Molecular Infectious Disease Epidemiology: Survival Analysis and Algorithms Linking Phylogenies to Transmission Trees

Recent work has attempted to use whole-genome sequence data from pathogens to reconstruct the transmission trees linking infectors and infectees in outbreaks. However, transmission trees from one outbreak do not generalize to future outbreaks. Reconstruction of transmission trees is most useful to public health if it leads to generalizable scientific insights about disease transmission. In a survival analysis framework, estimation of transmission parameters is based on sums or averages over the possible transmission trees. A phylogeny can increase the precision of these estimates by providing partial information about who infected whom. The leaves of the phylogeny represent sampled pathogens, which have known hosts. The interior nodes represent common ancestors of sampled pathogens, which have unknown hosts. Starting from assumptions about disease biology and epidemiologic study design, we prove that there is a one-to-one correspondence between the possible assignments of interior node hosts and the transmission trees simultaneously consistent with the phylogeny and the epidemiologic data on person, place, and time. We develop algorithms to enumerate these transmission trees and show these can be used to calculate likelihoods that incorporate both epidemiologic data and a phylogeny. A simulation study confirms that this leads to more efficient estimates of hazard ratios for infectiousness and baseline hazards of infectious contact, and we use these methods to analyze data from a foot-and-mouth disease virus outbreak in the United Kingdom in 2001. These results demonstrate the importance of data on individuals who escape infection, which is often overlooked. The combination of survival analysis and algorithms linking phylogenies to transmission trees is a rigorous but flexible statistical foundation for molecular infectious disease epidemiology.Comment: 28 pages, 11 figures, 3 table

The Role of Sulfatide in Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is characterized by the accumulation of amyloid beta plaques, neurofibrillary tangles (NFT) and loss of cortical neurons that control memory and cognition. The cause of NFTs and Aβ plaques is not clear, though it is known that they are formed by enzymes which are preferentially sequestered to membrane domains called lipid rafts. Sulfatide (ST) is a glycosphingolipid that is essential for the proper structure and function of lipid rafts. In mice that lack ST, membrane domains that are normally maintained by adhesive contacts and functional lipid rafts are improperly formed and are unstable. In these ST null mice, voltage gated sodium channels, neuronal proteins that normally cluster at the nodes of Ranvier, initially accumulate in the node but are not retained with age. Taken together the findings from the ST null mice indicate that membrane organization is compromised. Recently, a published report demonstrated that ST is significantly reduced in AD. Based on this observation combined with the findings from the ST null mice, I propose that membrane architecture is also altered in AD and this alteration may facilitate AD pathogenesis. To test this hypothesis, I have used an immunohistochemical approach to assess neuronal membrane organization in AD and non-AD brain samples. Analysis of the sodium channel clusters was chosen since these nodal domains provide an easy assessment tool for membrane organization. In the current study, sodium channel domains were not altered and no change in isoform expression was observed. Based on these findings, membrane organization does not appear to be altered in AD. It is important to note, however, that sodium channel clusters are restricted to a specific region of the axon and thus membrane organization within other regions of the axon and in other regions of the neuron may be altered. Additionally, assessment of the brain samples, using thin layer chromatography, did not show a reduction in ST levels between the AD and non-AD brains. Therefore, my study strongly suggests that further analysis of ST levels in AD brains should be conducted to resolve the contrasting results between the current study and the previously published work

Application of Electrical Resistivity Geophysical Monitoring for Detection of Preferential Flow

Preferential flow is a common occurrence during infiltration yet is often not accounted for in predictive flow models. This has implications for contaminant transport in that the extent of constituent plumes are often underestimated, thereby reducing the effectiveness of any remediation efforts. Electrical resistivity monitoring could be a useful tool to determine if infiltration is bypassing parts of the subsurface through preferential flow pathways and to better inform predictive models. The viability of this method was evaluated through simple electrical simulations and with multiple column experiments across scales using advanced observation techniques like 4D computed tomography. Electrical resistivity was used to monitor the progression of uniform wetting fronts as well as preferential flow and infiltration through macropore networks. Results indicate that certain characteristics in the response of apparent resistivity to preferential flow are distinct from uniform flow. Vertical bulk resistivity reduces rapidly as wetting in a macropore network increases the connectivity between electrodes. Strong positive spikes in electrical anisotropy are observed during preferential flow events and the arrival of a wetting front observed through resistivity monitoring occurs much earlier than predicted using bulk soil properties. These characteristics indicate that electrical resistivity monitoring is a viable method for the application of detecting preferential flow during infiltration in a heterogeneous system

NO-INDEPENDENT MODULATION OF SOLUBLE GUANYLYL CYCLASE (sGC) ACTIVITY AND FUNCTION

Soluble guanylyl cyclase (sGC) plays a key role in the nitric oxide (NO) signaling pathway, where it functions as an NO receptor and generator of a secondary intracellular messenger, cGMP. In addition to NO, investigators have identified a number of proteins that interact with sGC and modulate its function. For example, the interaction of sGC with ADP-ribosylation factor GTPase activating protein 1 (AGAP1) governs sGC’s intracellular distribution and therefore mediates localized production of cGMP. Interactions of sGC with heat-shock protein 90 (HSP90) or HSP70 promote the extent of sGC activation upon NO stimulation, while interaction of sGC with the η subunit of chaperonin-containing T-complex polypeptide 1 (CCTη) or with protein disulfide isomerase (PDI) decreases NO-stimulated cGMP production. Previous experiments demonstrated that the G-protein signaling modulator protein, activator of G-protein signaling 3 (AGS3), attenuates the response of sGC to activators in cell lysates. In this report, we provide evidence that sGC activity and responsiveness are increased in AGS3-deficient mice. We found that AGS3-deficient mice not only have a lower resting blood pressure than their wild-type counterparts, but also are more sensitive to sGC agonists (DEA-NO and BAY41-2272). Hematoxylin and eosin staining of aorta sections did not show any significant no morphological differences between AGS3-/- and wild type mice. However, sGC in aortic lysates from AGS3-/- mice generated a higher level of cGMP in response to the NO-donor, DEA-NO, than in wild type lysates. These data indicate that, in the absence of AGS3, sGC activity is increased within smooth muscle cells of aortic tissue. In summary, the data from the present study suggests that AGS3 is a negative regulator of sGC vascular function

128-bit multicomparator

A 128-bit multicomparator was designed to perform the search-sort function on arbitrary length data strings. Devices can be cascaded for longer block lengths or paralleled for bit-parallel, word-serial applications. The circuit utilizes a 3-phase static-dynamic shift register cell for data handling and a unique gated EXCLUSIVE-NOR circuit to accomplish the compare function. The compare operation is performed bit parallel between a `data' register and a `key' register with a third `mask' register containing DON'T CARE bits that disable the comparator. The multicomparator was fabricated using p-channel silicon-gate metal-oxide-semiconductor (MOS) technology on a 107/spl times/150 mil chip containing 3350 devices. With transistor-transistor logic (TTL) input, data rates in excess of 2 MHz have been attained. The average power dissipation was 250 mW in the dynamic mode and 300 mW in the static mode

Design and performance of beam test electronics for the PHENIX Multiplicity Vertex Detector

The system architecture and test results of the custom circuits and beam test system for the Multiplicity-Vertex Detector (MVD) for the PHENIX detector collaboration at the Relativistic Heavy Ion Collider (RHIC) are presented in this paper. The final detector per-channel signal processing chain will consist of a preamplifier-gain stage, a current-mode summed multiplicity discriminator, a 64-deep analog memory (simultaneous read-write), a post-memory analog correlator, and a 10-bit 5 {mu}s ADC. The Heap Manager provides all timing control, data buffering, and data formatting for a single 256-channel multi-chip module (MCM). Each chip set is partitioned into 32-channel sets. Beam test (16-cell deep memory) performance for the various blocks will be presented as well as the ionizing radiation damage performance of the 1.2 {mu} n-well CMOS process used for preamplifier fabrication

Quantifying the habitat and zoogeomorphic capabilities of spawning European barbel Barbus barbus, a lithophilous cyprinid

© 2019 The Authors. River Research and Applications published by Wiley Periodicals, Inc. Suitable gravel availability is critical for the spawning success of lithophilous fishes, including redd builders. Redd construction during spawning can alter substrate characteristics, thereby influencing hydraulic conditions and sediment transport, highlighting the importance of spawning as a zoogeomorphic activity. Here, interactions between redd-building fish and their spawning environment were investigated for European barbel Barbus barbus with a comparative approach across three English rivers: Teme (western), Great Ouse (eastern) and Idle (central). Sediment characteristics of spawning habitats were similar across the rivers, including subsurface fine sediment (<2 mm) content (≈20% dry weight), but elevated subsurface silt content and coarser surface sediments were found in the river Teme. Water velocities were similar at spawning sites despite differences in channel width and depth. Redds were characterized by a pit and tailspill, with no differences in surface grain-size characteristics between these and the surrounding riverbed, but with topographic alteration (dimensions and tailspill amplitude) in line with those of salmonids. Estimates of the fraction of the bed that spawning barbel were capable of moving exceeded 97% in all rivers. Estimated reproductive potential varied significantly between the rivers Idle and Teme (3,098 to 9,715 eggs/m2), which was largely due to differences in barbel lengths affecting fecundity. Larger barbel, capable of producing and depositing more eggs, but in more spatially extensive redds, meaning fewer redds per given surface area of riverbed. Predictions of barbel egg mortality based on sand content were low across both rivers. The effects of silt on barbel egg and larvae development are unknown, but the levels detected here would significantly impact salmon egg mortality. Similarities in fish length to redd area and the size of moveable grains by spawning barbel and salmon suggest they have similar geomorphic effects on sediments, although fine sediment tolerance is highly divergent

OXIDATION RATES OF MAJOR FATTY ACIDS IN FASTING NEONATAL PIGS

Thirty-two pigs were used to compare the oxidation rates of uniformly labeled (U-14C) palmitic (16:0), stearic (18:0), oleic (18:1) and linoleic (18:2) acids in fasting neonatal pigs. The pigs were allowed to nurse the sow for 24 to 48 h following birth. Subsequently, they were removed, an indwelling catheter was surgically placed in the external iliac vein and the pigs were fasted for 12 h to attain a postabsorptive state. The 14C fatty acids were administered as a single infusion (10 / μCi) via the catheter, and recovery of the label as expired 14CO2 was determined at 45-min intervals for a 6-h period. Blood samples were taken following the infusion (15, 60, 120, 240, 360 min) to monitor activity maintained within the free fatty acid (FFA) fraction of the plasma pool. The oxidation rate of each fatty acid was corrected for the difference in dose dilution using a uniform factor based on plasma concentration of 18:1. The cumulative 6-h 14CO2 recovery rates (percentage of dose) were 19.1, 6.6, 30.1 and 13.1% for 16:0, 18:0, 18:1 and 18:2, respectively. Oleic acid was oxidized at a more (P\u3c.05) rapid rate than the other fatty acids. Palmitic acid and 18:2 were oxidized more rapidly than 18:0, although the difference between 18:0 and 18:2 was not significant. Plasma FFA pools differed with respect to the proportion of infused activity remaining at various times after administration. At 60 and 120 min postinfusion, the greatest (P\u3c.05) proportion of activity was maintained in the 18:1 pool (11.9 and 6.6%, respectively, vs 7.7 and 4.3% for 16:0, 6.9 and 3.9% for 18:2 and 3.6 and 2.2% for 18:0). Palmitic acid and 18:2 had a greater (P\u3c.05) level of activity in the plasma FFA pool at 60 min than did 18:0. This same pattern was observed through 2 h, but by 240 min postinfusion, the proportion of activity remaining in each of the plasma pools was similar. Rate of oxidation appeared to correspond with plasma concentration and proportion of activity remaining in the plasma FFA pool

OXIDATION RATES OF MAJOR FATTY ACIDS IN FASTING NEONATAL PIGS

Thirty-two pigs were used to compare the oxidation rates of uniformly labeled (U-14C) palmitic (16:0), stearic (18:0), oleic (18:1) and linoleic (18:2) acids in fasting neonatal pigs. The pigs were allowed to nurse the sow for 24 to 48 h following birth. Subsequently, they were removed, an indwelling catheter was surgically placed in the external iliac vein and the pigs were fasted for 12 h to attain a postabsorptive state. The 14C fatty acids were administered as a single infusion (10 / μCi) via the catheter, and recovery of the label as expired 14CO2 was determined at 45-min intervals for a 6-h period. Blood samples were taken following the infusion (15, 60, 120, 240, 360 min) to monitor activity maintained within the free fatty acid (FFA) fraction of the plasma pool. The oxidation rate of each fatty acid was corrected for the difference in dose dilution using a uniform factor based on plasma concentration of 18:1. The cumulative 6-h 14CO2 recovery rates (percentage of dose) were 19.1, 6.6, 30.1 and 13.1% for 16:0, 18:0, 18:1 and 18:2, respectively. Oleic acid was oxidized at a more (P\u3c.05) rapid rate than the other fatty acids. Palmitic acid and 18:2 were oxidized more rapidly than 18:0, although the difference between 18:0 and 18:2 was not significant. Plasma FFA pools differed with respect to the proportion of infused activity remaining at various times after administration. At 60 and 120 min postinfusion, the greatest (P\u3c.05) proportion of activity was maintained in the 18:1 pool (11.9 and 6.6%, respectively, vs 7.7 and 4.3% for 16:0, 6.9 and 3.9% for 18:2 and 3.6 and 2.2% for 18:0). Palmitic acid and 18:2 had a greater (P\u3c.05) level of activity in the plasma FFA pool at 60 min than did 18:0. This same pattern was observed through 2 h, but by 240 min postinfusion, the proportion of activity remaining in each of the plasma pools was similar. Rate of oxidation appeared to correspond with plasma concentration and proportion of activity remaining in the plasma FFA pool