Scribble (Scrib) is a conserved polarity protein acting as a scaffold involved in multiple cellular and developmental processes. Recent evidence from our group indicates that
is also essential for ...brain development as early global deletion of
in the dorsal telencephalon induced cortical thickness reduction and alteration of interhemispheric connectivity. In addition,
conditional knockout (cKO) mice have behavioral deficits such as locomotor activity impairment and memory alterations. Given
broad expression in multiple cell types in the brain, we decided to determine the neuronal contribution of
for these phenotypes. In the present study, we further investigate the function of
specifically in excitatory neurons on the forebrain formation and the control of locomotor behavior. To do so, we generated a novel neuronal glutamatergic specific
cKO mouse line called Nex
cKO. Remarkably, cortical layering and commissures were impaired in these mice and reproduced to some extent the previously described phenotype in global
cKO. In addition and in contrast to our previous results using
cKO, the
cKO mutant mice exhibited significantly reduced locomotion. Altogether, the novel cKO model described in this study further highlights an essential role for
in forebrain development and locomotor behavior.
Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has ...never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.
Augmenting adaptive immunity is a critical goal for developing next-generation cancer therapies. T and B cells infiltrating the tumor dramatically influence cancer progression through complex ...interactions with the local microenvironment. Cancer cells evade and limit these immune responses by hijacking normal immunologic pathways. Current experimental models using conventional primary cells, cell lines, or animals have limitations for studying cancer-immune interactions directly relevant to human biology and clinical translation. Therefore, engineering methods to emulate such interplay at local and systemic levels are crucial to expedite the development of better therapies and diagnostic tools. In this review, we discuss the challenges, recent advances, and future directions toward engineering the tumor-immune microenvironment (TME), including key elements of adaptive immunity. We first offer an overview of the recent research that has advanced our understanding of the role of the adaptive immune system in the tumor microenvironment. Next, we discuss recent developments in 3D
models and engineering approaches that have been used to study the interaction of cancer and stromal cells with B and T lymphocytes. We summarize recent advancement in 3D bioengineering and discuss the need for 3D tumor models that better incorporate elements of the complex interplay of adaptive immunity and the tumor microenvironment. Finally, we provide a perspective on current challenges and future directions for modeling cancer-immune interactions aimed at identifying new biological targets for diagnostics and therapeutics.
We analyze the trajectories of 313 particles seen in the near‐Bennu environment between December 2018 and September 2019. Of these, 65% follow suborbital trajectories, 20% undergo more than one ...orbital revolution around the asteroid, and 15% directly escape on hyperbolic trajectories. The median lifetime of these particles is ∼6 hr. The trajectories are sensitive to Bennu's gravitational field, which allows us to reliably estimate the spherical harmonic coefficients through degree 8 and to resolve nonuniform mass distribution through degree 3. The particles are perturbed by solar radiation pressure, enabling effective area‐to‐mass ratios to be estimated. By assuming that particles are oblate ellipsoids of revolution, and incorporating photometric measurements, we find a median axis ratio of 0.27 and diameters for equivalent‐volume spheres ranging from 0.22–6.1 cm, with median 0.74 cm. Our size distribution agrees well with that predicted for fragmentation due to diurnal thermal cycling. Detailed models of known accelerations do not produce a match to the observed trajectories, so we also estimate empirical accelerations. These accelerations appear to be related to mismodeling of radiation pressure, but we cannot rule out contributions from mass loss. Most ejections take place at local solar times in the afternoon and evening (12:00–24:00), although they occur at any time of day. We independently identify ten ejection events, some of which have previously been reported. We document a case where a particle ricocheted off the surface, revealing a coefficient of restitution 0.57±0.01 and demonstrating that some apparent ejections are not related to surface processes.
Plain Language Summary
The Origins, Spectral Interpretation, Resource Identification, Security, Regolith Explorer (OSIRIS‐REx) mission discovered that near‐Earth asteroid (101955) Bennu is periodically ejecting small particles from its surface, placing it in the uncommon class of “active asteroids.” We linked together individual detections of ejected particles and used numerical models of the forces acting on them to ascertain their trajectories and fates. We found that most particles have suborbital trajectories, meaning they fall back to Bennu's surface shortly after being ejected, but some orbit Bennu for days at a time, and some escape directly into space. From the particle trajectories, we are able to estimate their sizes (comparable to pebbles, from a few millimeters to a few centimeters in diameter) and shapes (probably flake like). Their trajectories also make it possible to estimate Bennu's gravity field more precisely than spacecraft measurements and help shed light on the possible causes of the ejections.
Key Points
Most of the 313 particles we study have suborbital trajectories, but some orbit Bennu and others directly escape
The particles appear to have flake‐like shapes and have effective diameters 0.22–6.1 cm with median 0.74 cm
Ejections tend to take place in the local afternoon and evening but can occur anytime
Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor ...protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and partial corpus callosum and hippocampal commissure agenesis. We correlated these phenotypes with a disruption in various developmental mechanisms of corticogenesis including neurogenesis, neuronal migration and axonal connectivity. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, our results show that Scrib is essential for early brain development due to its role in several developmental cellular mechanisms that could underlie some of the deficits observed in complex neurodevelopmental pathologies.
Parasitic wasps constitute one of the largest group of venomous animals. Although some physiological effects of their venoms are well documented, relatively little is known at the molecular level on ...the protein composition of these secretions. To identify the majority of the venom proteins of the endoparasitoid wasp Chelonus inanitus (Hymenoptera: Braconidae), we have randomly sequenced 2111 expressed sequence tags (ESTs) from a cDNA library of venom gland. In parallel, proteins from pure venom were separated by gel electrophoresis and individually submitted to a nano-LC-MS/MS analysis allowing comparison of peptides and ESTs sequences.
About 60% of sequenced ESTs encoded proteins whose presence in venom was attested by mass spectrometry. Most of the remaining ESTs corresponded to gene products likely involved in the transcriptional and translational machinery of venom gland cells. In addition, a small number of transcripts were found to encode proteins that share sequence similarity with well-known venom constituents of social hymenopteran species, such as hyaluronidase-like proteins and an Allergen-5 protein.An overall number of 29 venom proteins could be identified through the combination of ESTs sequencing and proteomic analyses. The most highly redundant set of ESTs encoded a protein that shared sequence similarity with a venom protein of unknown function potentially specific of the Chelonus lineage. Venom components specific to C. inanitus included a C-type lectin domain containing protein, a chemosensory protein-like protein, a protein related to yellow-e3 and ten new proteins which shared no significant sequence similarity with known sequences. In addition, several venom proteins potentially able to interact with chitin were also identified including a chitinase, an imaginal disc growth factor-like protein and two putative mucin-like peritrophins.
The use of the combined approaches has allowed to discriminate between cellular and truly venom proteins. The venom of C. inanitus appears as a mixture of conserved venom components and of potentially lineage-specific proteins. These new molecular data enrich our knowledge on parasitoid venoms and more generally, might contribute to a better understanding of the evolution and functional diversity of venom proteins within Hymenoptera.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study we elucidate the structural distinctions between amorphous and crystalline Ni2P nanoparticles synthesized using tri-n-octylphosphine (TOP), through X-ray absorption spectroscopy (XAS), ...X-ray diffraction (XRD), and inductively coupled plasma (ICP). We determine the differences in their chemical and atomic structure, which have not been previously reported, yet are essential for understanding their potential as nanocatalysts. These structural characteristics are related to the corresponding nanoparticle magnetic properties analyzed by performing magnetic measurements. XAS results reveal a significant P concentration in the amorphous nanoparticle sample – placing the stoichiometry close to Ni2P – despite XRD results that show only fcc Ni contributions. By comparing the long-range structural order from XRD to the short-range radial structure from EXAFS we conclude that both techniques are necessary to obtain a complete structural picture of amorphous and crystalline nanoparticle phases due to the limitations of XRD amorphous characterization. We find that phases are amorphous with respect to XRD when their offsets (deviations) from bulk interatomic distances have a standard deviation as high as ∼4.82. Phases with lower standard deviation (e.g., ≲1.22), however, are detectable as crystalline through XRD. The possible presence of amorphous phases should be considered when using XRD alone for nanoparticle characterization. This is particularly important when highly reactive reagents such as TOP are used in synthesis. By characterizing amorphous nickel phosphide nanoparticles that have a comparable stoichiometry to Ni2P, we confirm that TOP serves as a highly effective phosphorus source, even at temperatures as low as 230 °C. Unintended amorphous structure domains may significantly affect nanoparticle properties, and in turn, their functionality.
Scribble (Scrib) is a key regulator of apicobasal polarity, presynaptic architecture, and short-term synaptic plasticity in Drosophila. In mammals, its homolog Scrib1 has been implicated in cancer, ...neural tube closure, and planar cell polarity (PCP), but its specific role in the developing and adult nervous system is unclear. Here, we used the circletail mutant, a mouse model for PCP defects, to show that Scrib1 is located in spines where it influences actin cytoskeleton and spine morphing. In the hippocampus of these mutants, we observed an increased synapse pruning associated with an increased number of enlarged spines and postsynaptic density, and a decreased number of perforated synapses. This phenotype was associated with a mislocalization of the signaling pathway downstream of Scrib1, leading to an overall activation of Rac1 and defects in actin dynamic reorganization. Finally, Scrib1-deficient mice exhibit enhanced learning and memory abilities and impaired social behavior, two features relevant to autistic spectrum disorders. Our data identify Scrib1 as a crucial regulator of brain development and spine morphology, and suggest that Scrib1(crc/+) mice might be a model for studying synaptic dysfunction and human psychiatric disorders.
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