Topological Characterization of Hamming and Dragonfly Networks and its Implications on Routing

Current HPC and datacenter networks rely on large-radix routers. Hamming graphs (Cartesian products of complete graphs) and dragonflies (two-level direct networks with nodes organized in groups) are some direct topologies proposed for such networks. The original definition of the dragonfly topology is very loose, with several degrees of freedom such as the inter- and intra-group topology, the specific global connectivity and the number of parallel links between groups (or trunking level). This work provides a comprehensive analysis of the topological properties of the dragonfly network, providing balancing conditions for network dimensioning, as well as introducing and classifying several alternatives for the global connectivity and trunking level. From a topological study of the network, it is noted that a Hamming graph can be seen as a canonical dragonfly topology with a large level of trunking. Based on this observation and by carefully selecting the global connectivity, the Dimension Order Routing (DOR) mechanism safely used in Hamming graphs is adapted to dragonfly networks with trunking. The resulting routing algorithms approximate the performance of minimal, non-minimal and adaptive routings typically used in dragonflies, but without requiring virtual channels to avoid packet deadlock, thus allowing for lower-cost router implementations. This is obtained by selecting properly the link to route between groups, based on a graph coloring of the network routers. Evaluations show that the proposed mechanisms are competitive to traditional solutions when using the same number of virtual channels, and enable for simpler implementations with lower cost. Finally, multilevel dragonflies are discussed, considering how the proposed mechanisms could be adapted to them

Pre-clinical characterization of GMP grade CCL21-gene modified dendritic cells for application in a phase I trial in Non-Small Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Our previous studies have demonstrated that transduction of human dendritic cells (DC) with adenovirus encoding secondary lymphoid chemokine, CCL21, led to secretion of biologically active CCL21 without altering DC phenotype or viability. In addition, intratumoral injections of CCL21-transduced DC into established murine lung tumors resulted in complete regression and protective anti-tumor immunity. These results have provided the rationale to generate a clinical grade adenoviral vector encoding CCL-21 for <it>ex vivo </it>transduction of human DC in order to assess intratumoral administration in late stage human lung cancer.</p> <p>Methods</p> <p>In the current study, human monocyte-derived DC were differentiated by exposure to GM-CSF and IL-4 from cryopreserved mononuclear cells obtained from healthy volunteers. Transduction with clinical grade adenoviral vector encoding CCL21 (1167 viral particles per cell) resulted in secretion of CCL21 protein.</p> <p>Results</p> <p>CCL21 protein production from transduced DC was detected in supernatants (24–72 hours, 3.5–6.7 ng/4–5 × 10⁶cells). DC transduced with the clinical grade adenoviral vector were > 88% viable (n = 16), conserved their phenotype and maintained integral biological activities including dextran uptake, production of immunostimulatory cytokines/chemokines and antigen presentation. Furthermore, supernatant from CCL21-DC induced the chemotaxis of T2 cells <it>in vitro</it>.</p> <p>Conclusion</p> <p>Viable and biologically active clinical grade CCL21 gene-modified DC can be generated from cryopreserved PBMC.</p

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia Type 3 pathogenesis

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.This research was supported by USPHS grant NS073976 (TKH) and P30 ES 06676 that support the NIEHS Center Cell Biology Core and Molecular Genomics Core of UTMB’s NIEHS Center for DNA sequencing. TKP is supported by CA129537 and CA154320. This work was also supported by Fundação para a Ciência e Tecnologia through the project [PTDC/SAU-GMG/101572/2008] and through fellowships [SFRH/BPD/91562/2012 to ASF, SFRH/BD/51059/2010 to ANC]. IB is supported by NIEHS R01 ES018948 and NIAID/AI06288

Excited state intramolecular double-proton transfer dynamics of [2,2′-bipyridyl]-3,3′-diol inside mesoporous silica nanochannels

The modulation of kinetics and pathways in the ESIPT process of proton transfer probes holds significant potential for advancing applications in bio-imaging, drug delivery, and OLEDs. One effective approach for achieving this modulation is altering the H-bonding donating capability of the surrounding medium. To investigate this, we conducted a comprehensive study on the excited state intramolecular double proton transfer process of [2,2′-bipyridyl]-3,3′-diol (BP(OH)2) within the confined spaces of silica nanochannels, namely, MCM-41. MCM-41, known for its versatile properties, has emerged as a promising host in various fields, such as drug delivery and heterogeneous catalysis. Upon encapsulation within the MCM-41, the double proton transfer process of BP(OH)2 is significantly modulated, which is reflected in both steady-state and time-resolved photophysical experiments. We have observed an almost 100 times increment in emission intensity and a 30 nm blue-shift in the emission maxima when the probe gets encapsulated inside the silica nanopores. Most importantly, the femtosecond up-conversion profile exhibits an interesting feature. The rise component of 10 ps, which was attributed to MK→DK conversion in bulk acetonitrile (MeCN), is not observed when the probe resides inside the MCM-41, suggesting the proton transfer is concerted rather than sequential, like in the case of bulk MeCN. This anomalous proton transfer mechanism inside the nanochannel was attributed to the weak H-bonding donating ability of the silanol groups, which could not stabilize the MK form, and thus favoured the concerted pathway over sequential. Moreover, DFT calculations corroborate the concerted pathway observed in the MCM-41 with the gas-phase calculations and the sequential mechanism observed in bulk MeCN with the solution-phase calculations

Ultrafast Fluorescence Dynamics of Highly Stable Copper Nanoclusters Synthesized inside the Aqueous Nanopool of Reverse Micelles

Herein, we have reported a new strategy for the synthesis of highly stable fluorescent copper nanoclusters (CuNCs) with l-cysteine (Cys) as a protecting ligand within the water nanopool of reverse micelles (RMs). In the present work, efforts are also given to address the origin of excitation-dependent fluorescence spectral shift of CuNCs. From our experiments, we have elucidated that the broad fluorescence from CuNCs in RMs consists of two spectrally overlapped bands corresponding to the metal-core and surface states of CuNCs. The intrinsic emission of CuNCs distributed in shorter wavelength regions (<470 nm) is mainly originated from the metal core. On the other hand, the extrinsic fluorescence band (>470 nm) is caused by surface states and consists of a much broader emission because of the presence of numerous surface states. The trapping of excited electrons in the various surface states leads to the emission in the longer wavelength regions and is believed to be responsible for excitation-dependent emission of CuNCs in RMs. Excited state dynamics, which controls the optical properties of CuNCs, have also been investigated by time-correlated single photon counting (TCSPC) and femtosecond fluorescence upconversion techniques. Femtosecond fluorescence upconversion and TCPSC decay profiles of CuNCs comprise of multitude of lifetime components spanning from <1 ps to few nanosecond timescales. We have rationalized the dynamics on the basis of several competing deactivation pathways and a broad distribution of radiative electron–hole recombination dynamics originating from core and surface states

Testing theory of change assumptions of health behavior change interventions: A blended approach exploring local contexts

This paper used a blended approach that involves multiple techniques to, first, test a set of assumptions around a health behavior change communication intervention theory of change (ToC) and, second, surface some unidentified assumptions involving the local context. The intervention was integrated with women’s self-help groups (SHGs) in Uttar Pradesh, India. The key assumption tested in this paper was the linkage between SHG membership, program exposure, and maternal, newborn, and child health practices. Learnings were substantiated through empirical investigations, including structural equation modeling and mediation analysis, as well as ‘co-learning’ workshops within the community. The workshops aimed to capture and interpret the heterogeneity of local contexts through deep dialogues with the community and program implementers at various levels. Statistical analyses indicated a significant association between the amount of women’s program exposure and their health practices. SHG membership was shown to affect maternal health practices; however, it did not have a direct effect on neonatal or child health practices. The ‘co-learning’ workshops revealed crucial aspects, such as prevailing socio-cultural norms, which prevented pregnant or recently delivered women from participating in SHG meetings. This paper encourages evaluators to work with the community to interpret and co-construct meaning in unpacking the contextual forces that seldom appear in the program ToC

Changes in hepatic polyamine levels during acute and chronic administration of aflatoxin B<SUB>1</SUB> to rats

A subacute dose of aflatoxin B1 (3 mg/kg body weight) increases liver putrescine levels within 1 hr after administration, with high levels persisting over 24 hr. Higher doses of the carcinogen elicited larger increases in liver polyaminelevels. A marked elevation of putrescine, spermidine and spermine were noted in aflatoxin B1-induced preneoplastic liver. Pretreatment of rats with phenobarbital prior to aflatoxin B1administration resulted in no synergistic or additive effects

Excited State Proton Transfer Dynamics of Topotecan Inside Biomimicking Nanocavity

The excited state proton transfer (ESPT) dynamics of a potentially important anticancer drug, Topotecan (TPT), has been explored in aqueous reverse micelle (RM) using steady-state and time-resolved fluorescence measurements. Both the time-resolved emission spectrum and time-resolved area normalized emission spectrum infer the generation of excited state zwitterionic form of TPT from the excited state cationic form of TPT, as a result of ESPT process from the −OH group of TPT to the nearby water molecule. The ESPT dynamics were found to be severely retarded inside the nanocavities of RMs, yielding time constants of 250 ps to 1.0 ns, which is significantly slower than the dynamics obtained in bulk water (32 ps). The observed slow ESPT dynamics in RM compared to bulk water is mainly attributed to the sluggish hydrogen-bonded network dynamics of water molecules inside the nanocavity of RM and the screening of the sodium ions present at the interface

Prototropical and Photophysical Properties of Ellipticine inside the Nanocavities of Molecular Containers

Host–guest interactions between an anticancer drug, ellipticine (EPT), and molecular containers (cucurbitruils (CB<i>n</i>) and cyclodextrins (CD)) are investigated with the help of steady state and time-resolved fluorescence measurements. Our experimental results confirm the formation of 1:1 inclusion complexes with CB7 and CB8. The protonated form of EPT predominantly prevails in the inclusion complexes due to the stabilization achieved through ion–dipole interaction between host and positively charged drug. Drug does not form an inclusion complex with CB6, which is smaller in cavity size compared to either CB7 or CB8. In the case of cyclodextrins, α-CD does not form an inclusion complex, whereas β-CD forms a 1:1 inclusion complex with the protonated form of the drug, and the binding affinity of EPT with β-CD is less compared to CB7/CB8. Interestingly, in the case of γ-CD, drug exists in different forms depending on the concentration of the host. At lower concentration of γ-CD, 1:1 inclusion complex formation takes place and EPT exists in protonated form due to accessibility of water by the drug in the inclusion complex, whereas, at higher concentration, a 2:1 inclusion complex (γ-CD:EPT) is observed, in which EPT is completely buried inside the hydrophobic cavity of the capsule formed by two γ-CD molecules, and we believe the hydrophobic environment inside the capsule stabilizes the neutral form of the drug in the 2:1 inclusion complex. Deep insight into the molecular picture of these host–guest interactions has been provided by the docking studies followed by quantum chemical calculations