Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction.

Abstract: The alarmone (p)ppGpp regulates diverse targets, yet its target specificity and evolution remain poorly understood. Here, we elucidate the mechanism by which basal (p)ppGpp inhibits the purine salvage enzyme HPRT by sharing a conserved motif with its substrate PRPP. Intriguingly, HPRT regulation by (p)ppGpp varies across organisms and correlates with HPRT oligomeric forms. (p)ppGpp-sensitive HPRT exists as a PRPP-bound dimer or an apo- and (p)ppGpp-bound tetramer, where a dimer-dimer interface triggers allosteric structural rearrangements to enhance (p)ppGpp inhibition. Loss of this oligomeric interface results in weakened (p)ppGpp regulation. Our results reveal an evolutionary principle whereby protein oligomerization allows evolutionary change to accumulate away from a conserved binding pocket to allosterically alter specificity of ligand interaction. This principle also explains how another (p)ppGpp target GMK is variably regulated across species. Since most ligands bind near protein interfaces, we propose that this principle extends to many other protein-ligand interactions.

(p)ppGpp
B. subtilis
allosteric regulation
bacterial homeostasis
biochemistry
chemical biology
enzyme oligomerization
protein evolution
signaling ligand


Vulvar cancer and sentinel lymph nodes: a new standard of care?

Abstract: The treatment of early-stage vulvar cancer has remained surgical over time. Fortunately, less invasive surgical options have emerged, decreasing the significant morbidity associated with treatment. In the past decade, sentinel lymph node (SLN) dissection alone in select patients with vulvar cancer has been shown to be safe, feasible and has decreased surgical morbidity. In addition, multiple recent studies have reported low groin recurrence rates in women that underwent SLN dissection alone, which are similar to groin recurrence rates seen among women that underwent complete inguinal lymph node dissection. We believe SLN dissection should be the standard of care in select patients at institutions with surgeons experienced in the SLN technique. We feel caution should be used when performing SLN dissections in large vulvar lesions and in midline lesions. Further information is needed regarding the appropriate treatment of positive sentinel lymph nodes and, in particular, on the management of micrometastases.

D002294:Carcinoma, Squamous Cell
D005260:Female
D006801:Humans
D008197:Lymph Node Excision
D008207:Lymphatic Metastasis
D009364:Neoplasm Recurrence, Local
D009367:Neoplasm Staging
D021701:Sentinel Lymph Node Biopsy
D059039:Standard of Care
D014846:Vulvar Neoplasms

vulvar
cancer
sentinel lymph node
morbidity
minimally invasive


DNA cleavage induced by [Cu(L)x(NO3)2] (L=2,2'-dipyridylamine, 2,2'-bipyridine, dipicolylamine, x=1 or 2): Effect of the ligand structure.

Abstract: The efficiency of [Cu(2,2'-bipyridine)2(NO3)]NO3, [Cu(2,2'-dipyridylamine)2(NO3)2], and [Cu(dipicolylamine)2(NO3)2] complexes (complex 1, 2 and 3, respectively) in oxidative DNA cleavage was examined by electrophoresis and linear dichroism (LD). Among the three Cu complexes, complex 1 showed the highest efficiency in super-coiled DNA (scDNA) cleavage in electrophoresis. The presence of tiron, a superoxide radical scavenger, suppressed the reaction almost completely. The LD signal at 260 nm decreased gradually as the time passed. The decrease in LD magnitude was explained best by the sum of the two single exponential curves. This suggests that the cleavage reaction involves two first order kinetic processes; an increase in flexibility due to scission of one of the strands and a shortening in the DNA stem due to cut of both strands of double stranded DNA (dsDNA). In agreement with the electrophoresis data, complex 1 exhibited the highest efficiency with the superoxide radical found to be the essential reactive oxygen species. The order of efficiency in both scDNA and dsDNA was as follows: complex 1>complex 2>complex 3. The electrochemical properties alone were insufficient to explain the observed efficiencies, even though reduction of the central Cu ion is essential for the oxidative DNA cleavage. This highlights the importance of an ability to ligate the molecular oxygen (or hydrogen peroxide) to the central Cu ion to produce the superoxide radical, in addition to the reduction of Cu ion, in oxidative DNA cleavage.

Kwon|Ji Hye|JH|
Park|Hee-Jin|HJ|
Chitrapriya|Nataraj|N|
Cho|Tae-Sub|TS|
Kim|Soojin|S|
Kim|Jinheung|J|
Hwang|In Hong|IH|
Kim|Cheal|C|
Kim|Seog K|SK|

DNA
DNA cleavage
Oxidation
Linear dichroism
Cu complex


Increase of serotype 8, ST53 clone, as the prevalent strain of Streptococcus pneumoniae causing invasive disease in Madrid, Spain (2012-2015).

Abstract:
INTRODUCTION
In recent years, Streptococcus pneumoniae serotype 8 has become the most prevalent cause of invasive pneumococcal disease (IPD) in Madrid, Spain. The objective of this study was to characterize the invasive clones of S. pneumoniae serotype 8 in Madrid over the 2012-2015 period.

METHODS
From January 2012 to December 2015, a total of 1543 invasive isolates were studied. Serotyping was carried out by Pneumotest-Latex agglutination and Quellung reaction. Susceptibilities to penicillin, erythromycin and levofloxacin were determined by the Etest®. All serotype 8 strains were typed by multilocus sequence typing (MLST) and by pulsed-field gel electrophoresis (PFGE).

RESULTS
Two hundred and forty-eight (248) serotype 8 strains were detected (16.1%) and 243 of them were available for molecular typing. Nine sequence types (STs) by MLST (8-ST53, 8-ST63, 8-ST404, 8-ST1107, 8-ST989, 8-ST1110, 8-ST2231, 8-ST3544 and 8-ST4301), and nine PFGE profiles were identified (one corresponding to each ST). The 8-ST53 clone was the most widespread, and increased from 53.8% among all serotype 8 isolates in 2012, to 90.1% in 2015. In contrast, the 8-ST63 clone, resistant to levofloxacin and erythromycin, decreased from 30.8%, among all serotype 8 strains in 2012, to 5.0% in 2015.

CONCLUSIONS
The increase in our region of S. pneumoniae serotype 8, not included in conjugated vaccines, occurred at the expense of the 8-ST53 clone. On the contrary, the 8-ST63 clone decreased. Since clone 8-ST63 has the theoretical advantage of its levofloxacin-erythromycin resistance in comparison to 8-ST53, the predominance of 8-ST53 over 8-ST63 is striking.

Sanz|Juan Carlos|JC|
Rodríguez-Avial|Iciar|I|
Ríos|Esther|E|
García-Comas|Luis|L|
Ordobás|María|M|
Cercenado|Emilia|E|

D000900:Anti-Bacterial Agents
D002999:Clone Cells
D006801:Humans
D008826:Microbial Sensitivity Tests
D058885:Multilocus Sequence Typing
D011008:Pneumococcal Infections
D065288:Serogroup
D013030:Spain
D013296:Streptococcus pneumoniae

Serotype 8
Streptococcus pneumoniae
MLST clones
Serotipo 8


Efficacy of First Line Systemic Chemotherapy and Multikinase Inhibitors in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis.

Abstract:
Background
Hepatocellular carcinoma (HCC) is the third most fatal cancer, with a 5-year survival rate of 18%. Standard frontline-therapy is multikinase inhibitors (MKIs), but accessibility is still limited, particularly in developing countries. This network meta-analysis (NMA) aimed to compare the efficacy of usual chemotherapy vs MKIs.

Method
Randomised-controlled trials (RCTs) comparing any among chemotherapy vs MKIs in treatment-naïve patients with advanced HCCs were identified from MEDLINE and SCOPUS databases. Overall survival (OS) and progression-free survival (PFS) probabilities and times were extracted from Kaplan-Meier curves using Digitizer, and then converted to individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate median OS and PFS. A two-stage NMA was applied for the overall response rate and adverse events (AEs) outcome.

Results
A total of 20 RCTs were eligible for NMA. Lenvatinib was the best treatment among single MKIs, with median OS and PFS of 9 and 6.3 months, without significant differences in AEs relative to other MKIs. Median OS and PFS were 0.70 (-0.42, 1.83) and 2.17 (1.41, 2.93) months longer with Lenvatinib than Sorafenib. Among chemotherapy agents, FOLFOX4 had the longest median OS and PFS at 7.9 and 4.3 months, respectively, without significant AEs compared to other chemotherapies. The combination of Sorafenib+Doxorubicin prolonged median OS and PFS to 12.7 and 6.3 months, respectively.

Conclusion
Use of the MKIs Lenvatinib or Sorafenib as first line systemic treatment for advanced HCC could be beneficial. However, FOLFOX4 might be the optimal choice in a developing country where the health-care budget is limited.

Oranratnachai|Songporn|S| Rattanasiri|Sasivimol|S| Pooprasert|Anantaporn|A| Tansawet|Amarit|A| Reungwetwattana|Thanyanan|T| Attia|John|J| Thakkinstian|Ammarin|A|

chemotherapy
multikinase inhibitors
hepatocellular carcinoma
network meta-analysis
first-line systemic treatment


Determinants of Attendance at a Physical Activity Focused Afterschool Program in Elementary School Children.

Abstract: Afterschool youth physical activity (PA) programs provide opportunities for increasing children's time engaged in moderate-to-vigorous physical activity (MVPA). However, low program attendance reduces the benefits of participating in these programs. The purpose of this study was to determine if enjoyment, athletic competence and motivation for PA predict youth attendance at a free afterschool PA program from 3rd to 5th grade. Data were collected from a larger randomized community trial examining the effectiveness of an afterschool program for increasing opportunities to engage in MVPA. Data were collected twice annually (fall/spring) over 3 school years (3rd - 5th grade) in 9 schools. Analyses were stratified by grade and sex, and a series of multi-level linear regression models were utilized to determine if baseline levels of the psychosocial determinants predicted annual attendance as a percentage of afterschool sessions attended. Amotivation for PA was negatively associated with attendance in boys and non-self-determined extrinsic motivation was positively associated with attendance in girls in the 5th grade. Age was associated with a 13.72% reduction in attendance in the 3rd grade, a 12.87% attendance reduction in the 4th grade, and a 7.93% attendance in reduction in the 5th grade. Race was also associated with attendance. Non-White youth attended the program 13.56% less in the 3rd grade, 17.35% less in the 4th grade, and 21.53% less in the 5th grade than White youth. The findings suggest that attendance to PA afterschool programming may be associated with children's motivational characteristics, but that other variables should be identified for further research.

Crimarco|Anthony|A|
Mayfield|Carlene|C|
Mitchell|Nathanael|N|
Beets|Michael W|MW|
Yin|Zenong|Z|
Moore|Justin B|JB|

Youth
athletic competence
motivation
multilevel modeling


Association of Breakfast Quality and Energy Density with Cardiometabolic Risk Factors in Overweight/Obese Children: Role of Physical Activity.

Abstract: There is a general belief that having breakfast is an important healthy lifestyle factor; however, there is scarce evidence on the influence of breakfast quality and energy density on cardiometabolic risk in children, as well as on the role of physical activity in this association. The aims of this paper were (i) to examine the associations of breakfast quality and energy density from both solids and beverages with cardiometabolic risk factors, and (ii) to explore whether physical activity levels may attenuate these relationships in children with overweight/obesity from two projects carried out in the north and south of Spain. Breakfast consumption, breakfast quality index (BQI) score, BEDs/BEDb (24 h-recalls and the KIDMED questionnaire), and physical activity (PA; accelerometry) were assessed, in 203 children aged 8⁻12 years who were overweight or obese. We measured body composition (Dual X-ray Absorptiometry), uric acid, blood pressure, lipid profile, gamma-glutamyl-transferase (GGT), glucose, and insulin, and calculated the HOMA and metabolic syndrome z-score. The BQI score was inversely associated with serum uric acid independently of a set of relevant confounders (β = -0.172, p = 0.028), but the relationship was attenuated after further controlling for total PA (p < 0.07). BEDs was positively associated with total and HDL cholesterol, and systolic blood pressure regardless of confounders (all p < 0.05), while BEDb was positively associated with HOMA in either active/inactive children (all p < 0.03). In conclusion, higher breakfast quality and lower breakfast energy density should be promoted in overweight/obesity children to improve their cardiometabolic health.

D002664:Child Nutritional Physiological Phenomena

breakfast quality
physical activity
uric acid
blood pressure
HOMA
cholesterol
breakfast energy density
cardiometabolic health
childhood obesity
skipping breakfast


Human Rhinovirus Inhibition Through Capsid "Canyon" Perturbation: Structural Insights into The Role of a Novel Benzothiophene Derivative.

Abstract: The challenge in targeting human rhinoviruses (HRV) over the years has been attributed to the wide variety in HRV serotypes. Nonetheless, the search for therapeutic agents against HRV continues unabated. These efforts have been augmented by the recent discovery of the novel benzothiophene derivative shown to inhibit HRV viral replication. Bound to subtype HRV-B14, the compound showed similar inhibitory activity as Pleconaril, a known capsid inhibitor. However, the molecular and structural basis of this inhibition remains unclear. In this in silico report, residue interaction network analysis revealed that the binding of the benzothiophene derivative into the "canyon" region of the active site of HRV-B14 distorts its initially extensively networked and compact residue profile. This was characterized by fewer inter-residue hydrogen bonds, reduced van der Waals interactions, and increased residue flexibility. Interestingly, however, the binding of this benzothiophene derivative decreased the flexibility of the north-south wall around the canyon region possibly impeding the "breathing motion" of HRV-B14, hence its inhibition. Atomistic insights also revealed the cruciality of Tyr152 toward inhibitor binding at HRV-B14. This was justified by the amino acid's high intermolecular interaction with both inhibitors. Findings provide important structural insights in the inhibitory activity the novel benzothiophene derivative, and reaffirm its promising potential as an alternative capsid inhibitor toward common cold therapy upon further experimental validation.

Human rhinovirus
Residue interaction network
Common cold
Molecular dynamics simulation


Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.

Abstract: Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most-studied anticancer targets nowadays. Since the discovery of the druggable allosteric binding site containing a G12C mutation, KRASG12C has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRASG12C covalent inhibitors. The workflow involved initial enumeration of virtual molecules tailored for the KRAS allosteric binding site. Tools such as pharmacophore modeling, docking, and free-energy perturbations were deployed to prioritize the compounds with the best profiles. The synthesized naphthyridinone scaffold showed the ability to react with G12C and inhibit KRASG12C . Analogues were prepared to establish structure-activity relationships, while molecular dynamics simulations and crystallization of the inhibitor-KRASG12C complex highlighted an unprecedented binding mode.

Mortier|Jérémie|J|0000-0001-8707-3867
Friberg|Anders|A|
Badock|Volker|V|
Moosmayer|Dieter|D|
Schroeder|Jens|J|
Steigemann|Patrick|P|
Siegel|Franziska|F|
Gradl|Stefan|S|
Bauser|Marcus|M|
Hillig|Roman C|RC|
Briem|Hans|H|
Eis|Knut|K|
Bader|Benjamin|B|
Nguyen|Duy|D|
Christ|Clara D|CD|

KRAS
molecular dynamics
free-energy perturbation (FEP)
medicinal chemistry
virtual library design


"The land of the sick and the land of the healthy": Disability, bureaucracy, and stigma among people living with poverty and chronic illness in the United States.

Abstract: Disability benefits have become an increasingly prominent source of cash assistance for impoverished American citizens over the past two decades. This development coincided with cuts and market-oriented reforms to state and federal welfare programs, characteristic of the wider political-economic trends collectively referred to as neoliberalism. Recent research has argued that contemporary discourses on 'disability fraudsters' and 'malingerers' associated with this shift represent the latest manifestation of age-old stigmatization of the 'undeserving poor'. Few studies, however, have investigated how the system of disability benefits, as well as these stigmatizing discourses, shapes the lived experience of disabling physical illness in today's United States. Here we present qualitative data from 64 semi-structured interviews with low-income individuals living with HIV and/or type 2 diabetes mellitus to explore the experience of long-term, work-limiting disability in the San Francisco Bay Area. Interviews were conducted between April and December 2014. Participants explained how they had encountered what they perceived to be excessive, obstructive, and penalizing bureaucracy from social institutions, leading to destitution and poor mental health. They also described being stigmatized as disabled for living with chronic ill health, and simultaneously stigmatized as shirking and malingering for claiming disability benefits as a result. Notably, this latter form of stigma appeared to be exacerbated by the bureaucracy of the administrating institutions. Participants also described intersections of health-related stigma with stigmas of poverty, gender, sexual orientation, and race. The data reveal a complex picture of poverty and intersectional stigma in this population, potentiated by a convoluted and inflexible bureaucracy governing the system of disability benefits. We discuss how these findings reflect the historical context of neoliberal cuts and reforms to social institutions, and add to ongoing debate around the future of public social provision for impoverished and chronically ill citizens under neoliberalism.

Whittle|Henry J|HJ|
Palar|Kartika|K|
Ranadive|Nikhil A|NA|
Turan|Janet M|JM|
Kushel|Margot|M|
Weiser|Sheri D|SD|

Disability
Stigma
United States
Welfare
Neoliberalism
HIV
Diabetes
Social insurance


Physisorption of enzymatically active chymotrypsin on titania colloidal particles.

Abstract: In this study we use a straightforward experimental method to probe the presence and activity of the proteolytic enzyme α-chymotrypsin adsorbed on titania colloidal particles. We show that the adsorption of α-chymotrypsin on the particles is irreversible and pH-dependent. At pH 8 the amount of adsorbed chymotrypsin is threefold higher compared to the adsorption at pH 5. However, we observe that the adsorption is accompanied by a substantial loss of enzymatic activity, and only around 6-9% of the initial enzyme activity is retained. A Michaelis-Menten kinetics analysis of both unbound and TiO2-bound chymotrypsin shows that the K(M) value is increased from ∼10 μM for free chymotrypsin to ∼40 μM for the particle bound enzyme. Such activity decrease could be related by the hindered accessibility of substrate to the active site of adsorbed chymotrypsin, or by adsorption-induced structural changes. Our simple experimental method does not require any complex technical equipment, can be applied to a broad range of hydrolytic enzymes and to various types of colloidal materials. Our approach allows an easy, fast and reliable determination of particle surface-bound enzyme activity and has high potential for development of future enzyme-based biotechnological and industrial processes.

Derr|Ludmilla|L|
Dringen|Ralf|R|
Treccani|Laura|L|
Hildebrand|Nils|N|
Ciacchi|Lucio Colombi|LC|
Rezwan|Kurosch|K|

D057927:Hydrophobic and Hydrophilic Interactions

Physisorption
Enzymatic activity
Chymotrypsin
Colloidal titania particles
Enzyme adsorption
TiO(2)


Muscle-Enriched MicroRNAs Isolated from Whole Blood Are Regulated by Exercise and Are Potential Biomarkers of Cardiorespiratory Fitness.

Abstract: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally. Evidence indicating miRNAs influence exercise-induced health and performance adaptations is mounting. Circulating miRNAs are responsible for intercellular communication and could serve as biomarkers for disease and exercise-related traits. Such biomarkers would contribute to exercise screening, monitoring, and the development of personalized exercise prescription. Accordingly, we investigated the impact of long-term strenuous aerobic exercise training and a single bout of maximal aerobic exercise on five muscle-enriched miRNAs implicated in exercise adaptations (miR-1, miR-133a, miR-181a, miR-486, and miR-494). We also determined linear correlations between miRNAs, resting heart rate, and maximum oxygen uptake (O2 max). We used TaqMan assay quantitative polymerase chain reaction to analyze the abundance of miR-1, miR-133a, miR-181a, miR-486, and miR-494 in resting whole blood of 67 endurance athletes and 61 healthy controls. Relative to controls, endurance athletes exhibited increased miR-1, miR-486, and miR-494 content (1.26- to 1.58-fold change, all p < 0.05). miR-1, miR-133a, and miR-486 were decreased immediately after maximal aerobic exercise (0.64- to 0.76-fold change, all p < 0.01) performed by 19 healthy, young men (20.7 ± 2.4 years). Finally, we observed positive correlations between miRNA abundance and O2 max (miR-1 and miR-486) and an inverse correlation between miR-486 and resting heart rate. Therefore, muscle-enriched miRNAs isolated from whole blood are regulated by acute and long-term aerobic exercise training and could serve as biomarkers of cardiorespiratory fitness.

non-coding RNA
VO2 max
epigenetics
myomiR
small RNA


Consumer Response to Composite Ratings of Nursing Home Quality.

Abstract: Health care report cards are intended to address information asymmetries and enable consumers to choose providers of better quality. However, the form of the information may matter to consumers. Nursing Home Compare, a website that publishes report cards for nursing homes, went from publishing a large set of indicators to a composite rating in which nursing homes are assigned one to five stars. We evaluate whether the simplified ratings motivated consumers to choose better-rated nursing homes. We use a regression discontinuity design to estimate changes in new admissions six months after the publication of the ratings. Our main results show that nursing homes that obtained an additional star gained more admissions, with heterogeneous effects depending on baseline number of stars. We conclude that the form of quality reporting matters to consumers, and that the increased use of composite ratings is likely to increase consumer response.

Perraillon|Marcelo Coca|MC|
Konetzka|R Tamara|RT|
He|Daifeng|D|
Werner|Rachel M|RM|


Morphological evaluation for diagnosis of dry eye related to meibomian gland dysfunction.

Abstract: The evaluation of morphological changes of the acini in the meibomian glands is important for the diagnosis and management of dry eye related to meibomian gland dysfunction. While several tools have been developed to detect meibomian gland structure, infrared imaging is generally used in clinical settings. Unlike the lipid component analysis of tear film in which quantitative analysis is possible, the meibomian glands are limited to qualitative analysis because of the low image quality of the diagnostic tools. This review describes diagnostic tools, especially in terms of morphological evaluation of the acini, which are visualized by the existence of lipid within them.

Yoo|Young-Sik|YS|
Na|Kyung-Sun|KS|
Kim|Dae Yu|DY|
Yang|Suk-Woo|SW|
Joo|Choun-Ki|CK|

Meibomian glands
Dry eye disease
Optical coherence tomography


Relationship of Oral Tumor Thickness with the rate of lymph node metastasis in Neck based on CT Scan.

Abstract:
OBJECTIVE
To determine the relationship of tumor thickness of oral lesions with metastasis in neck based on CT scan.

METHODS
A total of 58 oral squamous cell carcinoma patients having the median age of 46 (39-55) years. with either gender presented with malignant tumor of buccal mucosa and tongue were prospectively enrolled. A CT Scan with contrast was performed on all patients. Correlation of tumor thickness level with metastasis in neck was calculated using spearman's rank correlation coefficient test.

RESULTS
Median age of the patients was 46 (39-55) years with preponderance of male gender, i.e. 48 (82.8%). Strong positive significant correlation was observed in between transverse dimension (TS) tumor size and stages of tumor (rho 0.673, p-value <0.001), Anterioposterior (AP) tumor size and stages of tumor (rho 0.675, p-value <0.001), and Craniocaudal (CC) tumor size and stages of tumor (rho 0.771, p-value <0.001).

CONCLUSION
CT scan of neck with contrast can be used for predicting the positive presence of lymph node in neck with primary tumors having a size of more than 4 mm.

Khan|Sohail Ahmed|SA|
Zia|Sadaf|S|
Naqvi|Syeda Uzma|SU|
Adel|Hatem|H|
Adil|Syed Omair|SO|
Hussain|Munawar|M|

Oral Tumor thickness
CT Scan Neck
Neck dissection
Neck metastasis


Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling.

Abstract: In the Drosophila immune response, bacterial derived diaminopimelic acid-type peptidoglycan binds the receptors PGRP-LC and PGRP-LE, which through interaction with the adaptor protein Imd leads to activation of the NF-κB homolog Relish and robust antimicrobial peptide gene expression. PGRP-LC, PGRP-LE, and Imd each contain a motif with some resemblance to the RIP Homotypic Interaction Motif (RHIM), a domain found in mammalian RIPK proteins forming functional amyloids during necroptosis. Here we found that despite sequence divergence, these Drosophila cryptic RHIMs formed amyloid fibrils in vitro and in cells. Amyloid formation was required for signaling downstream of Imd, and in contrast to the mammalian RHIMs, was not associated with cell death. Furthermore, amyloid formation constituted a regulatable step and could be inhibited by Pirk, an endogenous feedback regulator of this pathway. Thus, diverse sequence motifs are capable of forming amyloidal signaling platforms, and the formation of these platforms may present a regulatory point in multiple biological processes.

Kleino|Anni|A|
Ramia|Nancy F|NF|
Bozkurt|Gunes|G|
Shen|Yanfang|Y|
Nailwal|Himani|H|
Huang|Jing|J|
Napetschnig|Johanna|J|
Gangloff|Monique|M|
Chan|Francis Ka-Ming|FK|
Wu|Hao|H|
Li|Jixi|J|
Silverman|Neal|N|

D053422:Receptor-Interacting Protein Serine-Threonine Kinases

D020133:Reverse Transcriptase Polymerase Chain Reaction

functional amyloid
Imd
NF-κB signaling
PGRP-LC
PGRP-LE
RHIM
innate immunity


Validation of the Male Osteoporosis Risk Estimation Score (MORES) in a primary care setting.

Abstract:
BACKGROUND
Primary care physicians are positioned to promote early recognition and treatment of men at risk for osteoporosis-related fractures; however, efficient screening strategies are needed. This study was designed to validate the Male Osteoporosis Risk Estimation Score (MORES) for identifying men at increased risk of osteoporosis.

METHODS
This was a blinded analysis of the MORES, administered prospectively in a cross-sectional sample of men aged 60 years or older. Participants completed a research questionnaire at an outpatient visit and had a dual-energy X-ray absorptiometry (DXA) scan to assess bone density. Sensitivity, specificity, and area under-the-curve (AUC) were estimated for the MORES. Effectiveness was assessed by the number needed-to-screen (NNS) to prevent one additional major osteoporotic fracture.

RESULTS
A total of 346 men completed the study. The mean age was 70.2 ± 6.9 years; 76% were non-Hispanic white. Fifteen men (4.3%) had osteoporosis of the hip. The operating characteristics were sensitivity 0.80 (95% confidence interval [CI], 0.52-0.96); specificity 0.70 (95% CI, 0.64-0.74), and AUC of 0.82 (95% CI, 0.71-0.92). Screening with the MORES yielded a NNS to prevent one additional major osteoporotic fracture over 10 years with 259 (95% CI, 192-449) compared to 636 for universal screening with a DXA.

CONCLUSION
This study validated the MORES as an effective and efficient approach to identifying men at increased risk of osteoporosis who may benefit from a diagnostic DXA scan.

Osteoporosis
Screening
Prevention
Decision Making
Men's Health
Primary Health Care


Second-line treatment for metastatic clear cell renal cell cancer: experts' consensus algorithms.

Abstract:
BACKGROUND
Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making.

MATERIALS AND METHODS
Eleven international experts were asked to provide their treatment strategies for second-line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach.

RESULTS
The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria.

CONCLUSION
In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred.

Rothermundt|C|C|
von Rappard|J|J|
Eisen|T|T|
Escudier|B|B|
Grünwald|V|V|
Larkin|J|J|
McDermott|D|D|
Oldenburg|J|J|
Porta|C|C|
Rini|B|B|
Schmidinger|M|M|
Sternberg|C N|CN|
Putora|P M|PM|

Renal cell cancer
Consensus
Algorithm
Diagnostic nodes


Herbal and Dietary Supplements-Induced Liver Injury in Latin America: Experience From the LATINDILI Network.

Abstract:
BACKGROUND
Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations.

OBJECTIVES
To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network.

METHODS
A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity.

RESULTS
From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%).

CONCLUSIONS
HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Bessone|Fernando|F|
García-Cortés|Miren|M|
Medina-Caliz|Inmaculada|I|
Hernandez|Nelia|N|
Parana|Raymundo|R|
Mendizabal|Manuel|M|
Schinoni|Maria I|MI|
Ridruejo|Ezequiel|E|
Nunes|Vinicius|V|
Peralta|Mirta|M|
Santos|Genario|G|
Anders|Margarita|M|
Chiodi|Daniela|D|
Tagle|Martin|M|
Montes|Pedro|P|
Carrera|Enrique|E|
Arrese|Marco|M|
Lizarzabal|M Isabel|MI|
Alvarez-Alvarez|Ismael|I|
Caballano-Infantes|Estefania|E|
Niu|Hao|H|
Pinazo|Jose|J|
Cabello|Maria R|MR|
Lucena|M Isabel|MI|
Andrade|Raúl J|RJ|

Latin America
LATINDILI Network
Herbal and Dietary Supplements
Hepatotoxicity
Drug-Induced Liver Injury
Herbal-Induced Liver Injury
Liver Toxicity


Modeling of Autism Using Organoid Technology.

Abstract: Autism is a neurodevelopmental disease caused by multiple mutations during development. However, a suitable disease model to study the molecular pathway of disease onset and progression is not available. Although many studies have used human stem cells such as induced pluripotent stem cells and embryonic stem cells to investigate the disease pathogenesis, these stem cell techniques are limited in their abilities to study the pathology and mechanism of pathogenesis of neurodevelopmental diseases such as autism. Therefore, researchers are focusing on the strengths of three-dimensional (3D) structures mimicking organs, organoids, for modeling autism. In this review, we highlight the advantages of 3D organoid systems to investigate the mechanisms of the pathogenesis of autism. Further, because the onset of autism is determined by genetic background, we suggest the application of the clustered regularly interspersed short palindromic repeat-associated protein 9 (CRISPR/Cas9) technique for genome editing in 3D organoid systems to study mutations that cause autism. We propose that 3D organoid systems combined with the CRISPR/Cas9 technique may advance autism research.

Choi|Hwan|H| Song|Juhyun|J| Park|Guiyeon|G| Kim|Jongpil|J|

Clustered regularly interspersed short palindromic repeat-associated protein 9 (CRISPR/Cas9)


Systema Temporis: A time-based dimensional framework for consciousness and cognition.

Abstract: This study uses a combined categorical-dimensional approach to depict a hierarchical framework for consciousness similar to, and contiguous with, factorial models of cognition (cf., intelligence). On the basis of the longstanding definition of time consciousness, the analysis employs a dimension of temporal extension, in the same manner that psychology has temporally organised memory (i.e., short-term, long-term, and long-lasting memories). By defining temporal extension in terms of the structure of time perception at short timescales (<100 s), memory and time consciousness are proposed to fit along the same logarithmic dimension. This suggests that different forms of time consciousness (e.g., experience, wakefulness, and self-consciousness) are embedded within, or supported by, the ascending timescales of different modes of memory (i.e., short-term, long-term, etc.). A secondary dimension is also proposed to integrate higher-order forms of consciousness/emotion and memory/cognition. The resulting two-dimensional structure accords with existing theories of cognitive and emotional intelligence.

Kent|Lachlan|L|
Van Doorn|George|G|
Klein|Britt|B|

Consciousness
Cognition
Intelligence
Time perception
Self-consciousness
Access consciousness
Phenomenal consciousness
Taxonomy


De-risking excipient particle size distribution variability with automated robust mixing: Integrating quality by design and process analytical technology.

Abstract:
BACKGROUND
Particle size distribution (PSD) variability in excipients affects mixing. In response, manufacturers rely on raw material control and rigidly defined process parameters to achieve quality. However, this status quo is costly; and diverges from regulatory exceptions for process robustness. Although robustness improves cost and material usage efficiency, it remains under-adopted.

METHOD
To address this gap, a robust batch mixing operation that mitigated the impact of PSD variability was evaluated, with blends comprising chlorpheniramine, microcrystalline cellulose and lactose. PSD of lactose was varied to simulate commercially-relevant variability. Due to PSD-induced rheological variations, the blends had different optimal mixing speeds. For the automation study, near infrared (NIR) spectroscopy; process optimization and endpoint detection algorithms; and control hardware were integrated within a cluster of software environments. NIR spectroscopy was employed for in-line PSD characterization and blend monitoring, to modulate mixing speed and detect endpoint (feedforward and feedback control).

RESULTS
NIR spectroscopy rapidly detected PSD variations by the 6th-9th rotations, to activate feedforward control, which mitigated the effect of PSD variability and reduced the mixing time by 13-34%. Endpoints were correctly detected. PSD variations and blend homogeneity were accurately predicted (relative standard error of prediction ≤ 2%).

CONCLUSION
The automated robust mixing operation was successful. Pertinently, NIR spectrometer can be adopted for multimodal sensing. Its applicability for production-driven characterization of raw materials in batch and continuous pharmaceutical processing should be further explored. Lastly, this study laid the groundwork for end-to-end implementation of process analytical technology in robust batch processing.

Lee|Wee Beng|WB|
Widjaja|Effendi|E|
Heng|Paul Wan Sia|PWS|
Chan|Lai Wah|LW|

Particle size distribution
Automation
Process analytical technology
Blending
Excipient variability
Near infrared spectroscopy
synTQ


Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.

Abstract:
OBJECTIVES
To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study.

METHODS
In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1-Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates.

RESULTS
Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1-Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group.

CONCLUSIONS
In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab.

TRIAL REGISTRATION NUMBER
NCT00929864.

Sokolove|Jeremy|J|
Schiff|Michael|M|
Fleischmann|Roy|R|
Weinblatt|Michael E|ME|
Connolly|Sean E|SE|
Johnsen|Alyssa|A|
Zhu|Jin|J|
Maldonado|Michael A|MA|
Patel|Salil|S|
Robinson|William H|WH|

Rheumatoid Arthritis
Ant-CCP
Autoantibodies
DMARDs (biologic)


SUMO Modification of OsFKBP20-1b Is Integral to Proper Pre-mRNA Splicing upon Heat Stress in Rice.

Abstract: OsFKBP20-1b, a plant-specific cyclophilin protein, has been implicated to regulate pre-mRNA splicing under stress conditions in rice. Here, we demonstrated that OsFKBP20-1b is SUMOylated in a reconstituted SUMOylation system in E.coli and in planta, and that the SUMOylation-coupled regulation was associated with enhanced protein stability using a less SUMOylated OsFKBP20-1b mutant (5KR_OsFKBP20-1b). Furthermore, OsFKBP20-1b directly interacted with OsSUMO1 and OsSUMO2 in the nucleus and cytoplasm, whereas the less SUMOylated 5KR_OsFKBP20-1b mutant had an impaired interaction with OsSUMO1 and 2 in the cytoplasm but not in the nucleus. Under heat stress, the abundance of an OsFKBP20-1b-GFP fusion protein was substantially increased in the nuclear speckles and cytoplasmic foci, whereas the heat-responsiveness was remarkably diminished in the presence of the less SUMOylated 5KR_OsFKBP20-1b-GFP mutant. The accumulation of endogenous SUMOylated OsFKBP20-1b was enhanced by heat stress in planta. Moreover, 5KR_OsFKBP20-1b was not sufficiently associated with the U snRNAs in the nucleus as a spliceosome component. A protoplast transfection assay indicated that the low SUMOylation level of 5KR_OsFKBP20-1b led to inaccurate alternative splicing and transcription under heat stress. Thus, our results suggest that OsFKBP20-1b is post-translationally regulated by SUMOylation, and the modification is crucial for proper RNA processing in response to heat stress in rice.

D004926:Escherichia coli
D018869:Heat-Shock Response
D012275:Oryza
D010940:Plant Proteins
D012326:RNA Splicing
D058207:Sumoylation

OsFKBP20-1b
pre-mRNA splicing
heat stress
SUMOylation
splicing factor


Developmental dyslexia: A new look at clinical features and brain mechanisms.

Abstract: Developmental dyslexia is the commonest "specific learning disorder" (DSM-5) or "developmental learning disorder with impairment in reading" (ICD-11). This impairment in reading acquisition is related to a defect in the installation of cognitive precursors necessary to master the grapheme-phoneme conversion. Its origin is largely genetic, but many environmental factors seem capable of modulating symptom intensity. Three types of presentation, roughly equal in occurrence, are useful to distinguish according to the associated disorders (language, attentional, and/or motor coordination), thus suggesting, at least in part, potentially different mechanisms at their origin. In adolescence and adulthood the clinical presentation tends to bear a more uniform pattern, covering a large range of severity depending on each person's ability to compensate for their deficit. Research has demonstrated dysfunction of specific brain areas during reading-related tasks (using fMRI), essentially in the left cerebral hemisphere, but also atypical patterns of connectivity (using diffusion imaging), further supplemented by functional connectivity studies at rest. The current therapeutic recommendations emphasize the need for multidisciplinary care, giving priority, depending on the clinical form, to the language, psychomotor, or neuropsychologic aspects of rehabilitation. Various training methods whose effectiveness has been scientifically tested are reviewed, emphasizing those exploiting the hypothesis of a lack of intermodal connectivity between separate cognitive systems.

Dyslexia
Learning disorders
Rehabilitation
Attentional processes
Brain imaging
Phonology


Addiction consultation services - Linking hospitalized patients to outpatient addiction treatment.

Abstract:
BACKGROUND
Approximately 15% of hospitalized patients have an active substance use disorder (SUD). Starting treatment for SUD, including medications, during acute hospitalizations can engage patients in addiction care. In July 2015, the Boston Medical Center Addiction Consult Service (ACS), began providing inpatient diagnostic, management, and discharge linkage consultations. We describe this implementation.

METHODS
The ACS staff recorded SUDs diagnoses and medication recommendations and tracked follow-up data for affiliated outpatient office-based addiction clinics and methadone maintenance programs. We assessed the number of consults, SUDs diagnoses, medications recommended and initiated, and outpatient addiction clinic follow-up.

RESULTS
Over 26weeks, the BMC ACS completed 337 consults: 78% had an opioid use disorder (UD), 37% an alcohol UD, 28% a cocaine UD, 9% a benzodiazepine UD, 3% a cannabinoid (including K2) UD, and <1% a methamphetamine UD. Methadone was initiated in 70 inpatients and buprenorphine in 40 inpatients. Naltrexone was recommended 45 times (for opioid UD, alcohol UD, or both). Of the patients initiated on methadone, 76% linked to methadone clinic, with 54%, 39%, and 29% still retained at 30, 90, and 180days, respectively. For buprenorphine, 49% linked to clinic, with 39%, 27%, and 18% retained at 30, 90, and 180days, respectively. For naltrexone, 26% linked to clinic, all with alcohol UD alone.

CONCLUSIONS
A new inpatient addiction consultation service diagnosed and treated hospitalized patients with substance use disorders and linked them to outpatient addiction treatment care. Initiating addiction medications, particularly opioid agonists, was feasible in the inpatient setting. Optimal linkage and retention of hospitalized patients to post-discharge addiction care warrants further innovation and program development.

Trowbridge|Paul|P|
Weinstein|Zoe M|ZM|
Kerensky|Todd|T|
Roy|Payel|P|
Regan|Danny|D|
Samet|Jeffrey H|JH|
Walley|Alexander Y|AY|

Addiction consultation
Inpatient
Linkage to care
Opioid agonists treatment


HEAR: Approach for Heartbeat Monitoring with Body Movement Compensation by IR-UWB Radar.

Abstract: Further applications of impulse radio ultra-wideband radar in mobile health are hindered by the difficulty in extracting such vital signals as heartbeats from moving targets. Although the empirical mode decomposition based method is applied in recovering waveforms of heartbeats and estimating heart rates, the instantaneous heart rate is not achievable. This paper proposes a Heartbeat Estimation And Recovery (HEAR) approach to expand the application to mobile scenarios and extract instantaneous heartbeats. Firstly, the HEAR approach acquires vital signals by mapping maximum echo amplitudes to the fast time delay and compensating large body movements. Secondly, HEAR adopts the variational nonlinear chirp mode decomposition in extracting instantaneous frequencies of heartbeats. Thirdly, HEAR extends the clutter removal method based on the wavelet decomposition with a two-parameter exponential threshold. Compared to heart rates simultaneously collected by electrocardiograms (ECG), HEAR achieves a minimum error rate 4.6% in moving state and 2.25% in resting state. The Bland⁻Altman analysis verifies the consistency of beat-to-beat intervals in ECG and extracted heartbeat signals with the mean deviation smaller than 0.1 s. It indicates that HEAR is practical in offering clinical diagnoses such as the heart rate variability analysis in mobile monitoring.


Interventions for mental health problems in children and adults with severe intellectual disabilities: a systematic review.

Abstract:
OBJECTIVE
Mental health problems are more prevalent in people with than without intellectual disabilities, yet treatment options have received little attention. The aim of this study was to identify and evaluate the effectiveness of pharmacological and psychological interventions in the treatment of mental health problems in children and adults with severe and profound intellectual disabilities, given their difficulties in accessing standard mental health interventions, particularly talking therapies, and difficulties reporting drug side effects.

DESIGN
A systematic review using electronic searches of PsycINFO, PsycTESTS, EMBASE, MEDLINE, CINAHL, ERIC, ASSIA, Science Citation Index, Social Science Citation Index and CENTRAL was conducted to identify eligible intervention studies. Study selection, data extraction and quality appraisal were performed by two independent reviewers.

PARTICIPANTS
Study samples included at least 70% children and/or adults with severe or profound intellectual disabilities or reported the outcomes of this subpopulation separate from participants with other levels of intellectual disabilities.

INTERVENTIONS
Eligible intervention studies evaluated a psychological or pharmacological intervention using a control condition or pre-post design.

OUTCOMES
Symptom severity, frequency or other quantitative dimension (e.g., impact), as assessed with standardised measures of mental health problems.

RESULTS
We retrieved 41 232 records, reviewed 573 full-text articles and identified five studies eligible for inclusion: three studies evaluating pharmacological interventions, and two studies evaluating psychological interventions. Study designs ranged from double-blind placebo controlled crossover trials to single-case experimental reversal designs. Quality appraisals of this very limited literature base revealed good experimental control, poor reporting standards and a lack of follow-up data.

CONCLUSIONS
Mental ill health requires vigorous treatment, yet the current evidence base is too limited to identify with precision effective treatments specifically for children or adults with severe and profound intellectual disabilities. Clinicians therefore must work on the basis of general population evidence, while researchers work to generate more precise evidence for people with severe and profound intellectual disabilities.

PROSPERO REGISTRATION NUMBER
CRD 42015024469.

Vereenooghe|Leen|L|0000-0001-9772-1151
Flynn|Samantha|S|
Hastings|Richard P|RP|
Adams|Dawn|D|
Chauhan|Umesh|U|
Cooper|Sally-Ann|SA|0000-0001-6054-7700
Gore|Nick|N|
Hatton|Chris|C|
Hood|Kerry|K|
Jahoda|Andrew|A|
Langdon|Peter E|PE|
McNamara|Rachel|R|
Oliver|Chris|C|
Roy|Ashok|A|
Totsika|Vasiliki|V|
Waite|Jane|J|

D016032:Randomized Controlled Trials as Topic

mental health
intellectual disabilities
systematic review
pharmacotherapies
psychological therapies


Single-Photon Near-Infrared-Responsiveness from the Molecular to the Supramolecular Level via Platination of Pentacenes.

Abstract: Near-infrared (NIR) responsiveness is important for various applications. Currently, single-photon NIR-responsive systems are rare compared to systems that display two-photon absorption and triplet-triplet annihilation processes. Supramolecular stacking of photo-responsive chromophores results in decreased efficiency due to space-confinement effects. Herein we show that σ-platination of pentacenes is a feasible protocol to build single-photon NIR-responsive systems, with advantages including a low HOMO-LUMO energy gap, high photochemical efficiency, and pathway specificity. The pentacene-to-endoperoxidation transformation is accompanied by color and absorbance changes. The high photo-oxygenation efficiency of σ-platinated pentacenes facilitates NIR responsiveness in one-dimensional supramolecular polymers, resulting in the disappearance of supramolecular chirality signals and disruption of self-assembled nanofibers. Overall, the σ-platination strategy opens up new avenues toward NIR photo-responsive materials at the molecular and supramolecular levels.

supramolecular polymers
self-assembly
metalloligands
photoresponsive materials
polycyclic aromatic hydrocarbons


Selected Pharmaceuticals in Different Aquatic Compartments: Part I-Source, Fate and Occurrence.

Abstract: Potential risks associated with releases of human pharmaceuticals into the environment have become an increasingly important issue in environmental health. This concern has been driven by the widespread detection of pharmaceuticals in all aquatic compartments. Therefore, 22 pharmaceuticals, 6 metabolites and transformation products, belonging to 7 therapeutic groups, were selected to perform a systematic review on their source, fate and occurrence in different aquatic compartments, important issues to tackle the Water Framework Directive (WFD). The results obtained evidence that concentrations of pharmaceuticals are present, in decreasing order, in wastewater influents (WWIs), wastewater effluents (WWEs) and surface waters, with values up to 14 mg L-1 for ibuprofen in WWIs. The therapeutic groups which presented higher detection frequencies and concentrations were anti-inflammatories, antiepileptics, antibiotics and lipid regulators. These results present a broad and specialized background, enabling a complete overview on the occurrence of pharmaceuticals in the aquatic compartments.

Pereira|André|A| Silva|Liliana|L| Laranjeiro|Célia|C| Lino|Celeste|C| Pena|Angelina|A|

D004784:Environmental Monitoring
D006801:Humans
D004364:Pharmaceutical Preparations
D018570:Risk Assessment
D045483:Rivers
D062065:Waste Water
D014874:Water Pollutants, Chemical
D018508:Water Purification

pharmaceuticals
aquatic compartments
environmental contaminants
pharmaceuticals occurrence


Effects of Nutrition on Cognitive Function in Adults with or without Cognitive Impairment: A Systematic Review of Randomized Controlled Clinical Trials.

Abstract: New dietary approaches for the prevention of cognitive impairment are being investigated. However, evidence from dietary interventions is mainly from food and nutrient supplement interventions, with inconsistent results and high heterogeneity between trials. We conducted a comprehensive systematic search of randomized controlled trials (RCTs) published in MEDLINE-PubMed, from January 2018 to July 2021, investigating the impact of dietary counseling, as well as food-based and dietary supplement interventions on cognitive function in adults with or without cognitive impairment. Based on the search strategy, 197 eligible publications were used for data abstraction. Finally, 61 articles were included in the analysis. There was reasonable evidence that dietary patterns, as well as food and dietary supplements improved cognitive domains or measures of brain integrity. The Mediterranean diet showed promising results, whereas the role of the DASH diet was not clear. Healthy food consumption improved cognitive function, although the quality of these studies was relatively low. The role of dietary supplements was mixed, with strong evidence of the benefits of polyphenols and combinations of nutrients, but with low evidence for PUFAs, vitamin D, specific protein, amino acids, and other types of supplements. Further well-designed RCTs are needed to guide the development of dietary approaches for the prevention of cognitive impairment.

cognitive impairment
dietary interventions
food
supplements
diet
healthy
Alzheimer’s disease
subjective cognitive decline


Diverse phylogenomic datasets uncover a concordant scenario of laurasiatherian interordinal relationships.

Abstract: Resolving the interordinal relationships in the mammalian superorder Laurasiatheria has been among the most intractable problems in higher-level mammalian systematics, with many conflicting hypotheses having been proposed. The present study collected three different sources of genome-scale data with comprehensive taxon sampling of laurasiatherian species, including two protein-coding datasets (4,186 protein-coding genes for an amino acid dataset comprising 2,761,247 amino acid residues and a nucleotide dataset comprising 5,516,340 nucleotides from 1st and 2nd codon positions), an intronic dataset (1,210 introns comprising 1,162,723 nucleotides) and an ultraconserved elements (UCEs) dataset (1,246 UCEs comprising 1,946,472 nucleotides) from 40 species representing all six laurasiatherian orders and 7 non-laurasiatherian outgroups. Remarkably, phylogenetic trees reconstructed with the four datasets using different tree-building methods (RAxML, FastTree, ASTRAL and MP-EST) all supported the relationship (Eulipotyphla, (Chiroptera, ((Carnivora, Pholidota), (Cetartiodactyla, Perissodactyla)))). We find a resolution of interordinal relationships of Laurasiatheria among all types of markers used in the present study, and the likelihood ratio tests for tree comparisons confirmed that the present tree topology is the optimal hypothesis compared to other examined hypotheses. Jackknifing subsampling analyses demonstrate that the results of laurasiatherian tree reconstruction varied with the number of loci and ordinal representatives used, which are likely the two main contributors to phylogenetic disagreements of Laurasiatheria seen in previous studies. Our study provides significant insight into laurasiatherian evolution, and moreover, an important methodological strategy and reference for resolving phylogenies of adaptive radiation, which have been a long-standing challenge in the field of phylogenetics.

Lv|Xue|X|
Hu|Jingyang|J|
Hu|Yiwen|Y|
Li|Yitian|Y|
Xu|Dongming|D|
Ryder|Oliver A|OA|
Irwin|David M|DM|
Yu|Li|L|

Laurasiatheria
Intronic dataset
Adaptive radiations
Coding dataset
Phylogenomic analyses
UCE dataset


Bleeding associated with low-dose aspirin: Comparison of data from the COMPASS randomized controlled trial and routine clinical practice.

Abstract: Randomized controlled trials (RCTs) have strong internal validity but often have limited external validity. Observational studies have good generalizability and an increasing role in key healthcare decision making. We compared incidence rates of intracranial and major gastrointestinal bleeds in the low-dose aspirin arm (N = 9126) of the COMPASS double-blind RCT (conducted at 602 centres in 33 countries) with those from an observational cohort of preventative low-dose aspirin users (N = 54,140) in a primary care database representative of the UK general population - The IQVIA Medical Research Data UK (IMRD-UK). In our observational study analysis, we restricted follow-up to 2 years to be comparable with the duration of the COMPASS trial. Among low-dose aspirin users, incidence rates per 1000 person-years (95% confidence intervals [CIs]) in the IMRD-UK cohort and COMPASS trial participants, respectively, were 0.6 (0.5-0.8) vs. 1.4 (0.9-2.1) for intracranial bleeds, and 3.5 (3.1-3.8) vs. 3.7 (2.9-4.8) for major gastrointestinal bleeds. These broadly comparable bleeding rates among COMPASS trial participants and an observational cohort of low-dose aspirin users in IMRD-UK support the use of the latter for generating robust therapeutic evidence, and indicate that the rates from the COMPASS trial are broadly consistent with realistic population-based rates.

García Rodríguez|Luis A|LA|
Vora|Pareen|P|
Brobert|Gunnar|G|
Soriano-Gabarró|Montse|M|
Cea Soriano|Lucía|L|

Aspirin
Trials
Observational
Gastrointestinal bleeding
Intracranial bleeding


Diagnostic Value of Plasma MicroRNAs for Lung Cancer Using Support Vector Machine Model.

Abstract: Aim: Small single-stranded non-coding RNAs (miRNAs) play an important role in carcinogenesis through degrading target mRNAs. However, the diagnostic value of miRNAs was not explored in lung cancers. In this study, a support-vector-machine (SVM) model for diagnosis of lung cancer was established based on plasma miRNAs biomarkers, clinical symptoms and epidemiology material. Methods: The expressions of plasma miRNA were examined with SYBR Green-based quantitative real-time PCR. Results: We identified that the expressions of 10 plasma miRNAs (miR-21, miR-20a, miR-210, miR-145, miR-126, miR-223, miR-197, miR-30a, miR-30d, miR-25), smoking status, fever, cough, chest pain or tightness, bloody phlegm, haemoptysis, were significantly different between lung cancer and control groups (P<0.05). The accuracies of the combined SVM, miRNAs SVM, symptom SVM, combined Fisher, miRNAs Fisher and symptom Fisher were 96.34%, 80.49%, 84.15%, 84.15%, 75.61%, and 80.49%, respectively; AUC of these six model were 0.976, 0.841, 0.838, 0.865, 0.750, and 0.801, respectively. The accuracy and AUC of combined SVM were higher than the other 5 models (P<0.05). Conclusions: Our findings indicate that SVM model based on plasma miRNAs biomarkers may serve as a novel, accurate, noninvasive method for auxiliary diagnosis of lung cancer.

Wang|Wei|W| Ding|Mingcui|M| Duan|Xiaoran|X| Feng|Xiaolei|X| Wang|Pengpeng|P| Jiang|Qingfeng|Q| Cheng|Zhe|Z| Zhang|Wenjuan|W| Yu|Songcheng|S| Yao|Wu|W| Cui|Liuxin|L| Wu|Yongjun|Y| Feng|Feifei|F| Yang|Yongli|Y|

Lung cancer
Support vector machine
Diagnosis
Plasma miRNAs


A Network of Paralogous Stress Response Transcription Factors in the Human Pathogen Candida glabrata.

Abstract: The yeast Candida glabrata has become the second cause of systemic candidemia in humans. However, relatively few genome-wide studies have been conducted in this organism and our knowledge of its transcriptional regulatory network is quite limited. In the present work, we combined genome-wide chromatin immunoprecipitation (ChIP-seq), transcriptome analyses, and DNA binding motif predictions to describe the regulatory interactions of the seven Yap (Yeast AP1) transcription factors of C. glabrata. We described a transcriptional network containing 255 regulatory interactions and 309 potential target genes. We predicted with high confidence the preferred DNA binding sites for 5 of the 7 CgYaps and showed a strong conservation of the Yap DNA binding properties between S. cerevisiae and C. glabrata. We provided reliable functional annotation for 3 of the 7 Yaps and identified for Yap1 and Yap5 a core regulon which is conserved in S. cerevisiae, C. glabrata, and C. albicans. We uncovered new roles for CgYap7 in the regulation of iron-sulfur cluster biogenesis, for CgYap1 in the regulation of heme biosynthesis and for CgYap5 in the repression of GRX4 in response to iron starvation. These transcription factors define an interconnected transcriptional network at the cross-roads between redox homeostasis, oxygen consumption, and iron metabolism.

Merhej|Jawad|J|
Thiebaut|Antonin|A|
Blugeon|Corinne|C|
Pouch|Juliette|J|
Ali Chaouche|Mohammed El Amine|Mel A|
Camadro|Jean-Michel|JM|
Le Crom|Stéphane|S|
Lelandais|Gaëlle|G|
Devaux|Frédéric|F|

yeast
regulatory networks
ChIP-seq
transcriptome
Yap
evolution


Internet trolling and everyday sadism: Parallel effects on pain perception and moral judgment.

Abstract:
OBJECTIVE
This research seeks to clarify the association between online trolling and sadistic personality, and to provide evidence that the reward and rationalization processes at work in sadism are likewise manifest in online trolling.

METHOD
Online respondents (community adults and university students; total N = 1,715) completed self-report measures of personality and trolling behavior. They subsequently engaged in one of two judgment tasks. In Study 1, respondents viewed stimuli depicting scenes of emotional/physical suffering and provided ratings of (a) perceived pain intensity and (b) pleasure experienced while viewing the photos. In Study 2, the iTroll questionnaire was developed and validated. It was then administered alongside a moral judgment task.

RESULTS
Across both studies, online trolling was strongly associated with a sadistic personality profile. Moreover, sadism and trolling predicted identical patterns of pleasure and harm minimization. The incremental contribution of sadism was sustained even when controlling for broader antisocial tendencies (i.e., the Dark Triad, callous-unemotionality, and trait aggression).

CONCLUSIONS
Results confirm that online trolling is motivated (at least in part) by sadistic tendencies. Coupled with effective rationalization mechanisms, sadistic pleasure can be consummated in such everyday behaviors as online trolling.

Buckels|Erin E|EE|0000-0002-8782-3776
Trapnell|Paul D|PD|
Andjelovic|Tamara|T|
Paulhus|Delroy L|DL|

everyday sadism
online trolling
Dark Triad
Dark Tetrad
cyber deviance


Photoinduced Strain-Assisted Synthesis of a Stiff-Stilbene Polymer by Ring-Opening Metathesis Polymerization.

Abstract: Developing a novel strategy to synthesize photoresponsive polymers is of significance owing to their potential applications. We report a photoinduced strain-assisted synthesis of main-chain stiff-stilbene polymers by using ring-opening metathesis polymerization (ROMP), activating a macrocyclic π-bond connected to a stiff-stilbene photoswitch through a linker. Since the linker acts as an external constraint, the photoisomerization to the E-form leads to the stiff-stilbene being strained and thus reactive to ROMP. The photoisomerization of Z-form to E-form was investigated using time-dependent NMR studies and UV/Vis spectroscopy. The DFT calculation showed that the E-form was less stable due to a lack of planarity. By the internal strain developed due to the linker constraint through photoisomerization, the E-form underwent ROMP by a second generation Grubbs catalyst. In contrast, Z-form did not undergo polymerization under similar conditions. The MALDI-TOF spectrum of E-form after polymerization showed the presence of oligomers of >5.2 kDa.

ring-opening metathesis polymerization
photoswitches
strain
isomerism


Peritraumatic dissociation revisited: associations with autonomic activation, facial movements, staring, and intrusion formation.

Abstract:
Background
Peritraumatic dissociation is purported to emerge together with attenuated autonomic arousal, immobility, and staring. However, empirical evidence is scarce and heterogeneous. Moreover, it is still a matter of debate whether these responses predict intrusion formation.

Objective
The present trauma-analogue study examined associations between peritraumatic dissociation, autonomic activation, facial movements, staring, and intrusion formation.

Method
Seventy-one healthy women watched a highly aversive film, while autonomic activation (heart rate, respiratory sinus arrhythmia, skin conductance level), facial movements (temporal variations in corrugator electromyography), and staring (fixation duration, tracklength) were assessed. Afterwards, participants rated the intensity of dissociation during film viewing and reported intrusions and associated distress in a smartphone application for 24 hours.

Results
Peritraumatic dissociation was linked to higher autonomic arousal (higher heart rate and, on a trend-level, lower respiratory sinus arrhythmia), increased facial movements, and staring (lower tracklength). Peritraumatic dissociation, higher autonomic arousal (higher heart rate and lower respiratory sinus arrhythmia), staring (higher fixation duration), and, on a trend-level, more facial movements were linked to higher intrusion load (number x distress of intrusions) and together explained 59% of variance. Skin conductance level was neither linked to peritraumatic dissociation nor intrusion load.

Conclusions
Our results suggest that, at low-dissociation-levels observed in trauma-analogue studies, peritraumatic dissociation may occur together with heightened autonomic arousal and facial movements, indexing increased negative affect. Staring might, irrespectively of dissociation-levels, serve as objective marker for dissociation. Together, peritraumatic dissociation and its psychophysiological correlates might set the stage for later intrusion formation.

dissociation
psychophysiology
Trauma
eye-tracking
intrusive memories
posttraumatic stress disorder
stressful film
trauma-film


Preparation and Utilization of a 3D Human Liver Microtissue Model for Nanotoxicological Assessment.

Abstract: The liver is the principal detoxification center of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated with accumulative production of nanomaterials, there is an urgent need to consider the possibility of harmful health consequences of engineered NM exposure. It is understood that following exposure via inhalation, ingestion, or direct intravenous injection a fraction of NMs reach the liver. Traditional in vitro or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e., reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.). This chapter highlights a methodology for the preparation of a physiologically relevant 3D human liver microtissue model which addresses most of the negative issues associated with the models used in traditional in vitro hepatic toxicological investigations. The spheroids are a very promising model for the assessment of the toxicological effects associated with engineered NM exposure.

Liver
Nanotoxicology
Nanomaterials
3D microtissue spheroid
Hepatocytes
Kupffer cells


Ring and Gellhorn pessaries used in patients with pelvic organ prolapse: a retrospective study of 8 years.

Abstract:
AIM
The aim of this study was to identify factors associated with pessary fitting, continued use of pessary and satisfaction of patients with pelvic organ prolapse.

METHODS
A retrospective study was conducted in patients who received an initial pessary fitting. The clinical characteristics of these patients were recorded. The Pelvic Floor Disability Index PFDI-20 and PFIQ-7 were used to assess pelvic floor dysfunction and quality of life. Complications, satisfaction degree, and reasons for abandonment were recorded during the follow-up. T test and Chi square test in SPSS version 20 were used to analyze the data.

RESULTS
Three hundred women with symptomatic prolapse were selected for pessary fitting, whose average age was 67.8 ± 10.7 years. For two hundred and forty-nine (83%) women, the fitting was successful, of whom 162 used ring pessaries and 87 used Gellhorn pessaries. Forty-seven patients abandoned using a pessary at the end of our study. Most clinical characteristics were not significantly different between the successful and unsuccessful fitting groups (P > 0.05). The average score of CRADI-8 was lower in successful fitting group (11.9 ± 15.9) than that in unsuccessful fitting group (18.8 ± 19.9) (P < 0.05). 162 patients with successful pessary fitting completed the satisfaction survey, 79% of whom were satisfied or very satisfied. Erosions (24.4%) were the most common complication. Difficulty in inserting or removing (30.4%) and erosions (22.8%) were the main factors, which affected the satisfaction degree.

CONCLUSIONS
Patients with obvious symptoms of posterior pelvic prolapse are more likely to fit failure. Difficulty in inserting or removing and erosions are the main factors, which lead to the discontinuation of pessary use and decrease in the satisfaction degree.

Yang|Junfang|J| Han|Jinsong|J|0000-0002-6268-2225 Zhu|Fuli|F| Wang|Yu|Y|

Pelvic organ prolapse
Pessary fitting
Satisfaction
Complication


Therapeutics for tendon regeneration: a multidisciplinary review of tendon research for improved healing.

Abstract: Tendon injuries, known as tendinopathies, are common musculoskeletal injuries that affect a wide range of the population. Canonical tendon healing is characterized by fibrosis, scar formation, and the loss of tissue mechanical and structural properties. Understanding the regenerative tendon environment is an area of increasing interest in the field of musculoskeletal research. Previous studies have focused on utilizing individual elements from the fields of biomechanics, developmental biology, cell and growth factor therapy, and tissue engineering in an attempt to develop regenerative tendon therapeutics. Still, the specific mechanism for regenerative healing remains unknown. In this review, we highlight some of the current approaches of tendon therapeutics and elucidate the differences along the tendon midsubstance and enthesis, exhibiting the necessity of location-specific tendon therapeutics. Furthermore, we emphasize the necessity of further interdisciplinary research in order to reach the desired goal of fully understanding the mechanisms underlying regenerative healing.

D036341:Intercellular Signaling Peptides and Proteins

therapeutics tendon regeneration healing


Adapting legume crops to climate change using genomic approaches.

Abstract: Our agricultural system and hence food security is threatened by combination of events, such as increasing population, the impacts of climate change, and the need to a more sustainable development. Evolutionary adaptation may help some species to overcome environmental changes through new selection pressures driven by climate change. However, success of evolutionary adaptation is dependent on various factors, one of which is the extent of genetic variation available within species. Genomic approaches provide an exceptional opportunity to identify genetic variation that can be employed in crop improvement programs. In this review, we illustrate some of the routinely used genomics-based methods as well as recent breakthroughs, which facilitate assessment of genetic variation and discovery of adaptive genes in legumes. Although additional information is needed, the current utility of selection tools indicate a robust ability to utilize existing variation among legumes to address the challenges of climate uncertainty.

D057231:Climate Change
D018556:Crops, Agricultural
D007887:Fabaceae
D017343:Genes, Plant
D023281:Genomics
D000069600:Plant Breeding


Lethal protein in mass consumption edible mushroom Agrocybe aegerita linked to strong hepatic toxicity.

Abstract: Edible mushrooms are well-known for their health and nutritional benefits, however, undesirable effects have been reported in animals fed with these types of edible mushrooms (Nieminen et al., 2009). For health and safety reason, it is necessary to evaluate the toxicity of edible mushrooms, especially those that have been artificially cultured in recent decades. The aim of this study was to assess the safety of the edible mushroom Agrocybe aegerita, which is also known as Agrocybe cylindracea in Europe and America. Components from A. aegerita (Yt) were extracted in water and unexpectedly displayed lethal effect and median lethal dose (LD50) at 8.77 g/kg. Strong hepatic toxicity in BALB/c mice was observed when mice were administered with 25 and 250 mg/kg body weight/day of Yt for 6 days. To identify the hepatotoxic components, Yt was further separated into two components by Diaion HP-20 column chromatography to produce the proteins (Yp) and small molecules (Ys) fractions. Biochemical and histopathological analysis showed that Yp could induce liver injury. LC-MS/MS analysis of Yp identified the main causative agent as AAL (A. aegerita lectin), which was shown to have similar hepatotoxicity in the Yt and Yp fractions. In addition, proteinase treatment assays indicated that AAL is resistant to the degradation by digestive enzymes. We have shown that the strong hepatic toxicity is due to a lectin in A. aegerita. This study suggests that correct consumption of A. aegerita can avoid human health risk and help us better understand its nutritional and medicinal value.

Jin|Yanxia|Y|
Che|Tao|T|
Yin|Yalin|Y|
Yu|Guojun|G|
Yang|Qing|Q|
Liu|Wei|W|
Ye|Xiangdong|X|
Yu|Wenhui|W|
Alok|Shrestha|S|
Chen|Yijie|Y|
Wong|Barry Hon Cheung|BH|
Cheng|Pengfei|P|
Sun|Hui|H|

D056486:Chemical and Drug Induced Liver Injury

Agrocybe aegerita
Hepatotoxicity
Lectin AAL
Stability
Total protein


Effects of Larval Nutrition on Wolbachia-Based Dengue Virus Interference in Aedes aegypti (Diptera: Culicidae).

Abstract: In order to assess the broad-scale applicability of field releases of Wolbachia for the biological control of insect-transmitted diseases, we determined the relationship between the larval diet of Aedes aegypti L. mosquitoes infected with Wolbachia strains and their susceptibility to dengue virus (DENV) infection via intrathoracic injection and oral inoculation. Larvae were reared on diets that varied in the quantity of food which had the effect of modifying development time and adult body size. Wolbachia wMel infection was associated with highly significant reductions in dengue serotype 2 (DENV-2) infection rates of between 80 and 97.5% following intrathoracic injection of adults emerging from three diet levels. Reductions were 100% in two diet level treatments following oral inoculation. Similarly, wMelPop infection was associated with highly significant reductions in DENV-2 infection rates of between 95 and 100% for intrathoracic injection and 97.5 and 100% for oral inoculation across diet level treatments. Larval diet level had no significant effect on DENV-2 infection rates in the presence of Wolbachia infection in mosquitoes that were intrathoracically injected with the virus. This indicates that the effectiveness of Wolbachia on vector competence disruption within Ae. aegypti is unlikely to be compromised by variable larval nutrition in field settings.

Kho|Elise A|EA|
Hugo|Leon E|LE|
Lu|Guangjin|G|
Smith|David D|DD|
Kay|Brian H|BH|

D000824:Animal Nutritional Physiological Phenomena

larval nutrition
dengue virus
virus interference
Aedes aegypti
Wolbachia


Creating superhydrophobic and antibacterial surfaces on gold by femtosecond laser pulses.

Abstract: Femtosecond laser-induced surface structuring is a promising technique for the large-scale formation of nano- and microscale structures that can effectively modify materials' optical, electrical, mechanical, and tribological properties. Here we perform a systematic study on femtosecond laser-induced surface structuring on gold (Au) surface and their effect on both hydrophobicity and bacterial-adhesion properties. We created various structures including subwavelength femtosecond laser-induced periodic surface structures (fs-LIPSSs), fs-LIPSSs covered with nano/microstructures, conic and 1D-rod-like structures (  6 μm), and spherical nanostructures with a diameter  10 nm, by raster scanning the laser beam, at different laser fluences. We show that femtosecond laser processing turns originally hydrophilic Au to a superhydrophobic surface. We determine the optimal conditions for the creation of the different surface structures and explain the mechanism behind the formed structures and show that the laser fluence is the main controlling parameter. We demonstrate the ability of all the formed surface structures to reduce the adhesion of Escherichia coli (E. coli) bacteria and show that fs-LIPSSs enjoys superior antibacterial adhesion properties due to its large-scale surface coverage. Approximately 99.03% of the fs-LIPSSs surface is free from bacterial adhesion. The demonstrated physical inhibition of bacterial colonies and biofilm formation without antibiotics is a crucial step towards reducing antimicrobial-resistant infections.

Jalil|Sohail A|SA|
Akram|Mahreen|M|
Bhat|Javeed A|JA|
Hayes|Jeffrey J|JJ|
Singh|Subhash C|SC|
ElKabbash|Mohamed|M|
Guo|Chunlei|C|

Fs-LIPSSs
Superhydrophobic surfaces
Anti-bacterial surfaces
Nano- and microstructures


CWIN-sugar transporter nexus is a key component for reproductive success.

Abstract: Reproductive development is critical for completion of plant life cycle and realization of crop yield potential. Reproductive organs comprise multiple distinctive or even transgenerational tissues, which are symplasmically disconnected from each other for protection and better control of nutrition and development. Cell wall invertases (CWINs) and sugar transporters are often specifically or abundantly expressed in these apoplasmic interfaces to provide carbon nutrients and sugar signals to developing pollens, endosperm and embryo. Emerging evidence shows that some of those genes were indeed targeted for selection during crop domestication. In this Opinion paper, I discuss the functional significance of the localized expression of CWINs and sugar transporters in reproductive organs followed by an analysis on how their spatial patterning may be regulated at the molecular levels and how the localized CWIN activity may be exploited for improvement of reproductive output.

Cell wall invertase
Sugar transporter
Apoplasm
Pollen
Flower
Fruit
SWEET
Seed


Clinical significance of plasma MMP-2 and MMP-9 levels as biomarkers for tumor expression in breast cancer patients in Egypt.

Abstract: Matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9) are involved in the breakdown of extracellular matrix in normal physiological processes as well as in disease processes, such as cancer metastasis. We conducted this work to study the role of MMP-2 and MMP-9 in breast cancer by measuring their plasma concentrations before and after surgery. Also, to examine if their levels can reflect the stage of disease and prognosis. Forty-eight breast cancer patients and 13 patients with benign breast diseases were included in the study. MMP-2 and MMP-9 levels were measured by ELISA and semi-quantitative real-time PCR. MMP-2 and MMP-9 levels in plasma were determined by ELISA immediately before surgery and during 6 to 12 months after curative surgery. We observed a significant increase in the level of MMP-9 mRNA expression in breast cancer patients in comparison to their normal breast tissues and to tissues of benign breast disease. In all TNM tumor stages, the plasma levels of MMP-2 and MMP-9 were increased significantly before curative surgery in the studied patients with breast carcinoma and decreased significantly after surgery. Both MMP-2 and MMP-9 may be used as a possible marker for follow-up or as a marker that reflects the response of the disease to treatment.

Alrehaili|Amani Ahmed|AA|
Gharib|Amal Fathi|AF|
Karam|Rehab Ahmed|RA|
Alhakami|Reem Ali|RA|
El Sawy|Wael Hassan|WH|
Abd Elrahman|Tamer Mohamed|TM|

D015972:Gene Expression Regulation, Neoplastic


Optimization of PCR-RFLP Directly from the Skin and Nails in Cases of Dermatophytosis, Targeting the ITS and the 18S Ribosomal DNA Regions.

Abstract:
PURPOSE
A pan fungal primer targeting the Internal Transcribed Spacer (ITS) region and optimization of PCR-RFLP using a dermatophyte specific primer targeted the 18S ribosomal DNA (rDNA) region were performed for the identification of dermatophyte species and strains directly from clinical specimens.

MATERIALS AND METHODS
One hundred and thirty eight specimens (129 skin scrapings and 9 nail clippings) from clinically suspected cases of dermatophytosis were collected and subjected to direct microscopy and culture. Among them, 66 skin scrapings and 3 nail clippings were processed for genotyping by PCR-RFLP analysis using the Mva I, Hae III and the Dde I restriction enzymes.

RESULTS
Of the 138 specimens, 81 specimens were positive for dermatophytosis, the most common one being Trichophyton rubrum (47), followed by Trichophyton mentagrophytes (25) and Epidermophyton floccosum (9). Of the 47 T. rubrum isolates, 10 were T. rubrum var. raubitschekii which were identified phenotypically as urease positive and by DNA sequencing. Since they exhibited minor morphological and physiological features, they have currently been synonymized with T. rubrum. Of the 25 T. mentagrophytes isolates, three were Trichophyton interdigitale, which were identified by DNA sequencing. Among the 66 skin specimens smear, culture and PCR showed the presence of dermatophytes in 36 (54.54%), 42 (63.63%) and 47 (71.21%) cases respectively. Among the three nail specimens, only one was found to be positive for dermatophytosis by smear, culture and PCR.

CONCLUSION
Amplification of the dermatophyte specific primer is appropriate in the identification of dermatophytes directly from the clinical material. PCR targeting the ITS region by using the Mva I and the Dde I enzymes was equally good for the RFLP analysis. However, by using the above three restriction enzymes, no strain variations were detected among the T. rubrum and the T. mentagrophytes strains.

Elavarashi|Elangovan|E|
Kindo|Anupma Jyoti|AJ|
Kalyani|Jagannathan|J|

Dermatophytosis
Genotyping
DNA sequencing
PCR
RFLP


Simultaneous nitritation and p-nitrophenol removal using aerobic granular biomass in a continuous airlift reactor.

Abstract: The chemical and petrochemical industries produce wastewaters containing ammonium and phenolic compounds. Biological treatment of these wastewaters could be problematic due to the possible inhibitory effects exerted by phenolic compounds. The feasibility of performing simultaneous nitritation and p-nitrophenol (PNP) biodegradation using a continuous aerobic granular reactor was evaluated. A nitrifying granular sludge was bioaugmented with a PNP-degrading floccular sludge, while PNP was progressively added to the feed containing a high ammonium concentration. Nitritation was sustained throughout the operational period with ca. 85% of ammonium oxidation and less than 0.3% of nitrate in the effluent. PNP biodegradation was unstable and the oxygen limiting condition was found to be the main explanation for this unsteadiness. An increase in dissolved oxygen concentration from 2.0 to 4.5 mg O2 L(-1) significantly enhanced PNP removal, achieving total elimination. Acinetobacter genus and ammonia-oxidising bacteria were the predominant bacteria species in the granular biomass.

Jemaat|Zulkifly|Z|
Suárez-Ojeda|María Eugenia|ME|
Pérez|Julio|J|
Carrera|Julián|J|

Nitritation
Phenolic compounds
Oxygen limitation
Aerobic granules
Industrial wastewater


Health related quality of life in relation to asthma - Data from a cross sectional study.

Abstract: Objective: The aim of this study was to examine the effect of adult asthma on health-related quality of life (HRQoL) and psychological factors using the results of a cross-sectional nationwide survey. Methods: Data were obtained from 229,131 participants (5,989 with asthma and 223,142 without asthma) in the 2010 Korean Community Health Survey. We compared EuroQol (EQ)-5D and EQ-visual analogue scale (VAS) scores after adjusting for sociodemographic and psychosocial factors, as well as for comorbidities. Multiple logistic regression analysis was used to explore determinants of the lowest quartile HRQoL in the asthma group. Results: The mean EQ-5D and EQ-VAS scores were significantly lower in the asthma group (EQ-5D, 0.82; EQ-VAS, 64.2) compared with the non-asthma group (EQ-5D, 0.90; EQ-VAS, 73.2) (P < 0.001). The multivariate odds ratio (OR) for the lowest quartile of EQ-VAS in the asthma group versus the non-asthma group was 1.17 (95% confidence interval (CI), 1.04-1.32) and the OR for the lowest quartile of EQ-5D in the asthma group versus the non-asthma group was 1.47 (95% CI, 1.18-1.84). Asthma subjects were more likely than those without asthma to have some or severe problems with pain (OR, 1.34; 95% CI, 1.16-1.56) and anxiety/depression (OR, 1.08; 95% CI, 1.03-1.56). Conclusion: We found that asthma was associated with impaired HRQoL, in particular the presence of some or severe problems with anxiety/depression.


Complete spontaneous bone regeneration following partial mandibulectomy.

Abstract: Bone formation in small deposits following the loss of part of the mandible has often been reported in the literature, but reports of complete bone regeneration extending over the entire anterior mandible from angle to angle is rare. Even rarer, are reports on the behaviour of such new bone in terms of facial development, over a long term and the effect of load carrying on it. Presented here is an unusual case of bone regeneration after resection of a large portion of the mandible in a 12 year-old female patient with ameloblastoma in the anterior mandible. Inter-maxillary fixation, bone grafting, or insertion of any kind of implant was not employed. Spontaneous bone regeneration was noted six weeks after surgery, and the entire resected portion of the mandible completely regenerated when the patient was seen again six years later. Mandibular growth was not significantly affected and thirteen years after her treatment, including five years of partial denture usage over the new bone, the shape of the mandible is satisfactory without any evidence of bone resorption. The periosteum was totally preserved, perhaps accounting for the complete bone regeneration and normal mandibular growth and form.

Complete Spontaneous Bone Regeneration Mandibulectomy


Narrowing the gap between the number of athletes who dope and the number of athletes who are caught: scientific advances that increase the efficacy of antidoping tests.

Abstract: The analytical methods developed and applied by the antidoping laboratories have been continuously evolving over the past 50 years, with the aim of keeping pace with the constant evolution of doping strategies. Despite this, the number of adverse analytical tests reported worldwide by the network of the WADA-accredited laboratories still seems to underestimate the actual number of doped athletes. We investigate the most likely causes for this gap between the likely doping rate and the detection of athletes with positive doping tests. We consider laboratory and non-laboratory reasons that contribute to this gap. More specifically, laboratory issues are focused not only on those doping practices that may still be 'invisible' at the time of a doping test, but also on the possible role of non-conventional masking strategies. These include (1) the intake of banned drugs by specific novel drug delivery systems and (2) the coadministration of prohibited and non-prohibited drugs, taking advantage of the capacity of the latter to affect the metabolism, and consequently the detection, of the former. Non-laboratory issues include the lack of a sufficient level of 'intelligent testing', with the result that, even in the cases of doped athletes, the biological samples delivered to the antidoping laboratories for analysis may not contain those target analytes whose detection (and if necessary quantification above a decision limit) constitutes an adverse analytical finding. We present proposals to improve the efficacy of the doping control policies based on the analysis of biological samples and suggest how to constantly keep up with the continuous developments of new forms of doping.

Botrè|Francesco|F|
de la Torre|Xavier|X|
Donati|Francesco|F|
Mazzarino|Monica|M|


Chemical characterization, phytotoxic, and cytotoxic activities of essential oil of Mentha longifolia.

Abstract: The present study assessed the phytotoxic and cytotoxic potential of the essential oil (EO) extracted from aboveground parts of Mentha longifolia (L.) Huds. Gas chromatography-mass spectrometry revealed 39 compounds constituting 99.67% of the EO. The EO was rich in monoterpenoids (mostly oxygenated monoterpenes), which accounted for 89.28% of the oil. The major components in EO were monoterpene ketones such as piperitone oxide (53.83%) and piperitenone oxide (11.52%), followed by thymol (5.80%), and (E)-caryophyllene (4.88%). The phytotoxic activities of EO were estimated against Cyperus rotundus, Echinochloa crus-galli, and Oryza sativa (rice) through pre- and post-emergence assays at concentrations ranging from 10 to 250 μg/ml and 0.5-5%, respectively. In pre-emergence assay, the phytotoxic effect of EO was most pronounced on C. rotundus, thereby significantly affecting percent germination, plantlet growth, and chlorophyll content. On the contrary, the impact was comparatively lesser on rice, with ~ 40% germination in response to 250 μg/ml of EO treatment. In the post-emergence assay, the spray treatment of EO caused a loss of chlorophyll and wilting in test plants, and subsequently affected the growth of plants, even leading to death in some cases. The cytotoxic activity of EO (at 2.5-50 μg/ml) was studied in meristem cells in onion (Allium cepa L.) root tips. EO exposure to the onion roots induced various chromosomal aberrations such as chromosomal bridges, c-mitosis, stickiness, vagrant chromosomes, etc., and negatively affected the mitotic index. At 50 μg/ml, EO treatment triggered the complete death of roots. The study concludes that M. longifolia EO has phytotoxic activities due to the mito-depressive effect, along with other physiological effects on target plants. Therefore, EO of M. longifolia could be developed into a novel bioherbicide for sustainable management of weeds in agricultural systems.

Cytotoxicity
Essential oil
Weeds
Chromosomal abnormalities
Natural herbicides


Anatomic structures at risk in anteroposterior screw fixation of posterior malleolar fractures: A cadaver study.

Abstract:
INTRODUCTION
Percutaneous anterior-posterior (AP) screw is an option for posterior malleolus fracture fixation when the fracture fragment can be reduced indirectly by the mean of ligamentotaxis. However, anterior anatomic structures could be injured during screw placement.

MATERIALS AND METHODS
Eleven below-knee cadavers were employed for the placement of AP screws in an attempt of fixing assumed Haraguchi Type-I posterior malleolar fractures. Three entry points were selected as medial to the anterior tibial tendon (ATT), lateral to the ATT, and lateral to the extensor digitorum longus (EDL). Three AP screws were placed under guidance of fluoroscopy. After dissection, measurements were made (mm) from each screw to nearby structures. Distances were calculated and damage to structures was documented.

RESULTS
Mean, minimum, and maximum distances from the medial screw to the greater saphenous vein, TA, EHL, anterior tibial artery (ATA), and deep peroneal nerve (DPN), were 18.1 (12-25) mm, 2.0 (0-5) mm, 13.6 (9-20) mm, 16.6 (9-25) mm, and 20.1 (12-27) mm. From the middle screw to the ATA, DPN, TA, EHL, and EDL, were 1.2 (0-3) mm, 4.9 (3-9) mm, 3.8 (1-7) mm, 0.4 (0-2) mm, and 13.6 (10-18) mm. From the lateral screw to the superficial peroneal nerve (SPN), EDL, DPN, and ATA, were 10.8 (0-16) mm, 1.2 (0-4) mm, 15.9 (11-25) mm, 19 (15-27) mm. The SPN was found partially cut by the lateral screw on 1 specimen.

CONCLUSIONS
Lateral and middle percutaneous AP screw placement put certain anatomic structures at-risk of injury. Medial screw placement did not result in appreciable damage to adjacent structures. Entry point of AP screws should be selected with respect to posterior malleolar fracture and anatomic structures.

LEVEL OF EVIDENCE
IV.

Peng|Jianguang|J|
McKissack|Haley|H|
Yu|Jonathan|J|
He|Jun Kit|JK|
Montgomery|Tyler|T|
Moraes|Leonardo|L|
Alexander|Bradley|B|
Shah|Ashish|A|

Cadaver
Posterior malleolus fracture
Anterior-posterior screw
Iatrogenic injury


Fast IR-Actuated Shape-Memory Polymers Using in Situ Silver Nanoparticle-Grafted Cellulose Nanocrystals.

Abstract: In recent years, shape-memory polymers (SMPs) have gained a key position in the realm of actuating applications from daily life products to biomedical and aeronautic devices. Most of these SMPs rely mainly on shape changes upon direct heat exposure or after stimulus conversion (e.g., magnetic field and light) to heat, but this concept remains significantly limited when both remote control and fine actuation are demanded. In the present study, we propose to design plasmonic silver nanoparticles (AgNPs) grafted onto cellulose nanocrystals (CNCs) as an efficient plasmonic system for fast and remote actuation. Such CNC- g-AgNPs "nanorod-like" structures thereby allowed for a long-distance and strong coupling plasmonic effect between the AgNPs along the CNC axis, thus ensuring a fast photothermal shape-recovery effect upon IR light illumination. To demonstrate the fast and remote actuation promoted by these structures, we incorporated them at low loading (1 wt %) into poly(ε-caprolactone) (PCL)-based networks with shape-memory properties. These polymer matrix networks were practically designed from biocompatible PCL oligomers end-functionalized with maleimide and furan moieties in the melt on the basis of thermoreversible Diels-Alder reactions. The as-produced materials could find application in the realm of soft robotics for remote object transportation or as smart biomaterials such as self-tightening knots with antibacterial properties related to the presence of the AgNPs.

shape-memory polymers
cellulose nanocrystals
silver nanoparticles
plasmonic effect
IR light
poly(ε-caprolactone)


Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood.

Abstract:
PURPOSE
To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age.

METHOD
37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics.

RESULTS
Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n = 4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found.

CONCLUSIONS
Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.

Ehrstedt|Christoffer|C| Ahlsten|Gunnar|G| Strömberg|Bo|B| Lindskog|Cecilia|C| Casar-Borota|Olivera|O|

Somatostatin receptor
mTOR
Glioneuronal tumour
Childhood
Ganglioglioma
Medically refractory epilepsy