights in real time, and accurate medical care. The major analytical constituents of liquid biopsy contain the Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating cell-free microRNAs (cfmiRNAs), and circulating exosomes. Liquid biopsy has been widely utilized in CNS tumors in recent years, and the CTCs and ctDNA have become the hot topics for researching. In this review, we are going to explain the clinical potential of liquid biopsy biomarkers in CNS tumor by testing circulating miRNAs and exosomes to evaluate diagnose, prognosis, and response to treatment.

Aili|Yirizhati|Y| Maimaitiming|Nuersimanguli|N| Mahemuti|Yusufu|Y| Qin|Hu|H| Wang|Yongxin|Y| Wang|Zengliang|Z|

liquid biopsy
tumor
circulating miRNAs
exosomes
Central nervous system (CNS)
diagnosis
treatment respond


The role of bioassays in the evaluation of ecotoxicological aspects within the PEF/OEF protocols: The case of WWTPs.

Abstract: The suitability evaluation of any industrial process should rely on economic, technical, social and, in particular, environmental aspects. The Commission Recommendation 2013/179/UE enables the improvement and the harmonization of the conventional evaluation of environmental footprints, such as LCA (Life Cycle Assessment), Carbon and Water Footprint, by suggesting the assessment of life cycle environmental performance of products and organisations (PEF, OEF). Novelty aspects reside in including new impact categories (namely, human toxicity cancer effects, human toxicity not-cancer effects and eco-toxicity). This paper presents an application of PEF/OEF protocol to the example case of an activated sludge wastewater treatment plant. Strengths and criticisms of this approach are discussed, by taking into consideration the possible final goal of the suitability assessment. Valuably, the adoption of bioassays (i.e., the input of their results in the models for calculating the life cycle environmental performance) for a more reliable evaluation of the impact on the ecosystem and human health is proposed.

Pedrazzani|Roberta|R| Cavallotti|Irma|I| Bollati|Edoardo|E| Ferreri|Marta|M| Bertanza|Giorgio|G|

D057919:Biological Oxygen Demand Analysis

Bioassays
Footprint
Impact
Human toxicity
Eco-toxicity
Freshwater


Treatment of chronic deep vein thrombosis using ultrasound accelerated catheter-directed thrombolysis.

Abstract:
OBJECTIVE
To evaluate the feasibility, efficacy and safety of ultrasound-accelerated catheter-directed thrombolysis (UACDT) in the delayed treatment of lower extremity deep venous thrombosis (DVT).

DESIGN
Twelve patients with unilateral iliofemoral or femoropopliteal DVT (mean symptom duration 92 ± 44 days) were prospectively investigated.

METHOD
UACDT was performed using recombinant human tissue plasminogen activator delivered using the EKOS EkoSonic system. Stents were deployed if indicated by post-procedure venography. Follow-up comprised weekly duplex ultrasound for 1 month and monthly thereafter.

RESULTS
Successful thrombolysis occurred in 11/12 limbs (92%; complete 6/12, partial 5/12) after a mean infusion time of 26 ± 7 hours. 2/12 patients required angioplasty and stent insertion. At a mean follow-up of 9 (6-15) months, 10/11 (91%) veins were patent whereas 1/11 re-occluded at 2 months (patient with protein-C deficiency). 2/11 limbs developed symptoms/signs of post-thrombotic syndrome and 3/11 had developed deep vein reflux (duplex ultrasound). 2/12 patients experienced peri-catheter bleeding but no major hemorrhage or symptomatic pulmonary embolism occurred.

CONCLUSIONS
This preliminary evidence suggests that UACDT may be a safe and effective option for the delayed treatment of lower limb DVT.

Dumantepe|M|M|
Tarhan|I A|IA|
Ozler|A|A|

D000328:Adult
D000800:Angioplasty, Balloon
D002406:Catheterization, Peripheral
D002908:Chronic Disease
D005240:Feasibility Studies
D005260:Female
D005343:Fibrinolytic Agents
D006801:Humans
D035002:Lower Extremity
D008297:Male
D008875:Middle Aged
D010690:Phlebography
D011183:Postoperative Complications
D011446:Prospective Studies
D015607:Stents
D015912:Thrombolytic Therapy
D010959:Tissue Plasminogen Activator
D016896:Treatment Outcome
D018084:Ultrasonography, Interventional
D014654:Vascular Patency
D020246:Venous Thrombosis

Chronic deep vein thrombosis
Ultrasound
Catheter-directed thrombolysis
Post-thrombotic syndrome


National trends in the presentation of surgically resected appendiceal adenocarcinoma over a decade.

Abstract:
BACKGROUND
Rates of nonoperative management of acute appendicitis and appendiceal adenocarcinoma have increased over a decade, but the presentation and outcomes of appendiceal adenocarcinoma over this period is not well-characterized.

METHODS
Patients with surgically resected Stage I-III appendiceal adenocarcinoma were identified from the 2006 to 2015 National Cancer Data Base and classified into two cohorts, 2006-2010 and 2011-2015, based on year of diagnosis. Three-year overall survival (OS) was analyzed using Cox proportional hazards regression and Kaplan-Meier survival estimates.

RESULTS
Of 4233 patients, 1369 (32.3%) and 2864 (67.7%) were diagnosed in 2006-2010 and 2011-2015, respectively. Following multivariable analysis, patients in 2011-2015 were more likely to be <40 years of age (6.4% vs. 4.7%, odds ratio [OR] 1.53, p .015), present with pT4 tumors (40.2% vs. 34.4%, OR 1.46, p .004), and undergo hyperthermic intraperitoneal chemotherapy (4.4% vs. 2.4%, OR 1.97, p .001). Comparing patients diagnosed in 2011-2015 to 2006-2010, adjusted 3-year OS was no different among all patients (81.1% vs. 79%, p .778).

CONCLUSIONS
There has been an increase in the proportion of patients with pT4 appendix tumors over time, primarily among older (≥60 years) patients. Even so, these shifts in presentation have not resulted in differences in survival outcomes.

appendix cancer
cancer outcomes
cancer trends
oncologic outcomes
oncologic trends
peritoneal surface malignancy


Hierarchically porous metal-organic frameworks: synthesis strategies, structure(s), and emerging applications in decontamination.

Abstract: Metal-organic frameworks (MOFs) with high porosity have received much attention as promising materials for many applications owing to their unique properties. However, to date, most of the reported MOFs have microporous structures, which slow down diffusion/mass transfer and limit the accessibility of bulky molecules to its internal surface. Thus, it is crucial to develop an efficient way to create larger pores (mesoporous and/or macroporous) into microporous MOFs to form hierarchical porous metal-organic frameworks (HP-MOFs), which facilitate the diffusion and mass transfer of guest molecules. HP-MOFs are excellent and promising candidates for environmental applications under the background of environmental contaminations. In this review paper, we are primarily focusing on the latest progress in the preparation of HP-MOFs by employing template-assisted and template-free synthetic approaches for environmental cleaning applications. Particularly, the adsorptive purification of the most common toxic substances, including gases, dyes, heavy metal ions, and antibiotics from the environment using HP-MOFs as adsorbents is briefly discussed. The overall results clearly showed that the superiority of HP-MOFs compared with conventional microporous MOFs. Finally, we summarize the remaining challenges and provide personal perspectives on possible future development of HP-MOFs.

Kabtamu|Daniel Manaye|DM|
Wu|Yi-Nan|YN|
Li|Fengting|F|

Hierarchical porous structure
Metal–organic frameworks
Pollution Control
Template-directed synthesis
Template-free synthesis


Minding the gap: learning and visual scanning behaviour in nocturnal bull ants.

Abstract: Insects possess small brains but exhibit sophisticated behaviour, specifically their ability to learn to navigate within complex environments. To understand how they learn to navigate in a cluttered environment, we focused on learning and visual scanning behaviour in the Australian nocturnal bull ant, Myrmecia midas, which are exceptional visual navigators. We tested how individual ants learn to detour via a gap and how they cope with substantial spatial changes over trips. Homing M. midas ants encountered a barrier on their foraging route and had to find a 50 cm gap between symmetrical large black screens, at 1 m distance towards the nest direction from the centre of the releasing platform in both familiar (on-route) and semi-familiar (off-route) environments. Foragers were tested for up to 3 learning trips with the changed conditions in both environments. The results showed that on the familiar route, individual foragers learned the gap quickly compared with when they were tested in the semi-familiar environment. When the route was less familiar, and the panorama was changed, foragers were less successful at finding the gap and performed more scans on their way home. Scene familiarity thus played a significant role in visual scanning behaviour. In both on-route and off-route environments, panoramic changes significantly affected learning, initial orientation and scanning behaviour. Nevertheless, over a few trips, success at gap finding increased, visual scans were reduced, the paths became straighter, and individuals took less time to reach the goal.

Visual navigation
Scene familiarity
Gap learning
Success rate


Referential shift in Nicaraguan Sign Language: a transition from lexical to spatial devices.

Abstract: Even the simplest narratives combine multiple strands of information, integrating different characters and their actions by expressing multiple perspectives of events. We examined the emergence of referential shift devices, which indicate changes among these perspectives, in Nicaraguan Sign Language (NSL). Sign languages, like spoken languages, mark referential shift grammatically with a shift in deictic perspective. In addition, sign languages can mark the shift with a point or a movement of the body to a specified spatial location in the three-dimensional space in front of the signer, capitalizing on the spatial affordances of the manual modality. We asked whether the use of space to mark referential shift emerges early in a new sign language by comparing the first two age cohorts of deaf signers of NSL. Eight first-cohort signers and 10 second-cohort signers watched video vignettes and described them in NSL. Narratives were coded for lexical (use of words) and spatial (use of signing space) devices. Although the cohorts did not differ significantly in the number of perspectives represented, second-cohort signers used referential shift devices to explicitly mark a shift in perspective in more of their narratives. Furthermore, while there was no significant difference between cohorts in the use of non-spatial, lexical devices, there was a difference in spatial devices, with second-cohort signers using them in significantly more of their narratives. This suggests that spatial devices have only recently increased as systematic markers of referential shift. Spatial referential shift devices may have emerged more slowly because they depend on the establishment of fundamental spatial conventions in the language. While the modality of sign languages can ultimately engender the syntactic use of three-dimensional space, we propose that a language must first develop systematic spatial distinctions before harnessing space for grammatical functions.

referential shift
sign language
narratives
language creation
spatial language


Spanish version of Pregnancy Symptoms Inventory: transcultural adaptation and reliability.

Abstract:
AIM
To transcultural adapt and analyze the reliability of Spanish version of Pregnancy Symptoms Inventory (PSI) and assess the prevalence of pregnancy symptoms in Spanish pregnant women.

MATERIALS AND METHODS
A subsample of 120 healthy pregnant women answered the PSI twice and a sample of 280 report the prevalence and limitation of pregnancy symptoms. The reliability was examined by means of percent agreement and weighted Kappa coefficients. The prevalence of pregnancy symptoms was evaluated by the frequency of answers.

RESULTS
Perfect and perfect-acceptable agreement was observed in 82% and 96% of the pregnant women, respectively. Weighted Kappa coefficients ranged from 0.589 to 0.889, indicating a good reliability. The most frequent symptoms perceived by Spanish pregnant women were urinary frequency, poor sleep, increased vaginal discharge and tiredness.

CONCLUSION
Spanish Pregnancy Symptoms Inventory is a brief, conceptually equivalent and satisfactory reliable tool that allows an early assessment of the wide range of pregnancy symptoms in the health care practices.

Oviedo-Caro|Miguel A|MA|
Bueno-Antequera|Javier|J|
Munguía-Izquierdo|Diego|D|

Pregnancy symptoms
health-related quality of life
pregnancy discomfort
prenatal care
prenatal diagnosis


Mucocele-like lesions in the breast diagnosed with percutaneous biopsy: is surgical excision necessary?

Abstract:
OBJECTIVE
The purpose of this study was to determine the frequencies of atypia and cancer at excisional biopsy of lesions with a diagnosis of mucocele-like lesion (MLL) at percutaneous breast biopsy.

MATERIALS AND METHODS
Retrospective review of 9286 lesions subjected to percutaneous imaging-guided biopsy identified MLLs in 35 (0.38%) patients. Medical records, imaging studies, and histologic results were reviewed.

RESULTS
Of the 35 patients with core biopsy findings of MLL, 27 underwent stereotactic core needle biopsy (19 with microcalcifications, five with calcifications with an associated mass, and three with only a mass), and eight underwent ultrasound-guided core needle biopsy (four with a solid mass, three with a complex cystic mass). At core biopsy, 12 of 35 (34%) MLLs were associated with atypia (10 cases of atypical ductal hyperplasia, two of flat epithelial atypia), and 23 of 35 (66%) were benign MLL only. All 12 MLLs associated with atypia and 12 of 23 benign MLLs were surgically excised. Eleven patients did not undergo surgery, five of whom were lost to follow-up. One of the 12 (3% of the 35) MLLs associated with atypia was upgraded to DCIS. None were upgraded to invasive cancer. None of the benign MLLs were upgraded to malignancy, and findings at excision of four of the 23 (17%) benign MLLs led to a change in diagnosis to a high-risk lesion (three atypical ductal hyperplasia, one atypical lobular hyperplasia).

CONCLUSION
MLL is a rare diagnosis but is encountered in large-volume breast practices. The findings are nonspecific with a range of imaging appearances. No imaging test is reliable for differentiating MLL from other suspicious lesions or lesions with associated atypia. Surgery is clearly warranted for MLL associated with atypia at core needle biopsy because it may be upgraded to malignancy upon excision. However, if the presence of atypia at excision of benign MLL will change clinical management, then benign MLL at core needle biopsy warrants surgical excision in some cases. In patients whose treatment will not change if atypia is found at excision, close surveillance with short-interval follow-up is a reasonable alternative.

Ha|Daon|D|
Dialani|Vandana|V|
Mehta|Tejas S|TS|
Keefe|Whitney|W|
Iuanow|Elaine|E|
Slanetz|Priscilla J|PJ|

D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration


The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms.

Abstract: High metabolic and proliferative rates in cancer cells lead to production of large amounts of H+ and CO2 , and as a result, net acid extruding transporters are essential for the function and survival of cancer cells. We assessed protein expression of the Na+ /H+ exchanger NHE1, the Na+ - HCO3- cotransporter NBCn1, and the lactate-H+ cotransporters MCT1 and -4 by immunohistochemical analysis of a large cohort of breast cancer samples. We found robust expression of these transporters in 20, 10, 4 and 11% of samples, respectively. NHE1 and NBCn1 expression both correlated positively with progesterone receptor status, NHE1 correlated negatively and NBCn1 positively with HER2 status, whereas MCT4 expression correlated with lymph node status. Stable shRNA-mediated knockdown (KD) of either NHE1 or NBCn1 in the MDA-MB-231 triple-negative breast cancer (TNBC) cell line significantly reduced steady-state intracellular pH (pHi ) and capacity for pHi recovery after an acid load. Importantly, KD of any of the three transporters reduced in vivo primary tumor growth of MDA-MB-231 xenografts. However, whereas KD of NBCn1 or MCT4 increased tumor-free survival and decreased in vitro proliferation rate and colony growth in soft agar, KD of NHE1 did not have these effects. Moreover, only MCT4 KD reduced Akt kinase activity, PARP and CD147 expression and cell motility. This work reveals that different types of net acid extruding transporters, NHE1, NBCn1 and MCT4, are frequently expressed in patient mammary tumor tissue and demonstrates for the first time that they promote growth of TNBC human mammary tumors in vivo via distinct but overlapping mechanisms.


Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy.

Abstract: Oxidative therapy, a strategy that specifically increases reactive oxygen species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues (2a-v and 15a-e) were designed, synthesized and evaluated for their pharmacological properties. Most of the compounds exhibited potent antiproliferative activities against five human cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast cancer cells and inhibited TrxR enzymatic activity. In addition, 2c increased ROS levels and resulted in marked apoptosis by regulating apoptosis-related proteins expressed in the breast cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast cancer candidate warranting further investigation.

Qian|Jianqiang|J|
Xu|Zhongyuan|Z|
Meng|Chi|C|
Liu|Ji|J|
Hsu|Pei-Ling|PL|
Li|Yangyang|Y|
Zhu|Weizhong|W|
Yang|Yumin|Y|
Morris-Natschke|Susan L|SL|
Lee|Kuo-Hsiung|KH|
Zhang|Yanan|Y|
Ling|Yong|Y|

D023041:Xenograft Model Antitumor Assays

Benzylidenecyclohexenones
Reactive oxygen species (ROS)
Piperlongumine
Thioredoxin reductase (TrxR)
Antitumor activities


The effect of educational attainment on cognition of older adults: results from the Mexican Health and Aging Study 2001 and 2012.

Abstract: Objective: This paper seeks to document changes in the effect of educational attainment on cognitive function of older adults in Mexico, and measure gender differences using data from two time periods. Methods: The data come from the Mexican Health and Aging Study (MHAS), taking the cross-sections of adults aged 60 years or older interviewed in 2001 and 2012. We perform an OLS regression using standardized z-scores for five individual cognitive domains and for total cognition. Results: Total cognitive scores and educational attainment were higher for men than women in both years. When cognitive components were analyzed separately, women had higher verbal memory and verbal recall scores than men. The gender gap in overall cognition score was smaller in 2012 compared to 2001, while the gender gap in educational attainment was larger in 2012 than in 2001. Even though men had higher educational attainment than women, the effect of educational attainment on cognition was higher for women. Similarly, the difference between total scores for each task for men compared to women decreased between 2012 and 2001, except for verbal learning and verbal recall where the gender difference widened. Conclusions: If younger cohorts of women continue to progressively achieve higher levels of education, the gender gap in old-age cognition should close. Additional work should determine the mechanisms through which added formal education seems to translate into higher cognitive gains for women compared to men.

D000073216:Mental Status and Dementia Tests

educational attainment
Mexican Health and Aging Study
Cognitive functioning
gender differences


Acinetobacter baumannii Resistance: A Real Challenge for Clinicians.

Abstract: Acinetobacter baumannii (named in honor of the American bacteriologists Paul and Linda Baumann) is a Gram-negative, multidrug-resistant (MDR) pathogen that causes nosocomial infections, especially in intensive care units (ICUs) and immunocompromised patients with central venous catheters. A. baumannii has developed a broad spectrum of antimicrobial resistance, associated with a higher mortality rate among infected patients compared with other non-baumannii species. In terms of clinical impact, resistant strains are associated with increases in both in-hospital length of stay and mortality. A. baumannii can cause a variety of infections; most involve the respiratory tract, especially ventilator-associated pneumonia, but bacteremia and skin wound infections have also been reported, the latter of which has been prominently observed in the context of war-related trauma. Cases of meningitis associated with A. baumannii have been documented. The most common risk factor for the acquisition of MDR A baumannii is previous antibiotic use, following by mechanical ventilation, length of ICU/hospital stay, severity of illness, and use of medical devices. Current efforts focus on addressing all the antimicrobial resistance mechanisms described in A. baumannii, with the objective of identifying the most promising therapeutic scheme. Bacteriophage- and artilysin-based therapeutic approaches have been described as effective, but further research into their clinical use is required.

Acinetobacter baumannii
antibiotic resistance
septicemia


Economic analysis of opportunities to accelerate Alzheimer's disease research and development.

Abstract: The development of disease-modifying treatments for Alzheimer's disease (AD) faces a number of barriers. Among these are the lack of surrogate biomarkers, the exceptional size and duration of clinical trials, difficulties in identifying appropriate populations for clinical trials, and the limitations of monotherapies in addressing such a complex multifactorial disease. This study sets out to first estimate the consequent impact on the expected cost of developing disease-modifying treatments for AD and then to estimate the potential benefits of bringing together industry, academic, and government stakeholders to co-invest in, for example, developing better biomarkers and cognitive assessment tools, building out advanced registries and clinical trial-readiness cohorts, and establishing clinical trial platforms to investigate combinations of candidate drugs and biomarkers from the portfolios of multiple companies. Estimates based on interviews with experts on AD research and development suggest that the cost of one new drug is now $5.7 billion (95% confidence interval (CI) $3.7-9.5 billion) and could be reduced to $2.0 billion (95% CI $1.5-2.9 billion). The associated acceleration in the arrival of disease-modifying treatments could reduce the number of case years of dementia by 7.0 million (95% CI 4.4-9.4 million) in the United States from 2025 through 2040.

Scott|Troy J|TJ|
O'Connor|Alan C|AC|
Link|Albert N|AN|
Beaulieu|Travis J|TJ|

D000544:Alzheimer Disease
D035843:Biomedical Research
D002800:Cholinesterase Inhibitors
D002986:Clinical Trials as Topic
D055808:Drug Discovery
D006801:Humans
D014481:United States

Alzheimer's disease
biomarkers
dementia
R&D
efficiency
drug development
infrastructure
public-private partnership


Advances in 3D cell culture technologies enabling tissue-like structures to be created in vitro.

Abstract: Research in mammalian cell biology often relies on developing in vitro models to enable the growth of cells in the laboratory to investigate a specific biological mechanism or process under different test conditions. The quality of such models and how they represent the behavior of cells in real tissues plays a critical role in the value of the data produced and how it is used. It is particularly important to recognize how the structure of a cell influences its function and how co-culture models can be used to more closely represent the structure of real tissue. In recent years, technologies have been developed to enhance the way in which researchers can grow cells and more readily create tissue-like structures. Here we identify the limitations of culturing mammalian cells by conventional methods on two-dimensional (2D) substrates and review the popular approaches currently available that enable the development of three-dimensional (3D) tissue models in vitro. There are now many ways in which the growth environment for cultured cells can be altered to encourage 3D cell growth. Approaches to 3D culture can be broadly categorized into scaffold-free or scaffold-based culture systems, with scaffolds made from either natural or synthetic materials. There is no one particular solution that currently satisfies all requirements and researchers must select the appropriate method in line with their needs. Using such technology in conjunction with other modern resources in cell biology (e.g. human stem cells) will provide new opportunities to create robust human tissue mimetics for use in basic research and drug discovery. Application of such models will contribute to advancing basic research, increasing the predictive accuracy of compounds, and reducing animal usage in biomedical science.

D000826:Animal Testing Alternatives
D000818:Animals
D018929:Cell Culture Techniques
D049109:Cell Proliferation
D018920:Coculture Techniques
D006801:Humans
D018874:Spheroids, Cellular
D013234:Stem Cells
D023822:Tissue Engineering
D054457:Tissue Scaffolds

3D cell culture
technology
in vitro
tissue structure


Retrospective Comparison of Estimated GFR using 2006 MDRD, 2009 CKD-EPI and Cockcroft-Gault with 24 Hour Urine Creatinine Clearance.

Abstract:
INTRODUCTION
The assessment of Glomerular Filtration Rate (GFR) is essential for clinical practice in assessing kidney function, drug dosing, detecting and estimating the prognosis of Chronic Kidney Disease (CKD). The most common practical method for assessing GFR is performed with a 24 hour/timed urine collection for creatinine clearance evaluation. The estimation of eGFR by creatinine based formulae is known to be a rapid and reliable means of approximation of creatinine clearance.

AIM
To compare eGFR using three commonly used Formulae {Modification of Diet in Renal Disease Study Equation (MDRD 2006), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2009) and Cockcroft-Gault Formula} with 24 hour creatinine clearance and to identify which amongst the 3 formulae for eGFR closely correlates with 24 hour creatinine clearance in a secondary care hospital.

MATERIALS AND METHODS
We retrospectively collected laboratory data requested for 24 hour creatinine clearance in the period from January 2014 to August 2016. Totally 91 laboratory request for 24 hour creatinine clearance data were obtained. The paired-t-test was used for comparison since all parameters used in the study were numerical, all patients came from same population and all had paired results.

RESULTS
The eGFR by MDRD formulae had a statistically insignificant p-value (p > 0.05) i.e., good approximation in the IInd, IIIrd, IVth and Vth stages of CKD on comparison with 24 hour creatinine clearance. The eGFR by CKD-EPI formulae had a statistically insignificant p-value (p > 0.05) in the IInd, IVth and Vth stages of CKD. The eGFR by Cockcroft-Gault Formulae had a statistically insignificant p-value (p > 0.05) in the Ist, IInd and Vth stages of CKD.

CONCLUSION
The Creatinine based GFR estimation provides a more accurate assessment of 24 hour creatinine clearance and kidney function than measuring serum creatinine alone but have certain limitations in few clinical circumstances. No single equation will be optimal for all populations. But the result of this study showed MDRD 2006 formulae to be more accurate than CKD-EPI 2009 and Cockcroft-Gault formulae in estimating GFR, detection of CKD, drug dosing and estimating prognosis.

Kidney function
Drug dosing
Chronic kidney disease
Dialysis


Enhanced heat shock protein 25 immunoreactivity in cranial nerve motoneurons and their related fiber tracts in rats prenatally-exposed to X-irradiation.

Abstract: Alterations in histoarchitecture of the brainstem were examined immunohistochemically in 4-week-old rats with a single whole body X-irradiation at a dose of 0.5, 1.0, or 1.5 Gy on embryonic day (ED) 15 using anti-heat shock protein 25 (HSP25). HSP25 immunostaining was seen in the neuronal perikarya of cranial nerve motoneurons, that is, the motor and mesencephalic nuclei of the trigeminal nerve, facial nucleus, abducens nucleus and accessory facial nucleus in the pons, and the ambiguous nucleus, dorsal nucleus of vagus nerve and hypoglossus nucleus in the medulla oblongata of intact controls. In 0.5 to 1.5 Gy-irradiated rats, HSP25 immunostaining in those neurons was more intense than in controls, while the most intense immunostaining was marked in 1.5 Gy-irradiated rats. HSP25 immunostaining was also apparent in the spinal tract of the trigeminal nerve and facial nerve tracts in 0.5 to 1.5 Gy-irradiated rats, but was faint in controls. Interestingly, HSP25 immunostaining was aberrantly enhanced in dendritic arbors in the magnocellular region of medial vestibular nucleus of 0.5-1.5 Gy-irradiated rats. Those arbors were identified as excitatory secondary vestibulo-ocular neurons by double immunofluorescence for HSP25 and SMI-32. The results suggest an increase of HSP25 expression in cranial nerve motoneurons and their related fiber tracts from prenatal exposure to ionizing irradiation. This may be an adaptive response to chronic hypoxia due to malformed brain arteries caused by prenatal ionizing irradiation.

Sawada|Kazuhiko|K| Saito|Shigeyoshi|S| Horiuchi-Hirose|Miwa|M| Murase|Kenya|K|

D018507:Gene Expression Regulation, Developmental

cranial nerves
brainstem
pons
medulla oblongata
ionizing irradiation
immunohistochmistry


The Relation Between Health and Earnings in Self-Employment.

Abstract: Multiple studies have shown that, on average, the self-employed are healthier than wage workers. The link between the health of self-employed individuals and their financial performance in terms of earnings is, however, less understood. Based on human capital theory, we expect a positive link between health and earnings among the self-employed. For two reasons we expect the relationship between health and earnings to be stronger for the self-employed than for wage workers. First, the self-employed can more easily adapt their production activities such that they yield the highest returns to their human capital, including their health. Second, in the short term, the earnings of the self-employed are more dependent on the ability to work than the wages of wage workers. Our empirical analysis draws on data from the Household, Income and Labor Dynamics in Australia (HILDA) survey, a longitudinal dataset (2001-2017). Our outcome variable is an individual's total income derived from wage work and/or running a business. Health is measured using multi-item constructs for General health, Physical health, and Mental health from the Short Form Health Survey (SF-36). We distinguish between wage workers and self-employed individuals with and without employees. Fixed-effects regressions reveal a significant positive relationship between health and earnings in self-employment as well as in wage work. As expected, this relationship is significantly stronger in self-employment than in wage work (for General health and Physical health, but not for Mental health). The latter result holds particularly for self-employment without employees. We provide evidence that the higher returns can be partly explained by the fact that the earnings in self-employment are more dependent on the ability to work (as proxied by the number of working hours) than earnings in wage work. We also find a negative relationship between health and job termination. Again, this relationship is stronger for the self-employed (without employees) than for wage workers (for General health and Mental health, but not for Physical health).

Hessels|Jolanda|J|
Rietveld|Cornelius A|CA|
van der Zwan|Peter|P|

health
earnings
self-employment
human capital
HILDA data


Spermine and Spermidine Alter Gene Expression and Antigenic Profile of Borrelia burgdorferi.

Abstract: Borrelia burgdorferi, the agent of Lyme disease, responds to numerous host-derived signals to alter adaptive capabilities during its enzootic cycle in an arthropod vector and mammalian host. Molecular mechanisms that enable B. burgdorferi to detect, channel, and respond to these signals have become an intense area of study for developing strategies to limit transmission/infection. Bioinformatic analysis of the borrelial genome revealed the presence of polyamine transport components (PotA, PotB, PotC, and PotD), while homologs for polyamine biosynthesis were conspicuously absent. Although potABCD is cotranscribed, the level of PotA was elevated under in vitro growth conditions mimicking unfed ticks compared to the level in fed ticks, while the levels of PotD were similar under the aforementioned conditions in B. burgdorferi Among several polyamines and polyamine precursors, supplementation of spermine or spermidine in the borrelial growth medium induced synthesis of major regulators of gene expression in B. burgdorferi, such as RpoS and BosR, with a concomitant increase in proteins that contribute to colonization and survival of B. burgdorferi in the mammalian host. Short transcripts of rpoS were elevated in response to spermidine, which was correlated with increased protein levels of RpoS. Transcriptional analysis of rpoZ and B. burgdorferirel (rel ; bb0198) in the presence of spermidine revealed the interplay of multiple regulatory factors in B. burgdorferi gene expression. The effect of spermidine on the levels of select borrelial proteins was also influenced by serum factors. These studies suggest that multiple host-derived signals/nutrients and their transport systems contribute to B. burgdorferi adaptation during the vector and vertebrate host phases of infection.

Lin|Ying-Han|YH|
Romo|Jesus A|JA|
Smith|Trever C|TC|
Reyes|Ann N|AN|
Karna|S L Rajasekhar|SLR|
Miller|Christine L|CL|
Van Laar|Tricia A|TA|
Yendapally|Raghunandan|R|
Chambers|James P|JP|
Seshu|J|J|

D015964:Gene Expression Regulation, Bacterial

Borrelia burgdorferi
Lyme disease
polyamines


Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca2+-Dependent Cyclic GMP Synthesis.

Abstract: Over 100 mutations in GUCY2D that encodes the photoreceptor guanylate cyclase GC-E are known to cause two major diseases: autosomal recessive Leber congenital amaurosis (arLCA) or autosomal dominant cone-rod dystrophy (adCRD) with a poorly understood mechanism at the molecular level in most cases. Only few mutations were further characterized for their enzymatic and molecular properties. GC-E activity is under control of neuronal Ca2+-sensor proteins, which is often a possible route to dysfunction. We investigated five recently-identified GC-E mutants that have been reported in patients suffering from arLCA (one large family) and adCRD/maculopathy (four families). Microsatellite analysis revealed that one of the mutations, c.2538G > C (p.K846N), occurred de novo. To better understand the mechanism by which mutations that are located in different GC-E domains develop different phenotypes, we investigated the molecular consequences of these mutations by expressing wildtype and mutant GC-E variants in HEK293 cells. Analyzing their general enzymatic behavior, their regulation by Ca2+ sensor proteins and retinal degeneration protein 3 (RD3) dimerization domain mutants (p.E841K and p.K846N) showed a shift in Ca2+-sensitive regulation by guanylate cyclase-activating proteins (GCAPs). Mutations in the cyclase catalytic domain led to a loss of enzyme function in the mutant p.P873R, but not in p.V902L. Instead, the p.V902L mutation increased the guanylate cyclase activity more than 20-fold showing a high GCAP independent activity and leading to a constitutively active mutant. This is the first mutation to be described affecting the GC-E catalytic core in a complete opposite way.

Wimberg|Hanna|H| Lev|Dorit|D| Yosovich|Keren|K| Namburi|Prasanthi|P| Banin|Eyal|E| Sharon|Dror|D| Koch|Karl-Wilhelm|KW|

guanylate cyclase
Leber congenital amaurosis
cone-rod dystrophy
GCAP
GUCY2D mutation
RD3 protein


Frequency and risk factors for mental disorders following pancreatitis: a nationwide cohort study.

Abstract: Objective: To investigate the frequency and risk factors for mental disorders following pancreatitis. Methods: Patients with acute pancreatitis (AP) and chronic pancreatitis (CP) were identified (n = 18,074) from a nationwide database in New Zealand (1998-2015). They were followed from their first hospital admissions for AP or CP to incident mental disorders. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression analyses. Results: CP (vs AP) was associated with a significantly higher risk of mental disorders (adjusted HR = 2.00 [95% CI = 1.53-2.62]). Pre-existing diabetes (adjusted HR = 8.99 [95% CI = 6.23-12.96] for AP and adjusted HR = 3.42 [95% CI = 2.37-4.96] for CP) and post-pancreatitis diabetes mellitus (adjusted HR = 7.10 [95% CI = 4.14-12.19] for AP and adjusted HR = 2.97 [95% CI = 1.83-4.82] for CP) were risk factors for mental disorders in individuals following pancreatitis. Severe (adjusted HR = 2.07 [95% CI = 1.39-3.06] vs mild) and recurrent (adjusted HR = 1.62 [95% CI = 1.07-2.45] vs single episode) attacks were associated with significantly higher risks of mental disorders following AP. Conclusions: Patients following CP, recurrent AP, severe AP, and those with diabetes are at high risk for developing mental disorders.

Cho|Jaelim|J|
Walia|Monika|M|
Scragg|Robert|R|
Petrov|Maxim S|MS|

Mental disorders
Pancreatitis
Cohort study
Prevention