Miracle-dz/UniFAR-FTUs huggingface dataset:
Small GTPase patterning: How to stabilise cluster coexistence

Many biological processes have to occur at specific locations on the cell membrane. These locations are often specified by the localised activity of small GTPase proteins. Some processes require the formation of a single cluster of active GTPase, also called unipolar polarisation (here “polarisation”), whereas others need multiple coexisting clusters. Moreover, sometimes the pattern of GTPase clusters is dynamically regulated after its formation. This raises the question how the same interacting protein components can produce such a rich variety of naturally occurring patterns. Most currently used models for GTPase-based patterning inherently yield polarisation. Such models may at best yield transient coexistence of at most a few clusters, and hence fail to explain several important biological phenomena. These existing models are all based on mass conservation of total GTPase and some form of direct or indirect positive feedback. Here, we show that either of two biologically plausible modifications can yield stable coexistence: including explicit GTPase turnover, i.e., breaking mass conservation, or negative feedback by activation of an inhibitor like a GAP. Since we start from two different polarising models our findings seem independent of the precise self-activation mechanism. By studying the net GTPase flows among clusters, we provide insight into how these mechanisms operate. Our coexistence models also allow for dynamical regulation of the final pattern, which we illustrate with examples of pollen tube growth and the branching of fungal hyphae. Together, these results provide a better understanding of how cells can tune a single system to generate a wide variety of biologically relevant patterns. Author summary Where to form a bud? Where to reinforce the cell wall? In which direction to move? These are all important decisions a cell may have to make. Proper patterning of the cell membrane is a critical part of such decisions. These patterns are often specified by the local activity of proteins called small GTPases. Mathematical models have been an important tool in understanding the mechanisms behind small GTPase-based patterning. Most of these models, however, only allow for the formation of a single cluster of active GTPase and thus cannot explain patterns of multiple coexisting GTPase clusters. A previously proposed mechanism for such coexistence can only explain a temporary, unstable coexistence, and fails to explain several key biological phenomena. In this manuscript, we investigate two mechanisms that can produce patterns of many stably coexisting GTPase clusters. Using a combination of modelling techniques, we show why these mechanisms work. We also show that these mechanisms allow for the addition of new clusters to an existing pattern, as is observed for example during the branching of fungal hyphae. With our results, we now have handles to explain the full range of naturally occurring small GTPase patterns.
Modified MHC Class II–Associated Invariant Chain Induces Increased Antibody Responses against Plasmodium falciparum Antigens after Adenoviral Vaccination

Adenoviral vectors can induce T and B cell immune responses to Ags encoded in the recombinant vector. The MHC class II invariant chain (Ii) has been used as an adjuvant to enhance T cell responses to tethered Ag encoded in adenoviral vectors. In this study, we modified the Ii adjuvant by insertion of a furin recognition site (Ii-fur) to obtain a secreted version of the Ii. To test the capacity of this adjuvant to enhance immune responses, we recombined vectors to encode Plasmodium falciparum virulence factors: two cysteine-rich interdomain regions (CIDR) α1 (IT4var19 and PFCLINvar30 var genes), expressed as a dimeric Ag. These domains are members of a highly polymorphic protein family involved in the vascular sequestration and immune evasion of parasites in malaria. The Ii-fur molecule directed secretion of both Ags in African green monkey cells and functioned as an adjuvant for MHC class I and II presentation in T cell hybridomas. In mice, the Ii-fur adjuvant induced a similar T cell response, as previously demonstrated with Ii, accelerated and enhanced the specific Ab response against both CIDR Ags, with an increased binding capacity to the cognate endothelial protein C receptor, and enhanced the breadth of the response toward different CIDRs. We also demonstrate that the endosomal sorting signal, secretion, and the C-terminal part of Ii were needed for the full adjuvant effect for Ab responses. We conclude that engineered secretion of Ii adjuvant–tethered Ags establishes a single adjuvant and delivery vehicle platform for potent T and B cell–dependent immunity.
Analysis of marginal bone loss and implant stability quotient by resonance frequency analysis in different osteointegrated implant systems. Randomized prospective clinical trial

Background The aim of the present prospective clinical study is to compare the stability of the implant-bone interface by the ISQ quotient and marginal bone loss (MBL) rate during one year of follow-up in four system implants with the same surface and different design. Material and Methods Prospective randomized clinical trial of 21 patients in which four implant systems with the same surface and different design were placed. Patients were treated by the same operator following a similar surgical protocol with submerged technique. The second surgery to perform the prosthesis was performed at 3 months. All patients went to their review at 6 months and a year. A periapical radiograph for crestal bone analysis and an Implant stability quotient by resonance frequency analysis (ISQ) analysis were taken at baseline and the reviews. Results No statistically significant differences were found in the Implant stability quotient by resonance frequency analysis and Marginal Bone Loss in the four types of implants. The ISQ increased from the moment of insertion of the implant until the revision to the year, showing an increase of the stability implant, being this increasing less between the 6 months and the year. Conclusions Differences in the design of the four implants tested in this study did not show statistically significant differences in any of the variables studied, so the implant design does not influence implant stability and marginal bone loss in the first year after placement. Key words:Marginal bone loss, implant stability quotient, dental implant, clinical trial.
Country‐Level Gender Equality and Adolescents’ Contraceptive Use in Europe, Canada and Israel: Findings from 33 Countries

CONTEXT Although an association between gender equality and contraceptive use has been confirmed among adult samples, few studies have explored this relationship among adolescents. An examination of whether adolescents’ contraceptive use is more prevalent in countries with higher levels of gender equality is needed to fill this gap. METHODS Nationally representative data from 33 countries that participated in the 2013–2014 Health Behaviour in School‐Aged Children study and country‐level measures of gender equality—using the 2014 Global Gender Gap Index—were analyzed. Multilevel multinomial logistic regression analyses were employed to assess associations between gender equality and contraceptive use (condom only, pill only and dual methods) at last intercourse as reported by 4,071 females and 4,110 males aged 14–16. RESULTS Increasing gender equality was positively associated with contraceptive use among both males and females. For every 0.1‐point increase on the equality scale, the likelihood of condom use at last intercourse rose (odds ratio, 2.1 for females), as did the likelihood of pill use (6.5 and 9.6, respectively, for males and females) and dual method use (2.1 and 5.6, respectively). Associations with pill use and dual use remained significant after national wealth and income inequality were controlled for. Overall, associations were stronger for females than for males. CONCLUSIONS More research is needed to identify potential causal pathways and mechanisms through which gender equality and adolescents’ contraceptive use may influence one another.
Patterns of seed bank and vegetation diversity along a tidal freshwater river.

PREMISE OF THE STUDY Species richness and diversity may increase with spatial scale related to increased area and heterogeneity of habitat. Yet, in bidirectional hydrologically connected tidal ecosystems, secondary dispersal via hydrochory has the potential to homogenize seed banks, and both life history characteristics and tolerances to environmental conditions influence the composition of plant communities. How species richness, diversity, and composition of seed banks and vegetation change along environmental gradients and at different spatial scales is not well understood. METHODS We explored the relationships of seed bank and vegetation diversity across 135 plots along a tidal freshwater river in the Delaware Estuary, USA. Species richness and diversity were partitioned across three hierarchical spatial scales: individual plots, transects perpendicular to the tidal channel, and river kilometers. Community structure was also examined as it related to distance from the tidal channel and location along the tidal river. KEY RESULTS Species richness was 89 in the seed bank and 54 in the vegetation. Species-area relationships revealed that species richness reached a near maximum asymptote inland (20 m from channel) for the seed bank and at the edge (0 m) for the vegetation. Rare occurrences of species in the seed bank and vegetation were greatest 5 m from the channel edge. As spatial scale increased, seed bank richness increased, associated with the progressive accumulation of species. Seed bank diversity, however, was maximized within small plot areas and along the river. Diversity of the vegetation was maximized locally due to the abundance of a few common species. CONCLUSIONS These findings suggest that suites of common species contributed to high localized vegetation diversity, yet large spatial scales maximized the number and diversity of species in the seed bank and vegetation through rare encounters, as well as the complexity of the landscape.
Expression profiling of long noncoding RNAs associated with vasculogenic mimicry in osteosarcoma

Osteosarcoma (OS) is the most common highly malignant bone tumor in teens. Vasculogenic mimicry (VM) is defined as de novo extracellular matrix‐rich vascular‐like networks formed by highly aggressive tumor cells. We previously reported the presence of VM and it is an unfavorable prognostic factor in OS patients. Long noncoding RNAs (lncRNAs) are aberrantly expressed in OS and involved in cancer cell VM. However, lncRNAs in VM formation of OS have not been investigated. We, therefore, profiled the expression of lncRNAs in highly aggressive OS cell line 143B compared with its parental poorly aggressive cell line HOS. The differentially expressed (DE) lncRNAs and messenger RNA (mRNAs) were subjected to constructed lncRNA‐mRNA coexpressed network. The top‐ranked hub gene lncRNA n340532 knockdown 143B cells were used for in vitro and in vivo VM assays. The annotation of DE lncRNAs was performed according to the coexpressed mRNAs by Gene Ontology and pathway analysis. A total of 1360 DE lncRNAs and 1353 DE mRNAs were screened out. lncRNA MALAT1 and FTX, which have known functions related to VM formation and tumorigenesis were identified in our data. The coexpression network composed of 226 lncRNAs and 118 mRNAs in which lncRNA n340532 had the highest degree number. lncRNA n340532 knockdown reduced VM formation in vitro. The suppression of n340532 also exhibited potent anti‐VM and antimetastasis effect in vivo, suggesting its potential role in OS VM and metastasis. Furthermore, n340532 coexpressed with 10 upregulation mRNAs and 3 downregulation mRNAs. The enriched transforming growth factor‐β signaling pathway, angiogenesis and so forth were targeted by those coexpressed mRNAs, implying n340532 may facilitate VM formation in OS through these pathways and gene functions. Our findings provide evidence for the potential role of lncRNAs in VM formation of OS that could be used in the clinic for anti‐VM therapy in OS.
Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction.

AIMS Guidelines differ in their recommendations on therapy to prevent gastrointestinal bleeding for patients treated with dual antiplatelet treatment (DAPT). We sought to investigate the effectiveness of proton pump inhibitors (PPIs) to prevent upper gastrointestinal (UGI) bleeding in patients using DAPT following myocardial infarction (MI) in relation to current European Society of Cardiology guidelines recommendations. METHODS AND RESULTS We linked Danish nationwide registries to identify patients taking DAPT 7 days following hospital discharge for an acute MI, and excluded individuals on anticoagulation therapy. We used multiple Cox regression modelling, to compute average risk of UGI bleeding in relation to PPI use. The associated treatment efficacy was compared based on guideline risk assessment. We studied 46 301 patients on DAPT after MI. Only 35% of patients at higher risk of UGI bleeding received recommended treatment with a PPI based on the guideline criteria. The 1--year risk of UGI bleeding was 1.0% [95% confidence interval (CI) 0.9-1.1%] and 1.7% (CI 1.5-2.0%) for high-risk patients. Overall PPI compared with no therapy, was associated with a risk ratio for UGI bleeding of 0.62 (CI 0.48-0.77) corresponding to an absolute risk difference of 0.44% (CI 0.39-0.48%). Proton pump inhibitor therapy was associated with a similar absolute risk difference [0.47% (CI 0.43-0.51%)] for high-risk patients. CONCLUSION Proton pump inhibitor therapy is used less than suggested by guidelines in patients treated with DAPT following MI and was generally associated with reduced risk of UGI bleeding. Considering the overall low risk of bleeding, more focus should be on identifying patients benefiting the most from PPI therapy.
Why do women fast during breast cancer chemotherapy? A qualitative study of the patient experience

BACKGROUND Why do patients practice fasting? The effects of fasting before treatment with chemotherapy for cancer in humans are currently unknown. However, there is an apparent enthusiasm for fasting among cancer patients. This qualitative study provides data on the motivations to fast and the experience of fasting among a population of women with breast cancer. METHOD Sixteen semi-structured interviews were conducted, and two researchers independently performed a thematic analysis. To ensure the internal validity of the study, patients had the possibility to rate their agreement with the study results through a satisfaction questionnaire. RESULTS Six main themes were identified in this study: main reasons to fast, alternative authorities to the oncologist, adapting the fast to social and lifestyle constraints, fasting effects felt during chemotherapy, barriers and facilitators of fasting during chemotherapy, and seeking for a more integrative medicine. Patients' primary motivation to fast was to lower the negative side effects of chemotherapy. Fasting was also reported as a coping strategy to give them a greater sense of control over their treatment and to reduce their anxiety. CLINICAL IMPLICATIONS Results from the study suggest that, if discouraged from fasting, patients may turn to complementary health care practitioners for support. Medical professionals may thus not know of patients' fasting practice. Health psychologists could play a key role fostering the dialogue between different health professionals and the patient. They could also help to meet patients' needs during cancer treatment to reduce treatment anxiety. Statement of contribution What is already known on this subject? Fasting diet in cancer treatment has become an important topic since Raffaghello et al. published their study on mice in 2008. While the (positive) effects of fasting in humans remain to be proven, there has been a significant enthusiasm for this practice among patients in the last few years. However, patients' motivations to fast remain unclear to the scientific community and clinicians. What does this study add? This study is the first to investigate patients' motivations to fast and patients' experience of fasting in a cancer population. Patients' primary motivation to fast was to lower the side effects of chemotherapy. Fasting acts as an active coping strategy that helps to reduce anxiety. Unsupported patients may turn to complementary health care practitioners.
Predictive models in ecotoxicology: Bridging the gap between scientific progress and regulatory applicability—Remarks and research needs

This paper concludes a special series of 7 articles (4 on toxicokinetic–toxicodynamic [TK–TD] models and 3 on quantitative structure‐activity relationship [QSAR] models) published in previous issues of Integrated Environmental Assessment and Management (IEAM). The present paper summarizes the special series articles and highlights their contribution to the topic of increasing the regulatory applicability of effect models. For both TK–TD and QSAR approaches, we then describe the main research needs. The use of TK–TD models for describing sublethal effects must be better developed, particularly through the improvement of the dynamic energy budget (DEBtox) approach. The potential of TK–TD models for moving from lower (molecular) to higher (population) hierarchical levels is highlighted as a promising research line. Some relevant issues to improve the acceptance of QSAR models at the regulatory level are also described, such as increased transparency of the performance assessment and of the modeling algorithms, model documentation, relevance of the chosen target for regulatory needs, and improved mechanistic interpretability. Integr Environ Assess Manag 2019;00:000–000. © 2019 SETAC
Accumulation of prion protein in the vagus nerve in creutzfeldt–jakob disease

Disease‐associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease‐associated prion protein (PrPSc) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt–Jakob disease (CJD), we applied 3 different anti‐PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. Four of 31 VV‐2 type sporadic CJD and 7 of 30 genetic CJD cases showed vagal PrPSc immunodeposits with distinct morphology. Thus, PrPSc in CJD affects the vagus nerve analogously to α‐synuclein in Parkinson disease. The morphologically diverse deposition of PrPSc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrPSc. Ann Neurol 2019;85:782–787
Generation of antibody-based therapeutics targeting the Idiotype of B-cell Malignancies.

Background A feature of many B-cell tumors is a surface-expressed immunoglobulin (sIg). The complementarity determiningregions (CDRs)of the sIg, termed the 'idiotype', are unique to each tumor. We report on a phage selection strategy to generate anti-idiotype therapeutics that react with sIg CDR3 sequences: the MEC1 B-cell tumor line was used as proof of concept. Methods To create a mimetic of the MEC1 idiotype, CDR3 sequences from heavy and light chains of the sIg were grafted into a scFv framework scaffold. Using the Tomlinson I phage library of human scFvs, we enriched for binders to MEC1 CDR3 sequences over unrelated CDR3 sequences. Results By ELISA we identified 10 binder phage. Of these, five were sequenced, found to be unique and characterized further. By flow cytometry each of the five phage bound to MEC1 cells, albeit with different patterns of reactivity. To establish specificity of binding and utility, the scFv sequences from two of these binders (phage 1, and 7) were converted into antibody-toxin fusion proteins (immunotoxins) and also cloned into a human IgG1 expression vector. Binder-1 and -7 immunotoxins exhibited specific killing of MEC1 cells with little toxicity for non-target B-cell lines. The full-length antibody recreated from the binder-1 scFv so exhibited specific binding. Conclusion Our results establish the utility of using engrafted CDR3 sequences for selecting phage that recognize the idiotype of B-cell tumors.
Isoflavone intake and risk of gastric cancer: a population-based prospective cohort study in Japan.

BACKGROUND Isoflavones are structurally similar to 17β-estradiol and may be able to prevent gastric cancer. However, there is contradictory evidence concerning the relation between the intake of soy food, which is rich in isoflavones, and gastric cancer. The association with gastric cancer might differ between isoflavones and soy foods, and research on the effects of isoflavone intake alone on gastric cancer is needed. OBJECTIVE We investigated the association between isoflavone intake and the incidence of gastric cancer. DESIGN We conducted a large, population-based prospective study of 39,569 men and 45,312 women aged 45-74 y. Dietary soy and isoflavone intakes were measured by using a validated food-frequency questionnaire in 1995 and 1998. RESULTS During 806,550 person-years of follow-up, we identified 1249 new gastric cancer cases. Isoflavone intake was not associated with gastric cancer in either men or women. Compared with the lowest quartile, the HR and 95% CI for developing gastric cancer in the fourth quartile of isoflavone intake was 1.00 (0.81, 1.24) for men and 1.07 (0.77, 1.50) for women. In a stratified analysis by exogenous female hormones (women only), however, we found an increasing trend in risk of gastric cancer associated with higher isoflavone intakes among exogenous female hormone users (P-trend = 0.03) but not for nonusers (P-interaction = 0.04). CONCLUSION The current study does not support the hypothesis that higher intakes of isoflavones prevent gastric cancer in either men or women.
ESBL‐production in Escherichia coli and Klebsiella pneumoniae isolates from Nigeria

The worldwide increase in infections caused by extended‐spectrum beta‐lactamase‐ (ESBL) and AmpC‐producing Enterobacteriaceae (ESBL‐E) is a concern. Surveillance is extensive in Europe, North America, and Asia. Yet, there is no summarizing surveillance in Africa. This study aimed to perform a preliminary investigation on the prevalence of ESBL‐E in the northeastern part of Nigeria. However, of the 60 samples collected, we were able to culture 15 Escherichia coli and 7 Klebsiella spp. only. In the collection of clinical hospital samples, we found eight of 15 E. coli isolates to be ESBL (53%) and two out of seven Klebsiella spp. to be ESBL/AmpC (29%). Due to the limitations of this study, our findings cannot take a broad view on the prevalence of ESBL‐E, in Nigeria and other parts of Africa. Yet, to know which genes encode ESBL in Nigeria, and to know exact prevalence of every ESBL gene would be of importance.