Spiers Memorial Lecture: Molecular mechanics and molecular electronics

We describe our research into building integrated molecular electronics circuitry for a diverse set of functions, and with a focus on the fundamental scientific issues that surround this project. In particular, we discuss experiments aimed at understanding the function of bistable [2]rotaxane molecular electronic switches by correlating the switching kinetics and ground state thermodynamic properties of those switches in various environments, ranging from the solution phase to a Langmuir monolayer of the switching molecules sandwiched between two electrodes. We discuss various devices, low bit-density memory circuits, and ultra-high density memory circuits that utilize the electrochemical switching characteristics of these molecules in conjunction with novel patterning methods. We also discuss interconnect schemes that are capable of bridging the micrometre to submicrometre length scales of conventional patterning approaches to the near-molecular length scales of the ultra-dense memory circuits. Finally, we discuss some of the challenges associated with fabricated ultra-dense molecular electronic integrated circuits

Fundamental scaling relationships revealed in the optical light curves of tidal disruption events

We present fundamental scaling relationships between properties of the optical/UV light curves of tidal disruption events (TDEs) and the mass of the black hole that disrupted the star. We have uncovered these relations from the late-time emission of TDEs. Using a sample of 63 optically-selected TDEs, the latest catalog to date, we observed flattening of the early-time emission into a near-constant late-time plateau for at least two-thirds of our sources. Compared to other properties of the TDE lightcurves (e.g., peak luminosity or decay rate) the plateau luminosity shows the tightest correlation with the total mass of host galaxy ($p$-value of $2 \times 10^{-6}$, with a residual scatter of 0.3 dex). Physically this plateau stems from the presence of an accretion flow. We demonstrate theoretically and numerically that the amplitude of this plateau emission is strongly correlated with black hole mass. By simulating a large population of TDEs, we determine a plateau luminosity-black hole mass scaling relationship well described by $\log_{10} \left(M_{\bullet}/M_{\odot} \right) = 1.50 \log_{10} \left( L_{\rm plat}/10^{43} {\rm erg \, s^{-1}} \right) + 9.0$. The observed plateau luminosities of TDEs and black hole masses in our large sample are in excellent agreement with this simulation. Using the black hole mass predicted from the observed TDE plateau luminosity, we reproduce the well-known scaling relations between black hole mass and galaxy velocity dispersion. The large black hole masses of 10 of the TDEs in our sample allow us to provide constraints on their black hole spins, favouring rapidly rotating black holes. We add 49 (34) black hole masses to the galaxy mass (velocity dispersion) scaling relationships, updating and extending these correlations into the low black hole mass regime.Comment: 24 pages + appendices, 20 figures. Submitted to MNRAS, comments welcom

A solid-state switch containing an electrochemically switchable bistable poly[n]rotaxane

Electrochemically switchable bistable main-chain poly[n]rotaxanes have been synthesised using a threading-followed-by-stoppering approach and were incorporated into solid-state, molecular switch tunnel junction devices. In contrast to single-station poly[n]rotaxanes of similar structure, the bistable polymers do not fold into compact conformations held together by donor–acceptor interactions between alternating stacked p-electron rich and p-electron deficient aromatic systems. Films of the poly[n]rotaxane were incorporated into the devices by spin-coating, and their thickness was easily controlled. The switching functionality was characterised both (1) in solution by cyclic voltammetry and (2) in devices containing either two metal electrodes or one metal and one silicon electrode. Devices with one silicon electrode displayed hysteretic responses with applied voltage, allowing the devices to be switched between two conductance states, whereas devices containing two metal electrodes did not exhibit switching behaviour. The electrochemically switchable bistable poly[n]rotaxanes offer significant advantages in synthetic efficiency and ease of device fabrication as compared to bistable small-molecule [2]rotaxanes

Self‐management for adults with epilepsy: Aggregate Managing Epilepsy Well Network findings on depressive symptoms

ObjectiveTo assess depressive symptom outcomes in a pooled sample of epilepsy self‐management randomized controlled trials (RCTs) from the Managing Epilepsy Well (MEW) Network integrated research database (MEW DB).MethodsFive prospective RCTs involving 453 adults with epilepsy compared self‐management intervention (n = 232) versus treatment as usual or wait‐list control outcomes (n = 221). Depression was assessed with the nine‐item Patient Health Questionnaire. Other variables included age, gender, race, ethnicity, education, income, marital status, seizure frequency, and quality of life. Follow‐up assessments were collapsed into a visit 2 and a visit 3; these were conducted postbaseline.ResultsMean age was 43.5 years (SD = 12.6), nearly two‐thirds were women, and nearly one‐third were African American. Baseline sample characteristics were mostly similar in the self‐management intervention group versus controls. At follow‐up, the self‐management group had a significantly greater reduction in depression compared to controls at visit 2 (P < .0001) and visit 3 (P = .0002). Quality of life also significantly improved in the self‐management group at visit 2 (P = .001) and visit 3 (P = .005).SignificanceAggregate MEW DB analysis of five RCTs found depressive symptom severity and quality of life significantly improved in individuals randomized to self‐management intervention versus controls. Evidence‐based epilepsy self‐management programs should be made more broadly available in neurology practices.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151320/1/epi16322_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151320/2/epi16322.pd

Feeding rates of malaria vectors from a prototype attractive sugar bait station in Western Province, Zambia: results of an entomological validation study

Background: Attractive targeted sugar bait (ATSB) stations are a promising new approach to malaria vector control that could compliment current tools by exploiting the natural sugar feeding behaviors of mosquitoes. Recent proof of concept work with a prototype ATSB® Sarabi Bait Station (Westham Co., Hod-Hasharon, Israel) has demonstrated high feeding rates and significant reductions in vector density, human biting rate, and overall entomological inoculation rate for Anopheles gambiae sensu lato (s.l.) in the tropical savannah of western Mali. The study reported here was conducted in the more temperate, rainier region of Western Province, Zambia and was designed to confirm the primary vector species in region and to estimate corresponding rates of feeding from prototype attractive sugar bait (ASB) Sarabi Bait Stations. Methods: The product evaluated was the Sarabi v1.1.1 ASB station, which did not include insecticide but did include 0.8% uranine as a dye allowing for the detection, using UV fluorescence light microscopy, of mosquitoes that have acquired a sugar meal from the ASB. A two-phase, crossover study design was conducted in 10 village-based clusters in Western Province, Zambia. One study arm initially received 2 ASB stations per eligible structure while the other initially received 3. Primary mosquito sampling occurred via indoor and outdoor CDC Miniature UV Light Trap collection from March 01 through April 09, 2021 (Phase 1) and from April 19 to May 28, 2021 (Phase 2). Results: The dominant vector in the study area is Anopheles funestus s.l., which was the most abundant species group collected (31% of all Anophelines; 45,038/144,5550), had the highest sporozoite rate (3.16%; 66 positives out of 2,090 tested), and accounted for 94.3% (66/70) of all sporozoite positive specimens. Of those An. funestus specimens further identified to species, 97.2% (2,090/2,150) were An. funestus sensu stricto (s.s.). Anopheles gambiae s.l. (96.8% of which were Anopheles arabiensis) is a likely secondary vector and Anopheles squamosus may play a minor role in transmission. Overall, 21.6% (9,218/42,587) of An. funestus specimens and 10.4% (201/1,940) of An. gambiae specimens collected were positive for uranine, translating into an estimated daily feeding rate of 8.9% [7.7–9.9%] for An. funestus (inter-cluster range of 5.5% to 12.7%) and 3.9% [3.3–4.7%] for An. gambiae (inter-cluster range of 1.0–5.2%). Feeding rates were no different among mosquitoes collected indoors or outdoors, or among mosquitoes from clusters with 2 or 3 ASBs per eligible structure. Similarly, there were no correlations observed between feeding rates and the average number of ASB stations per hectare or with weekly rainfall amounts. Conclusions: Anopheles funestus and An. gambiae vector populations in Western Province, Zambia readily fed from the prototype Sarabi v1.1.1 ASB sugar bait station. Observed feeding rates are in line with those thought to be required for ATSB stations to achieve reductions in malaria transmission when used in combination with conventional control methods (IRS or LLIN). These results supported the decision to implement a large-scale, epidemiological cluster randomized controlled trial of ATSB in Zambia, deploying 2 ATSB stations per eligible structure

Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT, but evidence for their effectiveness and safety in larger animals is lacking. HD transgenic sheep express the full-length human HTT with 73 CAG repeats. AAV9 was used to deliver unilaterally to HD sheep striatum an artificial miRNA targeting exon 48 of the human HTT mRNA under control of two alternative promoters: U6 or CβA. The treatment reduced human mutant (m) HTT mRNA and protein 50-80% in the striatum at 1 and 6 months post injection. Silencing was detectable in both the caudate and putamen. Levels of endogenous sheep HTT protein were not affected. There was no significant loss of neurons labeled by DARPP32 or NeuN at 6 months after treatment, and Iba1-positive microglia were detected at control levels. It is concluded that safe and effective silencing of human mHTT protein can be achieved and sustained in a large-animal brain by direct delivery of an AAV carrying an artificial miRNA

Two-Dimensional Molecular Electronics Circuits

Addressing an array of bistable [2]rotaxanes through a two‐dimensional crossbar arrangement provides the device element of a current‐driven molecular electronic circuit. The development of the [2]rotaxane switches through an iterative, evolutionary process is described. The arrangement reported here allows both memory and logic functions to use the same elements

Draxin acts as a molecular rheostat of canonical Wnt signaling to control cranial neural crest EMT

Neural crest cells undergo a spatiotemporally regulated epithelial-to-mesenchymal transition (EMT) that proceeds head to tailward to exit from the neural tube. In this study, we show that the secreted molecule Draxin is expressed in a transient rostrocaudal wave that mirrors this emigration pattern, initiating after neural crest specification and being down-regulated just before delamination. Functional experiments reveal that Draxin regulates the timing of cranial neural crest EMT by transiently inhibiting canonical Wnt signaling. Ectopic maintenance of Draxin in the cranial neural tube blocks full EMT; while cells delaminate, they fail to become mesenchymal and migratory. Loss of Draxin results in premature delamination but also in failure to mesenchymalize. These results suggest that a pulse of intermediate Wnt signaling triggers EMT and is necessary for its completion. Taken together, these data show that transient secreted Draxin mediates proper levels of canonical Wnt signaling required to regulate the precise timing of initiation and completion of cranial neural crest EMT