Continuously tunable modulation scheme for precision control of optical cavities with variable detuning

We present a scheme for locking optical cavities with arbitrary detuning by many linewidths from resonance using an electro-optic modulator that can provide arbitrary ratios of amplitude-to-phase modulation. We demonstrate our scheme on a Fabry–Perot cavity, and show that a well-behaved linear error signal can be obtained by demodulating the reflected light from a cavity that is detuned by several linewidths.National Science Foundation (U.S.) (PHY-0757058

Orienting Patients to Greater Opioid Safety: Models of Community Pharmacy-Based Naloxone

The leading cause of adult injury death in the USA is drug overdose, the majority of which involves prescription opioid medications. Outside of the USA, deaths by drug overdose are also on the rise, and overdose is a leading cause of death for drug users. Reducing overdose risk while maintaining access to prescription opioids when medically indicated requires careful consideration of how opioids are prescribed and dispensed, how patients use them, how they interact with other medications, and how they are safely stored. Pharmacists, highly trained professionals expert at detecting and managing medication errors and drug-drug interactions, safe dispensing, and patient counseling, are an under-utilized asset in addressing overdose in the US and globally. Pharmacies provide a high-yield setting where patient and caregiver customers can access naloxone—an opioid antagonist that reverses opioid overdose—and overdose prevention counseling. This case study briefly describes and provides two US state-specific examples of innovative policy models of pharmacy-based naloxone, implemented to reduce overdose events and improve opioid safety: Collaborative Pharmacy Practice Agreements and Pharmacy Standing Orders

A Face Versus Non-Face Context Influences Amygdala Responses to Masked Fearful Eye Whites

The structure of the mask stimulus is crucial in backward masking studies and we recently demonstrated such an effect when masking faces. Specifically, we showed that activity of the amygdala is increased to fearful facial expressions masked with neutral faces and decreased to fearful expressions masked with a pattern mask—but critically both masked conditions discriminated fearful expressions from happy expressions. Given this finding, we sought to test whether masked fearful eye whites would produce a similar profile of amygdala response in a face vs non-face context. During functional magnetic resonance imaging scanning sessions, 30 participants viewed fearful or happy eye whites masked with either neutral faces or pattern images. Results indicated amygdala activity was increased to fearful vs happy eye whites in the face mask condition, but decreased to fearful vs happy eye whites in the pattern mask condition—effectively replicating and expanding our previous report. Our data support the idea that the amygdala is responsive to fearful eye whites, but that the nature of this activity observed in a backward masking design depends on the mask stimulus

2\u27-O-Methyl at 20-mer Guide Strand 3\u27 Termini May Negatively Affect Target Silencing Activity of Fully Chemically Modified siRNA

Small interfering RNAs (siRNAs) have the potential to treat a broad range of diseases. siRNAs need to be extensively chemically modified to improve their bioavailability, safety, and stability in vivo. However, chemical modifications variably impact target silencing for different siRNA sequences, making the activity of chemically modified siRNA difficult to predict. Here, we systematically evaluated the impact of 3\u27 terminal modifications (2\u27-O-methyl versus 2\u27-fluoro) on guide strands of different length and showed that 3\u27 terminal 2\u27-O-methyl modification negatively impacts activity for \u3e60% of siRNA sequences tested but only in the context of 20- and not 19- or 21-nt-long guide strands. These results indicate that sequence, modification pattern, and structure may cooperatively affect target silencing. Interestingly, the introduction of an extra 2\u27-fluoro modification in the seed region at guide strand position 5, but not 7, may partially compensate for the negative impact of 3\u27 terminal 2\u27-O-methyl modification. Molecular modeling analysis suggests that 2\u27-O-methyl modification may impair guide strand interactions within the PAZ domain of argonaute-2, which may affect target recognition and cleavage, specifically when guide strands are 20-nt long. Our findings emphasize the complex nature of modified RNA-protein interactions and contribute to design principles for chemically modified siRNAs

Development of a CsI Calorimeter for the Compton-Pair (ComPair) Balloon-Borne Gamma-Ray Telescope

There is a growing interest in astrophysics to fill in the observational gamma-ray MeV gap. We, therefore, developed a CsI:Tl calorimeter prototype as a subsystem to a balloon-based Compton and Pair-production telescope known as ComPair. ComPair is a technology demonstrator for a gamma-ray telescope in the MeV range that is comprised of 4 subsystems: the double-sided silicon detector, virtual Frisch grid CdZnTe, CsI calorimeter, and a plastic-based anti-coincidence detector. The prototype CsI calorimeter is composed of thirty CsI logs, each with a geometry of $1.67 \times 1.67 \times 10 \ \mathrm{cm^3}$. The logs are arranged in a hodoscopic fashion with 6 in a row that alternate directions in each layer. Each log has a resolution of around $8 \%$ full-width-at-half-maximum (FWHM) at $662 \ \mathrm{keV}$ with a dynamic energy range of around $250\ \mathrm{keV}-30 \ \mathrm{MeV}$. A $2\times2$ array of SensL J-series SiPMs read out each end of the log to estimate the depth of interaction and energy deposition with signals read out with an IDEAS ROSSPAD. We also utilize an Arduino to synchronize with the other ComPair subsystems that comprise the full telescope. This work presents the development and performance of the calorimeter, its testing in thermal and vacuum conditions, and results from irradiation by $2-25 \ \mathrm{MeV}$ monoenergetic gamma-ray beams. The CsI calorimeter will fly onboard ComPair as a balloon experiment in the summer of 2023

Star polymers reduce IAPP toxicity via accelerated amyloid aggregation

Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting the aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes. The binding of PHEA elevated the beta-sheet content in IAPP aggregates while rendered a new morphology of ‘stelliform’ amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rod-like scaffolds for IAPP binding and subsequently accelerated IAPP aggregation by increased local peptide concentration. The tertiary structure of the star nanoparticles was found to be essential to drive the specific interactions required to impel the accelerated IAPP aggregation. This study shed new light on the structure-toxicity relationship of IAPP and points to the potential of exploiting star polymers as a new class of therapeutic agents against amyloidogenesis

Visual and Verbal Serial List Learning in Patients with Statistically-Determined Mild Cognitive Impairment.

Background and Objective: Prior research with patients with mild cognitive impairment (MCI) suggests that visual versus verbal episodic memory test performance may be more sensitive to emergent illness. However, little research has examined visual versus verbal episodic memory performance as related to MCI subtypes. Research Design and Methods: Patients were diagnosed with non-MCI, amnestic MCI (aMCI), and combined mixed/dysexecutive MCI (mixed/dys MCI). Visual and verbal episodic memory were assessed with the Brief Visuospatial Memory Test-Revised (BVMT-R) and the 12-word Philadelphia (repeatable) Verbal Learning Test (P[r]VLT), respectively. Results: BVMT-R and P(r)VLT scores yielded similar between-group patterns of performance. Non-MCI patients scored better than other groups on all parameters. aMCI and mixed/dys MCI did not differ on immediate or delayed free recall. Both delayed BVMT-R and P(r)VLT recognition test performance dissociated all three groups. Logistic regression analyses found that BVMT-R delayed free recall and delayed recognition scores correctly classified more patients with MCI (75.40%) than analogous P(r)VLT scores (66.20%). Visual versus verbal memory within-group analyses found no differences among non-MCI patients; P(r)VLT immediate free recall was worse among aMCI patients, but BVMT-R immediate free recall and delayed recognition were worse among mixed/dys MCI patients. Discussion and Implications: Between-group analyses found convergent patterns of performance such that both tests identified elements of amnesia. However, logistic and within-group analyses found differing performance patterns suggesting that impaired visual episodic memory performance may be specific to emergent illness in mixed/dys MCI. Complementary but divergent neurocognitive networks may underlie visual versus verbal episodic memory performance in some patients with MCI