G protein-coupled receptors as targets for transformative neuropsychiatric therapeutics

G protein-coupled receptors (GPCRs) constitute the largest family of druggable genes in the human genome. Even though perhaps 30% of approved medications target GPCRs, they interact with only a small number of them. Here, we consider whether there might be new opportunities for transformative therapeutics for neuropsychiatric disorders by specifically targeting both known and understudied GPCRs. Using psychedelic drugs that target serotonin receptors as an example, we show how recent insights into the structure, function, signaling, and cell biology of these receptors have led to potentially novel therapeutics. We next focus on the possibility that nonpsychedelic 5-HT2A receptor agonists might prove to be safe and rapidly acting antidepressants. Finally, we examine understudied and orphan GPCRs using the MRGPR family of receptors as an example

A Multi-Parameter Measurement System for MEMS Anemoters for Data Collection with Machine Learning Outcomes

In order to generate consistent and comprehensive datasets for the application ofmachine learning algorithms to MEMS thermal flow sensors, a measurement set up was created.This system allows automatic data collection of large datasets involving parameters such as the angle of attack, humidity, temperature and flow speed. The electrical output signals in both the time and frequency domain can be measured for both AC and DC actuation. The setup has been able to fully characterize an anemometer by exposing it to flows of 0 to 5 m/s in steps of 0.02 m/s under anglesfrom -45 to 45° in steps of 5° at a constant temperature of 25 °C and humidity of 30 %RH and complete the measurement in 8 hours

5-HT2ASNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is essential for the actions of classical psychedelic drugs. In this study, we examined whether sequence variations in the 5-HT2AR gene affect the signaling of four commonly used psychedelic drugs. We examined the in vitro pharmacology of seven non-synonymous single-nucleotide polymorphisms (SNPs), which give rise to Ser12Asn, Thr25Asn, Asp48Asn, Ile197Val4.47, Ala230Thr, Ala447Val, and His452Tyr variant 5-HT2A serotonin receptors. We found that these non-synonymous SNPs exert statistically significant, although modest, effects on the efficacy and potency of four therapeutically relevant psychedelics. Significantly, the in vitro pharmacological effects of the SNP drug actions at 5-HT2AR are drug specific

A Machine Learning Enhanced MEMS Thermal Anemometer for Detection of Flow, Angle of Attack, and Relative Humidity

By optimizing machine learning (ML), the accuracy of a thermal anemometer has been improved (511%) when compared to conventional linear regression. In addition, ML has extended the functionality allowing for additional angle of attack and humidity information to be determined. The miniature sensor (0.16 cm 2 ) has been fabricated with a straightforward silicon on insulator (SOI) fabrication procedure. The sensor paired with ML could offer a cost-effective, small, and reliable solution for monitoring air in industrial and agricultural sensor grid applications, such as data centers and greenhouses. This proof of principle shows that thermal anemometers can have their accuracy and functionality enhanced through ML, enabling the estimation of multiple physical parameters with a single sensor

Long-Ranged Correlations in Sheared Fluids

The presence of long-ranged correlations in a fluid undergoing uniform shear flow is investigated. An exact relation between the density autocorrelation function and the density-mometum correlation function implies that the former must decay more rapidly than $1/r$, in contrast to predictions of simple mode coupling theory. Analytic and numerical evaluation of a non-perturbative mode-coupling model confirms a crossover from $1/r$ behavior at ''small'' $r$ to a stronger asymptotic power-law decay. The characteristic length scale is $\ell \approx \sqrt{\lambda_{0}/a}$ where $$ is the sound damping constant and $a$ is the shear rate.Comment: 15 pages, 2 figures. Submitted to PR

Structures of the entire human opioid receptor family

Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-Gi complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief

First Observation of Coherent π0\pi^0 Production in Neutrino Nucleus Interactions with Eν<E_{\nu}< 2 GeV

The MiniBooNE experiment at Fermilab has amassed the largest sample to date of $\pi^0$s produced in neutral current (NC) neutrino-nucleus interactions at low energy. This paper reports a measurement of the momentum distribution of $\pi^0$s produced in mineral oil (CH$_2$) and the first observation of coherent $\pi^0$ production below 2 GeV. In the forward direction, the yield of events observed above the expectation for resonant production is attributed primarily to coherent production off carbon, but may also include a small contribution from diffractive production on hydrogen. Integrated over the MiniBooNE neutrino flux, the sum of the NC coherent and diffractive modes is found to be (19.5 $\pm$1.1 (stat) $\pm$2.5 (sys))% of all exclusive NC $\pi^0$ production at MiniBooNE. These measurements are of immediate utility because they quantify an important background to MiniBooNE's search for $\nu_{\mu} \to \nu_e$ oscillations.Comment: Submitted to Phys. Lett.

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Disaster Situation and Humanitarian Emergency – In-Between Responses to the Refugee Crisis in Germany

In 2015, the needs of hundreds of thousands of refugees who arrived in Germany could only be met by deploying all available civil protection units. This article presents procedures and practices of state and non-state formal actors in the field of civil protection and related crisis management structures implemented and established across the board in the municipalities, the Federal Government and mass shelters, in particular in Bavaria. From a disaster research and humanitarian studies perspective we use the concept of “patterns of interpretation” to analyse the application of the “humanitarian emergency” and the “disaster situation” procedures to discuss whether the situation can really be categorized as “either-or” or whether the coexistence of the two served a function in managing such a complex situation. Finally, we discuss some developments that occurred after 2015/16 and consider the extent to which these developments shift or expand the existing patterns of interpretation

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe