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

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

Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring

BACKGROUND: The ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed. METHODS: We evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs. RESULTS: A large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 ± 0.07 for one and 1.83 ± 0.07 nmol/L for two). CONCLUSIONS: Polypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians

Pathogenic Connexin-31 Forms Constitutively Active Hemichannels to Promote Necrotic Cell Death

Mutations in Connexin-31 (Cx31) are associated with multiple human diseases including erythrokeratodermia variabilis (EKV). The molecular action of Cx31 pathogenic mutants remains largely elusive. We report here that expression of EKV pathogenic mutant Cx31R42P induces cell death with necrotic characteristics. Inhibition of hemichannel activity by a connexin hemichannel inhibitor or high extracellular calcium suppresses Cx31R42P-induced cell death. Expression of Cx31R42P induces ER stress resulting in reactive oxygen species (ROS) production, in turn, to regulate gating of Cx31R42P hemichannels and Cx31R42P induced cell death. Moreover, Cx31R42P hemichannels play an important role in mediating ATP release from the cell. In contrast, no hemichannel activity was detected with cells expressing wildtype Cx31. Together, the results suggest that Cx31R42P forms constitutively active hemichannels to promote necrotic cell death. The Cx31R42P active hemichannels are likely resulted by an ER stress mediated ROS overproduction. The study identifies a mechanism of EKV pathogenesis induced by a Cx31 mutant and provides a new avenue for potential treatment strategy of the disease

Three-Dimensional Microscopy Characterization of Death Receptor 5 Expression by Over-Activated Human Primary CD4+ T Cells and Apoptosis

Activation-induced cell death is a natural process that prevents tissue damages from over-activated immune cells. TNF-Related apoptosis ligand (TRAIL), a TNF family member, induces apoptosis of infected and tumor cells by binding to one of its two death receptors, DR4 or DR5. TRAIL was reported to be secreted by phytohemagglutinin (PHA)-stimulated CD4+ T cells in microvesicles

Household and community socioeconomic and environmental determinants of child nutritional status in Cameroon

BACKGROUND: Undernutrition is a leading cause of child mortality in developing countries, especially in sub-Saharan Africa. We examine the household and community level socioeconomic and environmental factors associated with child nutritional status in Cameroon, and changes in the effects of these factors during the 1990s economic crisis. We further consider age-specific effects of household economic status on child nutrition. METHODS: Child nutritional status was measured by weight-for-age (WAZ) and height-for-age (HAZ) z-scores. Data were from Demographic and Health Surveys conducted in 1991 and 1998. We used analysis of variance to assess the bivariate association between the explanatory factors and nutritional status. Multivariate, multilevel analyses were undertaken to estimate the net effects of both household and community factors. RESULTS: Average WAZ and HAZ declined respectively from -0.70 standard deviations (SD), i.e. 0.70 SD below the reference median, to -0.83 SD (p = 0.006) and from -1.03 SD to -1.14 SD (p = 0.026) between 1991 and 1998. These declines occurred mostly among boys, children over 12 months of age, and those of low socioeconomic status. Maternal education and maternal health seeking behavior were associated with better child nutrition. Household economic status had an overall positive effect that increased during the crisis, but it had little effect in children under 6 months of age. Improved household (water, sanitation and cooking fuel) and community environment had positive effects. Children living in the driest regions of the country were consistently worst off, and those in the largest cities were best off. CONCLUSION: Both household and community factors have significant impact on child health in Cameroon. Understanding these relationships can facilitate design of age- and community-specific intervention programs