ALBERT

Description: Abstract Introduction of new navigation signals L2C (1227.60 MHz) and L5 (1176.45 MHz) to the existing GPS (Global Positioning System) spectrum, under the modernization program of GPS offers the improvement of position accuracy. The present study aims to understand the relative robustness of the L2C and L5 signals compared to legacy L1 C/A signal during periods of scintillations in terms of durations of cycle slips encountered from an anomaly crest location, Calcutta (22.58°N, 88.38°E geographic; magnetic dip 32°N). The data analyzed in this study were recorded during the vernal equinox of 2014 (February–April), a period of high solar activity of cycle 24. Results obtained from the comparative analyses, which are perhaps one of the first from the Indian longitude sector, indicate GPS L5 to be more robust than L1 C/A and L2C in terms of occurrence and duration of cycle slips under adverse ionospheric conditions. Furthermore, loss‐of‐lock events of duration greater than 6 s are found to be more frequent for S4 ≥ 0.6. It is found that frequency sensitivity of the GPS spectrum, in terms of occurrence of cycle slips and loss of locks are in conformity with earlier results from the equatorial region but are different from the high latitudes with respect to local time of occurrence and geomagnetic activity.

Description: Abstract Developing efficient, fast performing and thermally stable Silver iodide‐based fast ion conducting solids are of great interest for resistive switching applications, but still remain a challenge. Metallization in bulk, behavior of threshold voltage profile over composition, and corrosion reactions are few of the challenges. In this work, the switching behavior of bulk, fast ion conducting, vitreous (AgI)x‐(Ag2O)25‐(MoO3)75‐x, for 60 ≤ x ≤ 40 solids, has been investigated in order to understand the switching mechanism with the inert electrodes. By using inert electrodes, the switching becomes irreversible, memory type. The switching mechanism is the electrochemical metallization process. The inert electrodes restrain ionic mass transfer but exhibit low barrier to electron transfer allowing the cathodic metallization reaction to reach Nernst equilibrium faster. Cations involved in this process transport through the free volume within the solid structure and follows Mott‐Gurney model for electric field‐driven thermally activated ion hopping conductivity model. This model along with the thermal stability profile provides a narrow region within composition with better switching performance based on swiftness to reach threshold voltage and less power loss. Traces of anionic contribution to metallization are absent. Moreover, anodic oxidation involves reactions that cause bubble formation and corrosion.

Description: Abstract Phosphorus (P) is central to food production. Current understanding about the global phosphorus system is dominated by studies in wealthier nations where soil fertility, fertilizer supply chains, and agronomic tracking have long been established. In contrast, developing nations are experiencing major agricultural transitions and the associated phosphorus flows remain a significant knowledge gap. We compiled and analyzed several years of recent agricultural datasets for Bangladesh, currently the eighth most populous nation, using substance flow analysis for phosphorus. From 2000 to 2016, rice production increased by 〉50% and remained the dominant crop with remarkably higher phosphorus flow (49.96 kt in 2016) than all other crops. Phosphorus content of livestock products in 2016 exceeded 6.00 kt, more than double in the year 2000, driven primarily by phosphorus in milk and secondarily in meat/eggs. These agricultural changes coincided with a doubling of national phosphorus fertilizer consumption since 2000, a fourfold increase since the global food crisis (2009), and a pronounced rise in the phosphorus import dependency ratio, which was the highest among all countries compared. In turn, during 2010s fertilizer phosphorus use exceeded phosphorus as food + feed production leading to soil phosphorus accumulation, and loss as burned manure became one of the largest phosphorus flows in the entire system, equivalent to half of fertilizer use. This dramatic reconfiguration of the Bangladesh phosphorus system illustrates an important case of agricultural expansion and intensification that is still playing out, with similar situations occurring in developing nations where population growth rates are high, and access to commercial fertilizers has risen.

Description: Abstract From deformed quartzites in the Singhbhum Shear Zone, eastern India, we report shear fractures of varying surface roughness: very smooth, containing no lineation to strongly rough with prominent slickenlines. We reproduced them in analogue laboratory experiments, which suggest that the modes of shear failure (brittle versus ductile) and the fracture orientation are potential factors to control the fracture roughness. The experiments were conducted on cohesive sand‐talc models with varying sand:talc volume ratio. Pure sand models underwent Coulomb failure in the brittle regime; this failure mode switched to plastic yielding in the ductile regime with increasing talc content. Such a transition in failure behavior resulted in a remarkable variation in the fracture roughness characteristics. Shear fractures produced by Coulomb failure are smooth, and devoid of any slickenlines, whereas those produced by plastic yielding display strongly linear roughness, defined by cylindrical ridges along the slip direction. Such linear irregularities become more prominent with increasing fracture orientation (θ) to the compression direction (θ = 30 to 60°). We develop a new computational technique, based on controlled optical images to map the shear surface geometry from field casts and laboratory samples. Binarization of the irregular surface images (cantor set) provides 1‐D fractal dimension (D), which is used to quantify the roughness variability, and the degree of their anisotropy in terms of ΔD (difference in D across and along the slip direction). From numerical models, we finally show onset of wave instability in the mechanically distinct rupture zone as an alternative mechanism for slickenline formation.

Description: Inhibitor (neutralizing anti-drug antibody) formation against factor VIII (FVIII) is currently the most serious complication of FVIII replacement therapy for hemophilia A. The role of innate immune signals in this adaptive immune response is unclear. Lipopolysaccharide (LPS, the major component of the outer membrane in Gram-negative bacteria), which activates the innate immune sensor toll-like receptor 4 (TLR4), enhances inhibitor formation in hemophilia A mice. Intriguingly, earlier data suggested that activation of the endosomal DNA sensor TLR9 may actually suppress inhibitor formation. However, we demonstrated that a TLR9 agonist induced inhibitor formation against a factor IX transgene product in gene therapy for hemophilia B, which resulted from activation of monocyte-derived dendritic cells (moDCs) and enhancement of T follicular helper (Tfh) cell responses. Tfh cells drive germinal center (GC) formation and T cell help-dependent antibody formation. The aim of this study was to elucidate the role of TLR9 signaling in FVIII inhibitor formation in hemophilia A mice. Hemophilia A (F8e16-/-) B6/129 mice were co-injected IV (n=4) with FVIII (1.5 IU) and ODN-1826 (a class B CpG oligodeoxynucleotide, 50 µg), which is a TLR9 agonist, or injected on two consecutive days (n=3), first with ODN-1826 and then with FVIII on the next day. Control mice received FVIII only (n=5). Injections were performed once weekly for 4 weeks. Blood samples, spleens and subiliac (superficial inguinal) lymph nodes were collected for ELISA and Bethesda assays, and flow cytometry analysis. In our analysis, Tfh were defined as CD4+CXCR5+PD1+Bcl6- cells, while GC B cells were defined as CD19+GL7+CD95+. Tfh cell response and GC formation in the spleen were robustly enhanced by the TLR9 agonist compared to mice injected with FVIII only (2-fold for Tfh frequencies and 6-fold for GC B cells when co-injected; P〈 0.05). As a result, inhibitor titers increased 〉400-fold (on average from 6.4 to 2746.5 BU/ml). In contrast, anti-FVIII IgG1 levels increased only 2.5-fold. The differences between mice injected on two consecutive days and the FVIII-only group were not statistically significant. A time-course experiment was also carried out to monitor progress of immune response to FVIII (1.5 IU administered once weekly) in the absence of TLR9 agonist over time: 4 (n=4), 6 (n=4) and 8 weeks (n=5) after the initial antigen challenge. Inhibitor titers continued to rise beyond the fourth week of antigen challenges, reaching 46-fold higher values at eighth week (from 3 BU/ml in the fourth week to 138 BU/ml in the eighth week, p

Description: Background: Cytomegalovirus (CMV) reactivations are common post allogeneic stem cell transplant (ASCT) especially in developing countries like India, where most of the patients as well as donors are CMV seropositive. Ganciclovir is the drug of choice for preemptive therapy. However, myelosuppression which is a prominent side effect of ganciclovir, precludes its use in many post ASCT patients who are already cytopenic. Unavailability of second line agents like foscarnet and cidofovir in India leaves few therapeutic options for such patients. Artesunate is an inexpensive antimalarial agent and has been sporadically reported in literature to be effective in CMV reactivation in patients who are intolerant or resistant to ganciclovir. Here we report utility of artesunate in ASCT patients who could not be given or continued on ganciclovir due to cytopenias. This is the largest report of artesunate use in CMV reactivation to the best of our knowledge. Methods: All patients who underwent ASCT between April 2015 and October 2018 were included in this retrospective analysis. CMV IgG serology was tested at baseline for patients and donors. Conditioning regimen used was either myeloablative (CyTBI/BuCy) or reduced intensity with fludarabine in combination with either melphalan or treosulphan + 2 Gy TBI. Graft versus host disease (GVHD) prophylaxis used was calcineurin inhibitor (CNI), with methotrexate or mycofenolate mofetil (MMF) for matched sibling (MSD) and matched unrelated donor (MUD) transplants. MUD transplant recipients additionally received rabbit ATG (2.5-5 mg/kg). Post transplant cyclophosphamide (PTCy) with CNI and MMF was used for haploidentical transplants (HIT). CMV was monitored twice a week with quantitative polymerase chain reaction (QPCR) from start of conditioning till at least D+100 post ASCT or longer if patient was on immunosuppression. Those with a QPCR 〉500 copies/mL at 2 consecutive time points were started on preemptive therapy. Ganciclovir was preferred as first line agent, however in case of cytopenia, artesunate was used. In case cytopenia developed while patient was on ganciclovir, artesunate was started as second line. Artesunate dose was 2.4 mg/kg (upto 120 mg) twice daily. Artesunate was given till clearance of CMV (unquantifiable CMV DNA on QPCR at 2 consecutive time points) or intolerance. Artesunate failure was defined as 〉 1 log increase in CMV copies after 2 weeks of therapy or development of CMV end organ involvement while on therapy. Artesunate was considered to be effective if there was no log increase in CMV copy numbers at 2 weeks of therapy. Biopsies from relevant organs were performed to detect CMV disease, when clinically indicated. Results: One hundred and seventeen patients underwent ASCT in this period. There were 73 MSD, 34 HIT, 7 MUD, 3 mismatched sibling donor (MMSD) transplants. There were 78 episodes of CMV reactivation in 69 patients (58%). Incidence was highest in HIT -73% followed by MMSD - 66%, MUD- 57% and MSD - 43%. Artesunate was used in 25 patients for 27 (34%) of the total 78 episodes; as 1st line agent in 6, 2nd line in 13 and 3rd line in 8 episodes. Median CMV viral load was 1.6x 103 copies per mL at start of artesunate. Median duration of use was 14 days (range 6 to 49). It was used preemptively in 15 episodes and as therapeutic (end organ involvement) in 12. Five (19%) of the 27 CMV episodes cleared with artesunate. However artesunate was effective in controlling CMV proliferation (absence of log increase in CMV copy numbers at 2 weeks and absence of progression to end organ CMV disease) in 20(74%) of 27 episodes.Artesunate failure rate was 22% (6 of 27 episodes). Response could not be evaluated in 1 patient. The CMV kinetics of the 26 episodes is depicted in figure 1. Twenty two patients tolerated artesunate with no major toxicities. However, 3 patients developed haemolysis likely artesunate related, requiring stoppage of the drug. Conclusions: Artesunate has activity against CMV with failure rate of less than 25% and complete clearance in 20%. In resource limited settings, it may be used in patients who are cytopenic and intolerant to ganciclovir as it limits proliferation of CMV which was seen in about 3/4th of all episodes. Its role in CMV infection should be explored prospectively in settings where ganciclovir cannot be used and access to other CMV active drugs are limited. OffLabel Disclosure: Artesunate is an antimalarial drug which has been used for CMV reactivation in this study