Neurofibromatosis type 2 (NF-2) is a dominantly inherited genetic disorder that results from variants in the tumor suppressor gene, neurofibromin 2 (NF2). Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by inducible genetic knockout of nf2a/b, the zebrafish homologs of human NF2. Analysis of nf2a and nf2b expression revealed ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displayed lower expression levels. Induction of nf2a/b knockout at early stages increased the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggered the development of a spectrum of tumors, including vestibular Schwannomas, spinal Schwannomas, meningiomas and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.

• Klíčová slova
• Cancer, Inducible knockout, Meninges, Neurofibromatosis type 2, Schwann cells, Zebrafish,
• MeSH
• dánio pruhované * genetika   embryologie   MeSH
• geneticky modifikovaná zvířata MeSH
• genový knockout * MeSH
• larva metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• neurofibromatóza 2 genetika   patologie   metabolismus   MeSH
• neurofibromatózy genetika   patologie   metabolismus   MeSH
• neurofibromin 2 * genetika   metabolismus   nedostatek   MeSH
• proliferace buněk MeSH
• proteiny dánia pruhovaného * genetika   metabolismus   nedostatek   MeSH
• Schwannovy buňky metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• neurofibromin 2 * MeSH
• proteiny dánia pruhovaného * MeSH

Retinal pigment epithelium (RPE) is a critical cell monolayer forming the blood-retina-barrier (BRB) and a permeable bridge between the choriocapillaris and the retina. RPE is also crucial in maintaining photoreceptor function and for completing the visual cycle. Loss of the RPE is associated with the development of degenerative diseases like age-related macular degeneration (AMD). To treat diseases like AMD, pluripotent stem cell-derived RPE (pRPE) has been recently explored extensively as a regenerative module. pRPE like other ectodermal tissues requires specific lineage differentiation and long-term in vitro culturing for maturation. Therefore, understanding the differentiation process of RPE could be useful for stem cell-based RPE derivation. Developing pRPE-based transplants and delivering them into the subretinal space is another aspect that has garnered interest in the last decade. In this review, we discuss the basic strategies currently employed for stem cell-based RPE derivation, their delivery, and recent clinical studies related to pRPE transplantation in patients. We have also discussed a few limitations with in vitro RPE culture and potential solutions to overcome such problems which can be helpful in developing functional RPE tissue.

• Klíčová slova
• cell delivery, differentiation, embryonic stem cells, induced pluripotent stem cells, retinal pigment epithelium,
• MeSH
• buněčná diferenciace MeSH
• lidé MeSH
• makulární degenerace * terapie   metabolismus   MeSH
• pluripotentní kmenové buňky * MeSH
• retina MeSH
• retinální pigmentový epitel metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Phlebotomus (Ph.) sergenti is the main vector of Leishmania (L.) tropica (Trypanosomatida: Trypanosomatidae), the causative agent of anthroponotic cutaneous leishmaniasis in Morocco. This species has an extended geographical distribution, wider than that of the parasite. The main objective of our study was to analyze the genetic diversity of Ph. sergenti collected in four foci in Morocco: Taza, Foum Jemâa, El Hanchane, and Ouarzazate. We studied a set of diversity and population structure indices by sequencing two markers; nuclear EF-1α and mitochondrial Cyt b from 175 individual sand flies. Our results showed a considerable degree of intraspecific polymorphism with a high number of haplotypes identified in both genes. Many polymorphic sites detected in the Cyt b sequences (SCyt b = 45) indicate that it is the most polymorphic marker showing a distinct distribution of haplotypes according to their geographical origin, whereas the EF-1α marker showed no geographical isolation. Analysis by Tajima's D and Fu's Fs tests revealed a possible recent expansion of the populations, especially with the EF-1α marker, showing significant values in Taza and Ouarzazate sequences. The present study revealed significant genetic diversity within Ph. sergenti populations in Morocco. The results warrant further research using a combination of more than two markers including mitochondrial and non-mitochondrial markers, which may provide more information to clarify the genetic status of Ph. sergenti.

• Klíčová slova
• Cyt b, EF1-α, Phlebotomus, Morocco, genetic diversity,
• MeSH
• cytochromy b MeSH
• elongační faktor 1 genetika   MeSH
• leishmanióza kožní * parazitologie   MeSH
• Phlebotomus * genetika   parazitologie   MeSH
• populační genetika MeSH
• Psychodidae * parazitologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Maroko epidemiologie   MeSH
• Názvy látek
• cytochromy b MeSH
• elongační faktor 1 MeSH

We aimed to systematically review the prevalence of potentially inappropriate prescribing (PIP) in older adults in Central and Eastern Europe (CEE) in all care settings. We searched Embase and MEDLINE (up to June 2019) and checked the reference lists of the included studies and relevant reviews. Eligible studies used validated explicit or implicit tools to assess the PIP prevalence in older adults in CEE. All study designs were considered, except case‒control studies and case series. We assessed the risk of bias using the Joanna Briggs Institute Prevalence Critical Appraisal Tool and the certainty of evidence using the GRADE approach. Meta-analysis was inappropriate due to heterogeneity in the outcome measurements. Therefore, we used the synthesis without meta-analysis approach-summarizing effect estimates method. This review included twenty-seven studies with 139,693 participants. Most studies were cross-sectional and conducted in high-income countries. The data synthesis across 26 studies revealed the PIP prevalence: the median was 34.6%, the interquartile range was 25.9-63.2%, and the range was 6.5-95.8%. The certainty of this evidence was very low due to the risk of bias, imprecision, and inconsistency. These findings show that PIP is a prevalent issue in the CEE region. Further well-designed studies conducted across countries are needed to strengthen the existing evidence and increase the generalizability of findings.

• MeSH
• lidé MeSH
• nevhodné předepisování * MeSH
• prevalence MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• systematický přehled MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• východní Evropa epidemiologie   MeSH

Here, we report on the exceptionally well-preserved deer record from the locality of Pantalla (central Italy), dated in the Early Pleistocene (ca. 2.1-2.0 million years ago). The fossils show a combination of characters that allows an unambiguous attribution to 'Pseudodama' nestii, of which they represent one of the most informative collections to date. Our comparisons-also conducted through CT-based methods on endocranial structures-reveal that the cranial and postcranial skeleton of 'P.' nestii displays a mosaic of intermediate characters between extant Dama and Cervus, but also that the affinities with Dama are prevalent. Some Cervus-like features especially in cranial morphology, can be interpreted as plesiomorphic characters supporting a basal position of 'Pseudodama' among the Cervini. Interestingly, three bone anomalies are described in the two male crania of 'P.' nestii from Pantalla and are interpreted as palaeotraumatological evidence resulting from different injuries suffered by the deer during their life. This allows opening a treasure trove of information on paleobiological aspects, including ontogeny and antler cycle and function.

• MeSH
• lebka anatomie a histologie   MeSH
• parohy * MeSH
• vysoká zvěř * anatomie a histologie   MeSH
• zkameněliny MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Itálie MeSH

The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field's spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer's disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer's disease, thus holding great promise in the DBS treatment of the disease.

• MeSH
• Alzheimerova nemoc * diagnostické zobrazování   terapie   MeSH
• cortex entorhinalis diagnostické zobrazování   fyziologie   MeSH
• hluboká mozková stimulace * metody   MeSH
• kognice MeSH
• krysa rodu Rattus MeSH
• magnetická rezonanční tomografie metody   MeSH
• mozek MeSH
• septální jádra * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Paedomorphosis is a heterochronic syndrome in which adult individuals display features of their immature forms. In beetles, this phenomenon occurs widely in the superfamily Elateroidea, including the net-winged beetles (Lycidae), and, due to the usual flightlessness of paedomorphic females, it is hypothesized to cause speciation rates higher than in non-paedomorphic lineages. However, some fossils of paedomorphic lycids do not support this with palaeobiological data. Discovery of new Lycidae fossils attributed to the West Indian extant paedomorphic genus Cessator Kazantsev in the Dominican amber also suggests morphological stasis within this genus in the Greater Antilles. We describe Cessator anachronicus Ferreira and Ivie, sp. nov. based on adult males, as well as the first ever recorded fossil net-winged beetle larva of the same genus. We propose that the relatively young age of the studied fossils combined with the stable conditions in the forest floor of the Greater Antilles through the last tens of million years could explain the exceptionally conserved morphology in the net-winged beetles affected by the paedomorphic syndrome.

• MeSH
• brouci * anatomie a histologie   MeSH
• jantar * MeSH
• lesy MeSH
• zkameněliny MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Dominikánská republika MeSH
• Názvy látek
• jantar * MeSH

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

• Klíčová slova
• ALCL, Brg1, NPM-ALK,
• Publikační typ
• časopisecké články MeSH

Archaeological research is radically transforming the view that the Amazon basin and surrounding areas witnessed limited societal development before European contact. Nevertheless, uncertainty remains on the nature of the subsistence systems and the role that aquatic resources, terrestrial mammalian game, and plants had in supporting population growth, geographic dispersal, cultural adaptations and political complexity during the later stages of the pre-Columbian era. This is exacerbated by the general paucity of archaeological human remains enabling individual dietary reconstructions. Here we use stable carbon and nitrogen isotope analysis of bone collagen to reconstruct the diets of human individuals from São Luís Island (Brazilian Amazon coast) dated between ca. 1800 and 1000 cal BP and associated with distinct ceramic traditions. We expanded our analysis to include previously published data from Maracá and Marajó Island, in the eastern Amazon. Quantitative estimates of the caloric contributions from food groups and their relative nutrients using a Bayesian Mixing Model revealed distinct subsistence strategies, consisting predominantly of plants and terrestrial mammals and variably complemented with aquatic resources. This study offers novel quantitative information on the extent distinct food categories of polyculture agroforestry systems fulfilled the caloric and protein requirements of Late Holocene pre-Columbian populations in the Amazon basin.

• MeSH
• archeologie metody   MeSH
• Bayesova věta MeSH
• dějiny 15. století MeSH
• dějiny 16. století MeSH
• dějiny 17. století MeSH
• dějiny starověku MeSH
• dějiny středověku MeSH
• dieta dějiny   MeSH
• izotopy dusíku analýza   MeSH
• izotopy uhlíku analýza   MeSH
• kolagen chemie   MeSH
• kosti a kostní tkáň chemie   MeSH
• lidé MeSH
• přijímání potravy MeSH
• rostliny MeSH
• savci MeSH
• stravovací zvyklosti MeSH
• tělesné pozůstatky MeSH
• zvířata MeSH
• Check Tag
• dějiny 15. století MeSH
• dějiny 16. století MeSH
• dějiny 17. století MeSH
• dějiny starověku MeSH
• dějiny středověku MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Brazílie MeSH
• Názvy látek
• izotopy dusíku MeSH
• izotopy uhlíku MeSH
• kolagen MeSH

The Orange Carotenoid Protein (OCP) is a water-soluble protein that governs photoprotection in many cyanobacteria. The 35 kDa OCP is structurally and functionally modular, consisting of an N-terminal effector domain (NTD) and a C-terminal regulatory domain (CTD); a carotenoid spans the two domains. The CTD is a member of the ubiquitous Nuclear Transport Factor-2 (NTF2) superfamily (pfam02136). With the increasing availability of cyanobacterial genomes, bioinformatic analysis has revealed the existence of a new family of proteins, homologs to the CTD, the C-terminal domain-like carotenoid proteins (CCPs). Here we purify holo-CCP2 directly from cyanobacteria and establish that it natively binds canthaxanthin (CAN). We use small-angle X-ray scattering (SAXS) to characterize the structure of this carotenoprotein in two distinct oligomeric states. A single carotenoid molecule spans the two CCPs in the dimer. Our analysis with X-ray footprinting-mass spectrometry (XFMS) identifies critical residues for carotenoid binding that likely contribute to the extreme red shift (ca. 80 nm) of the absorption maximum of the carotenoid bound by the CCP2 dimer and a further 10 nm shift in the tetramer form. These data provide the first structural description of carotenoid binding by a protein consisting of only an NTF2 domain.

• MeSH
• bakteriální proteiny chemie   ultrastruktura   MeSH
• kanthaxanthin chemie   MeSH
• krystalografie rentgenová MeSH
• maloúhlový rozptyl MeSH
• nukleocytoplazmatické transportní proteiny chemie   genetika   ultrastruktura   MeSH
• proteinové domény genetika   MeSH
• sinice chemie   ultrastruktura   MeSH
• vazba proteinů účinky léků   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• bakteriální proteiny MeSH
• kanthaxanthin MeSH
• nukleocytoplazmatické transportní proteiny MeSH
• orange carotenoid protein, Synechocystis MeSH Prohlížeč