bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraductal Tubulopapillary Neoplasm of the Pancreas
Authors: Basturk Olca , Adsay Volkan , Askan Gokce , Dhall Deepti , Zamboni Giuseppe , Shimizu Michio , Cymes Karina , Carneiro Fatima , Balci Serdar , Sigel Carlie , Reid Michelle D. , Esposito Irene , Baldaia Helena , Allen Peter , Klöppel Günter , Klimstra David S.
Published: December 2016

Intraductal tubulopapillary neoplasm (ITPN) is a relatively recently described member of the pancreatic intraductal neoplasm family. Thus, the literature on its histologic and immunohistochemical features, clinical behavior, and its similarities and differences from other pancreatic neoplasms is limited. Thirty-three cases of ITPN, the largest series to date, were identified. Immunohistochemical labeling for cytokeratins, glycoproteins, pancreatic enzymes, markers for intestinal and neuroendocrine differentiation, and antibodies associated with genetic alterations previously described in pancreatic neoplasms was performed. Clinicopathologic features and survival was assessed. Seventeen patients were female and 14 were male. Mean age was 55 years (range, 25 to 79 y). Median overall tumor size was 4.5 cm (range, 0.5 to 15 cm). Forty-five percent of the tumors occurred in the head, 32% in the body/tail, and 23% showed diffuse involvement. Microscopically, the tumors were characterized by intraductal nodules composed of tightly packed small tubular glands lined by cuboidal cells lacking apparent mucin. Although it was often challenging to determine its extent, invasion was present in 71%. Almost all tumors labeled for CAM5.2, CK7, and CK19; most expressed CA19.9, MUC1, and MUC6. CDX2, MUC2, trypsin, chymotrypsin, chromogranin, and synaptophysin were not expressed. SMAD4 expression was retained in 100%; p16 expression and p53 overexpression was seen in 33% and 27%, respectively. Follow-up information was available for 22 patients (median follow-up, 45 mo; range, 11 to 173 mo). Two patients with invasive carcinoma died of disease at 23 and 41 months, respectively. One patient died of unrelated causes at 49 months. Twelve patients were alive with disease. Seven patients were alive with no evidence of disease. The overall 1-, 3-, and 5-year survival rates were 100% in patients without an invasive component and 100%, 91%, and 71%, respectively, in patients with an invasive component (P=0.7). ITPN is a distinct clinicopathologic entity in the pancreas. Despite the difficulties of determining the extent of invasive carcinoma in many cases, the overall outcome seems to be relatively favorable and substantially better than that of conventional pancreatic ductal adenocarcinoma, even when only the cases with invasive carcinoma are considered.
Duodenal Neoplasms of Gastric Phenotype
Authors: Hida Risa , Yamamoto Hidetaka , Hirahashi Minako , Kumagai Reiko , Nishiyama Kenichi , Gi Toshihiro , Esaki Motohiro , Kitazono Takanari , Oda Yoshinao
Published: December 2016

Duodenal neoplasm of gastric phenotype (DNGP) is very rare, and details of its histopathologic, genetic, and biological features are still unclear. Frequent gene mutations in GNAS, KRAS, and APC have been reported in pyloric gland adenomas and fundic gland-type neoplasms (initially reported as low-grade adenocarcinomas) of the stomach. Here we retrospectively analyzed 16 cases of extra-ampullary DNGP (benign to malignant), and we examined the mucin immunoprofile and oncogene mutations (GNAS, KRAS, APC, BRAF, and CTNNB1). The 16 DNGPs were histologically classified into adenomas (5 pyloric gland adenomas and 2 foveolar-type adenomas), neoplasms of uncertain malignant potential (NUMPs, n=6), and invasive adenocarcinomas (n=3). NUMPs consisted of slightly atypical epithelial cells with pale, eosinophilic, or basophilic cytoplasm growing in an anastomosing or branching glandular pattern, often with expansive submucosal extension. In contrast to invasive adenocarcinomas, NUMPs lacked significant nuclear irregularity, desmoplastic stromal reaction, lymphovascular invasion, and metastasis; their features were reminiscent of fundic gland-type neoplasms of the stomach. Immunophenotypically, most of NUMPs were predominantly positive for MUC6 with variable expressions of pepsinogen-I, H+K+ATPase, human gastric mucin, and MUC5AC. Molecular analyses revealed the gene mutations of GNAS in 6 (38%) of 16 DNGPs (4 [57%] adenomas, 1 [16%] NUMP, and 1 [33%] invasive adenocarcinoma) and APC in 4 of 15 (27%) DNGPs: no adenomas, 2 (33%) NUMPs, and 2 (67%) invasive adenocarcinomas. BRAF mutation was present in only 1 (16%) NUMP, and KRAS and CTNNB1 mutations were absent. In conclusion, gastric-phenotype adenomas and NUMPs of the duodenum are similar to their counterparts of the stomach, in terms of histologic, genetic, and clinicopathologic features. We propose the term “NUMP” as an intermediate category between adenoma and definitely invasive adenocarcinoma. Our findings may provide novel insights into the classification of undescribed but distinctive duodenal tumors showing similarity to gastric-phenotype neoplasms of the stomach.
Six-Month Follow-up of Supervised Spinal Stabilization Exercises for Low Back Pain in Adolescent Idiopathic Scoliosis
Authors: Zapata Karina A. , Wang-Price Sharon S. , Sucato Daniel J.
Published: December 2016

Purpose:

To evaluate the effectiveness of 8 weeks of weekly spinal stabilization exercises compared with 1-time treatment in participants with adolescent idiopathic scoliosis and low back pain at a 6-month follow-up.

Methods:

Thirty-two participants were evaluated at a 6-month follow-up. The supervised group received weekly spinal stabilization exercises. The unsupervised group received a 1-time treatment and home exercise program.

Results:

Both groups improved in all outcome measures. The supervised group had significantly reduced Numeric Pain Rating Scale and Improved Global Rating of Change scores, but had no differences in the revised Oswestry Back Pain Disability Questionnaire, or Patient-Specific Functional Scale scores in comparison with the unsupervised group.
Constraint-Induced Movement Therapy for Children With Brain Tumors
Authors: Sparrow Jessica , Zhu Liang , Gajjar Amar , Mandrell Belinda N. , Ness Kirsten K.
Published: December 2016

Purpose:

The purpose of this pilot study was to investigate the feasibility of a 3-week constraint-induced movement therapy program in children with brain tumors and upper extremity hemiplegia and to describe resultant change in extremity use.

Methods:

Affected arm use, health-related quality of life, and parent-reported feasibility of program participation were measured before and after the intervention and at a 3-month follow-up visit.

Results:

All 9 participants completed the entire study. The quality and amount of affected arm use improved significantly; gains were maintained at the 3-month follow-up evaluation. Some parents (44%) reported that program participation was difficult; however, all reported satisfaction with the program. Participants did not experience negative changes in health-related quality of life during the intervention, indicating that they tolerated the program well.

Conclusions:

Findings suggest that a child with hemiplegia as a result of a brain tumor can adhere to and benefit from a constraint-induced movement therapy program.
Psychiatric Symptoms in Patients Receiving Dolutegravir
Authors: Fettiplace Anna , Stainsby Chris , Winston Alan , Givens Naomi , Puccini Sarah , Vannappagari Vani , Hsu Ricky , Fusco Jennifer , Quercia Romina , Aboud Michael , Curtis Lloyd
Published: December 2016

Introduction:

Psychiatric symptoms (PSs) are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analyzed PSs observed with dolutegravir (DTG) and other frequently prescribed anchor drugs.

Methods:

Selected PSs (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during DTG treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and among cases spontaneously reported to ViiV Healthcare were analyzed.

Results:

In clinical trials, PSs were reported at low and similar rates in patients receiving DTG or comparators [atazanavir, darunavir, efavirenz, or raltegravir (RAL)]. Insomnia was most commonly reported. The highest rates were observed in SINGLE (DTG 17%, efavirenz 12%), with consistently lower rates in the other trials (DTG: 3%–8% versus comparator: 3%–7%). More efavirenz-treated patients withdrew because of PSs than patients treated with other anchor drugs. In OPERA, history of PSs at baseline was lowest in efavirenz-treated patients compared with patients treated with DTG, RAL, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for PSs were lowest for DTG (0%–0.6%) and highest for RAL (0%–2.5%). Spontaneously reported events were similar in nature to clinical trial data.

Conclusions:

Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, PSs are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation.
Brief Report: The Relationship Between Injection Drug Use Risk Behaviors and Markers of Immune Activation
Authors: Deren Sherry , Cleland Charles M. , Lee Haekyung , Mehandru Saurabh , Markowitz Martin
Published: December 2016

High levels of immune activation are reported for people who inject drugs. Studies of the relationship between injection behaviors and immune activation have yielded mixed results, in part due to lack of control for hepatitis C virus in analyses. This study, of 48 HIV-seronegative people who inject drugs, examines this relationship controlling for hepatitis C virus viremia. Frequency of injection was positively related to markers of immune activation (soluble CD14, %CD8+CD38+HLADR+ T cells), as was duration of injection (high-specificity C-reactive protein and d-dimer). Sharing injection equipment was not related to markers studied. Findings suggest that efforts to encourage injection cessation or reduction in frequency can have positive health benefits through reducing immune activation.
Brief Report: The Impact of Ledipasvir/Sofosbuvir on HIV-Positive and HIV-Negative Japanese Hemophilia Patients With 1, 4, and Mixed-Genotype HCV
Authors: Nagao Azusa , Hanabusa Hideji
Published: December 2016

Introduction:

Approximately 80% of patients with hemophilia who received nonheated coagulation factor concentrates in the early 1980s were infected with hepatitis C virus (HCV), and approximately 40% of them were infected with HIV.

Aim:

We evaluated the efficacy and safety of administering ledipasvir (LDV)/sofosbuvir (SOF) to Japanese patients with hemophilia.

Methods:

Forty-three patients with hemophilia with genotype 1 or 4 HCV were treated with LDV/SOF for 12 weeks. The efficacy, safety, and results of the laboratory tests were evaluated.

Results:

Twenty patients were coinfected with HIV and HCV. The sustained virological response (SVR) at 12 weeks after therapy was 90% in HIV-positive patients and 100% in HIV-negative patients. The efficacy of LDV/SOF was not significantly different between HIV-positive and HIV-negative patients (P = 0.12). However, the rate of SVR at 12 weeks after therapy in the patients with cirrhosis was significantly lower than that in patients without cirrhosis (P = 0.005). Overall, 20 patients (46%) had adverse events, and while the severity of most was mild to moderate, 3 were serious, including 1 death in the HIV-positive group. All patients completed treatment with no alterations in the antiretroviral regimen. No significant abnormalities in the renal function were detected in patients taking an antiretroviral regimen of tenofovir disoproxil fumarate.

Conclusions:

In this cohort study, LDV/SOF was effective and safe, but the SVR in patients with cirrhosis was lower than that in the noncirrhosis group. Thus, patients with hemophilia with genotype 1/4 HCV should be treated as early as possible before the onset of cirrhosis.
Cancer Measurement at Ultrasound
Authors: Catalano Orlando
Published: December 2016

Reliable and reproducible tumor measurement is fundamental in the oncologic decision making. In this article, we first highlight the importance of a precise tumor measurement, reviewing the correct modality of measuring tumor lesions at ultrasound. Then we analyze the measurement discrepancies between ultrasound and pathology as well as the discrepancies reported between ultrasound and other imaging modalities. Thereafter, basing on the existent literature and on our experience, we discuss the factors influencing the tumor size measurements at ultrasound. Finally, we illustrate the current strategies to improve the effectiveness of cancer lesions measurement.
Incidence of a Bifid Mandibular Condyle in Dry Mandibles
Authors: Nikolova Silviya Yanakieva , Toneva Diana Hristova , Lazarov Nikolai Elenkov
Published: December 2016

Background:

A bifid mandibular condyle (BMC) is a rare anatomical variation with an etiology not fully understood. Although there are numerous case reports regarding it, purposeful epidemiological investigations on the BMC frequency among different groups are scarce. This study aims to investigate the incidence and laterality of BMC among series of adult males from Bulgaria and perform a morphometric analysis of it.

Materials and methods:

A series of 500 dry intact mandibles from adult males was investigated. The condyles were macroscopically observed and when skulls were available, the corresponding mandibular fossae were also inspected. In the cases when bifid condyles were found, 27 measurements were taken.

Results:

Bifid mandibular condyle was observed in 4 (0.8%) mandibles. All of the cases were unilateral, 2 on the right side (0.4%) and 2 on the left (0.4%). The condyles were divided into medial and lateral heads by a sagittal fissure or a notch.

Conclusion:

The established frequency of BMC was comparable with those reported in Turkish and Korean populations. The lack of injury marks and traces implies a developmental etiology of this condition.
Musicogenic Epilepsy and Treatment of Affective Disorders: Case Report and Review of Pathogenesis
Authors: Cheng Jocelyn Y.
Published: December 2016

Musicogenic epilepsy is a rare syndrome in which music triggers seizures. Affective network processing appears to play a key role in epileptogenesis. Many people with epilepsy suffer from comorbid affective disorders, the shared basis of which involves similar pathophysiologies, including deficiencies of serotonergic and noradrenergic function. Seizures and mood disorders may thus have reciprocal effects on one another, particularly in emotionally precipitated syndromes such as musicogenic epilepsy. I report a man with long-standing depression and anxiety who developed focal epilepsy that evolved into musicogenic seizures. His case suggests a pathophysiologic basis for this shared phenomenon.
Knowns and Unknowns About Delirium in Stroke: A Review
Authors: Klimiec Elzbieta , Dziedzic Tomasz , Kowalska Katarzyna , Slowik Agnieszka , Klimkowicz-Mrowiec Aleksandra
Published: December 2016

Delirium is a transient condition characterized by sudden and fluctuating disturbances in cognitive function. The condition can be considered a sign of the brain’s vulnerability and diminished resilience to insult. Among the many clinical manifestations are cognitive, psychomotor, and sleep disturbances. Delirium is associated with longer hospital stays, worse functional outcomes, and higher mortality. Although up to 48% of patients who have had a stroke develop delirium, the condition has been studied much less in these patients than in general medicine, surgical, and intensive care patients. Coexisting neurologic deficits in patients with stroke limit the use of screening tools that are widely accepted in other populations. The variability of reported assessment methods highlights the need for delirium screening guidelines in stroke. Further, risk factors that are specific to stroke may play an important role in the etiology of delirium, along with such well-known factors as older age and infections. The delirium literature lacks data on differences in clinical manifestations and course in the various types of stroke. Here we review predisposing factors, diagnostic methods, and biomarkers of delirium in stroke and discuss aspects that need further research.
Persistent Interictal Musical Hallucination in a Patient With Mesial Temporal Sclerosis-Related Epilepsy: First Case Report and Etiopathological Hypothesis
Authors: Borelli Paolo , Vedovello Marcella , Braga Massimiliano , Pederzoli Massimo , Beretta Sandro
Published: December 2016

Musical hallucination is a disorder of complex sound processing of instrumental music, songs, choirs, chants, etc. The underlying pathologies include moderate to severe acquired hearing loss (the auditory equivalent of Charles Bonnet syndrome), psychiatric illnesses (depression, schizophrenia), drug intoxication (benzodiazepines, salicylate, pentoxifylline, propranolol), traumatic lesions along the acoustic pathways, and epilepsy. The hallucinations are most likely to begin late in life; 70% of patients are women. Musical hallucination has no known specific therapy. Treating the underlying cause is the most effective approach; neuroleptic and antidepressant medications have only rarely succeeded.

Musical hallucination in epilepsy typically presents as simple partial seizures originating in the lateral temporal cortex. To our knowledge, no formal report of musical hallucination in the interictal state has been published before. In contrast, other interictal psychotic features are a relatively common complication, especially in patients with long-standing drug-resistant epilepsy.

We describe a 62-year-old woman with a long history of mesial temporal lobe epilepsy whose musical hallucination was solely interictal. We speculate on the possible link between temporal epilepsy and her hallucination. We hypothesize that, as a result of her epileptic activity-induced damage, an imbalance developed between the excitatory and inhibitory projections connecting the mesial temporal cortex to the other auditory structures. These structures may have generated hyperactivity in the lateral temporal cortex through a “release” mechanism that eventually resulted in musical hallucination.
Ten simple rules for structuring papers
Authors: Mensh Brett , Kording Konrad
Published: December 2016

Good scientific writing is essential to career development and to the progress of science. A well-structured manuscript allows readers and reviewers to get excited about the subject matter, to understand and verify the paper’s contributions, and to integrate these contributions into a broader context. However, many scientists struggle with producing high-quality manuscripts and typically get little training in paper writing. Focusing on how readers consume information, we present a set of 10 simple rules to help you get across the main idea of your paper. These rules are designed to make your paper more influential and the process of writing more efficient and pleasurable.
NeuroNLP: a natural language portal for aggregated fruit fly brain data
Authors: Ukani Nikul H. , Tomkins Adam , Yeh Chung-Heng , Bruning Wesley , Fenichel Allison L. , Zhou Yiyin , Huang Yu-Chi , Florescu Dorian , Ortiz Carlos Luna , Richmond Paul , Lo Chung-Chuan , Coca Daniel , Chiang Ann-Shyn , Lazar Aurel A.
Published: December 2016

NeuroNLP, is a key application on the Fruit Fly Brain Observatory platform (FFBO,http://fruitflybrain.org), that provides a modern web-based portal for navigating fruit fly brain circuit data. Increases in the availability and scale of fruit fly connectome data, demand new, scalable and accessible methods to facilitate investigation into the functions of the latest complex circuits being uncovered. NeuroNLP enables in-depth exploration and investigation of the structure of brain circuits, using intuitive natural language queries that are capable of revealing the latent structure and information, obscured due to expansive yet independent data sources. NeuroNLP is built on top of a database system call NeuroArch that codifies knowledge about the fruit fly brain circuits, spanning multiple sources. Users can probe biological circuits in the NeuroArch database with plain English queries, such as “show glutamatergic local neurons in the left antennal lobe” and “show neurons with dendrites in the left mushroom body and axons in the fan-shaped body”. This simple yet powerful interface replaces the usual, cumbersome checkboxes and dropdown menus prevalent in today’s neurobiological databases. Equipped with powerful 3D visualization, NeuroNLP standardizes tools and methods for graphical rendering, representation, and manipulation of brain circuits, while integrating with existing databases such as the FlyCircuit. The userfriendly graphical user interface complements the natural language queries with additional controls for exploring the connectivity of neurons and neural circuits. Designed with an open-source, modular structure, it is highly scalable/flexible/extensible to additional databases or to switch between databases and supports the creation of additional parsers for other languages. By supporting access through a web browser from any modern laptop or smartphone, NeuroNLP significantly increases the accessibility of fruit fly brain data and improves the impact of the data in both scientific and educational exploration.
Fractone bulbs derive from ependymal cells and their laminin composition influence the stem cell niche in the subventricular zone
Authors: Nascimento Marcos Assis , Sorokin Lydia , Coelho-Sampaio Tatiana
Published: December 2016

Fractones are extracellular matrix structures in the neural stem cell niche of the subventricular zone (SVZ), where they appear as round deposits named bulbs or thin branching lines called stems. Their cellular origin and what determines their localization at this site is poorly studied and it remains unclear whether they influence neural stem and progenitor cells formation, proliferation and/or maintenance. To address these questions, we analyzed whole mount preparations of the lateral ventricle by confocal microscopy using different extracellular matrix and cell markers. We found that bulbs are rarely connected to stems and that they contain laminin α5 and α2 chains, respectively. Fractone bulbs were profusely distributed throughout the SVZ and appeared associated with the center of pinwheels, a critical site for adult neurogenesis. We demonstrate that bulbs appear at the apical membrane of ependymal cells at the end of the first week after birth. The use of transgenic mice lacking laminin α5 gene expression (Lama5) in endothelium and in FoxJ1-expressing ependymal cells, revealed ependymal cells as the source of laminin α5-containing fractone bulbs. Loss of laminin α5 from bulbs correlated with a 60% increase in cell proliferation, as determined by PH3 staining, and with a selective reduction in the number of quiescent neural stem cells in the SVZ. These results indicate that fractones are a key component of the SVZ and suggest that laminin α5 modulates the physiology of the neural stem cell niche.

Significance Statement

Our work unveils key aspects of fractones, extracellular matrix structures present in the SVZ that still lack a comprehensive characterization. We show that fractones extensively interact with neural stem cells, whereas some of them are located precisely at pinwheel centers, which are hotspots for adult neurogenesis. Our results also demonstrate that fractones increase in size during aging and that their interactions with NSPCs become more complex in old mice. Lastly, we show that fractone bulbs are produced by ependymal cells and that their laminin content regulates neural stem cells.
Pharmacogenetics of antidepressant response: a polygenic approach
Authors: García-González Judit , Tansey Katherine E. , Hauser Joanna , Henigsberg Neven , Maier Wolfgang , Mors Ole , Placentino Anna , Rietschel Marcella , Souery Daniel , Žagar Tina , Czerski Piotr M. , Jerman Borut , Buttenschøn Henriette N. , Schulze Thomas G. , Zobel Astrid , Farmer Anne , Aitchison Katherine J. , Craig Ian , McGuffin Peter , Giupponi Michel , Perroud Nader , Bondolfi Guido , Evans David , O’Donovan Michael , Peters Tim J. , Wendland Jens R. , Lewis Glyn , Kapur Shitij , Perlis Roy , Arolt Volker , Domschke Katharina ,   Major Depressive Disorder Working Group of the Psychiatric Genomic Consortium, Breen Gerome , Curtis Charles , Sang-Hyuk Lee , Kan Carol , Newhouse Stephen , Patel Hamel , Baune Bernhard T. , Uher Rudolf , Lewis Cathryn M. , Fabbri Chiara
Published: December 2016

Background

Major depressive disorder (MDD) has a high personal and socio-economic burden and more than 60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.

Methods

Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).

Results

No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.

Discussion

We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.
A theory of working memory without consciousness or sustained activity
Authors: Trübutschek Darinka , Marti Sébastien , Ojeda Andrés , King Jean-Rémi , Mi Yuanyuan , Tsodyks Misha , Dehaene Stanislas
Published: December 2016

Working memory and conscious perception are thought to share similar brain mechanisms, yet recent reports of non-conscious working memory challenge this view. Combining visual masking with magnetoencephalography, we demonstrate the reality of non-conscious working memory and dissect its neural mechanisms. In a spatial delayed-response task, participants reported the location of a subjectively unseen target above chance-level after a long delay. Conscious perception and conscious working memory were characterized by similar signatures: a sustained desynchronization in the alpha/beta band over frontal cortex, and a decodable representation of target location in posterior sensors. During non-conscious working memory, such activity vanished. Our findings contradict models that identify working memory with sustained neural firing, but are compatible with recent proposals of ‘activity-silent’ working memory. We present a theoretical framework and simulations showing how slowly decaying synaptic changes allow cell assemblies to go dormant during the delay, yet be retrieved above chance-level after several seconds.
Rapid identification of optimal drug combinations for personalized cancer therapy using microfluidics
Authors: Eduati Federica , Utharala Ramesh , Madhavan Dharanija , Neumann Ulf Peter , Cramer Thorsten , Saez-Rodriguez Julio , Merten Christoph A.
Published: December 2016

Functional screening of live patient cancer cells holds great potential for personalized medicine and allows to overcome the limited translatability of results from existing in-vitro and ex-vivo screening models. Here we present a plug-based microfluidics approach enabling the testing of drug combinations directly on cancer cells from patient biopsies. The entire procedure takes less than 48 hours after surgery and does not require ex vivo cultivation. We screened more than 1100 samples for different primary human tumors (each with 56 conditions and at least 20 replicates), and obtained highly specific sensitivity profiles. This approach allowed us to derive optimal treatment options which we further validated in two different pancreatic cancer cell lines. This workflow should pave the way for rapid determination of optimal personalized cancer therapies at assay costs of less than US$ 150 per patient.
Benefits of siderophore release lie in mediating diffusion limitation at low iron solubility
Authors: Leventhal Gabriel E. , Ackermann Martin , Schiessl Konstanze T.
Published: December 2016

Siderophores are chelators released by many bacteria to take up iron. In contrast to iron receptors located at the cell surface, released siderophores are at risk of being lost to environmental sinks. Here, we asked the question whether the release itself is essential for the function of siderophores, which could explain why such a risky strategy is widespread. We developed a reaction-diffusion model to determine the impact of siderophore release on overcoming iron limitation caused by poor solubility in aerobic, pH-neutral environments. We found that secretion of siderophores can efficiently accelerate iron uptake at low solubility, since secreted siderophores solubilize slowly diffusing large iron aggregates to small, quickly diffusing iron-siderophore complexes. At high iron solubility, however, when the iron-siderophore complex is no longer considerably smaller than the iron source itself, siderophore secretion can also slow down iron uptake. In addition, we found that cells can synergistically share their siderophores, depending on their distance and the level of iron aggregation. Overall, our study helps understand why siderophore secretion is so widespread: Even though a large fraction of secreted siderophores is lost, the solubilization of iron through secreted siderophores can efficiently increase iron uptake, especially if siderophores are produced cooperatively by several cells.
Stress-induced formation of cell wall-deficient cells in filamentous actinomycetes
Authors: Ramijan K. , Ultee E. , Willemse J. , Wondergem A.J. , Heinrich D. , Briegel A. , van Wezel G.P. , Claessen D.
Published: December 2016

The cell wall is a shape-defining structure that envelopes almost all bacteria. One of its main functions is to serve as a protection barrier to environmental stresses. Bacteria can be forced in a cell wall-deficient state under highly specialized conditions, which are invariably aimed at interrupting cell wall synthesis. Therefore, the relevance of such cells has remained obscure. Here we show that many filamentous actinomycetes have a natural ability to generate a new, cell wall-deficient cell type in response to hyperosmotic stress, which we call S-cells. This wall-deficient state is transient, as S-cells are able to switch to the canonical mycelial mode-of-growth. Remarkably, prolonged exposure of S-cells to hyperosmotic stress yielded variants that are able to proliferate indefinitely without their cell wall. This is the first report that demonstrates the formation of wall-deficient cells as a natural adaptation strategy and their potential transition into stable wall-less forms solely caused by prolonged exposure to osmotic stress. Given that actinomycetes are potent antibiotic producers, our work also provides important insights into how biosynthetic gene clusters and resistance determinants may disseminate into the environment.
Exosomes purified from a single cell type have diverse morphology and composition
Authors: Zabeo Davide , Cvjetkovic Aleksander , Lässer Cecilia , Schorb Martin , Lötvall Jan , Höög Johanna
Published: December 2016

Extracellular vesicles (EVs) are produced by all known organisms and have important roles in cell communication and physiology. Exosomes are known in the literature to be small round EVs (40 to 100 nm in diameter) and are commonly purified with a serial ultracentrifugation protocol followed by density gradient floatation. Great morphological diversity has been described before regarding EVs found in body fluids such as blood plasma, breast milk and ejaculate. However, a detailed morphological analysis has never been performed on exosomes purified from a single cell type.

Therefore, the aim of this study was to analyze and quantify via multiple electron microscopy techniques the morphology of exosomes purified from the human mast cell line HMC-1. The results revealed a novel spectrum of diversity in exosomes, which suggests that subpopulations of exosomes with different and specific functions might also exist. Our findings therefore argue that a new and more efficient way of defining exosome subpopulations is necessary. A system was proposed where exosomes were classified into nine different categories according to their size and shape. Three additional morphological features could also be found in exosomes regardless of their classification.

These findings show that morphological diversity is found among exosomes purified from a single cell line, similarly to what was previously observed for EVs in body fluids. This knowledge can help improving the interpretation of experimental results and widening our general understanding of the biological functions of exosomes.
Diffusion or advection? Mass transfer and diffusive boundary layer landscapes of the brown algaFucus vesiculosus
Authors: Lichtenberg Mads , Nøerregaard Rasmus Dyrmose , Kühl Michael
Published: December 2016

The role of hyaline hairs on the thallus of brown-algae in the genusFucusis long debated and several functions have been proposed. We used a novel motorized setup for 2D-and 3D-mapping with O2-microsensors to investigate the spatial heterogeneity of the diffusive boundary layer (DBL) and O2flux around single and multiple tufts of hyaline hairs on the thallus ofFucus vesiculosus. Flow was a major determinant of DBL thickness, where higher flow decreased DBL thickness and increased O2flux between algal thallus and the surrounding seawater. However, the topography of the DBL varied and did not directly follow the contour of the underlying thallus. Areas around single tufts of hyaline hairs exhibited both increased and decreased DBL thickness as compared to areas over smooth thallus surfaces. Over thallus areas with several hyaline hair tufts, the overall effect was a local increase in the DBL thickness. We also found indications for advective O2transport driven by pressure gradients or vortex-shedding downstream from dense tufts of hyaline hairs alleviating local mass-transfer resistance imposed by thickened DBL. Mass-transfer dynamics around hyaline hair tufts are thus more complex than hitherto assumed and may have important implications for algal physiology and plant-microbe interactions.
Individual-versus group-optimality in the production of secreted bacterial compounds
Authors: Schiessl Konstanze T. , Ross-Gillespie Adin , Cornforth Daniel M. , Weigert Michael , Bigosch Colette , Brown Sam P. , Ackermann Martin , Kümmerli Rolf
Published: December 2016

How unicellular organisms optimize the production of compounds is a fundamental biological question. While it is typically thought that production is optimized at the individual-cell level, secreted compounds could also allow for optimization at the group level, leading to a division of labor where a subset of cells produces and shares the compound with everyone. Using mathematical modelling, we show that the evolution of such division of labor depends on the cost function of compound production. Specifically, for any trait with saturating benefits, linear costs promote the evolution of uniform production levels across cells. Conversely, production costs that diminish with higher output levels favor the evolution of specialization – especially when compound shareability is high. When experimentally testing these predictions with pyoverdine, a secreted iron-scavenging compound produced byPseudomonas aeruginosa, we found linear costs and, consistent with our model, detected uniform pyoverdine production levels across cells. We conclude that for shared compounds with saturating benefits, the evolution of division of labor is facilitated by a diminishing cost function. More generally, we note that shifts in the level of selection from individuals to groups do not solely require cooperation, but critically depend on mechanistic factors, including the distribution of compound synthesis costs.
Novel chromosome organization pattern in actinomycetales–overlapping replication cycles combined with diploidy
Authors: Böhm Kati , Meyer Fabian , Rhomberg Agata , Kalinowski Jörn , Donovan Catriona , Bramkamp Marc
Published: December 2016

Bacteria regulate chromosome replication and segregation tightly with cell division to ensure faithful segregation of DNA to daughter generations. The underlying mechanisms have been addressed in several model species. It became apparent that bacteria have evolved quite different strategies to regulate DNA segregation and chromosomal organization. We have investigated here how the actinobacteriumCorynebacterium glutamicumorganizes chromosome segregation and DNA replication. Unexpectedly, we find thatC. glutamicumcells are at least diploid under all conditions tested and that these organisms have overlapping C-periods during replication with both origins initiating replication simultaneously. Based on experimentally obtained data we propose growth rate dependent cell cycle models forC. glutamicum.
Domain prediction with probabilistic directional context
Authors: Ochoa Alejandro , Singh Mona
Published: December 2016

Motivation

Protein domain prediction is one of the most powerful approaches for sequence-based function prediction. While domain instances are typically predicted independently of each other, newer approaches have demonstrated improved performance by rewarding domain pairs that frequently co-occur within sequences. However, most of these approaches have ignored the order in which domains preferentially co-occur and have also not modeled domain co-occurrence probabilistically.

Results

We introduce a probabilistic approach for domain prediction that models “directional” domain context. Our method is the first to score all domain pairs within a sequence while taking their order into account, even for non-sequential domains. We show that our approach extends a previous Markov model-based approach to additionally score all pairwise terms, and that it can be interpreted within the context of Markov random fields. We formulate our underlying combinatorial optimization problem as an integer linear program, and demonstrate that it can be solved quickly in practice. Finally, we perform extensive evaluation of domain context methods and demonstrate that incorporating context increases the number of domain predictions by ∼15%, with our approach dPUC2 (Domain Prediction Using Context) outperforming all competing approaches.

Availability

dPUC2 is available athttp://github.com/alexviiia/dpuc2.
KBG syndrome involving a single-nucleotide duplication in ANKRD11
Authors: Kleyner Robert , Malcolmson Janet , Tegay David , Ward Kenneth , Maughan Annette , Maughan Glenn , Nelson Lesa , Wang Kai , Robison Reid , Lyon Gholson J.
Published: December 2016

KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.
Medium-energy microprobe station at the SXRMB of the CLS
Authors: Xiao Qunfeng , Maclennan Aimee , Hu Yongfeng , Hackett Mark , Leinweber Peter , Sham Tsun-Kong
Published: December 2016

Micro-XAFS and chemical imaging techniques have been widely applied for studies of heterogeneously distributed systems, mostly in hard X-ray (>5 keV) or in soft X-ray (<1.5 keV) energies. The microprobe endstation of the SXRMB (soft X-ray microcharacterization beamline) at the Canadian Light Source is optimized at the medium energy (1.7–5 keV), and it has been recently commissioned and is available for general users. The technical design and the performance (energy range, beam size and flux) of the SXRMB microprobe are presented. Examples in chemical imaging and micro-XAFS in the medium energy for important elements such as P, S and Ca for soil and biological samples are highlighted.
Solution of the structure of a calmodulin–peptide complex in a novel configuration from a variably twinned data set
Authors: Keller Jacob Pearson
Published: December 2016

Structure determination of conformationally variable proteins can prove challenging even when many possible molecular-replacement (MR) search models of high sequence similarity are available. Calmodulin (CaM) is perhaps the best-studied archetype of these flexible proteins: while there are currently ∼450 structures of significant sequence similarity available in the Protein Data Bank (PDB), novel conformations of CaM and complexes thereof continue to be reported. Here, the details of the solution of a novel peptide–CaM complex structure by MR are presented, in which only one MR solution of marginal quality was found despite the use of 120 different search models, an exclusivity enhanced by the presence of a high degree of hemihedral twinning (overall refined twin fraction = 0.43). Ambiguities in the initial MR electron-density maps were overcome by using MR-SAD: phases from the MR partial model were used to identify weak anomalous scatterers (calcium, sulfur and chloride), which were in turn used to improve the phases, automatically rebuild the structure and resolve sequence ambiguities. Retrospective analysis of consecutive wedges of the original data sets showed twin fractions ranging from 0.32 to 0.55, suggesting that the data sets were variably twinned. Despite these idiosyncrasies and obstacles, the data themselves and the final model were of high quality and indeed showed a novel, nearly right-angled conformation of the bound peptide.
Workplace training programs
Authors: Brunetti Irene , Corsini Lorenzo
Published: December 2016

Purpose

The purpose of this paper is to analyse the effect of an Italian training program on the re-employment probability of young unemployed workers. The program consists exclusively of workplace training and is coordinated by employment centers, even if it is fully implemented by firms.

Design/methodology/approach

The authors develop a discrete duration analysis. In particular, the authors compare the re-employment process of individuals that just finished their workplace training program with individuals that just ended their job. The authors specifically take into account the issue of self-selection adopting the propensity score matching estimation.

Findings

The results suggest that this workplace training program improves only the immediate re-employability of trained workers, failing to bestow them with durable human capital improvements. These results appear to be robust to spurious duration dependence and to self-selection. The analysis focuses on unobserved heterogeneity and, accounting for it, the authors show that the training implementation is useful to divide “good” trainees (in terms of unobserved heterogeneity) from “bad” ones.

Social implications

Therefore, the authors suggest that firms are exploiting training as a screening device and that the implemented program is successful in easing the connection between workers and firms, but it fails to provide a durable improvement in skills and in re-employment prospects.

Originality/value

The evaluation of this program is important because it focus specifically on the workplace component of training, whereas previous analyses focused on generic training, because it evaluates a program targeting youth unemployment which is one the most urgent economic issues and because it helps in understanding the actual processes adopted by firms when implementing workplace training.
Coal containerization
Authors: Yang Dong , Weng Jinxian , Hu Jia
Published: December 2016

Purpose

Shaanxi, Shanxi province and Inner Mongolia in north China are the nation’s leading producers of coal. In the past decades, a huge amount of coal has been transported from these areas to the central and south China via ports in Hebei Province and Port of Tianjin. Traditionally, coal is transported in bulk shipment. However, in recent years, an interesting phenomenon is that the lump coal is sorted out in the north and then moved in containers to the south. This paper aims to ascertain whether the coal containerization will become an alternative transport mode for moving lump coal from the north to the south of China. Based on extensive field investigation and data analyses, it is found that although the container mode appears to be more expensive than the bulk shipping mode, the cost difference between the two modes is not as significant as our expectation if we also take into factors like fragmented demand, environment pressure, geographic distribution characteristics of customers and so on.

Design/methodology/approach

Extensive field investigation, data analysis and economic decision model.

Findings

It is found that although the container mode appears to be more expensive than the bulk shipping mode, the cost difference between the two modes is not as significant as the authors’ expectation if they also take into factors like fragmented demand, environment pressure, geographic distribution characteristics of customers and so on.

Originality/value

Although the major focus has been placed on the food containerization, the coal containerization is still a new thing and has attracted only limited attention. This paper is making an initial attempt to profile the phenomenon of coal containerization in China. This attempt is believed to not only enrich the literature of coal containerization but also support the literature of bulk containerization.