POLD2 and KSP37 (FGFBP2) Correlate Strongly with Histology, Stage and Outcome in Ovarian Carcinomas

BACKGROUND:Epithelial ovarian cancer (EOC) constitutes more than 90% of ovarian cancers and is associated with high mortality. EOC comprises a heterogeneous group of tumours, and the causes and molecular pathology are essentially unknown. Improved insight into the molecular characteristics of the different subgroups of EOC is urgently needed, and should eventually lead to earlier diagnosis as well as more individualized and effective treatments. Previously, we reported a limited number of mRNAs strongly upregulated in human osteosarcomas and other malignancies, and six were selected to be tested for a possible association with three subgroups of ovarian carcinomas and clinical parameters. METHODOLOGY/PRINCIPAL FINDINGS:The six selected mRNAs were quantified by RT-qPCR in biopsies from eleven poorly differentiated serous carcinomas (PDSC, stage III-IV), twelve moderately differentiated serous carcinomas (MDSC, stage III-IV) and eight clear cell carcinomas (CCC, stage I-IV) of the ovary. Superficial scrapings from six normal ovaries (SNO), as well as biopsies from three normal ovaries (BNO) and three benign ovarian cysts (BBOC) were analyzed for comparison. The gene expression level was related to the histological and clinical parameters of human ovarian carcinoma samples. One of the mRNAs, DNA polymerase delta 2 small subunit (POLD2), was increased in average 2.5- to almost 20-fold in MDSC and PDSC, respectively, paralleling the degree of dedifferentiation and concordant with a poor prognosis. Except for POLD2, the serous carcinomas showed a similar transcription profile, being clearly different from CCC. Another mRNA, Killer-specific secretory protein of 37 kDa (KSP37) showed six- to eight-fold higher levels in CCC stage I compared with the more advanced staged carcinomas, and correlated positively with an improved clinical outcome. CONCLUSIONS/SIGNIFICANCE:We have identified two biomarkers which are markedly upregulated in two subgroups of ovarian carcinomas and are also associated with stage and outcome. The results suggest that POLD2 and KSP37 might be potential prognostic biomarkers

Cerebellar and premotor activity during a non-fatiguing grip task reflects motor fatigue in relapsing-remitting multiple sclerosis

Fatigue is a common and highly disabling symptom of multiple sclerosis. Patients experience an effort-independent general subjective feeling of fatigue as well as excessive fatigability when engaging in physical or mental activity. Previous research using functional magnetic resonance imaging (fMRI) has revealed heterogeneous findings, but some evidence implicates the motor system. To identify brain correlates of fatigue, 44 mildly impaired patients with relapsing-remitting multiple sclerosis and 25 age- and gender-matched healthy controls underwent functional magnetic resonance imaging at 3 Tesla, while they performed alternating blocks of rest and a non-fatiguing precision grip task. We investigated neural correlates of fatigue using the motor subscore of Fatigue Scale for Motor and Cognitive Functions (FSMCMOTOR) using the bilateral motor cerebellum, putamen, and dorsal premotor cortex as regions of interest. Patients and healthy controls performed the grip force task equally well without being fatigued. In patients, task-related activity in lobule VI of right motor cerebellum changed in proportion with individual FSMCMOTOR scores. In right dorsal premotor cortex, linear increases in activity across consecutive task blocks scaled with individual FSMCMOTOR scores in healthy controls, but not in patients. In premotor and dorsomedial prefrontal areas, patients were impaired at upscaling task-related activity the more they were affected by motor fatigue. The results support the notion that increased sensorimotor processing in the cerebellum contributes to the experience of motor fatigue and fatigability in multiple sclerosis. Additionally, downscaling of motivational input or sensorimotor processing in prefrontal and premotor areas may constitute an additional pathophysiological factor

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (TFH cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting TFH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust TFH cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of TFH cell differentiation and a promising target for TFH cell–skewing vaccine adjuvants

Pros and cons of different therapeutic antibody formats for recombinant antivenom development.

Antibody technologies are being increasingly applied in the field of toxinology. Fuelled by the many advances in immunology, synthetic biology, and antibody research, different approaches and antibody formats are being investigated for the ability to neutralize animal toxins. These different molecular formats each have their own therapeutic characteristics. In this review, we provide an overview of the advances made in the development of toxin-targeting antibodies, and discuss the benefits and drawbacks of different antibody formats in relation to their ability to neutralize toxins, pharmacokinetic features, propensity to cause adverse reactions, formulation, and expression for research and development (R&D) purposes and large-scale manufacturing. A research trend seems to be emerging towards the use of human antibody formats as well as camelid heavy-domain antibody fragments due to their compatibility with the human immune system, beneficial therapeutic properties, and the ability to manufacture these molecules cost-effectively

Identifiering av designprinciper för migrering av spel till iPhone

Syftet med denna uppsats var att identifiera designprinciper vid migrering av stationära spel till Apples iPhone. Litteraturstudier, heuristisk utvärdering, enkätundersökning och djupintervjuer användes som metoder. Resultaten visade på att framför allt inmatningsmetoder, brist på feedback och skärmstorlek är problemområden i migrerade spel. Slutsatser inkluderar att spel aldrig bör migreras exakt som de stationära versionerna, nya inmatningsmetoder hos mobiltelefoner bör utnyttjas bättre och det bör övervägas om vissa spel överhuvudtaget bör migreras beroende på genre.The purpose of this thesis was to identify design principles for use at migrations of stationary games to Apple’s iPhone. Literature studies, heuristic evaluation, survey and in-depth interviews were used as methods. The results showed that especially input methods, lack of feedback and screen size are problematic ares in migrated games. Conclusions include that games should never be migrated exactly like the stationary versions, new input methods in mobile phones should be utilized in a better way and it should be considered if some games are suitable to be migrated at all depending on genre

The Influence of Sex and Phenotype on Shoaling Decisions in Zebrafish

Fish typically choose shoalmates with similar phenotypic characteristics to themselves, thus creating shoals for which predators have difficulty identifying and attacking one specific individual. And while shoaling should provide similar anti-predator benefits to both males and females, the two sexes do not always make the same shoaling decisions. Here we explore the effect of phenotype on sex specificshoaling in three varieties of zebrafish (Danio rerio) and the closely related pearl danio(Danio albolineatus). We hypothesized that males and females of each type of zebrafish (wildtype, golden mutants and leopard mutants), as well as male and female pearl danios, would choose to shoal rather than be alone and, when given a choice of shoalmates, would shoal with fish of their own phenotype rather than dissimilar fish. As expected, our results show that most fish preferred to shoal rather than be alone. However, while both sexes of wildtype zebrafish responded identically to shoaling decisions, male and female mutant zebrafish and pearl danio fish differed in their response to such choices. When given a choice of shoalmates, wildtype zebrafish of both sexes showed no discrimination between different D. rerio strains, although they did choose to shoal with wild type conspecifics rather than pearl danios. The shoalmate preferences of the mutant zebrafish revealed that males showed no discrimination between shoals of their own variety and wildtype shoals, while mutant females preferred shoals of their own strain. Similarly, male pearl danios showed no discrimination between shoals of their own species and shoals of wildtype zebrafish, while pearl danio females preferred their own species. These results demonstrate the complex influence of sex and phenotype on shoaling behavior

Mapping grip-force related brain activity after a fatiguing motor task in multiple sclerosis

BACKGROUND: Motor fatigue is common in multiple sclerosis (MS), but its pathophysiology is still poorly understood. Here we used functional magnetic resonance imaging (fMRI) to delineate how the acute induction of motor fatigue alters functional activity of the motor system and how these activity changes are related to motor fatigue. METHOD: Forty-four right-handed mildly disabled patients with relapsing-remitting MS and 25 healthy controls performed a maximal tonic precision grip with their right hand until they developed motor fatigue. Before and after the fatiguing task, participants performed a non-fatiguing tonic grip force task, producing 15–20% of their maximum grip force based on visual feedback. Task related brain activity was mapped with blood-oxygen level dependent fMRI at 3 T. Statistical parametric mapping was used to identify relative changes in task-related activation from the pre-fatigue to the recovery MRI session. RESULTS: Following fatigue induction, task performance was perturbed in both groups, and task-related activation increased in the right (ipsilateral) primary motor hand area. In patients with MS, task-related activity increased bilaterally during the recovery phase in the ventrolateral portion of the middle putamen and lateral prefrontal cortex relative to controls. The more patients increased task-related activity in left dorsal premotor cortex after the fatiguing task, the less they experienced motor fatigue during daily life. CONCLUSION: Patients with MS show enhanced functional engagement of the associative cortico-basal ganglia loop following acute induction of motor fatigue in the contralateral hand. This may reflect increased mental effort to generate movements in the recovery phase after fatigue induction. The ability to recruit the contralateral dorsal premotor cortex after fatigue induction may constitute a protective mechanism against experiencing motor fatigue in everyday life

Latent Profile Analysis of Human Values: What is the Optimal Number of Clusters?

Latent Profile Analysis (LPA) is a method to extract homogeneous clusters characterized by a common response profile. Previous works employing LPA to human value segmentation tend to select a small number of moderately homogeneous clusters based on model selection criteria such as Akaike information criterion, Bayesian information criterion and Entropy. The question is whether a small number of clusters is all that can be gleaned from the data. While some studies have carefully compared different statistical model selection criteria, there is currently no established criteria to assess if an increased number of clusters generates meaningful theoretical insights. This article examines the content and meaningfulness of the clusters extracted using two algorithms: Variational Bayesian LPA and Maximum Likelihood LPA. For both methods, our results point towards eight as the optimal number of clusters for characterizing distinctive Schwartz value typologies that generate meaningful insights and predict several external variables