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Opioid use disorder is heritable, yet its genetic etiology is largely unknown. C57BL/6J and C57BL/6NJ mouse substrains exhibit phenotypic diversity in the context of limited genetic diversity which together can facilitate genetic discovery. Here, we found C57BL/6NJ mice were less sensitive to oxycodone (OXY)‐induced locomotor activation versus C57BL/6J mice in a conditioned place preference paradigm. Narrow‐sense heritability of OXY‐induced locomotor activity traits ranged from 0.22 to 0.31, implicating suitability for genetic analysis. Quantitative trait locus (QTL) mapping in an F2 cross identified a chromosome 1 QTL explaining 7%–12% of the variance in OXY locomotion and anxiety‐like withdrawal in the elevated plus maze. A second QTL for EPM withdrawal behavior on chromosome 5 near Gabra2 (alpha‐2 subunit of GABA‐A receptor) explained 9% of the variance. To narrow the chromosome 1 locus, we generated recombinant lines spanning 163–181 Mb, captured the QTL for OXY locomotor traits and withdrawal, and fine‐mapped a 2.45‐Mb region (170.16–172.61 Mb). Transcriptome analysis identified five, localized striatal cis‐eQTL transcripts and two were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9 codes for a potassium channel (GIRK3) that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows functional adaptations following chronic opioid administration. To summarize, we identified two candidate genes underlying the physiological and behavioral properties of opioids, with direct preclinical relevance to investigators employing these widely used substrains and clinical relevance to human genetic studies of opioid use disorder. We exploited near‐isogenic C57BL/6 substrains to fine‐map a 2.45‐Mb region containing DNA variants underlying oxycodone behaviors. We mapped a genomic region on distal chromosome 1 and identified genotype‐driven, differentially expressed mRNAs and proteins within this region and DNA variants. Atp1a2 and Kcnj9 as two likely candidate genes underlying oxycodone behavior.

Opioid use disorder is heritable, yet its genetic etiology is largely unknown. C57BL/6J and C57BL/6NJ mouse substrains exhibit phenotypic diversity in the context of limited genetic diversity which together can facilitate genetic discovery. Here, we found C57BL/6NJ mice were less sensitive to oxycodone (OXY)-induced locomotor activation versus C57BL/6J mice in a conditioned place preference paradigm. Narrow-sense heritability was estimated at 0.22-0.31, implicating suitability for genetic analysis. Quantitative trait locus (QTL) mapping in an F2 cross identified a chromosome 1 QTL explaining 7-12% of the variance in OXY locomotion and anxiety-like withdrawal in the elevated plus maze. A second QTL for EPM withdrawal behavior on chromosome 5 near (alpha-2 subunit of GABA-A receptor) explained 9% of the variance. To narrow the chromosome 1 locus, we generated recombinant lines spanning 163-181 Mb, captured the QTL for OXY locomotor traits and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). Transcriptome analysis identified five, localized striatal cis-eQTL transcripts and two were confirmed at the protein level (KCNJ9, ATP1A2). codes for a potassium channel (GIRK3) that is a major effector of mu opioid receptor signaling. codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows functional adaptations following chronic opioid administration. To summarize, we identified two candidate genes underlying the physiological and behavioral properties of opioids, with direct preclinical relevance to investigators employing these widely used substrains and clinical relevance to human genetic studies of opioid use disorder.

The social identity approach to leadership argues that leaders’ capacity to influence and inspire others is grounded in a shared sense of social identity (or ‘us-ness’) that those leaders create, advance, represent, and embed for the groups they lead. The approach therefore argues that a key task for leaders is to develop insights and skills of (social) identity leadership that allow them to motivate and mobilize groups and transform them into a potent social and organizational force. In contrast to other approaches and programs which focus on leaders’ leader identity (their ‘I-ness’), the 5R leadership development program supports the development of leaders’ social identity by raising awareness of the importance of social identity (‘we-ness’) for leadership and taking leaders through structured activities that help them build engaged and inclusive teams. The present research assessed the benefits of facilitated and learner self-directed versions of the 5R program ( N s = 27, 22 respectively) relative to a no-treatment control ( N = 27). Results (including those of an intention-to-treat analysis; N = 76) indicated that, relative to leaders in the control condition, those who participated in both forms of 5R reported large increases in identity leadership knowledge, as well as medium-sized increases in both team engagement (a compound factor comprised of team identification, team OCB, team efficacy, and work engagement) and ‘teamfulness’ (comprised of team reflexivity, team psychological safety, team goal clarity, and inclusive team climate). We reflect on the importance of teamfulness for leadership and team functioning and on the value of programs that help leaders develop this.

Long-term follow-up of 12 persons with Leber's congenital amaurosis treated with gene therapy showed that about half of them had improvements in retinal sensitivity (although the extent varied markedly among patients), followed by a decline. Leber’s congenital amaurosis is a group of inherited, early-onset, severe retinal dystrophies that cause substantial sight impairment in childhood. 1 One of the causes of this condition is mutations in the gene encoding RPE65 (retinal pigment epithelium–specific protein 65 kDa). The encoded retinoid isomerase converts all- trans retinyl esters to 11- cis retinal for the regeneration of visual pigment after exposure to light. RPE65 deficiency causes photoreceptor-cell dysfunction and impaired vision from birth. Severe dysfunction of rod photoreceptor cells, which are wholly reliant on retinal pigment epithelium–derived RPE65, causes severely impaired night vision. The function of cone photoreceptor cells, which mediate . . .

Circular dichroism spectra of naturally occurring molecules and also of synthetic chiral arrangements of plasmonic particles often exhibit characteristic bisignate shapes. Such spectra consist of peaks next to dips (or vice versa) and result from the superposition of signals originating from many individual chiral objects oriented randomly in solution. Here we show that by first aligning and then toggling the orientation of DNA-origami-scaffolded nanoparticle helices attached to a substrate, we are able to reversibly switch the optical response between two distinct circular dichroism spectra corresponding to either perpendicular or parallel helix orientation with respect to the light beam. The observed directional circular dichroism of our switchable plasmonic material is in good agreement with predictions based on dipole approximation theory. Such dynamic metamaterials introduce functionality into soft matter-based optical devices and may enable novel data storage schemes or signal modulators. Plasmonic resonances in nanoparticle helices arranged by the DNA origami method can give rise to strong circular dichroism at visible wavelengths. Schreiber et al . show that aligning and then toggling the orientation of such nanoparticle helices enables reversible switching of the dichroic response.

Three-methyl cytosine (3meC) are toxic DNA lesions, blocking base pairing. Bacteria and humans express members of the AlkB enzymes family, which directly remove 3meC. However, other organisms, including budding yeast, lack this class of enzymes. It remains an unanswered evolutionary question as to how yeast repairs 3meC, particularly in single-stranded DNA. The yeast Shu complex, a conserved homologous recombination factor, aids in preventing replication-associated mutagenesis from DNA base damaging agents such as methyl methanesulfonate (MMS). We found that MMS-treated Shu complex-deficient cells exhibit a genome-wide increase in A:T and G:C substitutions mutations. The G:C substitutions displayed transcriptional and replicational asymmetries consistent with mutations resulting from 3meC. Ectopic expression of a human AlkB homolog in Shu-deficient yeast rescues MMS-induced growth defects and increased mutagenesis. Thus, our work identifies a novel homologous recombination-based mechanism mediated by the Shu complex for coping with alkylation adducts.

We recently reported mid-wavelength infrared (MWIR) InAs/InAsSb type II strained-layer superlattice (T2SLS) unipolar barrier detectors and focal-plane arrays with significantly higher operating temperature than InSb. Herein, we document the development leading to the MWIR InAs/InAsSb T2SLS detectors at the NASA Jet Propulsion Laboratory. We also briefly compare the InAs/InAsSb T2SLS with some other approaches.

The electrostatic accelerator (ESA) EG-5 has been operating stationary in the Nuclear Physics Department of the Nuclear Physics Department of JINR (Dubna) since 1965. Along with an experimental nuclear reactor and a pulsed accelerator IREN, ESA EG-5 occupies its own unique niche as part of a complex of nuclear physics installations. The beams of high-energy particles obtained using EG-5 have the highest energy stability (± 15 keV per 2 MeV), due to which it is possible to conduct unique studies of the elemental composition of solids, including depth profiling, conducting studies of fast neutron nuclear reactions, etc. ESA EG-5 is a universal research device that allows conducting both studies of the elemental composition and physical, chemical and biological modification of objects of inanimate and living nature, respectively. EG-5 electrostatic accelerator at FLNP JINR, used to produce intense fluxes of fast particles (H + , He + , D + ) and neutrons; for elemental analysis of surface layers of various objects using beams of α-particles, using non-destructive techniques RBS, ERD and PIXE; for implantation of ions into the surface layers of various materials; to study the radiation resistance of materials. Unique opportunities will appear after the implementation of a microbeam spectrometer at the EG-5 accelerator in period since 2025.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1–5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.

A new algorithm for constructing multivariate interpolation Hermite polynomials in analytical form in a multidimensional hypercube is presented. These polynomials are determined from a specially constructed set of values of the polynomials themselves and their partial derivatives with continuous derivatives up to a given order on the boundaries of the finite elements. The effciency of the finite element schemes, algor thms and programs is demonstrated by solving the Helmholtz problem for a cube.