Compactification in the Lightlike Limit

We study field theories in the limit that a compactified dimension becomes lightlike. In almost all cases the amplitudes at each order of perturbation theory diverge in the limit, due to strong interactions among the longitudinal zero modes. The lightlike limit generally exists nonperturbatively, but is more complicated than might have been assumed. Some implications for the matrix theory conjecture are discussed.Comment: 13 pages, 3 epsf figures. References and brief comments added. Nonexistent divergent graph in 0+- model delete

Domain Wall Junctions are 1/4-BPS States

We study N=1 SUSY theories in four dimensions with multiple discrete vacua, which admit solitonic solutions describing segments of domain walls meeting at one-dimensional junctions. We show that there exist solutions preserving one quarter of the underlying supersymmetry -- a single Hermitian supercharge. We derive a BPS bound for the masses of these solutions and construct a solution explicitly in a special case. The relevance to the confining phase of N=1 SUSY Yang-Mills and the M-theory/SYM relationship is discussed.Comment: 18 pages, 4 figures, uses RevTeX. Brief comments concerning lattices of junctions added. Version to appear in Phys. Rev.

Deferasirox drives ROS-mediated differentiation and induces interferon-stimulated gene expression in human healthy haematopoietic stem/progenitor cells and in leukemia cells

Background: Administration of the iron chelator deferasirox (DFX) in transfusion-dependent patients occasionally results in haematopoiesis recovery by a mechanism remaining elusive. This study aimed to investigate at a molecular level a general mechanism underlying DFX beneficial effects on haematopoiesis, both in healthy and pathological conditions. Methods: Human healthy haematopoietic stem/progenitor cells (HS/PCs) and three leukemia cell lines were treated with DFX. N-Acetyl cysteine (NAC) and fludarabine were added as antioxidant and STAT1 inhibitor, respectively. In vitro colony-forming assays were assessed both in healthy and in leukemia cells. Intracellular and mitochondrial reactive oxygen species (ROS) as well as mitochondrial content were assessed by cytofluorimetric and confocal microscopy analysis; mtDNA was assessed by qRT-PCR. Differentiation markers were monitored by cytofluorimetric analysis. Gene expression analysis (GEA) was performed on healthy HS/PCs, and differently expressed genes were validated in healthy and leukemia cells by qRT-PCR. STAT1 expression and phosphorylation were assessed by Western blotting. Data were compared by an unpaired Student t test or one-way ANOVA. Results: DFX, at clinically relevant concentrations, increased the clonogenic capacity of healthy human CD34+ HS/PCs to form erythroid colonies. Extension of this analysis to human-derived leukemia cell lines Kasumi-1, K562 and HL60 confirmed DFX capacity to upregulate the expression of specific markers of haematopoietic commitment. Notably, the abovementioned DFX-induced effects are all prevented by the antioxidant NAC and accompanied with overproduction of mitochondria-generated reactive oxygen species (ROS) and increase of mitochondrial content and mtDNA copy number. GEA unveiled upregulation of genes linked to interferon (IFN) signalling and tracked back to hyper-phosphorylation of STAT1. Treatment of leukemic cell lines with NAC prevented the DFX-mediated phosphorylation of STAT1 as well as the expression of the IFN-stimulated genes. However, STAT1 inhibition by fludarabine was not sufficient to affect differentiation processes in leukemic cell lines. Conclusions: These findings suggest a significant involvement of redox signalling as a major regulator of multiple DFX-orchestrated events promoting differentiation in healthy and tumour cells. The understanding of molecular mechanisms underlying the haematological response by DFX would enable to predict patient's ability to respond to the drug, to extend treatment to other patients or to anticipate the treatment, regardless of the iron overload

Outcomes after primary and repeat thermal ablation of hepatocellular carcinoma with or without liver transplantation

Objectives Thermal ablation (TA) is an established treatment for early HCC. There is a lack of data on the efficacy of repeated TA for recurrent HCC, resulting in uncertainty whether good oncologic outcomes can be obtained without performing orthotopic liver transplantation (OLTx). This study analyses outcomes after TA, with a special focus on repeat TA for recurrent HCC, either as a stand-alone therapy, or in relationship with OLTx. Methods Data from a prospectively registered database on interventions for HCC in a tertiary hepatobiliary centre was completed with follow-up until December 2020. Outcomes studied were rate of recurrence after primary TA and after its repeat interventions, the occurrence of untreatable recurrence, OS and DSS after primary and repeat TA, and complications after TA. In cohorts matched for confounders, OSS and DSS were compared after TA with and without the intention to perform OLTx. Results After TA, 100 patients (56 center dot 8%) developed recurrent HCC, of whom 76 (76 center dot 0%) underwent up to four repeat interventions. During follow-up, 76 center dot 7% of patients never developed a recurrence unamenable to repeat TA or OLTx. OS was comparable after primary TA and repeat TA. In matched cohorts, OS and DSS were comparable after TA with and without the intention to perform OLTx. Conclusions We found TA to be an effective and repeatable therapy for primary and recurrent HCC. Most recurrences can be treated with curative intent. There are patients who do well with TA alone without ever undergoing OLTx

Non-birational twisted derived equivalences in abelian GLSMs

In this paper we discuss some examples of abelian gauged linear sigma models realizing twisted derived equivalences between non-birational spaces, and realizing geometries in novel fashions. Examples of gauged linear sigma models with non-birational Kahler phases are a relatively new phenomenon. Most of our examples involve gauged linear sigma models for complete intersections of quadric hypersurfaces, though we also discuss some more general cases and their interpretation. We also propose a more general understanding of the relationship between Kahler phases of gauged linear sigma models, namely that they are related by (and realize) Kuznetsov's `homological projective duality.' Along the way, we shall see how `noncommutative spaces' (in Kontsevich's sense) are realized physically in gauged linear sigma models, providing examples of new types of conformal field theories. Throughout, the physical realization of stacks plays a key role in interpreting physical structures appearing in GLSMs, and we find that stacks are implicitly much more common in GLSMs than previously realized.Comment: 54 pages, LaTeX; v2: typo fixe

BPS Domain Wall Junctions in Infinitely Large Extra Dimensions

We consider models of scalar fields coupled to gravity which are higher-dimensional generalizations of four dimensional supergravity. We use these models to describe domain wall junctions in an anti-de Sitter background. We derive Bogomolnyi equations for the scalar fields from which the walls are constructed and for the metric. From these equations a BPS-like formula for the junction energy can be derived. We demonstrate that such junctions localize gravity in the presence of more than one uncompactified extra dimension.Comment: 17 pages, uses RevTeX, new references adde

A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort

<p><b>Objectives</b> The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features.</p> <p><b>Methods</b> A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers.</p> <p><b>Results</b> A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively).</p> <p><b>Conclusions</b> The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.</p&gt

Why leveraging sex differences in immune trade‐offs may illuminate the evolution of senescence

The immune system affects senescence (declines in probabilities of survival or reproduction with age), by shaping late age vulnerability to chronic inflammatory diseases and infections. It is also a dynamic interactive system that must balance competing demands across the life course. Thus, immune system function remains an important frontier in understanding the evolution of senescence. Here, we review our expanding mechanistic understanding of immune function over the life course, in the context of theoretical predictions from life-history evolution. We are especially interested in stage- and sex-dependent costs and benefits of investment in the immune system, given differential life-history priorities of the life stages and sexes. We introduce the costs likely to govern immune allocation across the life course. We then discuss theoretical expectations for differences between the sexes and their likely consequences in terms of how the immune system is both modulated by and may modulate senescence, building on information from life-history theory, experimental immunology and demography. We argue that sex differences in immune function provide a potentially powerful probe of selection pressures on the immune system across the life course. In particular, differences in 'competing' and 'caring' between the sexes have evolved across the tree of life, providing repeated instances of divergent selection pressures on immune function occurring within the same overall bauplan. We conclude by detailing an agenda for future research, including development of theoretical predictions of the differences between the sexes under an array of existing models for sex differences in immunity, and empirical tests of such predictions across the tree of life. A free Plain Language Summary can be found within the Supporting Information of this article