Pauli graphs, Riemann hypothesis, Goldbach pairs

Let consider the Pauli group $\mathcal{P}_q=$ with unitary quantum generators $X$ (shift) and $Z$ (clock) acting on the vectors of the $q$-dimensional Hilbert space via $X|s> =|s+1>$ and $Z|s> =\omega^s |s>$, with $\omega=\exp(2i\pi/q)$. It has been found that the number of maximal mutually commuting sets within $\mathcal{P}_q$ is controlled by the Dedekind psi function $\psi(q)=q \prod_{p|q}(1+\frac{1}{p})$ (with $p$ a prime) \cite{Planat2011} and that there exists a specific inequality $\frac{\psi (q)}{q}>e^{\gamma}\log \log q$, involving the Euler constant $\gamma \sim 0.577$, that is only satisfied at specific low dimensions $q \in \mathcal {A}=\{2,3,4,5,6,8,10,12,18,30\}$. The set $\mathcal{A}$ is closely related to the set $\mathcal{A} \cup \{1,24\}$ of integers that are totally Goldbach, i.e. that consist of all primes $p2$) is equivalent to Riemann hypothesis. Introducing the Hardy-Littlewood function $R(q)=2 C_2 \prod_{p|n}\frac{p-1}{p-2}$ (with $C_2 \sim 0.660$ the twin prime constant), that is used for estimating the number $g(q) \sim R(q) \frac{q}{\ln^2 q}$ of Goldbach pairs, one shows that the new inequality $\frac{R(N_r)}{\log \log N_r} \gtrapprox e^{\gamma}$ is also equivalent to Riemann hypothesis. In this paper, these number theoretical properties are discusssed in the context of the qudit commutation structure.Comment: 11 page

Outcomes of Durable Mechanical Circulatory Support in Myocarditis: Analysis of the International Society for Heart and Lung Transplantation Registry for Mechanically Assisted Circulatory Support Registry

Myocarditis can be refractory to medical therapy and require durable mechanical circulatory support (MCS). The characteristics and outcomes of these patients are not known. We identified all patients with clinically-diagnosed or pathology-proven myocarditis who underwent mechanical circulatory support in the International Society for Heart and Lung Transplantation Registry for Mechanically Assisted Circulatory Support registry (2013-2016). The characteristics and outcomes of these patients were compared to those of patients with nonischemic cardiomyopathy (NICM). Out of 14,062 patients in the registry, 180 (1.2%) had myocarditis and 6,602 (46.9%) had NICM. Among patients with myocarditis, duration of heart failure was22%, 1-12 months in 22.6%, and \u3e1 year in 55.4%. Compared with NICM, patients with myocarditis were younger (45 vs. 52 years, P \u3c 0.001) and were more often implanted with Interagency Registry for Mechanically Assisted Circulatory Support profile 1 (30% vs. 15%, P \u3c 0.001). Biventricular mechanical support ( biventricular ventricular assist device [BIVAD] or total artificial heart) was implanted more frequently in myocarditis (18% vs. 6.7%, P \u3c 0.001). Overall postimplant survival was not different between myocarditis and NICM (left ventricular assist device: P = 0.27, BIVAD: P = 0.50). The proportion of myocarditis patients that have recovered by 12 months postimplant was significantly higher in myocarditis compared to that of NICM (5% vs. 1.7%, P = 0.0003). Adverse events (bleeding, infection, and neurologic dysfunction) were all lower in the myocarditis than NICM. In conclusion, although myocarditis patients who receive durable MCS are sicker preoperatively with higher needs for biventricular MCS, their overall MCS survival is noninferior to NICM. Patients who received MCS for myocarditis are more likely than NICM to have MCS explanted due to recovery, however, the absolute rates of recovery were low

An early history of T cell-mediated cytotoxicity.

After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications

Cytotoxic CD8⁺ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4 <sup>+</sup> T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8 <sup>+</sup> T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8 <sup>+</sup> T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8 <sup>+</sup> T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1) <sup>G93A</sup> mutant decreased spinal motoneuron loss. Using motoneuron-CD8 <sup>+</sup> T cell coculture systems, we found that mutant SOD1-expressing CD8 <sup>+</sup> T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1 <sup> G93A </sup> CD8 <sup>+</sup> T cells. Activated mutant SOD1 CD8 <sup>+</sup> T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8 <sup>+</sup> T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo

Pancreatic cancer is highly resistant to the currently available chemotherapeutic agents. Less than 5% of patients diagnosed with this disease could survive beyond 5 years. Thus, there is an urgent need for the development of novel, efficacious drugs that can treat pancreatic cancer. Herein we report the identification of artesunate (ART), a derivative of artemisinin, as a potent and selective antitumor agent against human pancreatic cancer cells in vitro and in vivo. ART exhibits selective cytotoxic activity against Panc-1, BxPC-3 and CFPAC-1 pancreatic cancer cells with IC50 values that are 2.3- to 24-fold less than that of the normal human hepatic cells (HL-7702). The pan caspase inhibitor zVAD-fmk did not inhibit the cytotoxic activity of ART. Electron microscopy of ART-treated cells revealed severe cytoplasmic swelling and vacuolization, swollen and internally disorganized mitochondria, dilation (but not fragmentation) of the nuclei without chromatin condensation, and cell lysis, yielding a morphotype that is typical of oncosis. The ART-treated cells exhibited a loss of mitochondrial membrane potential (ΔΨm) and ART-induced cell death was inhibited in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC). Importantly, ART produced a dose-dependent tumor regression in an in vivo pancreatic cancer xenografts model. The in vivo antitumor activity of ART was similar to that of gemcitabine. Taken together, our study suggests that ART exhibits antitumor activity against human pancreatic cancer via a novel form of oncosis-like cell death, and that ART should be considered a potential therapeutic candidate for treating pancreatic cancer

Caspase I-related protease inhibition retards the execution of okadaic acid- and camptothecin-induced apoptosis and PAI-2 cleavage, but not commitment to cell death in HL-60 cells

We have previously reported that the putative cytoprotective protease inhibitor, plasminogen activator inhibitor type 2 (PAI-2), is specifically cleaved during okadaic acid-induced apoptosis in a myeloid leukaemic cell line (Br J Cancer (1994) 70: 834–840). HL-60 cells exposed to okadaic acid and camptothecin underwent morphological and biochemical changes typical of apoptosis, including internucleosomal DNA fragmentation and PAI-2 cleavage. Significant endogenous PAI-2 cleavage was observed 9 h after exposure to okadaic acid; thus correlating with other signs of macromolecular degradation, like internucleosomal DNA fragmentation. In camptothecin-treated cells, PAI-2 cleavage was an early event, detectable after 2 h of treatment, and preceding internucleosomal DNA fragmentation. The caspase I selective protease inhibitor, YVAD-cmk, inhibited internucleosomal DNA fragmentation and PAI-2 cleavage of okadaic acid and camptothecin-induced apoptotic cells. YVAD-cmk rather sensitively and non-toxically inhibited camptothecin-induced morphology, but not okadaic acid-induced morphology. In in vitro experiments recombinant PAI-2 was not found to be a substrate for caspase I. The results suggest that caspase I selective protease inhibition could antagonize parameters coupled to the execution phase of okadaic acid- and camptothecin-induced apoptosis, but not the commitment to cell death. © 1999 Cancer Research Campaig

Bisphosphonates induce apoptosis in human breast cancer cell lines

Breast cancer has a prodigious capacity to metastasize to bone. In women with advanced breast cancer and bone metastases, bisphosphonates reduce the incidence of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that some bisphosphonates reduce the tumour burden in bone with a consequent increase in survival, raising the possibility that bisphosphonates may have a direct effect on breast cancer cells. We have investigated the in vitro effects of bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth, viability and induction of apoptosis in three human breast cancer cell lines (MDA-MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye assay, and cell viability was quantitated by MTS dye reduction. Induction of apoptosis was determined by identification of morphological features of apoptosis using time-lapse videomicroscopy, identifying morphological changes in nucleis using Hoechst staining, quantitation of DNA fragmentation, level of expression of bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly (ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced cell viability in all three cell lines. Zoledronate was the most potent bisphosphonate with IC50values of 15, 20 and 3 μM respectively in MDA-MB-231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35 and 25 μM, whereas clodronate and EB 1053 were more than two orders of magnitude less potent. An increase in the proportion of cells having morphological features characteristic of apoptosis, characteristic apoptotic changes in the nucleus, time-dependent increase in the percentage of fragmented chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of PARP, all indicate that bisphosphonates have direct anti-tumour effects on human breast cancer cells. © 2000 Cancer Research Campaig