Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia.

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia.

Filamin A- and formin 2-dependent endocytosis regulates proliferation via the canonical Wnt pathway.

Actin-associated proteins regulate multiple cellular processes, including proliferation and differentiation, but the molecular mechanisms underlying these processes are unclear. Here, we report that the actin-binding protein filamin A (FlnA) physically interacts with the actin-nucleating protein formin 2 (Fmn2). Loss of FlnA and Fmn2 impairs proliferation, thereby generating multiple embryonic phenotypes, including microcephaly. FlnA interacts with the Wnt co-receptor Lrp6. Loss of FlnA and Fmn2 impairs Lrp6 endocytosis, downstream Gsk3ß activity, and ß-catenin accumulation in the nucleus. The proliferative defect in Flna and Fmn2 null neural progenitors is rescued by inhibiting Gsk3ß activity. Our findings thus reveal a novel mechanism whereby actin-associated proteins regulate proliferation by mediating the endocytosis and transportation of components in the canonical Wnt pathway. Moreover, the Fmn2-dependent signaling in this pathway parallels that seen in the non-canonical Wnt-dependent regulation of planar cell polarity through the Formin homology protein Daam. These studies provide evidence for integration of actin-associated processes in directing neuroepithelial proliferation.

Current state and prospects of biotechnology in Central and Eastern European countries. Part I: Visegrad countries (CZ, H, PL, SK).

Innovation is a key determinant of sustainable growth. Biotechnology (BT) is one such industry that has witnessed a revolution in innovative ideas leading to the founding of many new companies based on providing products, solutions and services, stretching from the food industry to environmental remediation, and new medicines. BT holds much promise for the development of national and local economies, however, this requires a strategic approach involving actors within government, industry, and academia working in concert to maximize this potential. This first article reviews the current "state of play" in the field of BT within the Central Eastern European (CEE) countries. For the purposes of this article, CEE refers to the countries of Czech Republic, Hungary, Poland, and Slovakia (the so-called Visegrad - V4 countries). We examine the components that support the creation and development of a BT sector in CEE and also highlight the barriers to these objectives. Clearly setting priorities for the countries' policy agenda, as well as the alignment of Smart Specialization Strategy will help to focus efforts. Recent investments in R&D infrastructure within CEE have been substantial, but conditions will need to be optimized to harness these largely European investments for effective use towards SME high-tech development.

Current state and prospects of biotechnology in Central and Eastern European countries. Part II: new and preaccession EU countries(CRO, RO, B&H, SRB).

Innovation holds the potential for economic prosperity. Biotechnology (BT) has proved to be a viable vehicle for the development and utilization of technologies, which has brought not only advances to society, but also career opportunities to nation-states that have enabling conditions. In this review, we assess the current state of BT-related activities within selected new and preaccession EU countries (NPA) of CEE region namely Croatia, Romania, Bosnia and Herzegovina and Serbia, examining educational programs, research activity, enterprises, and the financing systems. The field of BT covers a broad area of activities, including medical, food and agriculture, aquaculture or marine, environmental, biofuels, bioinformatics, and many others. Under the European Commission (EC), member-states are to set their Research and Innovation Strategies for Smart Specialization (RIS3), to identify priorities or strengths in order to develop knowledge intensive economies. As the four countries highlighted in this review are in the early stages of implementing RIS3 or have not yet fully formulated, it presents an opportunity to learn from the successes and failures of those that have already received major structural funds from the EC. A critical point will be the ability of the public and private sectors' actors to align, in the implementation of RIS3 as new investment instruments emerge, and to concentrate efforts on a few select target goals, rather than distribute funding widely without respect to a long-term vision.

Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate.

Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion. Mouse mutations in Fmn1 cause aberrant fusion of carpal digits. We report here that FlnB and Fmn1 physically interact, are co-expressed in chondrocytes in the growth plate and share overlapping expression in the cell cytoplasm and nucleus. Loss of FlnB leads to a dramatic decrease in Fmn1 expression at the hypertrophic-to-ossification border. Loss of Fmn1-FlnB in mice leads to a more severe reduction in body size, weight and growth plate length, than observed in mice following knockout of either gene alone. Shortening of the long bone is associated with a decrease in chondrocyte proliferation and an overall delay in ossification in the double-knockout mice. In contrast to FlnB null, Fmn1 loss results in a decrease in the width of the prehypertrophic zone. Loss of both proteins, however, causes an overall decrease in the width of the proliferation zone and an increase in the differentiated hypertrophic zone. The current findings suggest that Fmn1 and FlnB have shared and independent functions. FlnB loss promotes prehypertrophic differentiation whereas Fmn1 leads to a delay. Both proteins, however, regulate chondrocyte proliferation, and FlnB may regulate Fmn1 function at the hypertrophic-to-ossification border, thereby explaining the overall delay in ossification.

Formin1 disruption confers oligodactylism and alters Bmp signaling.

Proper limb development requires concerted communication between cells within the developing limb bud. Several molecules have been identified which contribute to the formation of a circuitry loop consisting in large part of secreted proteins. The intracellular actin nucleator, Formin 1 (Fmn1), has previously been implicated in limb development, but questions remain after the identification of a Gremlin transcriptional enhancer within the 3' end of the Fmn 1 locus. To resolve this issue, a knockout mouse devoid of Fmn1 protein was created and characterized. The mice exhibit a reduction of digit number to four, a deformed posterior metatarsal, phalangeal soft tissue fusion as well as the absence of a fibula to 100% penetrance in the FVB genetic background. Importantly, this mutant allele does not genetically disrupt the characterized Gremlin enhancer, and indeed Gremlin RNA expression is upregulated at the 35 somite stage of development. Our data reveal increased Bone Morphogenetic Protein (Bmp) activity in mice which carry a disruption in Fmn1, as evidenced by upregulation of Msx1 and a decrease in Fgf4 within the apical ectodermal ridge. Additionally, these studies show enhanced activity downstream of the Bmp receptor in cells where Fmn1 is perturbed, suggesting a role for Fmn1 in repression of Bmp signaling.

The motivation for citizens' involvement in life sciences research is predicted by age and gender.

Open Science is an umbrella term encompassing multiple concepts as open access to publications, open data, open education and citizen science that aim to make science more open and transparent. Citizen science, an important facet of Open Science, actively involves non-scientists in the research process, and can potentially be beneficial for multiple actors, such as scientists, citizens, policymakers and society in general. However, the reasons that motivate different segments of the public to participate in research are still understudied. Therefore, based on data gathered from a survey conducted in Czechia, Germany, Italy, Spain, Sweden, and the UK (N = 5,870), this study explores five types of incentives that can motivate individuals to become involved in life sciences research. The results demonstrate that men and younger individuals are more persuaded by extrinsic motives (external benefits or rewards), as compared with women and older people, who are driven by intrinsic motives (that originates from within an individual). This paper shows that specific strata of the population are differentially motivated to engage in research, thereby providing relevant knowledge for effectively designing public involvement activities that target various groups of the public in research projects.

Nice Finish to 2014 and Looking Forward to 2015.

This editorial article summarizes last year's achievements and current plans for 2015 that focuses on attracting a high quality, variety of articles with more emphasis in engaging with academia and industry in the field of nanotechnology and biomedical research.

Turning the Page to Year 2016.

As we conclude another year (2015), Volume 2 completed, we are pleased with the number of quality published manuscripts. We are also excited to announce Nanobiomedicine has been indexed in DOAJ (Directory of Open Access Journals) (https://doaj.org/toc/1849-5435)! This was in part attributed with the help of our Special Editor, Dr. Barbara Smith, who spearheaded manuscripts highlighting innovative results that impacted the global health spectrum implementing new methods for disease diagnosis, including technological and product development for enhanced point-of-care and personalized health care. Dr. Smith undertook this endeavor as she transitioned from a post-doc position (from George Whitesides' lab at Harvard University) to a faculty position at Arizona State, getting acclimated and setting up her laboratory. We want to thank Dr. Smith for her time and commitment to our journal. It's worth noting, we had a high number of submissions throughout the year, however, the expectations of the manuscripts not published fell short due to our review process, indicating the emphasis of publishing high quality manuscripts. We thank all the reviewers for their time and feedback.

Formin1 mediates the induction of dendritogenesis and synaptogenesis by neurogenin3 in mouse hippocampal neurons.

Neurogenin3, a proneural transcription factor controlled by Notch receptor, has been recently shown to regulate dendritogenesis and synaptogenesis in mouse hippocampal neurons. However, little is known about the molecular mechanisms involved in these actions of Ngn3. We have used a microarray analysis to identify Ngn3 regulated genes related with cytoskeleton dynamics. One of such genes is Fmn1, whose protein, Formin1, is associated with actin and microtubule cytoskeleton. Overexpression of the Fmn1 isoform-Ib in cultured mouse hippocampal neurons induced an increase in the number of primary dendrites and in the number of glutamatergic synaptic inputs at 4 days in vitro. The same changes were provoked by overexpression of Ngn3. In addition downregulation of Fmn1 by the use of Fmn1-siRNAs impaired such morphological and synaptic changes induced by Ngn3 overexpression in neurons. These results reveal a previously unknown involvement of Formin1 in dendritogenesis and synaptogenesis and indicate that this protein is a key component of the Ngn3 signaling pathway that controls neuronal differentiation.

Altered histone acetylation is associated with age-dependent memory impairment in mice.

As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.

Formin 1-isoform IV deficient cells exhibit defects in cell spreading and focal adhesion formation.

BACKGROUND: Regulation of the cytoskeleton is a central feature of cell migration. The formin family of proteins controls the rate of actin nucleation at its barbed end. Thus, formins are predicted to contribute to several important cell processes such as locomotion, membrane ruffling, vesicle endocytosis, and stress fiber formation and disassociation. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigated the functional role of Formin1-isoform4 (Fmn1-IV) by using genetically null primary cells that displayed augmented protrusive behaviour during wound healing and delayed cell spreading. Cells deficient of Fmn1-IV also showed reduced efficiency of focal adhesion formation. Additionally, we generated an enhanced green fluorescence protein (EGFP)-fused Fmn1-IV knock-in mouse to monitor the endogenous subcellular localization of Fmn1-IV. Its localization was found within the cytoplasm and along microtubules, yet it was largely excluded from adherens junctions. CONCLUSIONS/SIGNIFICANCE: It was determined that Fmn1-IV, as an actin nucleator, contributes to protrusion of the cell's leading edge and focal adhesion formation, thus contributing to cell motility.

First snapshots of the HIV-1 RNA structure in infected cells and in virions.

With the increasing interest of RNAs in regulating a range of cell biological processes, very little is known about the structure of RNAs in tissue culture cells. We focused on the 5'-untranslated region of the human immunodeficiency virus type 1 RNA genome, a highly conserved RNA region, which contains structural domains that regulate key steps in the viral replication cycle. Up until now, structural information only came from in vitro studies. Here, we developed chemical modification assays to test nucleotide accessibility directly in infected cells and viral particles, thus circumventing possible biases and artifacts linked to in vitro assays. The secondary structure of the 5'-untranslated region in infected cells points to the existence of the various stem-loop motifs associated to distinct functions, proposed from in vitro probing, mutagenesis, and phylogeny. However, compared with in vitro data, subtle differences were observed in the dimerization initiation site hairpin, and none of the proposed long range interactions were observed between the functional domains. Moreover, no global RNA rearrangement was observed; structural differences between infected cells and viral particles were limited to the primer binding site, which became protected against chemical modification upon tRNA(3) (Lys) annealing in virions and to the main packaging signal. In addition, our data suggested that the genomic RNA could already dimerize in the cytoplasm of infected cells. Taken together, our results provided the first analysis of the dynamic of RNA structure of the human immunodeficiency virus type 1 RNA genome during virus assembly ex vivo.

Human immunodeficiency virus type 1 Vif is efficiently packaged into virions during productive but not chronic infection.

Packaging of the human immunodeficiency virus type 1 Vif protein into virus particles is mediated through an interaction with viral genomic RNA and results in the association of Vif with the nucleoprotein complex. Despite the specificity of this process, calculations of the amount of Vif packaged have produced vastly different results. Here, we compared the efficiency of packaging of Vif into virions derived from acutely and chronically infected H9 cells. We found that Vif was efficiently packaged into virions from acutely infected cells (60 to 100 copies per virion), while packaging into virions from chronically infected H9 cells was near the limit of detection (four to six copies of Vif per virion). Superinfection by an exogenous Vif-defective virus did not rescue packaging of endogenous Vif expressed in the chronically infected culture. In contrast, exogenous Vif expressed by superinfection of wild-type virus was readily packaged (30 to 40 copies per virion). Biochemical analyses suggest that the differences in the relative packaging efficiencies were not due to gross differences in the steady-state distribution of Vif in chronically or acutely infected cells but are likely due to differences in the relative rates of de novo synthesis of Vif. Despite its low packaging efficiency, endogenously expressed Vif was sufficient to direct the production of viruses with almost wild-type infectivity. The results from our study provide novel insights into the biochemical properties of Vif and offer an explanation for the reported differences regarding Vif packaging.