bluuebunny/crossref_metadata_2025 huggingface dataset:
Malic enzyme 1 is a potential marker of combined hepatocellular cholangiocarcinoma, subtype with stem‐cell features, intermediate‐cell type
Authors: Mihara Yutaro , Akiba Jun , Ogasawara Sachiko , Kondo Reiichiro , Fukushima Hiroto , Itadani Hiraku , Obara Hitoshi , Kakuma Tatsuyuki , Kusano Hironori , Naito Yoshiki , Okuda Koji , Nakashima Osamu , Yano Hirohisa
Published: May 2019

Aim

Combined hepatocellular cholangiocarcinoma, subtype with stem‐cell features, intermediate‐cell subtype (INT) shows various histological appearances and could be misdiagnosed as intrahepatic cholangiocarcinoma (iCCA). In the present study, we aimed to identify specific histological diagnostic markers of INT.

Methods

We extracted RNA from FFPE sections of six INT, five iCCA, and five hepatocellular carcinoma (HCC) cases and compared gene expression between INT, iCCA, and HCC by microarray analysis. We then undertook immunohistochemical (IHC) staining of potential key molecules identified by microarray analysis, the conventional hepatocytic marker, hepatocyte paraffin (HepPar)‐1, and the cholangiocytic markers, keratin (K) 7 and K19, on 35 INT, 25 iCCA, and 60 HCC cases.

Results

Microarray analysis suggested that malic enzyme 1 (ME1) was significantly upregulated in INT. Immunohistochemical analysis revealed that the positive rates of ME1 in INT, iCCA, and HCC were 77.1% (27/35), 28.0% (7/25), and 61.7% (37/60), respectively. Analysis of classification and regression trees based on IHC scores indicated that HepPar‐1 could be a good candidate for discriminating HCC from the others with high sensitivity (93.3%) and high specificity (96.7%). A multiple logistic regression model and receiver operating characteristic curve analysis based on the IHC scores of ME1, K7, and K19 generated a composite score that can discriminate between INT and iCCA. Using this composite score, INT could be discriminated from iCCA with high sensitivity (88.6%) and high specificity (88.0%).

Conclusions

We propose that ME1 is a useful diagnostic marker of INT when used in combination with other hepatocytic and cholangiocytic markers.
Insulinoma‐associated protein 1 expression in primary and metastatic neuroendocrine neoplasms of the gastrointestinal and pancreaticobiliary tracts
Authors: González Iván , Lu Hsiang‐Chih , Sninsky Jared , Yang Chen , Bishnupuri Kumar , Dieckgraefe Brian , Cao Dengfeng , Chatterjee Deyali
Published: May 2019

Aims

Insulinoma‐associated protein 1 (INSM1) is a transcription factor that is expressed in developing and mature neuroendocrine tissue. Recent studies have shown that INSM1 is a sensitive marker for neuroendocrine tumours. The aims of this study were to evaluate INSM1 expression in primary gastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) and in their known metastases, in order to assess its sensitivity as compared with chromogranin‐A (CgA) and synaptophysin (SYN), and to evaluate any change in expression between primary and metastatic disease.

Methods and results

We identified 30 patients with primary GEP‐NEN. Liver metastatic tissue was available for 26 patients; two patients had two metachronous metastatic foci, yielding a total of 28 metastatic cases. An additional two and seven non‐paired cases of primary and metastatic grade 3 GEP‐NEN, respectively, were included. To assess specificity, we evaluated the expression of these markers in other primary tumours (colorectal adenocarcinoma, acinar cell carcinoma, solid pseudopapillary neoplasm, cholangiocarcinoma, and hepatocellular carcinoma) and metastatic tumours in the liver (adrenal cortical, breast and prostate carcinomas) that may present as differential diagnoses. In our cohort, all of the primary GEP‐NENs and 94% of the metastatic GEP‐NENs expressed INSM1. INSM1 showed similar sensitivity to SYN and higher sensitivity than CgA in both primary and metastatic neoplasms. INSM1 has comparable specificity to CgA, and higher specificity than SYN.

Conclusions

The nuclear reactivity and the high sensitivity and specificity of INSM1 make it a preferred neuroendocrine marker. In conclusion, INSM1 can be used as a single first‐line marker for primary and metastatic GEP‐NEN.
On the association between oral piercings and periodontal conditions—A case series
Authors: Schmidt Julia Caroline , Calderaro Salvatore , Weiger Roland , Walter Clemens
Published: May 2019

Objective

To investigate the association between oral piercings and periodontal health or inflammation in patients seeking treatment at the University of Basel, Switzerland.

Material and methods

Records of patients from the pool of patients at the Department of Periodontology, Endodontology and Cariology were consecutively screened between November 2016 and January 2017. Eighteen patients with a tongue and/or a lip piercing were included. Three out of 18 patients wore both piercings, that is 14 tongue piercings and seven lip piercings were assessed. Epidemiologic, socio‐economic, piercing characteristics and clinical parameters were recorded. Periodontal findings in teeth close to the piercing were compared to the parameters of the total dentition.

Results

In patients with a tongue piercing (n = 14), percentages of sites with bleeding on probing, probing pocket depths ≥6 mm, clinical attachment loss ≥6 mm and gingival recessions ≥2 mm were more frequently increased in teeth close to the piercing compared to teeth not affected by the piercing. In patients with a lip piercing (n = 7), periodontal findings did not differ markedly in teeth close to the piercing compared to teeth not affected by the piercing.

Conclusions

Tongue piercings may negatively affect periodontal conditions of teeth with close proximity to the piercing.
Validation of the effectiveness of the Dental Practicality Index in predicting the outcome of root canal retreatments
Authors: Tifooni A. , Al‐Nuaimi N. , Dawood A. , Mannocci F. , Patel S.
Published: May 2019

Aim

To assess the effectiveness of the Dental Practicality Index (DPI) in predicting the outcome of root canal retreatment in posterior teeth.

Methodology

One hundred and thirty‐seven posterior teeth with symptoms and/or signs of post‐treatment endodontic disease requiring root canal retreatment and previously included in a clinical trial were selected. Clinical and radiographic examinations including digital periapical and cone beam computed tomography (CBCT) were obtained pre‐treatment and 1‐year postoperatively from a previous study. Two calibrated and trained assessors who were unaware of the treatment outcome assessed the pre‐treatment clinical records of these cases using the DPI. The DPI score was then compared to the outcome of the root canal retreatment. A Chi‐square/Fisher’s exact test was used to establish a relationship between categorical variables, the total score of DPI vs outcome.

Results

Retreated teeth with DPI scores equal to 6 or above had an unfavourable outcome of 50% vs 14% of teeth with DPI below 6. Teeth with DPI score equal to 3 or above had an unfavourable outcome of 23% versus 2%, for teeth below 3. Molar teeth with a DPI score below 3 had a favourable outcome percentage of 96%.

Conclusions

This study highlighted that using the DPI gave a good outcome prediction for root canal retreatments. However, further research, including the prospective assessment of a wider range of cases undertaken by a larger group of examiners is needed to further validate the DPI.
Biallelic mutations in the LPAR6 gene causing autosomal recessive wooly hair/hypotrichosis phenotype in five Pakistani families
Authors: Khan Ghulam M. , Hassan Noor , Khan Niamatullah , Humayun Muhammad , Khan Kafaitullah , Khaliq Samira , Rehman Fazal U. , Ahmed Sheikh , Shah Khadim , Khan Sher A. , Muhammad Noor , Wali Abdul , Khan Saadullah , Basit Sulman , Ayub Muhammad
Published: May 2019

Background

Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete absence of eyebrows and eyelashes. Autosomal recessive wooly hair/hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes.

Methods

To find out the molecular basis of the disease, five families with autosomal recessive wooly hair/hypotrichosis were recruited for genetic analysis. Direct Sanger sequencing of LIPH and LPAR6 genes was carried out using BigDye chain termination chemistry. P2RY5 protein homology models were developed to study the effect of mutation on protein structure in a family having novel mutation.

Results

Sanger sequencing revealed a novel homozygous missense mutation (c.47A>T) in the LPAR6 gene in family A, while recurrent mutation (c.436G>A) was detected in the rest of the four families (B‐E). Protein homology models for both native and mutant P2RY5 protein were developed to study the difference in subtle structural features because of Lys16Met (K16M) mutation. We observed that P2RY5K16M mutation results decrease in the number of ionic interactions detrimental to the protein stability. Protein modeling studies revealed that the novel mutation identified here decreased the number of ionic interactions by affecting physicochemical parameters of the protein, leading to an overall decrease in protein stability with no major secondary structural changes.

Conclusion

The molecular analysis further confirms the frequent involvement of LPAR6 in autosomal recessive wooly hair/hypotrichosis, while the bioinformatic study revealed that the missense mutation destabilizes the overall structure of P2RY5 protein.
Predicting properties of MgO·nAl2O3 by first‐principles calculation combined with bond valence models
Authors: Ren Lu , Wang Hao , Tu Bingtian , Zong Xiao , Wang Weimin , Fu Zhengyi
Published: May 2019

Spinel‐type oxides have attracted tremendous attentions owing to their wide applications. However, the complicated composition and structure of spinel‐type solid solution brought about challenge to explore the relationship among composition, structure, and properties. A new approach which combined first‐principles calculation with bond valence models was developed to explore the composition dependence of structure and properties for spinel‐type oxide solid solution. The first‐principles calculation was used to simulate the structural parameters of spinel‐type oxide solid solution. The mechanical and thermal properties of Mg1‐xAl2(1+x/3)O4 spinel‐type solid solution were estimated by bond valence models based on the structure which was reconstructed from the structural parameters determined by the first‐principles calculation. Besides, bond valence arguments were also used to assess the reliability of reconstructed structure. The results suggest that the extremely overbonded or underbonded atoms can be avoided in the reconstructed structure, which improves the stability of reconstructed structure. By comparing the results with experimental values, it can be seen that mechanical and thermal properties could be simulated exactly by the new approach and bulk modulus was used as an example to explore the relationship among composition, structure, and properties of Mg1‐xAl2(1+x/3)O4.
Effect of UV-C light or hydrogen peroxide wipes on the inactivation of methicillin-resistant Staphylococcus aureus, Clostridium difficile spores and norovirus surrogate
Authors: Wallace R.L. , Ouellette M. , Jean J.
Published: May 2019

Aims

The current study aimed to assess the potential of a new high dose ultraviolet (UV) disinfection device to inactivate methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile and a norovirus surrogate on handheld mobile devices, and to compare the efficacy of the UV-C device to hydrogen peroxide disinfection wipes.

Methods and Results

Suspensions of MRSA, C. difficile spores and a surrogate for norovirus (MS2) were inoculated onto glass or plastic coupons, with or without organic contamination and were exposed to continuous UV-C light for 15–60 s (165–646 mJ cm−2) in a self-contained UV-C chamber or treated with hydrogen peroxide wipes. Increasing the UV-C dose from 310 to 650 mJ cm−2 did not result in greater levels of inactivation. UV-C light inactivated all three micro-organisms, in the absence of organic contamination, by >2·9 log. Treatment of MRSA, C. difficile spores or MS2, in the presence of organic contamination, with UV-C light (310–646 mJ cm−2) resulted in 2·3–3·7 log reductions. Treatment of MRSA with UV-C light provided levels of inactivation comparable to treatment with hydrogen peroxide wipes used following the manufacturer’s instructions.

Conclusions

UV-C light and hydrogen peroxide wipes had strong antimicrobial activity against MRSA, C. difficile spores and a norovirus surrogate, in the presence or absence of organic contamination.

Significance and Impact of the Study

Chemical disinfection wipes are widely used in healthcare facilities, but they are not recommended for use on handheld mobile devices which may harbour pathogenic micro-organisms. The powerful bactericidal, sporicidal and virucidal activity of this high dose UV-C light device, shows that this technology is a promising alternative to chemical disinfectants, particularly for control of MRSA.
Multi‐variable approach pinpoints origin of oak wood with higher precision
Authors: Akhmetzyanov Linar , Buras Allan , Sass‐Klaassen Ute , den Ouden Jan , Mohren Frits , Groenendijk Peter , García‐González Ignacio
Published: May 2019

Aim

Spatial variations of environmental conditions translate into biogeographical patterns of tree growth. This fact is used to identify the origin of timber by means of dendroprovenancing. Yet, dendroprovenancing attempts are commonly only based on ring‐width measurements, and largely neglect additional tree–ring variables. We explore the potential of using wood anatomy as a dendroprovenancing tool, and investigate whether it increases the precision of identifying the origin of oak wood. Since different tree–ring variables hold different information on environmental conditions prevailing at specific times of the growing season—which vary between source regions—we hypothesize that their inclusion allows more precise dendroprovenancing.

Location

Europe, Spain.

Taxon

Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus faginea Lam., Quercus pyrenaica Willd.

Methods

We sampled four oak species across Northern Spain, i.e. from the Basque country and Cantabria and—in the Basque country—from low to high elevation (topographic/latitudinal gradient). We measured multiple tree–ring variables to (a) extract complementary variables; (b) present statistical relations among them; (c) analyse region‐specific variation in their patterns based on time–series of individual trees; and (d) determine underlying climate–growth relationships. Leave‐one‐out analysis was used to test whether a combination of selected variables allowed dendroprovenancing of a randomly selected tree within the area.

Results

A combination of latewood width (LW) and earlywood vessel size was used to pinpoint the origin of oak wood with higher precision than ring width or LW only. Variation in LW pinpointed the wood to east and west areas, whereas variation in vessels assigned wood to locations along a latitudinal/topographic gradient. The climatic triggers behind these gradients are respectively an east–west gradient in June–July temperature and a north–south gradient in winter/spring temperatures. The leave‐one‐out analyses supported the robustness of these results.

Main conclusions

Integration of multiple wood–xylem anatomical variables analysed with multivariate techniques leads to higher precision in the dendroprovenancing of ring‐porous oak species.
Zoogeographic patterns of pelagic oceanic cephalopods along the eastern Pacific Ocean
Authors: Ibáñez Christian M. , Braid Heather E. , Carrasco Sergio A. , López‐Córdova David A. , Torretti Gabriela , Camus Patricio A.
Published: May 2019

Aim

To analyse the diversity and distribution of oceanic pelagic cephalopods along the eastern Pacific Ocean assessing the existence of biogeographic structuring, and the role of physical variables in generating geographical patterns. We hypothesized that the control by environmental factors, and the effect of geometric constraints, determine the range size and limits of distribution of oceanic cephalopods along the eastern Pacific Ocean, generating a latitudinal gradient in species richness.

Location

Eastern Pacific Ocean (60°N – 60°S), from the Gulf of Alaska to the Southern Ocean.

Methods

Based on a literature review and >5,000 records obtained from collections, we constructed a presence–absence matrix including 61 latitudinal bands (2° each) along the Eastern Pacific, and estimated species richness and range endpoints at each band. Biogeographic units were determined by means of multivariate analyses. Species richness was compared with null model predictions in order to test for the existence of geometric constraints using the Mid‐Domain Null model. The effects on species richness of environmental variables (temperature, salinity and oxygen) were evaluated separately for surface and depth (0–1,000 m) data, by means of ordinary least squares regression and simultaneous autoregressive models. Rapoport's pattern was assessed by applying the Stevens’ method and the range midpoint method.

Results

Species richness was high across the tropics and decreased towards the both poles. We identified five biogeographic units, highlighting two major distribution breaks at 40°N and 42°S. Species richness was strongly related with environmental variables, although the combined variables accounted for a large fraction of the variance between 0 and 1,000 m (R2 = 0.99), while temperature was the best single predictor at the surface (R2 = 0.98). Species richness curves showed a mid‐domain effect (MDE), and the mean latitudinal range was higher in the tropics and at warm latitudes, generating an inverse Rapoport's pattern.

Main conclusions

Along the eastern Pacific Ocean oceanic cephalopods exhibit both a clear biogeographic patterning and an interhemispheric (poleward decreasing) diversity gradient, which appear strongly related with physical factors and external forcing, as well as with a MDE as a seemingly consequence of the naturally bounded domain of the Eastern Pacific.
Selective outcome reporting in randomized clinical trials of dental implants
Authors: Sendyk Daniel Isaac , Rovai Emanuel Silva , Souza Nathalia Vilela , Deboni Maria Cristina Zindel , Pannuti Claudio Mendes
Published: May 2019

Aim

Selective outcome reporting (SOR) is a type of bias that occurs when the primary outcome of a trial protocol is changed or omitted in the paper. The purpose of this study was to evaluate the prevalence of SOR in publications of randomized clinical trials (RCT) concerning dental implants.

Materials and Methods

Two reviewers independently screened protocols registered at ClinicalTrials.gov until February/2019. If the protocol met the eligibility criteria, the reviewers tried to identify the corresponding publication. Data extraction was carried out by the same reviewers. Primary and secondary outcomes were recorded for each trial and compared to outcomes previously described in protocols.

Results

A total of 49 protocols were included. SOR was identified in 27 (55.1%) trials. The major discrepancies were as follows: protocol‐defined primary outcome omitted in the publication (n = 6, 12.2%), new primary outcome introduced (n = 8, 16.3%), discrepancy in the primary outcome time frame (n = 17, 34.7%) and new secondary outcome introduced (n = 31, 63.3%). SOR was significantly associated with industry funding (p = 0.04) and timing of registration (p = 0.04).

Conclusions

Our results indicate a high rate of SOR in dental implants clinical trials. Use of registry data during the peer‐review process may help decreasing SOR.
Interventions for peri‐implantitis and their effects on further bone loss: A retrospective analysis of a registry‐based cohort
Authors: Karlsson Karolina , Derks Jan , Håkansson Jan , Wennström Jan L. , Petzold Max , Berglundh Tord
Published: May 2019

Objective

The aim of the present study was to assess interventions and their consequences with regard to further bone loss at sites diagnosed with peri‐implantitis.

Materials and Methods

In 2017, records of 70 patients diagnosed with moderate/severe peri‐implantitis at ≥1 implant sites 4 years earlier were obtained. Changes of marginal bone levels during the study period assessed on radiographs and predictors of disease progression were identified by Cox regression and mixed linear modelling. Patient files were analysed for professional interventions related to the treatment of peri‐implantitis.

Results

Mean bone loss (±SD) at implants diagnosed with moderate/severe peri‐implantitis was 1.1 ± 2.0 mm over the observation period of 3.3 years. While non‐surgical measures including submucosal and/or supra‐mucosal cleaning of implants were provided to almost all patients, surgical treatment of peri‐implantitis was limited to a subgroup (17 subjects). Surgically treated implant sites demonstrated a mean bone loss of 1.4 ± 2.4 mm prior to surgical intervention, while only minor changes (0.2 ± 1.0 mm) occurred after therapy. Clinical parameters (bleeding/suppuration on probing and probing depth) assessed at diagnosis were statistically significant predictors of disease progression.

Conclusions

Non‐surgical procedures were insufficient to prevent further bone loss at implant sites affected by moderate/severe peri‐implantitis. Surgical treatment of peri‐implantitis markedly diminished the progression of bone loss. Clinical assessments of bleeding on probing and probing depth at diagnosis predicted further bone loss.
UV light set‐ups for vitiligo photography, a comparative study on image quality and ease of use
Authors: Uitentuis S.E. , Bekkenk M.W. , van Geel N. , de Rie M.A. , Wolkerstorfer A.
Published: May 2019

Background

Ultraviolet (UV) light is an essential tool to assess the extent, spreading and staging of vitiligo. Different UV light set‐ups are used for vitiligo photography, including the following: (i) hand‐held Wood’s lamps; (ii) soft boxes with UV lamps; (iii) UV flash attached to the camera; and (iv) high output UV flash.

Objective

Our objective was to compare UV light set‐ups for vitiligo photography regarding image quality and ease of use.

Methods

Patients with vitiligo lesions with unclear borders were included. Two images were made with all four UV set‐ups per patient, for a large and a small area. Image quality was scored separately by three blinded vitiligo experts on five criteria: overall quality, clearness of borders, contrast and sharpness and for larger areas the shadows. The two professional medical photographers were asked to score the ease of use for each set‐up.

Results

A total of 88 photos were assessed from 11 patients. For larger areas, the frequency of a ‘good’ or ‘very good’ overall quality rating was 12.1% (Wood’s), 6.1% (soft boxes), 15.2% (camera flash) and 78.8% (high output flash). For smaller areas, the score ‘good’ or ‘very good’ was given to 54.5%, 3%, 66.6% and 84.8% in the same order. For the shadow criteria, each set‐up scored below 40% on a 'good' or 'very good' score. The high output flash was scored as most easy to use by the photographers.

Conclusion

When comparing four different UV light set‐ups for vitiligo photography, we concluded that the UV set‐ups strongly influenced the quality scores of the obtained images. The high output flash scored best for both small and large areas and for ease of use. For small areas, Wood’s lamp and camera flash were acceptable. All set‐ups scored badly for shadows, and more research is needed to find the optimal exposure to avoid shadows.
Use of dose–exposure–response relationships in Phase 2 and Phase 3 guselkumab studies to optimize dose selection in psoriasis
Authors: Lebwohl M. , Langley R.G. , Zhu Y. , Zhou H. , Song M. , Shen Y.K. , Parnell Lafferty K. , Reich K.
Published: May 2019

Background

Guselkumab is an anti‐interleukin‐23 monoclonal antibody for the treatment of moderate‐to‐severe psoriasis.

Objective

To evaluate the association between dose–response and exposure–response of guselkumab in Phase 2 and Phase 3 studies to optimize dose selection.

Methods

Serum guselkumab concentrations in Phase 2 and Phase 3 studies (VOYAGE 1 and VOYAGE 2) were measured using a validated immunoassay. Efficacy assessments included Physician's Global Assessment (PGA), Investigator's Global Assessment (IGA) and Psoriasis Area and Severity Index (PASI).

Results

In Phase 2, a positive dose–response relationship was observed for PASI and PGA (5‐mg through 100‐mg dose regimens). Exposure–response analysis showed that patients with steady‐state trough serum guselkumab concentrations ≥0.67 μg/mL achieved the highest levels of efficacy (PGA 0/1: 90.0%; PGA 0: 70.0%). The guselkumab 100‐mg every 8‐week (q8w) dose regimen, safe and well‐tolerated in Phase 2, provided the highest serum guselkumab concentrations among all regimens studied and was selected for Phase 3. In Phase 3, 72.5% of patients achieved guselkumab concentrations ≥0.67 μg/mL at week 28, the level associated with the highest clinical responses in Phase 2, with patients achieving response rates of IGA 0/1: 91.2%, IGA 0: 55.3%, PASI 90: 83.8% and PASI 100: 49.1% at week 28.

Conclusion

The 100‐mg guselkumab q8w dose regimen, based on the dose–exposure–response relationship from the Phase 2 study, produced the target serum concentration associated with high‐level efficacy in the majority of patients in Phase 3. Phase 3 data further confirmed that guselkumab 100mg q8w is the optimum dosing regimen for treating patients with moderate‐to‐severe psoriasis.
Kinetid Structure of Aphelidium and Paraphelidium (Aphelida) Suggests the Features of the Common Ancestor of Fungi and Opisthosporidia
Authors: Karpov Sergey A. , Cvetkova Victoria S. , Annenkova Nataliia V. , Vishnyakov Andrey E.
Published: May 2019

The aphelids (phylum Aphelida) are phagotrophic parasitoids of algae and represent the most basal branch in superphylum Opisthosporidia, which contains the Microsporidia, Rozellosporidia and Aphelida. Being the closest group to traditional fungi, the aphelids should have ancestral features of both phyla. As in chytrids and other zoosporic fungi, the structure of zoospores is the most informative and important morphological feature for the phylogeny and taxonomy of aphelids. Though a general zoospore description exists for some aphelid species, their flagellar apparatus (kinetid) structure, which contains pivotal taxonomic and phylogenetic characters, has not been studied. Here we represent the kinetid structure in two genera, Aphelidium and Paraphelidium, and demonstrate independent reduction in the kinetid in each genus. The kinetid‐mitochondrion connection found in Aphelidium and Paraphelidium is rare for opisthokonts in general, but present in the most basal branches of Fungi and Opisthosporidia. We suggest, therefore, that this connection represents an ancestral character for both these phyla.
Measurement of CSF α‐synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer’s disease
Authors: García‐Ayllón María‐Salud , Monge‐Argilés José‐Antonio , Monge‐García Victoria , Navarrete Francisco , Cortés‐Gómez Maria‐Angeles , Sánchez‐Payá José , Manzanares Jorge , Gasparini‐Berenguer Ruth , Leiva‐Santana Carlos , Sáez‐Valero Javier
Published: May 2019

Previous studies have indicated the potential of cerebrospinal fluid (CSF) α‐synuclein (α‐syn) to be an additional biomarker for improving differential diagnosis of Alzheimer’s disease (AD). We evaluated α‐syn diagnostic performance across a well‐characterized patient cohort with long‐term follow‐up. For this purpose, CSF α‐syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n = 25), 27 MCI cases due to AD (MCI‐AD; n = 32), 24 MCI cases due to Lewy body disease (MCI‐LBD; n = 24) and control subjects (Ctrl; n = 18). CSF α‐syn levels discriminate between the four groups. There were higher α‐syn levels in MCI‐AD patients and lower levels in MCI‐LBD patients. The combination of α‐syn and P‐tau resulted in a specificity of 99% and a sensitivity of 97% for MCI‐AD. MCI‐AD patients with early psychotic symptoms (n = 9) displayed a trend towards a decrease in P‐tau and α‐syn compared to the MCI‐AD patients without psychotic symptoms (n = 23). We conclude that adding CSF α‐syn to central core AD biomarkers improves an early differential diagnosis of MCI‐AD from other forms of MCI.

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Epigenetic inhibition of the tumor suppressor ARHI by light at night‐induced circadian melatonin disruption mediates STAT3‐driven paclitaxel resistance in breast cancer
Authors: Xiang Shulin , Dauchy Robert T. , Hoffman Aaron E. , Pointer David , Frasch Tripp , Blask David E. , Hill Steven M.
Published: May 2019

Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep‐wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemoresistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug‐resistant breast cancer. Signal transducer and activator of transcription 3 (STAT3), frequently overexpressed and activated in paclitaxel (PTX)‐resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppress the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed interleukin 6 (IL‐6)‐induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF‐7 breast cancer cells. Finally, analyses of the I‐SPY 1 trial demonstrate that elevated MT1 receptor expression is significantly correlated with pathologic complete response following neo‐adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression.
China engages with the global intellectual property governance: The recent trend
Authors: Cheng Wenting
Published: May 2019

As China becomes the second largest economy in the world, there have been increasing domestic demands requesting China to engage with the global governance of various issues more closely. In intellectual property (IP), China has recently engaged with global IP governance both responsively and actively. This paper answer the questions (a) how did China respond to the global IP up‐ratchet which sets higher IP standards; and (b) how did China actively promote its agenda for the global IP governance. This paper argues that China has a clearer and more consistent position in its responsive engagement than in active engagement. In other words, China is more affirmative in making defensive coalitions opposing TRIPS‐plus standards proposed by developed countries than promoting its own IP initiatives regionally or plurilaterally. China's positions in these defensive coalitions are the classic pro‐development, developing country positions. Its active IP engagement is more diversified. Specifically, China keeps a low profile and does not attempt to take the lead in IP negotiations at the Regional Compressive Economic Partnership. By contrast, China has emerged as a model exporter, focusing on IP capacity building in its IP arrangements in the Belt and Road Initiative (BRI) and BRICS.
Behavioural interdependence in a shrimp‐goby mutualism
Authors: Burns A. L. , Wilson A. D. M. , Ward A. J. W.
Published: May 2019

The partnership between non‐burrowing gobiid fishes and alpheid shrimps is one of the most remarkable interspecific mutualisms currently recognised in behavioural biology. The shrimp rely on tactile and chemical cues from their goby partners to warn them of approaching predators. In return, the shrimp construct and maintain the burrows which provide shelter for the goby. Although aspects of this relationship have been well studied, less is known about the interdependence of the two species’ activity patterns. We conducted field observations of an obligate shrimp‐goby mutualism, Ctenogobiops feroculus and its common shrimp partner Alpheus djeddensis. We found that individual gobies were consistent in their activity levels relative to conspecifics over a 3‐day period but were not consistent in terms of the time allocated to vigilance. Both the activity and the vigilance behaviour of the goby directly correlated with the behaviour of their shrimp partners; shrimp with a more active partner were themselves more active, and visibility of the shrimp increased as vigilance time increased. By quantifying the interactions between the two species, we have gained greater insights into the mechanistic underpinnings of these complex behavioural interactions.
Prospective evaluation of gadoxetic acid magnetic resonance for the diagnosis of hepatocellular carcinoma in newly detected nodules ≤2 cm in cirrhosis
Authors: Ayuso Carmen , Forner Alejandro , Darnell Anna , Rimola Jordi , García‐Criado Ángeles , Bianchi Luis , Vilana Ramón , Oliveira Rafael , Llarch Neus , Bruix Jordi
Published: May 2019

Background and Aims

Most of the published studies about the diagnostic accuracy of gadoxetic acid‐enhanced magnetic resonance (EOB‐MR) for the non‐invasive diagnosis of hepatocellular carcinoma (HCC) have had a retrospective design. Thus, we aimed to prospectively evaluate the diagnostic accuracy of EOB‐MR for the non‐invasive diagnosis of HCC in nodules ≤2 cm detected by screening ultrasound (US) in patients with cirrhosis.

Methods

Between July 2012 and October 2015, 62 consecutive asymptomatic Child‐Pugh A‐B cirrhotic patients with newly US‐detected solitary nodules between 1 and 2 cm were prospectively included in the study. Hepatic extracellular contrast‐enhanced MR (ECCE‐MR) followed by EOB‐MR were obtained in less than 1‐month interval. Two independent radiologists blindly reviewed the EOB‐MR studies, and the diagnosis of HCC was assigned when the lesion showed arterial enhancement followed by portal venous phase washout and/or hypointensity on the hepatobiliary phase (HBP). The final HCC diagnosis was made by ECCE‐MR according to the accepted non‐invasive criteria, or by biopsy in lesions with atypical vascular profile.

Results

Final diagnoses were as follows: HCC (n = 41), intrahepatic cholangiocarcinoma (n = 2), colorectal metastases (n = 1) and benign conditions (n = 18). The sensitivity and specificity of EOB‐MR for HCC diagnosis were 56.1% (95% CI: 39.7‐71.5) and 90.5% (95% CI: 69.6‐98.8), respectively, while sensitivity of ECCE‐MR was 63.4% (95% CI: 46.9‐77.9). The low rate of hypointense HCCs in the HBP and suboptimal liver uptake of contrast agent justify the low sensitivity of EOB‐MR for HCC diagnosis.

Conclusion

EOB‐MR does not surpass the diagnostic accuracy of ECCE‐MR for non‐invasive diagnosis of HCC in nodules ≤2 cm in cirrhotic patients.
Expert opinion on clinical experience with subcutaneous interferon beta‐1a in multiple sclerosis patients with different disease activity profiles
Authors: Bohlega Saeed , Alroughani Raed , Alkhawajah Mona , Alsaadi Taoufik , Daif Abdulkader , Elalamy Osama R. , Inshasi Jihad S. , Noori Suzan , Shakra Mustafa , Shatila Ahmed O. , Boghdady Ahmed El , Boshra Amir
Published: May 2019

Latest diagnostic criteria have increased the speed and accuracy of multiple sclerosis diagnosis. Early diagnosis of multiple sclerosis and early treatment initiation help in achieving better clinical outcomes. Accordingly, recent clinical studies include patients with less severe multiple sclerosis as compared to older studies, and in this milder multiple sclerosis population, many patients do not progress over 2 years. Interferon beta‐1a has been used for the treatment of relapsing multiple sclerosis for more than 20 years and has been assessed in multiple clinical trials of varying lengths. Clinical trials of subcutaneous interferon beta‐1a show efficacy in terms of relapse rate, magnetic resonance imaging outcomes, and long‐term disability measures in relapsing multiple sclerosis patients with different disease activity profiles. This article discusses multiple sclerosis experts’ opinions on the level of disease activity of the patient populations used in the clinical trials of subcutaneous interferon beta‐1a and on the effectiveness of subcutaneous interferon beta‐1a in these patient populations. Based on experts’ opinions, it can be concluded that patients with mild or moderate disease activity have a high potential of benefiting from high‐dose subcutaneous interferon beta‐1a.
Type designation of the oaks Quercus ballota and Q. rotundifolia (Fagaceae)
Authors: Ferrer‐Galego P. Pablo , Sáez Llorenç
Published: May 2019

The names Quercus ballota and Q. rotundifolia (Fagaceae), referring to taxa sometimes considered conspecific with the widely distributed Q. ilex, are discussed and typified. A specimen preserved at MPU is designated as the lectotype of Desfontaines's name Q. ballota. Lamarck's name Q. rotundifolia is neotypified using a specimen preserved at VAL, with several duplicates in other European herbaria.
Hydraulic traits explain differential responses of Amazonian forests to the 2015 El Niño‐induced drought
Authors: Barros Fernanda de V. , Bittencourt Paulo R. L. , Brum Mauro , Restrepo‐Coupe Natalia , Pereira Luciano , Teodoro Grazielle S. , Saleska Scott R. , Borma Laura S. , Christoffersen Bradley O. , Penha Deliane , Alves Luciana F. , Lima Adriano J. N. , Carneiro Vilany M. C. , Gentine Pierre , Lee Jung‐Eun , Aragão Luiz E. O. C. , Ivanov Valeriy , Leal Leila S. M. , Araujo Alessandro C. , Oliveira Rafael S.
Published: May 2019

Reducing uncertainties in the response of tropical forests to global change requires understanding how intra‐ and interannual climatic variability selects for different species, community functional composition and ecosystem functioning, so that the response to climatic events of differing frequency and severity can be predicted.

Here we present an extensive dataset of hydraulic traits of dominant species in two tropical Amazon forests with contrasting precipitation regimes – low seasonality forest (LSF) and high seasonality forest (HSF) – and relate them to community and ecosystem response to the El Niño–Southern Oscillation (ENSO) of 2015.

Hydraulic traits indicated higher drought tolerance in the HSF than in the LSF. Despite more intense drought and lower plant water potentials in HSF during the 2015‐ENSO, greater xylem embolism resistance maintained similar hydraulic safety margin as in LSF. This likely explains how ecosystem‐scale whole‐forest canopy conductance at HSF maintained a similar response to atmospheric drought as at LSF, despite their water transport systems operating at different water potentials.

Our results indicate that contrasting precipitation regimes (at seasonal and interannual time scales) select for assemblies of hydraulic traits and taxa at the community level, which may have a significant role in modulating forest drought response at ecosystem scales.
Responses of foliar phosphorus fractions to soil age are diverse along a 2 Myr dune chronosequence
Authors: Yan Li , Zhang Xinhou , Han Zhongming , Pang Jiayin , Lambers Hans , Finnegan Patrick M.
Published: May 2019

Plants respond to soil phosphorus (P) availability by adjusting leaf P among inorganic P (Pi) and organic P fractions (nucleic acids, phospholipids, small metabolites and a residual fraction). We tested whether phylogenetically divergent plants in a biodiversity hotspot similarly adjust leaf P allocation in response to P limitation by sampling along a 2 Myr chronosequence in southwestern Australia where nitrogen (N) limitation transitions to P limitation with increasing soil age.

Total P and N, and P allocated to five chemical fractions were determined for photosynthetic organs from Melaleuca systena (Myrtaceae), Acacia rostellifera (Fabaceae) and Hakea prostrata (Proteaceae). Soil characteristics were also determined.

Acacia rostellifera maintained phyllode total P and N concentrations at c. 0.5 and 16 mg g−1 DW, respectively, with a constant P‐allocation pattern along the chronosequence. H. prostrata leaves allocated less P to Pi, phospholipids and nucleic acids with increasing soil age, while leaf N concentration was constant. M. systena had the greatest variation in allocating leaf P, whereas leaf N concentration decreased 20% along the chronosequence.

Variation in P‐allocation patterns was only partially conserved among species along the chronosequence. Such variation could have an impact on species distribution and contribute to species richness in P‐limited environments.
Saliva NMR metabolomics: Analytical issues in pediatric oral health research
Authors: Pereira Joana L. , Duarte Daniela , Carneiro Tatiana J. , Ferreira Sara , Cunha Bárbara , Soares Daniela , Costa Ana Luísa , Gil Ana M.
Published: May 2019

Objectives

Saliva metabolome is a promising diagnostic tool concerning oral and systemic diseases. We aimed at establishing a suitable protocol for saliva collection and gauging the relative impacts of gender, dentition stage, and caries on the saliva metabolome of a small children cohort.

Subjects and methods

A nuclear magnetic resonance‐based metabolomics cross‐sectional study of children saliva (n = 38) compared the effects of: (a) stimulation and unstimulation conditions, and (b) collection through passive drool and using an absorbing device. Multivariate and univariate statistical analyses were applied to evaluate such effects and those related to gender, dentition stage and caries.

Results

No significant differences were found between unstimulated and stimulated saliva, and the former was used for subsequent studies. Swab collection induced significant changes in sample composition, indicating passive drool as preferential. The impacts of gender and dentition stage were not significant compared to that of caries, which induced variations in the levels of 21 metabolites. These comprised amino acids and monosaccharides observed for the first time to our knowledge regarding children caries, suggesting protein hydrolysis and deglycosylation.

Conclusions

Unstimulated passive drool saliva metabolome may carry a caries signature.
A case‐control analysis of skin contact allergy in children and adolescents
Authors: Francuzik Wojciech , Geier Johannes , Schubert Steffen , Worm Margitta
Published: May 2019

Background

Contact sensitization in children is increasing. The offending allergens differ depending on patient age and sex. We aimed to determine the sensitization profiles in children (aged 6‐12) and adolescents (aged 13‐18), to compare these to a control group of adults (aged 60‐66), and to evaluate differences in sensitization patterns between working and non‐working adolescents.

Patients/Materials/Methods

We analyzed Information Network of Departments of Dermatology (IVDK) data from 2009 to 2016 using multiple logistic regression analysis. Of the 99 082 patients documented in the IVDK database, 591 children, 2451 adolescents and 12 122 adults were included in further analysis.

Results

Nickel was the most frequent contact allergen among all age‐groups. Children and adolescents showed significantly lower reaction rates to fragrance mix, methyldibromo‐glutaronitrile, methylisothiazolinone, and propolis than adults. Positive reactions to sorbitan sesquioleate and mercapto mix among children and to cobalt among adolescents were significantly more frequent than in adults. Working adolescents had more often positive reactions to methyl(chloro)isothiazolinone (skin lesions predominantly on hands) and paraben mix (skin lesions predominantly on feet) when compared to non‐working peers. Patch‐tested children were more often diagnosed with atopic dermatitis than adults (P < 0.0001).

Conclusions

Contact allergens display age‐specific patterns, which should be considered in a standardized series targeting different patient populations (children and adolescents). Employed adolescents should preferably be tested with the baseline series to optimize allergen identification.
MdMYB46 could enhance salt and osmotic stress tolerance in apple by directly activating stress‐responsive signals
Authors: Chen Keqin , Song Mengru , Guo Yunna , Liu Lifu , Xue Hao , Dai Hongyan , Zhang Zhihong
Published: May 2019

To expand the cultivation area of apple (Malus×domestica Borkh.) and select resistant varieties by genetic engineering, it is necessary to clarify the mechanism of salt and osmotic stress tolerance in apple. The MdMYB46 transcription factor was identified, and the stress treatment test of MdMYB46‐overexpressing and MdMYB46‐RNAi apple lines indicated that MdMYB46 could enhance the salt and osmotic stress tolerance in apple. In transgenic Arabidopsis and apple, MdMYB46 promoted the biosynthesis of secondary cell wall and deposition of lignin by directly binding to the promoter of lignin biosynthesis‐related genes. To explore whether MdMYB46 could coordinate stress signal transduction pathways to cooperate with the formation of secondary walls to enhance the stress tolerance of plants, MdABRE1A, MdDREB2A and dehydration‐responsive genes MdRD22 and MdRD29A were screened out for their positive correlation with osmotic stress, salt stress and the transcriptional level of MdMYB46. The further verification test demonstrated that MdMYB46 could activate their transcription by directly binding to the promoters of these genes. The above results indicate that MdMYB46 could enhance the salt and osmotic stress tolerance in apple not only by activating secondary cell wall biosynthesis pathways, but also by directly activating stress‐responsive signals.
Pollen development at high temperature and role of carbon and nitrogen metabolites
Authors: Santiago James P. , Sharkey Thomas D.
Published: May 2019

Fruit and seed crop production heavily relies on successful stigma pollination, pollen tube growth, and fertilization of female gametes. These processes depend on production of viable pollen grains, a process sensitive to high‐temperature stress. Therefore, rising global temperatures threaten worldwide crop production. Close observation of plant development shows that high‐temperature stress causes morpho‐anatomical changes in male reproductive tissues that contribute to reproductive failure. These changes include early tapetum degradation, anther indehiscence, and deformity of pollen grains, all of which are contributing factors to pollen fertility. At the molecular level, reactive oxygen species (ROS) accumulate when plants are subjected to high temperatures. ROS is a signalling molecule that can be beneficial or detrimental for plant cells depending on its balance with the endogenous cellular antioxidant system. Many metabolites have been linked with ROS over the years acting as direct scavengers or molecular stabilizers that promote antioxidant enzyme activity. This review highlights recent advances in research on anther and pollen development and how these might explain the aberrations seen during high‐temperature stress; recent work on the role of nitrogen and carbon metabolites in anther and pollen development is discussed including their potential role at high temperature.