Npbwr1 signaling mediates fast antidepressant action

Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant

Calibration of Local Volatility Model with Stochastic Interest Rates by Efficient Numerical PDE Method

Long maturity options or a wide class of hybrid products are evaluated using a local volatility type modelling for the asset price S(t) with a stochastic interest rate r(t). The calibration of the local volatility function is usually time-consuming because of the multi-dimensional nature of the problem. In this paper, we develop a calibration technique based on a partial differential equation (PDE) approach which allows an efficient implementation. The essential idea is based on solving the derived forward equation satisfied by P(t; S; r)Z(t; S; r), where P(t; S; r) represents the risk neutral probability density of (S(t); r(t)) and Z(t; S; r) the projection of the stochastic discounting factor in the state variables (S(t); r(t)). The solution provides effective and sufficient information for the calibration and pricing. The PDE solver is constructed by using ADI (Alternative Direction Implicit) method based on an extension of the Peaceman-Rachford scheme. Furthermore, an efficient algorithm to compute all the corrective terms in the local volatility function due to the stochastic interest rates is proposed by using the PDE solutions and grid points. Different numerical experiments are examined and compared to demonstrate the results of our theoretical analysis

Nanomagnetism of magnetoelectric granular thin-film antiferromagnets

Antiferromagnets have recently emerged as attractive platforms for spintronics applications, offering fundamentally new functionalities compared to their ferromagnetic counterparts. While nanoscale thin film materials are key to the development of future antiferromagnetic spintronics technologies, experimental tools to explore such films on the nanoscale are still sparse. Here, we offer a solution to this technological bottleneck, by addressing the ubiquitous surface magnetisation of magnetoelectic antiferromagnets in a granular thin film sample on the nanoscale using single-spin magnetometry in combination with spin-sensitive transport experiments. Specifically, we quantitatively image the evolution of individual nanoscale antiferromagnetic domains in 200-nm thin-films of Cr$_2$O$_3$ in real space and across the paramagnet-to-antiferromagnet phase transition. These experiments allow us to discern key properties of the Cr$_2$O$_3$ thin film, including the mechanism of domain formation and the strength of exchange coupling between individual grains comprising the film. Our work offers novel insights into Cr$_2$O$_3$'s magnetic ordering mechanism and establishes single spin magnetometry as a novel, widely applicable tool for nanoscale addressing of antiferromagnetic thin films.Comment: 22 pages, 7 figure

Nanomagnetism of Magnetoelectric Granular Thin-Film Antiferromagnets

Antiferromagnets have recently emerged as attractive platforms for spintronics applications, offering fundamentally new functionalities compared with their ferromagnetic counterparts. Whereas nanoscale thin-film materials are key to the development of future antiferromagnetic spintronic technologies, existing experimental tools tend to suffer from low resolution or expensive and complex equipment requirements. We offer a simple, high-resolution alternative by addressing the ubiquitous surface magnetization of magnetoelectric antiferromagnets in a granular thin-film sample on the nanoscale using single-spin magnetometry in combination with spin-sensitive transport experiments. Specifically, we quantitatively image the evolution of individual nanoscale antiferromagnetic domains in 200 nm thin films of Cr 2 O 3 in real space and across the paramagnet-to-antiferromagnet phase transition, finding an average domain size of 230 nm, several times larger than the average grain size in the film. These experiments allow us to discern key properties of the Cr 2 O 3 thin film, including the boundary magnetic moment density, the variation of critical temperature throughout the film, the mechanism of domain formation, and the strength of exchange coupling between individual grains comprising the film. Our work offers novel insights into the magnetic ordering mechanism of Cr 2 O 3 and firmly establishes single-spin magnetometry as a versatile and widely applicable tool for addressing antiferromagnetic thin films on the nanoscale. © 2019 American Chemical Society

MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B

Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification ofER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulatingER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factorsTFEBandTFE3-master regulators of lysosomal biogenesis and autophagy-controlER-phagy by inducing the expression of theER-phagy receptorFAM134B. TheTFEB/TFE3-FAM134B axis promotesER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes byFGFsignaling, a critical regulator of skeletal growth.FGFsignaling inducesJNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits thePI3K-PKB/Akt-mTORC1 pathway and promotesTFEB/TFE3 nuclear translocation and enhancesFAM134B transcription. Notably,FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allowsER-phagy to respond to both metabolic and developmental cues

Delphi studies in social and health sciences—Recommendations for an interdisciplinary standardized reporting (DELPHISTAR). Results of a Delphi study

While different proposals exist for a guideline on reporting Delphi studies, none of them has yet established itself in the health and social sciences and across the range of Delphi vari ants. This seems critical because empirical studies demonstrate a diversity of modifications in the conduction of Delphi studies and sometimes even errors in the reporting. The aim of the present study is to close this gap and formulate a general reporting guideline

Dual domestications and origin of traits in grapevine evolution

We elucidate grapevine evolution and domestication histories with 3525 cultivated and wild accessions worldwide. In the Pleistocene, harsh climate drove the separation of wild grape ecotypes caused by continuous habitat fragmentation. Then, domestication occurred concurrently about 11,000 years ago in Western Asia and the Caucasus to yield table and wine grapevines. The Western Asia domesticates dispersed into Europe with early farmers, introgressed with ancient wild western ecotypes, and subsequently diversified along human migration trails into muscat and unique western wine grape ancestries by the late Neolithic. Analyses of domestication traits also reveal new insights into selection for berry palatability, hermaphroditism, muscat flavor, and berry skin color. These data demonstrate the role of the grapevines in the early inception of agriculture across Eurasia

Personalized bacteriophage therapy outcomes for 100 consecutive cases:a multicentre, multinational, retrospective observational study

In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127–0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage–antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. BT100 study, ClinicalTrials.gov registration: NCT05498363.</p