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"Raz, E"
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Cousin marriages
Juxtaposing contributions from geneticists and anthropologists, this volume provides a contemporary overview of cousin marriage and what is happening at the interface of public policy, the management of genetic risk and changing cultural practices in the Middle East and in multi-ethnic Europe. It offers a cross-cultural exploration of practices of cousin marriage in the light of new genetic understanding of consanguineous marriage and its possible health risks. Overall, the volume presents a reflective, interdisciplinary analysis of the social and ethical issues raised by both the discourse of risk in cousin marriage, as well as existing and potential interventions to promote \"healthy consanguinity\" via new genetic technologies.
eBook
TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP
TRPM8 is the molecular sensor for cold; however, the physiological role of TRPM8+ neurons at mucosal surfaces is unclear. Here we evaluated the distribution and peptidergic properties of TRPM8+ fibers in naive and inflamed colons, as well as their role in mucosal inflammation. We found that Trpm8−/− mice were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis, and that Trpm8−/− CD11c+ DCs (dendritic cells) showed hyperinflammatory responses to toll-like receptor (TLR) stimulation. This was phenocopied in calcitonin gene–related peptide (CGRP) receptor-deficient mice, but not in substance P receptor-deficient mice, suggesting a functional link between TRPM8 and CGRP. The DSS phenotype of CGRP receptor-deficient mice could be adoptively transferred to wild-type (WT) mice, suggesting that CGRP suppresses the colitogenic activity of bone marrow–derived cells. TRPM8+ mucosal fibers expressed CGRP in human and mouse colon. Furthermore, neuronal CGRP contents were increased in colons from naive and DSS-treated Trpm8−/− mice, suggesting deficient CGRP release in the absence of TRPM8 triggering. Finally, treatment of Trpm8−/− mice with CGRP reversed their hyperinflammatory phenotype. These results suggest that TRPM8 signaling in mucosal sensory neurons is indispensable for the regulation of innate inflammatory responses via the neuropeptide CGRP.
Journal Article
Mucosal immunity: aliment and ailments
The development of the primitive gut in the multicellular aquatic eukaryote was driven by the insufficient absorption of nutrients from the oceanic soup. The anatomy of this evolving specialized system invited its colonization by environmental prokaryotes and resulted in the establishment of the intestinal microflora. Innate immunity had previously evolved in gutless organisms such as plants and was fully functional in the gut of invertebrates. On the other hand, adaptive immunity evolved in vertebrates, most probably because of some selective pressure such as the adaptation to a predatory lifestyle. Interestingly, this form of immunity was localized first in their primitive gut. Although the newly generated eukaryote–prokaryote relationship in the gut evolved under mutualistic principles, its symbiotic nature is easily interrupted by extrinsic factors such the composition of the consumed food. Thus, it is argued below that a state of disequilibrium with the microflora (dysbiosis) results in potentially serious immune-related disadvantages to the host.
Journal Article
Use of Pipeline Embolization Devices for treatment of a direct carotid-cavernous fistula
Background
The use of minimally porous endoluminal devices (MPEDs) such as the Pipeline Embolization Device (PED) has been described for the treatment of brain aneurysms. The benefit of using MPEDs to assist embolization of a direct high-flow carotid cavernous fistula resulting from a ruptured cavernous carotid artery aneurysm is not well documented.
Methods
We describe our experience with deploying a tailored multidevice PED construct across the cavernous internal carotid artery (ICA) wall defect in combination with transarterial coil embolization using the “jailed microcatheter” technique.
Results
A 59-year-old woman presented with acute left-sided ophthalmoplegia. Diagnostic cerebral angiography demonstrated a ruptured giant cavernous carotid aneurysm with fistulous outflow via the ipsilateral left superior ophthalmic vein and into the pterygoid venous plexi bilaterally. Via the Marksman microcatheter, a total of three PEDs measuring 4.5 mm × 18 mm, 4.5 mm × 20 mm, and 4.75 mm × 16 mm were telescoped within the ICA across the aneurysm neck. Coiling of the aneurysm fundus and cavernous sinus via the “jailed” Rapidtransit microcatheter was subsequently achieved. A 2-year follow-up digital subtraction angiography (DSA) demonstrated stable obliteration of the aneurysm and the fistula, coincident with complete resolution of the patient’s symptoms.
Conclusions
Based on our long-term clinical and angiographic results, we advocate that the presented method be a valid treatment option for selected cases.
Journal Article
A note on distinct distances
We show that, for a constant-degree algebraic curve γ in ℝD, every set of n points on γ spans at least Ω(n4/3) distinct distances, unless γ is an algebraic helix, in the sense of Charalambides [2]. This improves the earlier bound Ω(n5/4) of Charalambides [2]. We also show that, for every set P of n points that lie on a d-dimensional constant-degree algebraic variety V in ℝD, there exists a subset S ⊂ P of size at least Ω(n4/(9+12(d−1))), such that S spans
$\\left({\\begin{array}{*{20}{c}} {|S|} \\\ 2 \\\\\end{array}} \\right)$
distinct distances. This improves the earlier bound of Ω(n1/(3d)) of Conlon, Fox, Gasarch, Harris, Ulrich and Zbarsky [4]. Both results are consequences of a common technical tool.
Journal Article
Dense Graphs Have Rigid Parts
While the problem of determining whether an embedding of a graph G in R2 is infinitesimally rigid is well understood, specifying whether a given embedding of G is rigid or not is still a hard task that usually requires ad hoc arguments. In this paper, we show that every embedding (not necessarily generic) of a dense enough graph (concretely, a graph with at least C0n3/2(logn)β edges, for some absolute constants C0>0 and β), which satisfies some very mild general position requirements (no three vertices of G are embedded to a common line), must have a subframework of size at least three which is rigid. For the proof we use a connection, established in Raz (Discrete Comput. Geom. 58(4), 986–1009 (2017)), between the notion of graph rigidity and configurations of lines in R3. This connection allows us to use properties of line configurations established in Guth and Katz (Ann. Math. 181(1), 155–190 (2015)). In fact, our proof requires an extended version of Guth and Katz result; the extension we need is proved by János Kollár in an appendix to our paper. We do not know whether our assumption on the number of edges being Ω(n3/2logn) is tight, and we provide a construction that shows that requiring Ω(nlogn) edges is necessary.
Journal Article
Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice
Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4+ T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6−/−) CD4+ T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-γ production, as well as a marked decrease in survival, interleukin- 17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10−/− model of colitis and generated Il10−/−/Dusp6−/− double-knockout mice. Il10−/−/Dusp6−/− mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6−/− mice. In summary, DUSP6 regulates CD4+ T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.
Journal Article
Primordial germ-cell development: the zebrafish perspective
Key Points
Primordial germ cells (PGCs) in zebrafish are specified by the inheritance of maternally provided cytoplasmic determinants, which are collectively known as the germ plasm.
Several molecules that are important for PGC development in zebrafish also have a role in germ-cell development in other organisms, invertebrates and vertebrates.
During the first day of embryonic development, PGCs migrate from the positions where they are formed towards their target — the somatic part of the gonad — where they differentiate into sperm and eggs.
During their migration, PGCs acquire directional cues from somatic cells that attract them towards their intermediate and final targets.
A crucial molecule that directs the migrating PGCs is the chemokine Sdf-1a, which is expressed in positions at which PGCs are found.
Reducing the level of Sdf-1a or its receptor Cxcr4b results in a severe PGC migration defect; conversely, expression of Sdf-1a in ectopic locations leads to accumulation of PGCs in those sites.
Primordial germ cells follow a characteristic developmental path that is manifested in the specialized regulation of basic cell functions and behaviour. Recent studies in zebrafish have greatly enhanced our understanding of the mode of specification of primordial germ cells, cell-fate maintenance and the migration of these cells towards their target, the gonad, where they differentiate into gametes.
Journal Article
On the d-dimensional algebraic connectivity of graphs
The
d
-dimensional algebraic connectivity
a
d
(
G
) of a graph
G
= (
V,E
), introduced by Jordán and Tanigawa, is a quantitative measure of the
d
-dimensional rigidity of
G
that is defined in terms of the eigenvalues of stiffness matrices (which are analogues of the graph Laplacian) associated to mappings of the vertex set
V
into ℝ
d
.
Here, we analyze the
d
-dimensional algebraic connectivity of complete graphs. In particular, we show that, for
d
≥ 3,
a
d
(
K
d
+1
) = 1, and for
n
≥ 2
d
,
⌈
n
2
d
⌉
−
2
d
+
1
≤
a
d
(
K
n
)
≤
2
n
3
(
d
−
1
)
+
1
3
.
Journal Article