Endosome-to-Golgi transport is required for the function of many key membrane proteins and lipids, including signaling receptors, small-molecule transporters, and adhesion proteins. The retromer ...complex is well-known for its role in cargo sorting and vesicle budding from early endosomes, in most cases leading to cargo fusion with the trans-Golgi network (TGN). Transport from recycling endosomes to the TGN has also been reported, but much less is understood about the molecules that mediate this transport step. Here we provide evidence that the F-BAR domain proteins TOCA-1 and TOCA-2 (Transducer of Cdc42 dependent actin assembly), the small GTPase CDC-42 (Cell division control protein 42), associated polarity proteins PAR-6 (Partitioning defective 6) and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex mediate the transport of MIG-14/Wls and TGN-38/TGN38 cargo proteins from the recycling endosome to the TGN in Caenorhabditis elegans . Our results indicate that CDC-42, the TOCA proteins, and the WAVE component WVE-1 are enriched on RME-1–positive recycling endosomes in the intestine, unlike retromer components that act on early endosomes. Furthermore, we find that retrograde cargo TGN-38 is trapped in early endosomes after depletion of SNX-3 (a retromer component) but is mainly trapped in recycling endosomes after depletion of CDC-42, indicating that the CDC-42–associated complex functions after retromer in a distinct organelle. Thus, we identify a group of interacting proteins that mediate retrograde recycling, and link these proteins to a poorly understood trafficking step, recycling endosome-to-Golgi transport. We also provide evidence for the physiological importance of this pathway in WNT signaling.
Significance Endosomes are membrane-bound organelles that are required for the sorting of membrane-associated proteins and lipids. Once integral membrane proteins reach the endosomal system they can be sent to the lysosome for degradation, recycled to the plasma membrane, or recycled to the Golgi apparatus. Here we provide insight into the molecules that mediate a poorly understood route to the Golgi from recycling endosomes. The mediators of this transport step that we identified include the membrane-binding and -bending TOCA proteins, the small GTPase CDC-42, associated polarity proteins PAR-6 and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex. Many transmembrane proteins likely use this same transport mechanism.
Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM treatment options have been the same for the past 30 years and have only modestly extended survival, despite aggressive ...multimodal treatments. The progressively better knowledge of GBM biology and a comprehensive analysis of its genomic profile have elucidated GBM heterogeneity, contributing to a more effective molecular classification and to the development of innovative targeted therapeutic approaches.
This article reports all the noteworthy innovations for immunotherapy and targeted therapy, providing insights into the current advances in trial designs, including combination therapies with immuno-oncology agents and target combinations.
GBM molecular heterogeneity and brain anatomical characteristics critically restrain drug effectiveness. Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific 'off-the-shelf' CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance: hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies.
Le site de la Toca da Pena correspond à une petite grotte qui se trouve dans le massif calcaire d’Antero, au sud de la Serra da Capivara et à 7 km à l’est-nord-est de la ville de Coronel José Dias. ...Des fouilles entreprises entre 2008 et 2014 ont permis de recueillir, associés à quelques artefacts lithiques, de nombreux vestiges osseux. Près de la moitié d’entre eux sont rapportés à Scelidodon piauiense, un paresseux terrestre de la taille d’un grand bœuf. Ce Mylodontidé est associé à Leopardus pardalis, Hippidion, Tayassu pecari, Mazama gouazoubira, Mazama americana et à Palaeolama niedae. Cette association faunique permet de dater ce site du Pléistocène supérieur ou du tout début de l’Holocène. Par ailleurs, cette faune de la Toca da Pena présente beaucoup de similitude avec celle de la Toca do Barrigudo, qui se trouve à moins d’un kilomètre et d’où provient l’holotype de l’espèce : Scelidodon piauiense Guérin & Faure, 2004.
Resumo Este artigo apresenta uma interpretação das práticas funerárias e pós-funerárias do sítio arqueológico Toca do Enoque, situado no Parque Nacional Serra das Confusões (Piauí, Brasil). As ...escavações arqueológicas possibilitaram a descoberta de três sepultamentos no local. Através de uma releitura dos contextos funerários escavados no sítio, foi possível propor a versão presumida dos processos de formação de cada depósito mortuário por meio de uma abordagem tafonômica. Dois sepultamentos eram individuais, o primeiro do tipo primário e não perturbado, enquanto o terceiro apresentou perturbações pós-deposicionais naturais e culturais. Ademais, o segundo sepultamento, uma ‘tumba de uso contínuo’ (ongoing tomb use) continha dez indivíduos e características complexas de formação, uso e reuso do depósito mortuário. As datações indiretas dos sepultamentos situam o uso funerário do abrigo por povos indígenas caçadores-coletores pré-ceramistas durante o Holoceno médio (c. 6.000-5.000 anos antes do presente).
Abstract This article presents an interpretation of the funerary and post-funerary practices of the archaeological site Toca do Enoque, located in the Serra das Confusões National Park (Piauí, Brazil). Archaeological excavations have made it possible to discover three burials at the site. Through a new lecture on the mortuary contexts excavated at the site, it was possible to propose the presumed reconstruction of each mortuary deposit formation processes through a taphonomic approach. Two burials were individual, the first primary and undisturbed, while the third had post-depositional natural and cultural disturbances. In addition, the second burial, an ongoing tomb use, contained ten individuals and complex characteristics of the mortuary deposit formation, use and reuse. Indirect burial dates place the funerary use of the shelter by indigenous groups, pre-ceramic hunter-gatherers, during the Middle Holocene (c. 6,000 – 5,000 years before the present).
A Toca do Paraguaio, assim como outros doze sítios do Holoceno antigo, localizados no Parque Nacional Serra da Capivara, no sudeste do Piauí, apresentam conjuntos culturais que atestam uma ...multiplicidade de comportamentos arcaicos datados entre 12 e 8 mil anos BP. Assim, com o objetivo de identificar similaridades e diferenças nesses comportamentos, bem como promover uma correlação entre os sítios datados desse período, realizou-se um levantamento de dados na bibliografia disponível, na documentação antiga relativa aos sítios e em observações diretas nos conjuntos arqueológicos, o que levou ao estabelecimento de um quadro preliminar cronocultural do Holoceno antigo no sudeste do Piauí. ARCHAEOLOGICAL CONTEXT OF THE PARAGUAYTOUCH AND ANCIENT HOLOCENE OCCUPATIONS IN SOUTHEAST PIAUÍ, BRAZIL ABSTRACT The Paraguaio rockshelter, as well as a set of twelve other sites dated to the Early Holocene and located in Serra da Capivara National Park in the southeast of Piauí, present cultural assemblages that attest to a multiplicity of archaic behaviors between 12 and 8 Kyr BP. Thus, in order to identify similarities and differences in these behavioral aspects, as well as to promote a correlation between the different sites on the southeastern border of the Parnaíba Basin, a data collection was done in the available bibliography, in the old documentation related to the sites and through direct observations in the archaeological records, which led to the establishment of an Early Holocene chronocultural preliminary framework for the southeast of Piauí Keywords: Early Holocene; Paraguaio rockshelter; Holocene Cultures; Lithic Industry; Rock-art; Funerary behavior
This paper introduces transparency-optimized control architectures (TOCAs) using two communication channels. Two classes of two-channel TOCAs are found, thereby showing that two channels are ...sufficient to achieve transparency. These TOCAs achieve a greater level of transparency but poorer stability than three-channel TOCAs and four-channel TOCAs. Stability of the two-channel TOCAs has been enhanced while minimizing transparency degradation by adding a filter; and a combined use of the two classes of two-channel TOCAs is proposed for both free space and constrained motion, which involve switching between two TOCAs for transition between free space and constrained motions. The stability condition of the switched teleoperation system is derived for practical applications. Through the one degree-of-freedom (DOF) experiment, the proposed two-channel TOCAs were shown to operate stably, while achieving better transparency under time delay than the other TOCAs.
Teachers serve as the natural raters of students within the school and classroom contexts. Yet teachers’ ratings of their students may vary based on these contextual factors. The current study ...explored the extent to which teacher perceptions of the school environment predict their longitudinal ratings of student behaviors. Data for this study come from 702 teachers in 42 elementary schools. Teachers self-reported their perceptions of the school context at a single time point, and provided ratings of their students’ behavior via the Teacher Observation of Classroom Adaption-Checklist (TOCA-C) across three school years. Latent profile analysis identified three latent classes of teachers based on their ratings of school organizational health, burnout, and efficacy. A regression framework demonstrated an association between the baseline profiles in relation to TOCA-C ratings of student behavior across 3 years. Teachers with more favorable perceptions of the environment had lower initial ratings of concentration problems, disruptive behavior, and internalizing symptoms, and higher ratings of prosocial behaviors and family involvement. They also showed slower growth in their ratings of emotion dysregulation and greater increases of their ratings of family involvement over time. This work is particularly important for determining the extent to which teacher ratings may be biased by teacher and contextual factors, and may have implications for the identification of teachers who may rate students poorly over time.
Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, used in combination with 5-fluorocytosine (5-FC) kills tumor by local production of 5-fluorouracil (5-FU), inducing local ...and systemic immunotherapeutic response resulting in long-term survival after cessation of 5-FC. Toca 511 and Toca FC (oral extended-release 5-FC) are under investigation in patients with recurrent high-grade glioma. Lomustine is a treatment option for patients with high-grade glioma.
We investigated the effects of lomustine combined with Toca 511 + 5-FC in syngeneic orthotopic glioma models. Safety and survival were evaluated in immune-competent rat F98 and mouse Tu-2449 models comparing Toca 511 + 5-FC to lomustine + 5-FC or the combination of Toca 511 + 5-FC + lomustine. After intracranial implantation of tumor, Toca 511 was delivered transcranially followed by cycles of intraperitoneal 5-FC with or without lomustine at the first or fourth cycle.
Coadministration of 5-FC with lomustine was well tolerated. In F98, combination Toca 511 + 5-FC and lomustine increased median survival, but "cures" were not achieved. In Tu-2449, combination Toca 511 + 5-FC and lomustine increased median survival and resulted in high numbers of cure. Rejection of tumor rechallenge occurred after treatment with Toca 511 + 5-FC or combined with lomustine, but not with lomustine + 5-FC. Mixed lymphocyte-tumor cell reactions using splenocytes from cured animals showed robust killing of target cells in an effector:target ratio-dependent manner with Toca 511 + 5-FC and Toca 511 + 5-FC + lomustine day 10.
The combination of Toca 511 + 5-FC and lomustine shows promising efficacy with no additive toxicity in murine glioma models. Immunotherapeutic responses resulting in long-term survival were preserved despite lomustine-related myelosuppression.
In this work, new fossils of Hydrochoerinae rodents (Caviomorpha: Caviidae: Hydrochoerinae) from the Quaternary of the intertropical region of Brazil are described, almost 180 years after the first ...fossils of these animals were found in Lagoa Santa, Minas Gerais. The fossils studied herein were collected in caves of States of Bahia (Toca dos Ossos and Lapa dos Brejões) and Minas Gerais (Lapa Vermelha cave, Lagoa Santa karst). The analyzed material is assigned to the extinct large rodent Neochoerus sulcidens and is composed of skull portion, upper and lower cheek teeth, mandible, humerus, innominate, femur, tibia, and calcaneus. The specimens were assigned to this taxon based on the presence of an M3 with 14 prisms; incisor alveolus reaching the pr. II do m2; anteriormost level of the palatine at the level of the Pr. II of the M2; and larger size than the living species. The p4 is mesiodistally longer than the m1 and m2, distinct from previous interpretations in which the mesiodistal length of the p4 of N. sulcidens would be smaller than the m2, indicating the presence of a variable character. Except for the differences in size, the postcranial bones of N. sulcidens are quite similar to H. hydrochaeris.
•New fossils of Hydrochoerinae rodents from the Quaternary of Brazil are described.•The analyzed material is assigned to the extinct large rodent Neochoerus sulcidens.•The taxonomic framework of Quaternary hydrochoerines requires a broad review because some taxa are supported by variable characteristics.
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