Finite-gap equations for strings on AdS_3 x S^3 x T^4 with mixed 3-form flux

We study superstrings on AdS_3 x S^3 x T^4 supported by a combination of Ramond-Ramond and Neveu-Schwarz-Neveu-Schwarz three form fluxes, and construct a set of finite-gap equations that describe the classical string spectrum. Using the recently proposed all-loop S-matrix we write down the all-loop Bethe ansatz equations for the massive sector. In the thermodynamic limit the Bethe ansatz reproduces the finite-gap equations. As part of this derivation we propose expressions for the leading order dressing phases. These phases differ from the well-known Arutyunov-Frolov-Staudacher phase that appears in the pure Ramond-Ramond case. We also consider the one-loop quantization of the algebraic curve and determine the one-loop corrections to the dressing phases. Finally we consider some classical string solutions including finite size giant magnons and circular strings.Comment: 44 pages, 3 figures. v2: references and a discussion about perturbative results adde

Two-loop Integrability of Planar N=6 Superconformal Chern-Simons Theory

Bethe ansatz equations have been proposed for the asymptotic spectral problem of AdS_4/CFT_3. This proposal assumes integrability, but the previous verification of weak-coupling integrability covered only the su(4) sector of the ABJM gauge theory. Here we derive the complete planar two-loop dilatation generator of N=6 superconformal Chern-Simons theory from osp(6|4) superconformal symmetry. For the osp(4|2) sector, we prove integrability through a Yangian construction. We argue that integrability extends to the full planar two-loop dilatation generator, confirming the applicability of the Bethe equations at weak coupling. Further confirmation follows from an analytic computation of the two-loop twist-one spectrum.Comment: 45 pages, v2: typos in (D.9) fixed, reference added, many small change

The low-energy limit of AdS(3)/CFT2 and its TBA

We investigate low-energy string excitations in AdS3 × S3 × T4. When the worldsheet is decompactified, the theory has gapless modes whose spectrum at low energies is determined by massless relativistic integrable S matrices of the type introduced by Al. B. Zamolodchikov. The S matrices are non-trivial only for excitations with identical worldsheet chirality, indicating that the low-energy theory is a CFT2. We construct a Thermodynamic Bethe Ansatz (TBA) for these excitations and show how the massless modes’ wrapping effects may be incorporated into the AdS3 spectral problem. Using the TBA and its associated Y-system, we determine the central charge of the low-energy CFT2 to be c = 6 from calculating the vacuum energy for antiperiodic fermions — with the vacuum energy being zero for periodic fermions in agreement with a supersymmetric theory — and find the energies of some excited states

Weakly coupled N=4 Super Yang-Mills and N=6 Chern-Simons theories from u(2|2) Yangian symmetry

In this paper we derive the universal R-matrix for the Yangian Y(u(2|2)), which is an abstract algebraic object leading to rational solutions of the Yang-Baxter equation on representations. We find that on the fundamental representation the universal R-matrix reduces to the standard rational R-matrix R = R_0(1 + P/u), where the scalar prefactor is surprisingly simple compared to prefactors one finds e.g. for sl(n) R-matrices. This leads precisely to the S-matrix giving the Bethe Ansatz of one-loop N = 4 Super Yang-Mills theory and two-loop N = 6 Chern-Simons theory.Comment: 16 page

Classical integrability and quantum aspects of the AdS(3) x S(3) x S(3) x S(1) superstring

In this paper we continue the investigation of aspects of integrability of the type IIA AdS(3) x S(3) x S(3) x S(1) and AdS(3) x S(3) x T(4) superstrings. By constructing a one parameter family of flat connections we prove that the Green-Schwarz string is classically integrable, at least to quadratic order in fermions, without fixing the kappa-symmetry. We then compare the quantum dispersion relation, fixed by integrability up to an unknown interpolating function h(lambda), to explicit one-loop calculations on the string worldsheet. For AdS(3) x S(3) x S(3) x S(1) the spectrum contains heavy, as well as light and massless modes, and we find that the one-loop contribution differs depending on how we treat these modes showing that similar regularization ambiguities as appeared in AdS(4)/CFT(3) occur also here.Comment: 29 pages; v2: updated references and acknowledgmen

Therapeutic targeting of replicative immortality

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

Financial support provided by The Medical Research Council-MR/K000292/1, Children with Cancer- 2013/144 and Blood Wise-14032 (AJW, LC, SC, AE, TV, HT and ID). KMG is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

The effects of human milk oligosaccharides on gut microbiota, metabolite profiles and host mucosal response in patients with irritable bowel syndrome

Background: Human milk oligosaccharide supplementation safely modulates fecal bifidobacteria abundance and holds the potential to manage symptoms in irritable bowel syndrome (IBS). Here, we aimed to determine the role of a 4:1 mix of 2′-O-fucosyllactose and lacto-N-neotetraose (2′FL/LNnT) on the modulation of the gut microbiota composition and host mucosal response, as well as the link between the bifidobacteria abundance and metabolite modulation, in IBS patients. Methods: Biological samples were collected from IBS patients (n = 58) at baseline and week 4 post-supplementation with placebo, 5 g or 10 g doses of 2′FL/LNnT. The gut microbiota composition, metabolite profiles and expression of genes related to host mucosal response were determined. Results: Moderate changes in fecal, but not mucosal, microbial composition (β-diversity) was observed during the intervention with higher dissimilarity observed within individuals receiving 10g 2′FL/LNnT compared to placebo. Both fecal and mucosal Bifidobacterium spp. increased after 2′FL/LNnT intake, with increased proportions of Bifidobacterium adolescentis and Bifidobacterium longum. Moreover, the intervention modulated the fecal and plasma metabolite profiles, but not the urine metabolite profile or the host mucosal response. Changes in the metabolite profiles were associated to changes in bifidobacteria abundance. Conclusion: Supplementation with 2′FL/LNnT modulated the gut microbiota, fecal and plasma metabolite profiles, but not the host mucosal response in IBS. Furthermore, the bifidogenic effect was associated with metabolite modulation. Overall, these findings support the assertion that 2′FL/LNnT supplementation modulate the intestinal microenvironment of patients with IBS, potentially related to health