bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baricitinib and tofacitinib off‐target profile, with a focus on Alzheimer's disease
Authors: Faquetti Maria L. , Slappendel Laura , Bigonne Hélène , Grisoni Francesca , Schneider Petra , Aichinger Georg , Schneider Gisbert , Sturla Shana J. , Burden Andrea M. 
Published: January 2024

AbstractINTRODUCTIONJanus kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer's disease (AD) due to their capacity to suppress inflammation via modulation of JAK/STAT signaling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact with unintended, often unknown, biological off‐targets, leading to associated effects. Nevertheless, the relevance of JAK inhibitors’ off‐target interactions in the context of AD remains unclear.METHODSPutative off‐targets of baricitinib and tofacitinib were predicted using a machine learning (ML) approach. After screening scientific literature, off‐targets were filtered based on their relevance to AD. Targets that had not been previously identified as off‐targets of baricitinib or tofacitinib were subsequently tested using biochemical or cell‐based assays. From those, active concentrations were compared to bioavailable concentrations in the brain predicted by physiologically based pharmacokinetic (PBPK) modeling.RESULTSWith the aid of ML and in vitro activity assays, we identified two enzymes previously unknown to be inhibited by baricitinib, namely casein kinase 2 subunit alpha 2 (CK2‐α2) and dual leucine zipper kinase (MAP3K12), both with binding constant (Kd) values of 5.8 μM. Predicted maximum concentrations of baricitinib in brain tissue using PBPK modeling range from 1.3 to 23 nM, which is two to three orders of magnitude below the corresponding binding constant.CONCLUSIONIn this study, we extended the list of baricitinib off‐targets that are potentially relevant for AD progression and predicted drug distribution in the brain. The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose. While additional research is needed to evaluate the potential impact of the off‐target interaction on AD, the combined approach of ML‐based target prediction, in vitro confirmation, and PBPK modeling may help prioritize drugs with a high likelihood of being effectively repurposed for AD.Highlights
This study explored JAK inhibitors' off‐targets in AD using a multidisciplinary approach.
We combined machine learning, in vitro tests, and PBPK modelling to predict and validate new off‐target interactions of tofacitinib and baricitinib in AD.
Previously unknown inhibition of two enzymes (CK2‐a2 and MAP3K12) by baricitinib were confirmed using in vitro experiments.
Our PBPK model indicates that baricitinib low brain permeability limits AD repurposing.
The proposed multidisciplinary approach optimizes drug repurposing efforts in AD research.
Safety of methotrexate administration in women with pregnancy of unknown location at high risk of ectopic pregnancy
Authors: Jin C. S. , Uzuner C. , Condous G. 
Published: January 2024

ABSTRACTObjectivesTo evaluate the safety of current guidelines on methotrexate (MTX) administration in women with pregnancy of unknown location (PUL) who are considered to have a high risk of underlying ectopic pregnancy (EP), and to investigate whether implementation of these guidelines would result in inadvertent exposure to MTX of viable intrauterine pregnancies (IUPs).MethodsThis was a retrospective observational study of consecutive clinically stable women who were classified with PUL at the early pregnancy unit of Nepean Hospital, Sydney, Australia, between 2007 and 2021. PUL was defined as a positive pregnancy test in the absence of signs of IUP or EP on transvaginal ultrasound. Patients with a PUL that behaved biochemically like an EP, but for which the location of pregnancy was not confirmed on ultrasound, were eligible for MTX to minimize the risk of subsequent tubal rupture. Criteria discussed in the guidelines of the American College of Obstetricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Care Excellence (NICE) were applied to the PUL database. The number of patients eligible to receive MTX and the number with an underlying viable IUP who would be inadvertently prescribed MTX were calculated.ResultsA total of 816 women with PUL were reviewed, of whom 724 had complete data and were included in the final analysis. Six patients had persistent PUL and the remaining 718 had a diagnosis of viable IUP, non‐viable IUP, EP or failed PUL. According to the ACOG, ASRM, RCOG and NICE guidelines, the rate of MTX administration among patients with PUL would have been 2.76%, 4.56%, 0.41% and 35.36%, respectively. However, no persistent PUL would have received MTX according to the ACOG, ASRM and RCOG protocols (the NICE protocol identified patients with persistent PUL with a sensitivity of 100%), and the majority of MTX treatments were unnecessary because those patients were later classified as having non‐viable IUP or failed PUL. Application of ACOG and ASRM guidance could result theoretically in inadvertent MTX administration to women with an underlying viable IUP at a rate of 4.1/1000 (3/724).ConclusionsCurrent guidelines used to predict high risk of EP in the PUL population lead to inadvertent MTX administration to women with an underlying viable IUP. These guidelines should be used wisely to ensure that no wanted pregnancy is exposed to MTX. Women with PUL should be monitored carefully, and MTX should be used judiciously when the location of pregnancy is yet to be confirmed. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Synthesis of (Arylimido)niobium(V) Bis(diethylamide) Complexes Containing Phenoxide Ligands
Authors: Nakashima Nonoka , Paosopa Sirichok , Nomura Kotohiro 
Published: January 2024

AbstractReaction of (arylimido)niobium(V) tris(diethylamide) complexes, Nb(NAr)(NEt2)3, prepared by treating Nb(NAr)Cl3(dme) (dme=1,2‐dimethoxyethane) with 3.0 equiv. of LiNEt2, with 1.0 equiv. of phenol afforded the corresponding phenoxide complexes, Nb(NAr)(NEt2)2(O‐2,6‐R2C6H3) [1 a–c, 2 a–c; Ar=2,6‐Me2C6H3 (1) 2,6‐iPr2C6H3 (2); R=tBu (a), iPr (b), Me (c)], which were identified by NMR spectroscopy, elemental analysis and the structures for 2 b, c were determined by X‐ray crystallographic analysis.
On quantum Poisson-Lie T-duality of WZNW models
Authors: Sakatani Yuho , Satoh Yuji 
Published: January 2024

Abstract
We study Poisson-Lie T-duality of the Wess-Zumino-Novikov-Witten (WZNW) models which are obtained from a class of Drinfel’d doubles and its generalization. In this case, the resultant WZNW models are known to be classically self-dual under Poisson-Lie T-duality. We describe an explicit construction of the associated currents, and discuss the conformal invariance under this duality. In a concrete example of the SU(2) WZNW model, we find that the self-duality is represented as a chiral automorphism of the $$ \hat{\mathfrak{su}} $$

su
̂

(2) affine Lie algebra, though the transformation of the currents is non-local and non-linear. This classical automorphism can be promoted to the quantum one through the parafermionic formulation of $$ \hat{\mathfrak{su}} $$

su
̂

(2), which in turn induces an isomorphism of the WZNW model. We thus find a full quantum equivalence of the dual pair under Poisson-Lie T-duality. The isomorphism is represented by a sign-change of a chiral boson or the order-disorder duality of the parafermionic conformal field theory as in Abelian T-duality on tori or in the mirror symmetry of the Gepner model.
Probing new physics with charge asymmetries in 2 same-sign leptons plus jets final states at the LHC
Authors: Arganda Ernesto , Da Rold Leandro , Juste Aurelio , Medina Anibal D. , Sandá Seoane Rosa M. 
Published: January 2024

Abstract
We study the impact of new physics models in the charge asymmetry defined for LHC final states consisting of two same-sign leptons (2SSl, with l = e, μ) plus jets (Njets ≥ 2), with a center-of-mass energy of $$ \sqrt{s} $$

s

= 13 TeV, where the main SM contribution is $$ t\overline{t}W $$
t

t
¯

W
production. Concretely, we consider three different new physics sources for the charge asymmetries: a heavy neutral scalar/pseudoscalar arising from the general two Higgs doublet model, an effective theory with dimension-6 four-quark operators, and a simplified R-parity-violating supersymmetric model with electroweakino production (higgsino-like or wino-like). We propose measuring the charge asymmetries differentially with respect to several kinematic observables, and inclusively/exclusively with the number of b-tagged jets in the final state (Nb ≥ {1, 2, 3}). Results are compared with the SM prediction using the χ2 criteria, expressing sensitivity in terms of the normal Gaussian significance. We show that some of the proposed new physics scenarios can be probed at the LHC even for the already recorded integrated luminosity of 139 fb−1. Finally, we also estimate the prospects for the potential LHC sensitivity to the considered new physics models in its high-luminosity phase.
Forward dijet production at the LHC within an impact parameter dependent TMD approach
Authors: Deganutti Federico , Royon Christophe , Schlichting Soeren 
Published: January 2024

Abstract
We investigate possible signatures of gluon saturation using forward p + A → j + j + X di-jet production processes at the Large Hadron Collider. In the forward rapidity region, this is a highly asymmetric process where partons with large longitudinal momentum fraction x in the dilute projectile are used as a probe to resolve the small x partonic content of the dense target. Such dilute-dense processes can be described in the factorization framework of Improved Transverse Momentum Distributions (ITMDs). We present a new model for ITMDs where we explicitly introduce the impact parameter (b) dependence in the ITMDs, to properly account for the nuclear enhancement of gluon saturation effects, and discuss the phenomenological consequences for p − Pb, p − Xe and p − O collisions at the LHC. While the case of p − p and e − p collisions is used to fix the model parameters, we find that, on average, the nuclear enhancement of the saturation scale is noticeably weaker than expected from naive scaling with a simple dependence on the atomic number. Since our model explicitly accounts for event-by-event fluctuations of the nuclear geometry, it can also be applied to study forward central correlations in p − A collisions.
Low-energy radiative backgrounds in CCD-based dark-matter detectors
Authors: Du Peizhi , Egaña-Ugrinovic Daniel , Essig Rouven , Sholapurkar Mukul 
Published: January 2024

Abstract
The reach of sub-GeV dark-matter detectors is at present severely affected by low-energy events from various origins. We present the theoretical methods to compute the single- and few-electron events that arise from secondary radiation emitted by high-energy particles as they pass through detector materials and perform a detailed simulation to quantify them at (Skipper) CCD-based experiments, focusing on the SENSEI data collected at Fermilab near the MINOS cavern. The simulations account for the generation of secondaries from Cherenkov and luminescent recombination radiation; photo-absorption in the bulk, backside layer, pitch adapter, and epoxy; the photon reflection and refraction at interfaces; thin-film interference; the roughness of the interfaces; the dynamics of charges produced in the highly doped CCD-backside-layers; and the partial charge collection on the CCD backside. We consider several systematic uncertainties, notably those stemming from the backside modeling, which we estimate with a “fiducial” and an “extreme” charge-diffusion model, with the former model being preferred due to better agreement with partial-charge collection data. We find that Cherenkov photons constitute about 30% of the observed single-electron events for both diffusion models; radiative recombination contributes negligibly to the event rate for the fiducial model, although it can dominate over Cherenkov for the extreme model. We also estimate the fraction of 2-electron events that arise from 1-electron event coincidences in the same pixel, finding that the entire 2-electron rate can be explained by coincidences of radiative events and spurious charge. Accounting for both radiative and non-radiative backgrounds, we project the sensitivity of future Skipper-CCD-based experiments to different dark-matter models. For light-mediator models with dark-matter masses of 1, 5, and 10 MeV, we find that future experiments with 10-kg-year exposures and successful background mitigation could have a sensitivity that is larger by 9, 3, and 2 orders of magnitude, respectively, when compared to an experiment without background improvements.
APC mutations disrupt β-catenin destruction complex condensates organized by Axin phase separation
Authors: Zhang Dan , Ni Qi-Qi , Wang Shu-Yang , He Wen-Feng , Hong Ze-Xuan , Liu Hui-Ye , Chen Xiao-Hong , Chen Li-Jie , Han Fang-Yi , Zhang Ling-Jie , Li Xiao-ming , Ding Yan-qing , Jiao Hong-li , Ye Ya-ping 
Published: January 2024

AbstractThe Wnt/β-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid–liquid-phase separation (LLPS) of Axin organized the β-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of β-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the β-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3β and CK1α were unsuccessfully recruited, preventing β-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of β-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.
Vascular injury activates the ELK1/SND1/SRF pathway to promote vascular smooth muscle cell proliferative phenotype and neointimal hyperplasia
Authors: Su Chao , Liu Mingxia , Yao Xuyang , Hao Wei , Ma Jinzheng , Ren Yuanyuan , Gao Xingjie , Xin Lingbiao , Ge Lin , Yu Ying , Wei Minxin , Yang Jie 
Published: January 2024

Abstract
Background
Vascular smooth muscle cell (VSMC) proliferation is the leading cause of vascular stenosis or restenosis. Therefore, investigating the molecular mechanisms and pivotal regulators of the proliferative VSMC phenotype is imperative for precisely preventing neointimal hyperplasia in vascular disease.

Methods
Wire-induced vascular injury and aortic culture models were used to detect the expression of staphylococcal nuclease domain-containing protein 1 (SND1). SMC-specific Snd1 knockout mice were used to assess the potential roles of SND1 after vascular injury. Primary VSMCs were cultured to evaluate SND1 function on VSMC phenotype switching, as well as to investigate the mechanism by which SND1 regulates the VSMC proliferative phenotype.

Results
Phenotype-switched proliferative VSMCs exhibited higher SND1 protein expression compared to the differentiated VSMCs. This result was replicated in primary VSMCs treated with platelet-derived growth factor (PDGF). In the injury model, specific knockout of Snd1 in mouse VSMCs reduced neointimal hyperplasia. We then revealed that ETS transcription factor ELK1 (ELK1) exhibited upregulation and activation in proliferative VSMCs, and acted as a novel transcription factor to induce the gene transcriptional activation of Snd1. Subsequently, the upregulated SND1 is associated with serum response factor (SRF) by competing with myocardin (MYOCD). As a co-activator of SRF, SND1 recruited the lysine acetyltransferase 2B (KAT2B) to the promoter regions leading to the histone acetylation, consequently promoted SRF to recognize the specific CArG motif, and enhanced the proliferation- and migration-related gene transcriptional activation.

Conclusions
The present study identifies ELK1/SND1/SRF as a novel pathway in promoting the proliferative VSMC phenotype and neointimal hyperplasia in vascular injury, predisposing the vessels to pathological remodeling. This provides a potential therapeutic target for vascular stenosis.

Graphical abstract
q-Painlevé equations on cluster Poisson varieties via toric geometry
Authors: Mizuno Yuma 
Published: January 2024

AbstractWe provide a relation between the geometric framework for q-Painlevé equations and cluster Poisson varieties by using toric models of rational surfaces associated with q-Painlevé equations. We introduce the notion of seeds of q-Painlevé type by the negative semi-definiteness of symmetric bilinear forms associated with seeds, and classify the mutation equivalence classes of these seeds. This classification coincides with the classification of q-Painlevé equations given by Sakai. We realize q-Painlevé systems as automorphisms on cluster Poisson varieties associated with seeds of q-Painlevé type.
A uniqueness criterion and a counterexample to regularity in an incompressible variational problem
Authors: Dengler M. , Bevan J. J. 
Published: January 2024

AbstractIn this paper we consider the problem of minimizing functionals of the form $$E(u)=\int _B f(x,\nabla u) \,dx$$

E

(
u
)

=

∫
B

f

(
x
,
∇
u
)

d
x

in a suitably prepared class of incompressible, planar maps $$u: B \rightarrow \mathbb {R}^2$$

u
:
B
→

R

2

. Here, B is the unit disk and $$f(x,\xi )$$

f
(
x
,
ξ
)

is quadratic and convex in $$\xi $$
ξ
. It is shown that if u is a stationary point of E in a sense that is made clear in the paper, then u is a unique global minimizer of E(u) provided the gradient of the corresponding pressure satisfies a suitable smallness condition. We apply this result to construct a non-autonomous, uniformly convex functional $$f(x,\xi )$$

f
(
x
,
ξ
)

, depending smoothly on $$\xi $$
ξ
but discontinuously on x, whose unique global minimizer is the so-called $$N-$$

N
-

covering map, which is Lipschitz but not $$C^1$$

C
1

.
Regression discontinuity design with principal stratification in the mixed proportional hazard model: an application to the long-run impact of education on longevity
Authors: Bijwaard Govert E. , Jones Andrew M. 
Published: January 2024

AbstractWe investigate the long-run impact of education on longevity using data for England and Wales from the Health and Lifestyle Survey. Longevity is modelled by survival analysis using a mixed proportional hazard model. For identification we propose a Regression Discontinuity Design implied by an increase in the minimum school leaving age in 1947 (from 14 to 15) combined with a principal stratification method for estimation of the mortality hazard rate. This method allows us to derive the causal effect of extended education on longevity. In line with earlier studies we do not find credible evidence of a causal impact of the additional years of schooling that were induced by the reform on longevity.
Experimental demonstration on detonation initiation by laser ignition and shock focusing in elliptical cavity
Authors: Sato T. , Matsuoka K. , Kawasaki A. , Itouyama N. , Watanabe H. , Kasahara J. 
Published: January 2024

AbstractAs a method of initiating detonation in a short distance with a small amount of energy, the combination of laser ignition and shock focusing in an elliptical cavity was proposed and experimentally demonstrated with a $$\hbox {C}_{2}\hbox {H}_{4}{-}\hbox {O}_{2}$$

C
2

H
4

-

O
2

mixture at 100 kPa and 297 K. In the experiment, an elliptical cavity and single rectangular cavities of different heights were used, and their flow-field patterns were visualized using high-speed schlieren imaging. Detonation initiation was achieved in the case of the elliptical cavity, and based on the Mach number change of the leading shock wave, two propagation phases were verified: the deceleration and acceleration phases. The deceleration phase was driven merely by the gasdynamic effect, wherein the initial shock wave (ISW) expanded spherically, and the acceleration phase began when the ISW shifted to planar propagation. In the acceleration phase, although gradual acceleration was observed in rectangular cavities, rapid acceleration occurred in the elliptical cavity. From the schlieren images, the second acceleration was caused not only by the concave reflected shock wave’s catching up with the ISW, but also by the fast-flames that were generated along the cavity corners and engulfed the ISW in the converging section of the elliptical cavity.
Improved sensitivity and automation of a multi-step upconversion lateral flow immunoassay using a 3D-printed actuation mechanism
Authors: Raiko Kirsti , Nääjärvi Oskari , Ekman Miikka , Koskela Sonja , Soukka Tero , Martiskainen Iida , Salminen Teppo 
Published: January 2024

AbstractThe development of sensitive point-of-care (POC) assay platforms is of interest for reducing the cost and time of diagnostics. Lateral flow assays (LFAs) are the gold standard for POC systems, but their sensitivity as such is inadequate, for example, in the case of cardiac diagnostics. The performance can be improved by incorporating different steps, such as pre-incubation to prolong the interaction time between sample and reporter for immunocomplex formation, and washing steps for background reduction. However, for POC assays, manual steps by the assay conductor are not desired. In this research, upconverting nanoparticles (UCNPs) were coated with poly(acrylic acid) (PAA) and conjugated to anti-cTnI antibodies, yielding non-clustering particles with low non-specific binding. The performance of cTnI-LFA in the PAA-anti-cTnI-UCNPs was compared to the same UCNPs with a commercial carboxyl surface. A kitchen-timer mechanism was embedded in a 3D-printed housing to produce a low-cost actuator facilitating a timed pre-incubation step for reporter and sample, and a washing step, to enable a multi-step cTnI-LFA with minimized manual labour. PAA-UCNPs showed improved mobility on nitrocellulose compared to those with a commercial surface. The mechanical actuator system was shown to improve sensitivity compared to a labour-intensive multi-step dipstick method, despite pre-incubation occurring during shaking and heating in the dipstick method. The limit of detection decreased from 7.6 to 1.5 ng/L cTnI in human plasma. The presented actuator can be easily modified for sensitivity improvement in the LFA for different analytes via pre-incubation and washing steps.
Graphical abstract