bluuebunny/crossref_metadata_2025 huggingface dataset:
Traditional Serrated Pathway–associated Colorectal Carcinoma
Authors: Tsai Jia-Huei , Jeng Yung-Ming , Yuan Chang-Tsu , Lin Yu-Lin , Cheng Mei-Ling , Liau Jau-Yu
Published: May 2019

The phenotypic characteristics of traditional serrated adenoma (TSA)-associated malignancies remain obscure. This study was a morphologic reappraisal of 27 colorectal carcinomas arising from TSA (TSA-CRCs) and 53 BRAF-mutated/microsatellite-stable colorectal carcinomas (BRAF-mut/MSS CRCs). Makinen’s criteria for serrated adenocarcinoma were applied to assess the morphologic similarity of the 2 entities. Tumor budding, another histologic feature of serrated adenocarcinoma, was also evaluated. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a commonly mutated gene in the serrated pathway, was assessed with immunohistochemistry. Tumors with aberrant PTEN expression were subjected to molecular analysis using quantitative methylation assay, exon sequencing, and fluorescence in situ hybridization. Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei. A majority (65%) of them qualified for the diagnosis of serrated adenocarcinoma. High-grade tumor budding was closely associated with serrated morphology and was a significant independent factor for poor patient survival in multivariate analysis (P=0.008). Aberrant PTEN expression was detected in nearly half of the cases of both entities (P=0.501). Among the 44 samples with aberrant PTEN expression, 8 harbored PTEN somatic mutations, which were characterized by random distribution without hotspot clustering, 12 had promoter hypermethylation, and 14 had deleted alleles. These findings support a unique model of colorectal carcinogenesis that is similar between TSA-CRCs and BRAF-mut/MSS CRCs. Both entities exhibited common histologic patterns and similar molecular alterations and may well constitute the TSA pathway.
Adenomyoepitheliomas of the Breast Frequently Harbor Recurrent Hotspot Mutations in PIK3-AKT Pathway-related Genes and a Subset Show Genetic Similarity to Salivary Gland Epithelial-Myoepithelial Carcinoma
Authors: Lubin Daniel , Toorens Erik , Zhang Paul J. , Jaffer Shabnam , Baraban Ezra , Bleiweiss Ira J. , Nayak Anupma
Published: May 2019

Adenomyoepitheliomas (AME) of the breast and epithelial-myoepithelial carcinomas (EMCs) of salivary gland are morphologically similar tumors defined by the presence of a biphasic population of ductal epithelial elements mixed with myoepithelial cells. We sought to explore the molecular profile of AMEs and determine whether they might also share the PLAG1, HMGA2, and HRAS alterations seen in EMCs. Tumor tissue from 19 AMEs was sequenced and analyzed using Ion AmpliSeq Cancer Hotspot Panel v2 covering ∼2800 COSMIC mutations across 50 cancer-related genes. Cases were additionally screened by FISH for PLAG1 and HMGA2 rearrangements. Of 19 AMEs (12 benign; 7 malignant), 2 cases failed the DNA extraction. Of the remaining 17 cases, 14 had at least one nonsynonymous mutation identified. The most common mutations were in PIK3CA (6/17) and AKT1 (5/17), which were mutually exclusive. Two tumors demonstrated mutations in APC, while 1 demonstrated an STK11 mutation. Mutations in ATM, EGFR, FGFR3 or GNAS were identified in 4 cases with concurrent AKT1 mutations. HRAS mutation co-occurring with PIK3CA mutation was noted in 1 case of ER-negative malignant AME. While 2 cases harbored alterations in HMGA2, none was positive for PLAG1 rearrangement. Our findings confirm that breast AMEs are genetically heterogeneous exhibiting recurrent mutually exclusive mutations of PIK3CA and AKT1 in a majority of cases. HRAS mutations co-occur with PIK3CA mutations in ER-negative AMEs and may possibly be linked to clinically aggressive behavior. We identified hotspot mutations in additional genes (APC, STK11, ATM, EGFR, FGFR3, and GNAS). We report the presence of HMGA2 alterations in 2/16 AMEs, supporting their relationship with EMC of salivary glands in at least a subset of cases. PIK3CA, AKT1 and HRAS may serve as potential actionable therapeutic targets in clinically aggressive AMEs.
Prognostic Significance of “Nonsolid” Microscopic Metastasis in Merkel Cell Carcinoma Sentinel Lymph Nodes
Authors: Erstine Emily M. , Tetzlaff Michael T. , Jia Xuefei , Aung Phyu P. , Prieto Victor G. , Funchain Pauline , Gastman Brian R. , Billings Steven D. , Ko Jennifer S.
Published: May 2019

Our recent work regarding Merkel cell carcinoma sentinel lymph node (SLN) metastasis found that “solid” pattern microscopic metastasis conferred worse prognosis than the “nonsolid” ones. The goals of the present study were to (1) compare the prognostic significance/outcomes of 2 diagnostic groups—patients with a nonsolid pattern of SLN metastasis and those with diagnostically negative SLN biopsies (SLNB), and (2) evaluate the durability of SLN metastasis after extensive sectioning. Five-level, step-wise sectioning at 250-μm intervals was performed in all SLN blocks with an immunohistochemical stain for CK20 on all levels. The presence and pattern of metastases were recorded and analyzed as were corresponding patient and tumor parameters. Median follow-up durations for all patients (n=38), positive SLNB (n=16) and negative SLNB (n=22) groups were 56.3, 50.4, and 66.8 months, respectively. Overall survival (OS) and disease-specific survival (DSS) did not differ between the 2 diagnostic groups (OS P=0.65, DSS P=0.37) but did differ by immune status (immunocompetent vs. immunosuppressed, OS P=0.03, DSS P=0.005) and primary tumor category (OS P<0.0001, DSS P=0.001). On deeper sectioning, all 16 diagnostically positive SLNB continued to show nonsolid microscopic metastasis, and 32% (7/22) diagnostically negative SLNB revealed nonsolid metastasis. DSS was worse for sinusoidal-pattern metastasis versus all others (P=0.02). Five of 38 patients (13%) died of disease; the only immunocompetent patient had sinusoidal-pattern metastasis discovered in a diagnostically negative SLNB. Our data suggest that outcome for nonsolid metastasis is similar to that of negative SLNB with the exception of the sinusoidal pattern, which was associated with worse outcome. Larger studies are warranted to quantify and compare microscopic metastatic tumor burden by pattern and confirm whether the sinusoidal pattern confers an intermediate prognostic risk between solid and other nonsolid microscopic metastases.
Severe Sepsis in Pediatric Liver Transplant Patients: The Emergence of Multidrug-Resistant Organisms
Authors: Alcamo Alicia M. , Alessi Lauren J. , Vehovic S. Noona , Bansal Neha , Bond Geoffrey J. , Carcillo Joseph A. , Green Michael , Michaels Marian G. , Aneja Rajesh K.
Published: May 2019

Objectives:

To describe characteristics of liver transplant patients with severe sepsis in the PICU.

Design:

Retrospective descriptive analysis.

Setting:

Tertiary children’s hospital PICU.

Patients:

Liver transplant recipients admitted January 2010 to July 2016 for pediatric severe sepsis.

Interventions:

None.

Measurements and Main Results:

Between January 2010 and July 2016, 173 liver transplants were performed, and 36 of these patients (21%) were admitted with severe sepsis (54 episodes total). Median age at admission was 2 years (1–6.5 yr), 47.2% were male. Bacterial infections were the most common (77.8%), followed by culture negative (12.9%) and viral infections (7.4%). Fungal infections accounted for only 1.9%. Median time from transplant for viral and culture negative infections was 18 days (8.25–39.75 d) and 25 days (9–41 d), whereas 54.5 days (17–131.25 d) for bacterial infections. Bloodstream and intra-abdominal were the most common bacterial sites (45% and 22.5%, respectively). Multidrug-resistant organisms accounted for 47.6% of bacterial sepsis. Vancomycin-resistant Enterococcus and extended-spectrum beta-lactamase producers were the most frequently identified multidrug-resistant organisms. Patients with multidrug-resistant organism sepsis demonstrated higher admission Pediatric Logistic Organ Dysfunction scores (p = 0.043) and were noted to have an odds ratio of 3.8 and 3.6 for mechanical ventilation and multiple organ dysfunction syndrome, respectively (p = 0.047 and p = 0.044). Overall mortality was 5.5% (n = 2 patients), with both deaths occurring in multidrug-resistant organism episodes.

Conclusions:

We report that multidrug-resistant organisms are increasingly being identified as causative pathogens for sepsis in pediatric liver transplant recipients and are associated with significantly higher odds for mechanical ventilation and higher organ failure. The emergence of multidrug-resistant organism infections in pediatric liver transplant patients has implications for patient outcomes, antibiotic stewardship, and infection prevention strategies.
Brief Report: HIV Shedding in the Female Genital Tract of Women on ART and Progestin Contraception: Extended Follow-up Results of a Randomized Clinical Trial
Authors: Kourtis Athena P. , Wiener Jeffrey , Hurst Stacey , Nelson Julie A.E. , Cottrell Mackenzie L. , Corbett Amanda , Chinula Lameck , Msika Albans , Haddad Lisa B. , Tang Jennifer H.
Published: May 2019

Background:

Progestin contraception has been linked to higher risk of female to male sexual HIV transmission.

Setting:

A clinical trial among HIV-infected women in Lilongwe, Malawi, randomized to initiation of depomedroxyprogesterone acetate injectable or levonorgestrel implant, and followed for up to 33 months, with the outcome of HIV shedding in the genital tract.

Methods:

We compared the frequency and magnitude of HIV genital shedding before and after initiation of contraception and between study arms among women receiving antiretroviral therapy (ART). Genital HIV RNA was measured in TearFlo Strips using the Abbott RealTime HIV-1 assay.

Results:

Among 68 HIV-infected Malawian women on ART, randomization to depot medroxyprogesterone acetate compared with the levonorgestrel implant was not associated with genital shedding and neither progestin contraceptive was associated with increased HIV genital shedding, for up to 33 months after contraceptive initiation. Having detectable plasma HIV [adjusted risk ratio (RR) 10.5; 95% confidence interval (CI): 3.18 to 34.7] and detectable genital shedding before contraceptive initiation (adjusted RR 3.53; 95% CI: 1.31 to 9.47) were associated with a higher risk of detectable genital shedding after contraceptive initiation. Higher plasma efavirenz concentrations were associated with a lower risk of detectable genital shedding (adjusted RR 0.85; 95% CI: 0.73 to 0.99, per increase of 1000 ng/mL).

Conclusion:

Among HIV-infected women receiving ART, our results provide evidence that progestin contraception does not impact women's risk of transmission of HIV to partners. Our finding that detectable genital shedding before contraceptive initiation independently predicts shedding suggests that there may be other individual-level biological or behavioral factors that increase the risk for shedding.
Daily Vaginal Swabs and Mobile Phone Sex Report for Assessing HIV Virion Exposure Prospectively Among a Cohort of Young Sexually Active Women in South Africa (HVTN 915)
Authors: Lemos Maria P. , Lazarus Erica , Isaacs Abby , Dietrich Janan , Morgan Cecilia , Huang Yunda , Grove Doug , Andrasik Michele , Laher Fatima , Hural John , Chung Eva , Dragavon Joan , Puren Adrian , Gulati Reena K. , Coombs Robert , McElrath Margaret Juliana , Gray Glenda , Kublin James G.
Published: May 2019

Background:

Measurements of HIV exposure could help identify subpopulations at highest risk of acquisition and improve the design of HIV prevention efficacy trials and public health interventions. The HVTN 915 study evaluated the feasibility of self-administered vaginal swabs for detection of HIV virions to assess exposure.

Methods:

Fifty 18- to 25-year-old sexually active HIV-seronegative women using contraception were enrolled in Soweto, South Africa. Participants self-administered daily vaginal swabs and answered sexual behavior questions through mobile phone for 90 days. Clinician-administered vaginal swabs, behavioral questionnaires, HIV diagnostic testing, and counseling were performed at 8 clinic visits. Glycogen concentrations assessed adherence to swabbing. Y-chromosome DNA (Yc-DNA) assessed the accuracy of reported condom use. HIV exposure was measured by virion polymerase chain reaction in swabs from 41 women who reported unprotected vaginal sex during follow-up.

Results:

Glycogen was detected in 315/336 (93.8%) participant-collected and in all clinician-collected swabs. Approximately 20/39 daily swabs (51.3%) linked to mobile reports of unprotected sex tested positive for Yc-DNA, whereas 10/187 swabs collected after 3 days of abstinence or protected sex (5.3%) had detectable Yc-DNA. No participant became HIV infected during the study; yet, exposure to HIV was detected by nucleic acids in 2 vaginal swabs from 1 participant, collected less than 1 hour after coitus.

Conclusion:

There was high adherence to daily vaginal swabbing. Daily mobile surveys had accurate reporting of unprotected sex. Detection of HIV in self-collected vaginal swabs from an uninfected participant demonstrated it was possible to measure HIV exposure, but the detection rate was lower than expected.
Neuronal Intranuclear Inclusion Disease
Authors: Yadav Nishtha , Raja Pritam , Shetty Safal S. , Jitender Saini , Prasad Chandrajit , Kamble Nitish L. , Mahadevan Anita , M. Netravathi
Published: May 2019

Introduction:

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder pathologically characterized by localized neuronal loss, and presence of eosinophilic intranuclear inclusions in neurons and glial cells.

Case Report:

A 50-year-old man presented with rapidly progressive dementia, behavioral changes, gait disturbances, and incontinence of 3 months duration. His brain magnetic resonance imaging showed diffuse T2/FLAIR hyperintensity of basal ganglia, thalami, cerebral peduncles, ventral pons, and supratentorial white matter with a frontal predominance. Hyperintensity was noted along the corticosubcortical junction on diffusion-weighted images. NIID was suspected and the patient underwent triple biopsy of the sural nerve with adjacent skin and biceps biopsy. Biopsy revealed ubiquitin-positive intranuclear inclusions surrounding the myofibers, and vascular smooth muscles suggestive of NIID.

Conclusions:

NIID is a rare neurodegenerative disorder usually diagnosed postmortem. The rectal and skin biopsy had proved helpful in antemortem diagnosis. We have increased the diagnostic armamentarium by showing the presence of intranuclear inclusions in smooth muscle cells of the muscle. Hence, a high degree of suspicion, magnetic resonance imaging features, with nerve/muscle/skin biopsy can help in diagnosis of NIID.
Analysis of Finnish blue mussel (Mytilus edulisL.) shell: Biomineral ultrastructure, organic-rich interfacial matrix and mechanical behavior
Authors: Mohammadi Pezhman , Wagermaier Wolfgang , Penttila Merja , Linder Markus B.
Published: May 2019

Studying various marine biomineralized ultrastructures reveals the appearance of common architectural designs and building blocks in materials with fascinating mechanical properties that match perfectly to their biological tasks. Advanced mechanical properties of biological materials are attributed to evolutionary optimized molecular architectures and structural hierarchy. One example which has not yet been structurally investigated in great detail is the shell ofMytilus edulisL. (Finnish blue mussel) found in the archipelago of SW-Finland. Through a combination of various state-of-the-art techniques such as high-resolution electron microscopy imaging, Fourier-transformed infrared spectroscopy, powder X-ray diffraction, synchrotron wide-angle X-ray diffraction, nanoindentation and protein analysis, both the inorganic mineralized components as well as the organic-rich matrix were extensively characterized. We found very similar ultra-architecture across the shell ofM. edulisL. as compared to the widely studied and closely relatedM. edulis. However, we also found interesting differences, for instance in the thickness and degree of orientation of the mineralized layers indicating dissimilar properties and related alterations in the biomineralization processes. Our results show that the shell ofM. edulisL. has a gradient of mechanical properties, with the increase in the stiffness and the hardness from anterior to the posterior region of the shell. The shell is made from distinct and recognizable mineralized layers each varying in thickness and microstructural features. At posterior regions of the shell, moving from dorsal to ventral side, these layers are an oblique prismatic layer, a prismatic layer and a nacreous layer, in which the oblique prismatic layer is found to be the main and thickest mineralized layer of the shell. Probing the calcified rods in the oblique prismatic layer using high resolution SEM imaging revealed opening of channels with a diameters of 40-50 nm and lengths up to a micrometer extending through the rods. The chitin and protein have been found to be the main component of the organic-rich interfacial matrix as expected. Protein analysis showed two abundant proteins with sizes around 100 kD and 45 kD which likely not only regulates biomineralization and adhesion of the crystals but also governing the intrinsic-extrinsic toughening in the shell. Overall, this detailed analysis provides new structural insights into biomineralization of marine shells in general.
Diversification in evolutionary arenas – assessment and synthesis
Authors: Nürk Nicolai M. , Linder H. Peter , Onstein Renske E. , Larcombe Matthew J. , Hughes Colin E. , Fernández Laura Piñeiro , Schlüter Philipp M. , Valente Luis , Beierkuhnlein Carl , Cutts Vanessa , Donoghue Michael J. , Edwards Erika J. , Field Richard , Flantua Suzette G.A. , Higgins Steven I. , Jentsch Anke , Liede-Schumann Sigrid , Pirie Michael D.
Published: May 2019

Understanding how and why rates of evolutionary diversification vary is a key issue in evolutionary biology, ecology, and biogeography, and the metaphorical concepts of adaptive radiation and evolutionary stasis describe two opposing aspects causing variation in diversification rates. Here we review the central concepts in the evolutionary diversification literature and synthesize these into a simple, general framework for studying rates of diversification and quantifying their underlying dynamics, which can be applied across clades and regions and across spatial and temporal scales. Our framework describes the diversification rate (d) as a function of the abiotic environment (a), the biotic environment (b) and clade-specific phenotypes or traits (c); thusd∼a,b,c. We refer to the four components (a–d) and their interactions collectively as the ‘Evolutionary Arena’. We outline analytical approaches to this framework and present a case study on conifers, for which we parameterise the general model. We also discuss three conceptual examples: theLupinusradiation in the Andes in the context of emerging ecological opportunity and fluctuating connectivity due to climatic oscillations; oceanic island radiations in the context of island formation and erosion; and biotically driven radiations of the Mediterranean orchid genusOphrys. The results of the conifer case study are consistent with the long-standing scenario that low competition and high rates of niche evolution promote diversification. The conceptual examples illustrate how using the synthetic Evolutionary Arena framework helps to identify and structure future directions for research on evolutionary radiations. In this way, the Evolutionary Arena framework promotes a more general understanding of variation in evolutionary rates by making quantitative results comparable between case studies, thereby allowing new syntheses of evolutionary and ecological processes to emerge.
Constructing a Timescale of Biotic Recovery across the Cretaceous–Paleogene Boundary, Corral Bluffs, Denver Basin, Colorado
Authors: Fuentes Anthony J. , Clyde William C. , Weissenburger Ken , Bercovici Antoine , Lyson Tyler R. , Miller Ian M. , Ramezani Jahandar , Schmitz Mark D. , Johnson Kirk R.
Published: May 2019

The Cretaceous–Paleogene (K–Pg) boundary interval represents one of the most significant mass extinctions and ensuing biotic recoveries in Earth history. Earliest Paleocene fossil mammal faunas corresponding to the Puercan North American Land Mammal Age (NALMA) are thought to be highly endemic and potentially diachronous, necessitating precise chronostratigraphic controls at key fossil localities to constrain recovery dynamics in continental biotas following the K–Pg mass extinction. The Laramide synorgenic sedimentary deposits within the Denver Basin preserve one of the most continuous and fossiliferous records of the K–Pg boundary interval in North America. However, poor exposure in much of the Denver Basin makes it difficult to correlate between outcrops. In order to constrain fossil localities across the basin, previous studies have relied upon chronostratigraphic methods such as magnetostratigraphy. Here we present a new high-resolution magnetostratigraphy of 10 lithostratigraphic sections spanning the K–Pg boundary interval at Corral Bluffs located east of Colorado Springs in the southern part of the Denver Basin. Fossil localities from Corral Bluffs have yielded limited dinosaur remains, mammal fossils assigned to the Puercan NALMA, and numerous fossil leaf localities. Palynological analysis identifying the K–Pg boundary in three sections and two independent but nearly identical206Pb/238U age estimates for the same volcanic ash, provide key temporal calibration points. Our paleomagnetic analysis has identified clear polarity reversal boundaries from Chron C30n to Chron C28r across the sections. It is now possible to place the fossil localities at Corral Bluffs within the broader basin-wide chronostratigraphic framework and evaluate them in the context of K–Pg boundary extinction and recovery.
Cofactor selectivity in methylmalonyl-CoA mutase, a model cobamide-dependent enzyme
Authors: Sokolovskaya Olga M. , Mok Kenny C. , Park Jong Duk , Tran Jennifer L. A. , Quanstrom Kathryn A. , Taga Michiko E.
Published: May 2019

Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). Thein vitrobinding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCMin vitrolargely correlate within vivocobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria.
DDAP: docking domain affinity and biosynthetic pathway prediction tool for type I polyketide synthases
Authors: Li Tingyang , Tripathi Ashootosh , Yu Fengan , Sherman David H. , Rao Arvind
Published: May 2019

DDAP is a tool for predicting the biosynthetic pathways of the products of type I modular polyketide synthase (PKS) with the focus on providing a more accurate prediction of the ordering of proteins and substrates in the pathway. In this study, the module docking domain (DD) affinity prediction performance on a hold-out testing data set reached AUC = 0.88; the MRR of pathway prediction reached 0.67. DDAP has advantages compared to previous informatics tools in several aspects: (i) it does not rely on large databases, making it a high efficiency tool, (ii) the predicted DD affinity is represented by a probability (0 to 1), which is more intuitive than raw scores, (iii) its performance is competitive compared to the current popular rule-based algorithm. To the best of our knowledge, DDAP is so far the first machine learning based algorithm for type I PKS pathway prediction. We also established the first database of type I modular PKSs, featuring a comprehensive annotation of available docking domains information in bacterial biosynthetic pathways.

Availability and implementation

The DDAP database is available at https://tylii.github.io/ddap. The prediction algorithm DDAP is freely available on GitHub (https://github.com/tylii/ddap) and released under the MIT license.

Contact

ukarvind@umich.edu
How does the mood stabilizer lithium bind ATP, the energy currency of the cell
Authors: Haimovich A. , Goldbourt A.
Published: May 2019

Lithium, in the form of a salt, is a mood stabilizer and a leading drug for the treatment of bipolar disorder. It has a very narrow therapeutic range and a variety of side effects. Lithium can replace magnesium and other cations in enzymes and small molecules, among them ATP, thereby affecting and inhibiting many biochemical pathways. The form of binding of lithium ions to ATP is not known.

Here we extract the binding environment of lithium in solid ATP using a multi-nuclear multi-dimensional solid-state NMR approach.

We determine that the coordination sphere of lithium includes, at a distance of 3.0(±0.4) Å, three phosphates; the two phosphates closest to the ribose ring from one ATP molecule, and the middle phosphate from another ATP molecule. A water molecule most probably completes the fourth coordination. Despite the use of excess lithium in the preparations, sodium ions still remain bound to the sample, at distances of 4.3-5.5 Å from Li, and coordinate the first phosphate and two terminal phosphates.

In conclusion, solid-state NMR enables to unravel the exact coordination of lithium in ATP showing binding to three phosphates from two molecules, none of which are the terminal gamma phosphate. The methods we use are applicable to study lithium bound to a variety of ATP-bound enzymes, or to other cellular targets of lithium, consequently suggesting a molecular basis for its mode of action.
Quantitative and rapid Plasmodium falciparum malaria diagnosis and artemisinin-resistance detection using a CMOS Lab-on-Chip platform
Authors: Malpartida-Cardenas K. , Miscourides N. , Rodriguez-Manzano J. , Yu L. S. , Baum J. , Georgiou P.
Published: May 2019

Early and accurate diagnosis of malaria and drug-resistance is essential to effective disease management. Available rapid malaria diagnostic tests present limitations in analytical sensitivity, drug-resistant testing and/or quantification. Conversely, diagnostic methods based on nucleic acid amplification stepped forwards owing to their high sensitivity, specificity and robustness. Nevertheless, these methods commonly rely on optical measurements and complex instrumentation which limit their applicability in resource-poor, point-of-care settings. This paper reports the specific, quantitative and fully-electronic detection of Plas-modium falciparum, the predominant malaria-causing parasite worldwide, using a Lab-on-Chip platform developed in-house. Furthermore, we demonstrate on-chip detection of C580Y, the most prevalent single-nucleotide polymorphism associated to artemisinin-resistant malaria. Real-time non-optical DNA sensing is facilitated using Ion-Sensitive Field-Effect Transistors, fabricated in unmodified complementary metal-oxide-semiconductor technology, coupled with loop-mediated isothermal amplification. This work holds significant potential for the development of a fully portable and quantitative malaria diagnostic that can be used as a rapid point-of-care test.
Real-time optoacoustic tracking of single moving micro-objects in deep tissue-mimicking phantoms
Authors: Aziz Azaam , Medina-Sánchez Mariana , Claussen Jing , Schmidt Oliver G.
Published: May 2019

Medical imaging plays an important role in diagnosis and treatment of multiple diseases. It is a field under continuous development which seeks for improved sensitivity and spatiotemporal resolution to allow the dynamic monitoring of diverse biological processes that occur at the micro- and nanoscale. Emerging technologies for targeted diagnosis and therapy such as nanotherapeutics, micro-implants, catheters and small medical tools also need to be precisely located and monitored while performing their function inside the human body. In this work, we show for the first time the real-time tracking of moving single micro-objects below centimeter thick tissue-mimicking phantoms, using multispectral optoacoustic tomography (MSOT). This technique combines the advantages of ultrasound imaging regarding depth and resolution with the molecular specificity of optical methods, thereby facilitating the discrimination between the spectral signatures of the micro-objects from those of intrinsic tissue molecules. The resulting MSOT signal is further improved in terms of contrast and specificity by coating the micro-objects’ surface with gold nanorods, possessing a unique absorption spectrum, which will allow their discrimination from surrounding biological tissues when translated to in vivo settings.
Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation
Authors: Bernabeu Miguel O. , Köry Jakub , Grogan James A. , Markelc Bostjan , Beardo Albert , d’Avezac Mayeul , Enjalbert Romain , Kaeppler Jakob , Daly Nicholas , Hetherington James , Krüger Timm , Maini Philip K. , Pitt-Francis Joe M. , Muschel Ruth J. , Alarcón Tomás , Byrne Helen M.
Published: May 2019

Oxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumour, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that RBC transport plays in establishing oxygen heterogeneity in tumour tissue. We focus on heterogeneity driven by network effects, which are challenging to observe experimentally due to the reduced fields of view typically considered. Motivated by our findings of abnormal vascular patterns linked to deviations from current RBC transport theory, we calculate average vessel lengths and diameters from tumour allografts of three cancer cell lines and observe a substantial reduction in the ratio compared to physiological conditions. Mathematical modelling reveals that small values of the ratio λ (i.e. λ < 6) can bias haematocrit distribution in tumour vascular networks and drive heterogeneous oxygenation of tumour tissue. Finally, we show an increase in the value of λ in tumour vascular networks following treatment with the anti-angiogenic cancer agent DC101. Based on our findings, we propose λ as an effective way of monitoring the efficacy of antiangiogenic agents and as a proxy measure of perfusion and oxygenation in tumour tissue undergoing anti-angiogenic treatment.

Significance statement

Oxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal tumour vascular structure. We investigate the role that anomalies in RBC transport play in establishing oxygen heterogeneity in tumour tissue. We introduce a metric to characterise tumour vasculature (mean vessel length-to-diameter ratio, λ) and demonstrate how it predicts tissue oxygen heterogeneity. We also report an increase in λ following treatment with the antiangiogenic agent DC101. Together, we propose λ as an effective way of monitoring the action of anti-angiogenic agents and a proxy measure of oxygen heterogeneity in tumour tissue. Unravelling the causal relationship between tumour vascular structure and tissue oxygenation will pave the way for new personalised therapeutic approaches.
The calcium channel subunit α2δ-3 organizes synapses via a novel activity-dependent, autocrine BMP signaling pathway
Authors: Hoover Kendall M. , Gratz Scott J. , Herrmann Kelsey A. , Qi Nova , Liu Alexander , Perry-Richardson Jahci J. , Vanderzalm Pamela J. , O’Connor-Giles Kate M. , Broihier Heather T.
Published: May 2019

Synapses are highly specialized for neurotransmitter signaling, yet activity-dependent growth factor release also plays critical roles at synapses. While efficient neurotransmitter signaling is known to rely on precise apposition of release sites and neurotransmitter receptors, molecular mechanisms enabling high-fidelity growth factor signaling within the synaptic microenvironment remain obscure. Here we show that the auxiliary calcium channel subunit α2δ-3 promotes the function of a novel activity-dependent autocrine BMP signaling pathway at the Drosophila NMJ. α2δ proteins have conserved synaptogenic activity, although how they execute this function has remained elusive. We find that α2δ-3 provides an extracellular scaffold for autocrine BMP signaling, suggesting a new mechanistic framework for understanding α2δ’s conserved role in synapse organization. We further establish a transcriptional requirement for activity-dependent, autocrine BMP signaling in determining synapse density, structure, and function. We propose that activity-dependent, autocrine signals provide neurons with continuous feedback on their activity state and are thus well poised to modulate synapse structure and function.
ARGONAUTE5 Mediates Fine-Tuning of Vegetative-to-Reproductive Phase Transition Through Its Interaction with miR156 in Arabidopsis
Authors: Roussin-Léveillée Charles , Silva-Martins Guilherme , Moffett Peter
Published: May 2019

Vegetative-to-reproductive phase change is a finely tuned process in plants, largely controlled by the age-regulated microRNA156 (miR156), which functions by suppressing the transcripts of SQUAMOSA-PROMOTER BINDING LIKE (SPL) transcription factors. ARGONAUTE proteins (AGO) are essential effectors of miRNA-mediated gene regulation. However, which AGO(s) mediate(s) the control of flowering time remains unclear. Here, we demonstrate a role for AGO5 in vegetative-to-reproductive phase transition through the modulation of SPL transcription factors. We show that AGO5 interacts physically and functionally with miR156 and that ago5 mutants present an early flowering phenotype in Arabidopsis. Furthermore, in ago5 mutants, the repression of flowering caused by miR156 overexpression is largely reversed, whereas leaf morphology remains unaffected. Our results thus indicate a specific role for AGO5 in mediating miR156 activity in meristematic, but not vegetative, tissue. As such, our data suggest a spatiotemporal regulation of the miR156 aging pathway, mediated through different AGO proteins in different tissues.
Impact of food safety training on the knowledge, practice, and attitudes of food handlers working in fast-food restaurants
Authors: Elobeid Tahra , Savvaidis Ioannis , Ganji Vijay
Published: May 2019

Purpose

In many developing countries, the main source of food related illness is the fast foods restaurants. Health inspections of fast-food restaurants may not be sufficient to ensure and enforce the food safety regulations. The purpose of this paper is to investigate the food safety knowledge, attitudes and practices (KAP) of fast food handlers in Qatar.

Design/methodology/approach

Data were collected from 102 fast-food handlers through a structured survey. The questionnaire comprised questions on food safety KAP. The association between scores for KAP among the food handlers was measured with Spearman’s rank correlation.

Findings

A significant direct association was found throughout the different criteria of food safety KAP. In total, 90 percent of fast food handlers had undergone formal training on food safety. Although fast food handlers thought they had overall good knowledge on food safety (93.9 percent), results showed that they had a poor knowledge on proper cleaning of equipment, cross-contamination, foodborne diseases, food danger zone and correct procedures for thawing of frozen food. Only (34.7 percent) of the food handlers correctly identified Salmonella as a food pathogen.

Originality/value

Based on the current findings, the authors believe that continuous food safety and hygiene training should be implemented in all food service operations especially in fast-food restaurants in Qatar to ensure that all food handlers have the knowledge and the skill to provide safe food.
Understanding the consumption of traditional-local foods through the experience perspective
Authors: Savelli Elisabetta , Bravi Laura , Murmura Federica , Pencarelli Tonino
Published: May 2019

Purpose

The purpose of this paper is to understand whether an experiential perspective can be usefully adopted in the context of traditional-local foods (TLFs) by assuming a consumer perspective that analyses attitudes and behaviours of young people towards truffles. In particular, it examines which values drive the consumption of truffles and whether they are perceived as an experiential-based food or simply a nutritional-based one.

Design/methodology/approach

The research was carried out through a survey conducted on a sample of 720 Italian university students from January to May 2016. The data were processed using analysis of variance, principal component analysis and a two-step cluster analysis.

Findings

The results show that the search for pleasure and gratification can be very important for young consumers and that gratification plays a critical role in the consumption of fresh truffles along with convenience. This confirms that TLFs, like truffles, can be highly appreciated by young consumers for their emotional content, which allows them to have a personal experience when buying and consuming them.

Originality/value

The study contributes to the literature by enriching the overall understanding of young people’s food behaviour and by deepening the adoption of the experiential perspective within the TLF business. Moreover, it has practical and useful implications for promoting the consumption of TLFs among the young and for managing TLFs as well as the rural areas from where they originate.
Cultural and contextual influences on corporate social responsibility
Authors: Ling Ya-Hui
Published: May 2019

Purpose

The purpose of this paper is to examine the influence of managerial cultural values and the contextual environment (country of origin and country of operation) on corporate social responsibility (CSR) investments in three Asian countries.

Design/methodology/approach

A total of 150 questionnaires were collected from 150 companies located in Taiwan, Malaysia and Singapore. The potential influence of ethnicity on cultural values was controlled by collecting data from ethnic Chinese managers.

Findings

The results show that senior managers, especially their cultural values, play a crucial role in directing Asian companies’ CSR investments. In addition, the context (a firm’s country of origin and country of operation) also differentiates the cultural values and CSR investments in these three countries.

Originality/value

The study adds to the understanding of the influence of managerial cultural values and context on various aspects of CSR. Especially, the study offers valuable managerial implications for CSR implementation from the Chinese management perspective. Considering the fast global expansion of Chinese companies, the results concerning how Chinese managers’ cultural values influence their CSR investments priority offer valuable managerial implications. The comparisons of cultural values and CSR investments priority among ethnic Chinese managers in different contextual environments also serve as good starting points for future studies.
Performance assessment of shooting methods using parallel cloud computing
Authors: Agundis-Tinajero Gibran , Peña Gallardo Rafael , Segundo-Ramírez Juan , Visairo-Cruz Nancy , Guerrero Josep M.
Published: May 2019

Purpose

The purpose of this study is to present the performance evaluation of three shooting methods typically applied to obtain the periodic steady state of electric power systems, with the aim to check the benefits of the use of cloud computing regarding relative efficiency and computation time.

Design/methodology/approach

The mathematical formulation of the methods is presented, and their parallelization potential is explained. Two case studies are addressed, and the solution is computed with the shooting methods using multiple computer cores through cloud computing.

Findings

The results obtained show a reduction in the computation time and increase in the relative efficiency by the application of these methods with parallel cloud computing, in the problem of obtainment of the periodic steady state of electric power systems in an efficient way. Additionally, the characteristics of the methods, when parallel cloud computing is used, are shown and comparisons among them are presented.

Originality/value

The main advantage of employment of parallel cloud computing is a significant reduction of the computation time in the solution of the problem of a heavy computational load caused by the application of the shooting methods.
A qualitative framework for selection of optimization algorithm for multi-objective trade-off problem in construction projects
Authors: Panwar Abhilasha , Tripathi Kamalendra Kumar , Jha Kumar Neeraj
Published: May 2019

Purpose

The purpose of this paper is to develop a qualitative framework for the selection of the most appropriate optimization algorithm for the multi-objective trade-off problem (MOTP) in construction projects based on the predefined performance parameters.

Design/methodology/approach

A total of 6 optimization algorithms and 13 performance parameters were identified through literature review. The experts were asked to indicate their preferences between each pair of optimization algorithms and performance parameters. A multi-criteria decision-making tool, namely, consistent fuzzy preference relation was applied to analyze the responses of the experts. The results from the analysis were applied to evaluate their relative weights which were used to provide a ranking to the algorithms.

Findings

This study provided a qualitative framework which can be used to identify the most appropriate optimization algorithm for the MOTP beforehand. The outcome suggested that non-dominated sorting genetic algorithm (NSGA) was the most appropriate algorithm whereas linear programming was found to be the least appropriate for MOTPs.

Originality/value

The devised framework may provide a useful insight for the construction practitioners to choose an effective optimization algorithm tool for preparing an efficient project schedule aiming toward the desired optimal improvement in achieving the various objectives. Identification of the absolute best optimization algorithm is very difficult to attain due to various problems such as the inherent complexities and intricacies of the algorithm and different class of problems. However, the devised framework offers a primary insight into the selection of the most appropriate alternative among the available algorithms.
The diversity of knowledge sources and its impact on firm-level innovation
Authors: Abdul Basit Shoaib , Medase Kehinde
Published: May 2019

Purpose

The combination of different knowledge sources has been considered conducive for innovation performance. While the literature has advanced regarding the combination of knowledge inputs as in internal and external research and development (R&D), the evolvement of knowledge blend from customers and competitors has also received substantial attention. The purpose of this paper is to delineate the sources of information from the customers into private and public and examine their direct effect on firm-level innovation. While the extant literature is mixed regarding this, no clear-cut results have emerged yet on the effect of knowledge combination from the private and public customers with internal R&D and human capital on innovation activities. This study, however, shed more lights on the inconclusiveness of the effect of knowledge diversity on firm-level innovation.

Design/methodology/approach

Using the microdata from the German Community Innovation Survey 2013, the authors employ a binary instrumental variable treatment model with Heckman selection, a suitable strategy to estimate binary variables to cope with a possible endogeneity issue.

Findings

The paper demonstrates that knowledge from customers in the private and public sector, and competitors are positively and significantly associated with innovation. The authors find evidence of a positive and significant effect of the combination of firm internal knowledge competencies with information from the public sector. In contrary, the blend of knowledge competencies with information from customers in the private sector and information from the competitors results in decline to innovation. The results also show that the blend of internal R&D with knowledge source from the customers in the public sector appears to have a stronger influence in the manufacturing sector than services. The results offer strong evidence of the positive link between knowledge diversity and firm-level innovation performance.

Practical implications

The results have significant managerial implications on the role of the blend of different sources of information in supporting a compelling internal knowledge development to optimise innovation performance.

Originality/value

This study is foremost to focus on knowledge sources from the customers in the public and private sector and its relationship with R&D and human capital in supporting a successful introduction of innovation.
Human resource strategies for organizational ambidexterity
Authors: Kim Andrea
Published: May 2019

Purpose

The purpose of this paper is to propose a comprehensive framework that delineates how human resource (HR) practices are differentially configured for exploitative and explorative innovation as well as how the sets of HR practices support these two types of innovation.

Design/methodology/approach

Based on the structural ambidexterity approach and a bottom-up process in the multilevel theories, this research derives the need for the differential managerial structures for exploitation and exploration at the unit level. In addition, the Input–Process–Outcome model of team effectiveness and multilevel theories are employed to discuss the internal nature (e.g. resources, work styles) of exploiting and exploring units. Finally, building on strategic HR management literature, this research configures exploitation-targeted and exploration-targeted HR systems and delves into how these differentiated HR systems generate differential inputs of human capital resources and thereby foster exploitative and explorative innovation processes.

Findings

This research proposes several factors for exploitation and exploration, including: necessary inputs (i.e. commitment, narrowness, and cohesion for exploitation vs thoughtfulness, breadth, and openness for exploration), idiosyncratic innovation processes (i.e. convergent collective cognition vs divergent collective cognition), and differentiated HR systems comprised of different forms of unit staffing (homogeneity vs heterogeneity), performance appraisal, incentives, and training and development (short-term vs long-term orientation).

Originality/value

The proposed theoretical framework contributes to an improved understanding of the psychological foundation of organizational ambidexterity and systematizing how diverse HR practices work together to elicit exploitative and explorative innovation from employees.