Relative clause constructions in New Indo-Aryan languages: Hierarchies of macro roles

Since the seminal work by Keenan & Comrie (1977), typological studies have shown that languages vary with respect to the range of arguments that can be relativized on. In this study, we systematically examine what can be relativized in five New Indo-Aryan (NIA) languages: Hindi-Urdu, Nepali, Early Nepali, Sinhala, and Bengali. Inspired by typological studies on relative clauses, we conducted our examination using a novel systematic methodology. First, we examined both headless and headed relative clauses. Second, we examined relativization on arguments for each of the macro roles S, A, P, T, and R. Lastly, we examined every participial strategy for relative clause constructions when a language had different participles for tense or aspect. Our investigation showed that there are both similarities and differences in the relativizability of NPs in relative clause constructions in the five NIA languages examined. On the one hand, in each language examined, arguments of the same range of macro roles can be relativized on in both headed and headless relative clauses. On the other hand, the five languages differ as to which macro roles can be relativized on. Based on this difference of the relativizability of NPs and our novel methodology, we propose hierarchies of relativizability for these NIA languages. The hierarchies are the onset-oriented hierarchy {S} > {A} > {P, T, R} for relative clause constructions by imperfective/nonpast participles and the termination-oriented hierarchy {S, P, T} > {A} > {R} for those by perfective/past participles. We explained these hierarchies in terms of viewpoint, localist metaphor, and a metonymy relationship.&nbsp

Development of PET and SPECT Probes for Glutamate Receptors

L-Glutamate and its receptors (GluRs) play a key role in excitatory neurotransmission within the mammalian central nervous system (CNS). Impaired regulation of GluRs has also been implicated in various neurological disorders. GluRs are classified into two major groups: ionotropic GluRs (iGluRs), which are ligand-gated ion channels, and metabotropic GluRs (mGluRs), which are coupled to heterotrimeric guanosine nucleotide binding proteins (G-proteins). Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of GluRs could provide a novel view of CNS function and of a range of brain disorders, potentially leading to the development of new drug therapies. Although no satisfactory imaging agents have yet been developed for iGluRs, several PET ligands for mGluRs have been successfully employed in clinical studies. This paper reviews current progress towards the development of PET and SPECT probes for GluRs

Elevated amyloid-β plaque deposition in dietary selenium-deficient Tg2576 transgenic mice

Selenium-containing proteins (e.g., glutathione peroxidases) are important antioxidants in neuronal defense against oxidative stress. In this study, the production of amyloid-β (Aβ) plaques in the brain of the Tg2576 transgenic mice was investigated under dietary selenium-deficient conditions. The 16-week-old mice were fed a selenium-deficient diet (0.004 μg-selenium g-1-diet) or a selenium-adequate diet (0.386 μg-selenium g -1 diet) for 76 weeks. The selenium concentrations of the organs/tissues in the selenium-deficient diet-fed mice were significantly decreased in comparison to those in the selenium-adequate diet-fed mice; 1.7% of that in the selenium-adequate diet-fed mice in the liver and 43% of that in the selenium-adequate diet-fed mice in the brain. The Aβ plaques formed in the brain were fluorescently stained with thioflavin T, and then the obtained images of the brain slices were qualitatively analyzed. The feeding of the selenium-deficient diet to the Tg2576 transgenic mice resulted in more than a two-fold increase in the total area of the Aβ plaques in comparison to that of the selenium-adequate diet. The elevated Aβ plaque deposition in the selenium-deficient mice can be explained as a consequence of decrease in the selenium concentration, which suggests that the selenium status is associated with the production and/or the clearance of the Aβ peptide. The selenium-deficiency could possibly promote the onset and/or progression of Alzheimer\u27s disease (AD) dementia, if the Aβ peptides initiate a sequence of events that lead to AD dementia. Consequently, the results shown here suggest that AD has an important relation with the selenium status in vivo

Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

We report radioiodinated chalcone derivatives as new SPECT imaging probes for amyloid β (Aβ) plaques. The monoethyleneoxy derivative 2 and allyloxy derivative 8 showed a high affinity for Aβ(1-42) aggregates with Ki values of 24 and 4.5 nM, respectively. Fluorescent imaging demonstrated that 2 and 8 clearly stained thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In vitro autoradiography revealed that [125I]2 displayed no clear accumulation toward Aβ plaques in the brain sections of Tg2576 mice, whereas the accumulation pattern of [125I]8 matched with the presence of Aβ plaques both in the brain sections of Tg2576 mice and an AD patient. In biodistribution studies using normal mice, [125I]2 showed preferable in vivo pharmacokinetics (4.82%ID/g at 2 min and 0.45%ID/g at 60 min), while [125I]8 showed only a modest brain uptake (1.62%ID/g at 2 min) with slow clearance (0.56%ID/g at 60 min). [125I]8 showed prospective binding properties for Aβ plaques, although further structural modifications are needed to improve the blood brain barrier permeability and washout from brain

Coset Construction for Duals of Non-relativistic CFTs

We systematically analyze backgrounds that are holographic duals to non-relativistic CFTs, by constructing them as cosets of the Schrodinger group and variants thereof. These cosets G/H are generically non-reductive and we discuss in generality how a metric on such spaces can be determined from a non-degenerate H-invariant symmetric two-form. Applying this to the d=2 Schrodinger algebra, we reproduce the five-dimensional backgrounds proposed as duals of fermions at unitarity, and under reasonable physical assumptions, we demonstrate uniqueness of this background. The proposed gravity dual of the Lifshitz fixed-point, for which Galileian symmetry is absent, also fits into this organizational scheme and uniqueness of this background can also be shown.Comment: 12 pages; v2: typos corrected, references adde

Development of alkoxy styrylchromone derivatives for imaging of cerebral amyloid-β plaques with SPECT

Abstract We report here the development of radioiodinated styrylchromone derivatives with alkoxy groups as single photon emission computed tomography (SPECT) imaging probes for cerebral amyloid-β (Aβ) plaques. Among the derivatives, the methoxy derivative 14 and the dimethoxy derivative 15 displayed relatively high affinity for the Aβ(1-42) aggregates with Ki values of 22 and 46 nM, respectively. Fluorescent imaging demonstrated that 14 and 15 clearly labeled thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In the in vivo studies, [125I]14 and [125I]15 showed high initial brain uptake expressed as the percentage of the injected dose per gram (2.25% and 2.49% ID/g at 2 min, respectively) with favorable clearance (0.12% and 0.20% ID/g at 180 min, respectively) from the brain tissue of normal mice. Furthermore, in vitro autoradiography confirmed that [125I]15 binds thioflavin-S positive regions in Tg2576 mouse brain sections. The derivative 15 may be a potential scaffold for the development of in vivo imaging probes targeting Aβ plaques in the brain. In particular, further structural modifications are required to improve the compounds binding affinity for Aβ

Depth of response may predict clinical outcome in patients with recurrent/metastatic head and neck cancer treated with pembrolizumab-containing regimens

BackgroundPembrolizumab-containing regimens are standards of care for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). The depth of response (DpR) predicts the survival of patients with several types of solid cancers; however, its association with the survival outcomes of patients with R/M HNSCC treated with pembrolizumab-containing regimens remains unclear.MethodsThis study included 66 patients with R/M HNSCC who received a pemblolizumab-containing regimen as a first-line therapy at Tohoku University Hospital, Sendai, Japan. The patients’ characteristics, combined positive score, baseline tumor size, tumor response, DpR, overall survival (OS), progression-free survival (PFS), PFS2, and adverse events were reviewed. The associations between DpR and survival outcomes were analyzed.ResultsThe 1 year-OS and 1 year-PFS rates of pembrolizumab-containing regimens were 69.4% and 24.4%, respectively. The response rate was 28.8%. The mean and median values of tumor change from baseline were 5.1% and −9.0%. In the correlation analysis, a significant negative correlation was observed between tumor change rate from baseline and survival outcomes (OS: r= −0.41, p=0.0017; PFS: r=−0.49, p<0.001). In the multivariate analysis, DpR with tumor change of ≤−45 was associated with better OS and PFS.ConclusionDpR induced by pembrolizumab-containing regimens may be a predictive factor for OS and PFS in patients with R/M HNSCC

Human immune and gut microbial parameters associated with inter-individual variations in COVID-19 mRNA vaccine-induced immunity

COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, the mechanisms underlying this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we identified several factors that are associated with COVID-19 vaccine-induced adaptive immune responses. BNT162b2-induced T cell response is positively associated with late monocyte responses and inversely associated with baseline mRNA expression of activation protein 1 (AP-1) transcription factors. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with mRNA expression of AP-1, as well as a gene encoding an enzyme producing prostaglandin E2 (PGE2), which promotes AP-1 expression, and inversely correlated with BNT162b2-induced T-cell responses. These results suggest that baseline AP-1 expression, which is affected by commensal microbial activity, is a negative correlate of BNT162b2-induced T-cell responses.journal articl

Coupling Ion Specificity of the Flagellar Stator Proteins MotA1/MotB1 of Paenibacillus sp. TCA20

The bacterial flagellar motor is a reversible rotary molecular nanomachine, which couples ion flux across the cytoplasmic membrane to torque generation. It comprises a rotor and multiple stator complexes, and each stator complex functions as an ion channel and determines the ion specificity of the motor. Although coupling ions for the motor rotation were presumed to be only monovalent cations, such as H+ and Na+, the stator complex MotA1/MotB1 of Paenibacillus sp. TCA20 (MotA1TCA/MotB1TCA) was reported to use divalent cations as coupling ions, such as Ca2+ and Mg2+. In this study, we initially aimed to measure the motor torque generated by MotA1TCA/MotB1TCA under the control of divalent cation motive force; however, we identified that the coupling ion of MotA1TCAMotB1TCA is very likely to be a monovalent ion. We engineered a series of functional chimeric stator proteins between MotB1TCA and Escherichia coli MotB. E. coli ΔmotAB cells expressing MotA1TCA and the chimeric MotB presented significant motility in the absence of divalent cations. Moreover, we confirmed that MotA1TCA/MotB1TCA in Bacillus subtilis ΔmotABΔmotPS cells generates torque without divalent cations. Based on two independent experimental results, we conclude that the MotA1TCA/MotB1TCA complex directly converts the energy released from monovalent cation flux to motor rotation