| 5321. |
- Zhang, Si Min, et al.
(author)
-
NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir
- 2021
-
In: Cell Chemical Biology. - : Elsevier BV. - 2451-9456 .- 2451-9448. ; 28:12, s. 1693-1702
-
Journal article (peer-reviewed)abstract
- Ganciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV.
|
|
| 5322. |
- Zhang, Yuning, et al.
(author)
-
Off-Stoichiometric Thiol-Ene Chemistry to Dendritic Nanogel Therapeutics
- 2019
-
In: Advanced Functional Materials. - : Wiley-VCH Verlag. - 1616-301X .- 1616-3028. ; 29:18
-
Journal article (peer-reviewed)abstract
- A novel platform of dendritic nanogels is herein presented, capitalizing on the self-assembly of allyl-functional polyesters based on dendritic-linear-dendritic amphiphiles followed by simple cross-linking with complementary monomeric thiols via UV initiated off-stoichiometric thiol-ene chemistry. The facile approach enabled multigram creation of allyl reactive nanogel precursors, in the size range of 190–295 nm, being readily available for further modifications to display a number of core functionalities while maintaining the size distribution and characteristics of the master batch. The nanogels are evaluated as carriers of a spread of chemotherapeutics by customizing the core to accommodate each individual cargo. The resulting nanogels are biocompatible, displaying diffusion controlled release of cargo, maintained therapeutic efficacy, and decreased cargo toxic side effects. Finally, the nanogels are found to successfully deliver pharmaceuticals into a 3D pancreatic spheroids tumor model.
|
|
| 5323. |
- Zhang, Yi-Qi, et al.
(author)
-
Homo-coupling of terminal alkynes on a noble metal surface
- 2012
-
In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 3
-
Journal article (peer-reviewed)abstract
- The covalent linking of acetylenes presents an important route for the fabrication of novel carbon-based scaffolds and two-dimensional materials distinct from graphene. To date few attempts have been reported to implement this strategy at well-defined interfaces or monolayer templates. Here we demonstrate through real space direct visualization and manipulation in combination with X-ray photoelectron spectroscopy and density functional theory calculations the Ag surface-mediated terminal alkyne Csp−H bond activation and concomitant homo-coupling in a process formally reminiscent of the classical Glaser–Hay type reaction. The alkyne homo-coupling takes place on the Ag(111) noble metal surface in ultrahigh vacuum under soft conditions in the absence of conventionally used transition metal catalysts and with volatile H2 as the only by-product. With the employed multitopic ethynyl species, we demonstrate a hierarchic reaction pathway that affords discrete compounds or polymeric networks featuring a conjugated backbone. This presents a new approach towards on-surface covalent chemistry and the realization of two-dimensional carbon-rich or all-carbon polymers.
|
|
| 5324. |
- Zheng, Hou-Feng, et al.
(author)
-
WNT16 influences bone mineral density, Cortical bone thickness, bone strength, and Osteoporotic fracture risk
- 2012
-
In: PLoS genetics. - SAN FRANCISCO, USA : PUBLIC LIBRARY SCIENCE. - 1553-7404. ; 8:7, s. e1002745-
-
Journal article (peer-reviewed)abstract
- We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10(-12), and -0.16 SD per G allele, P = 1.2×10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10(-6) and rs2707466: OR = 1.22, P = 7.2×10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10(-13)
|
|
| 5325. |
- Zhou, Qing, et al.
(author)
-
Persistence of ctDNA in breast cancer patients during neoadjuvant treatment is a significant predictor of poor tumour response.
- 2021
-
In: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 28:4, s. 697-707
-
Journal article (peer-reviewed)abstract
- Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally-invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions.We profiled 93 genes in tissue from 193 early breast cancer patients. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR), residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release.At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR 0.062, 95% CI 0.01-0.48, P=0.0077).Out of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were non-responders (RCB II, n=8; RCB III, n=22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, while 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result.Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.
|
|
| 5326. |
- Zhu, Jian-Xin, et al.
(author)
-
Electronic correlation and magnetism in the ferromagnetic metal Fe3GeTe2
- 2016
-
In: PHYSICAL REVIEW B. - : American Physical Society. - 2469-9950. ; 93:14
-
Journal article (peer-reviewed)abstract
- Motivated by the search for design principles of rare-earth-free strong magnets, we present a study of electronic structure and magnetic properties of the ferromagnetic metal Fe3GeTe2 within the local-density approximation (LDA) of the density-functional theory, and its combination with dynamical mean-field theory (DMFT). To compare these calculations, we measure magnetic and thermodynamic properties as well as x-ray magnetic circular dichroism and the photoemission spectrum of single-crystal Fe3GeTe2. We find that the experimentally determined Sommerfeld coefficient is enhanced by an order of magnitude with respect to the LDA value. This enhancement can be partially explained by LDA+DMFT. In addition, the inclusion of dynamical electronic correlation effects provides the experimentally observed magnetic moments, and the spectral density is in better agreement with photoemission data. These results establish the importance of electronic correlations in this ferromagnet.
|
|
| 5327. |
- Zhu, Yangzhi, et al.
(author)
-
A Microfluidic Contact Lens to Address Contact Lens-Induced Dry Eye
- 2023
-
In: Small. - : Wiley. - 1613-6810 .- 1613-6829. ; 19:11
-
Journal article (peer-reviewed)abstract
- The contact lens (CL) industry has made great strides in improving CL-wearing experiences. However, a large amount of CL wearers continue to experience ocular dryness, known as contact lens-induced dry eye (CLIDE), stemming from the reduction in tear volume, tear film instability, increased tear osmolarity followed by inflammation and resulting in ocular discomfort and visual disturbances. In this article, to address tear film thinning between the CL and the ocular surface, the concept of using a CL with microchannels to deliver the tears from the pre-lens tear film (PrLTF) to the post-lens ocular surface using in vitro eye-blink motion is investigated. This study reports an eye-blink mimicking system with microfluidic poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogel with integrated microchannels to demonstrate eye-blink assisted flow through microchannels. This in vitro experimental study provides a proof-of-concept result that tear transport from PrLTF to post-lens tear film can be enhanced by an artificial eyelid motion in a pressure range of 0.1–5 kPa (similar to human eyelid pressure) through poly(HEMA) microchannels. Simulation is conducted to support the hypothesis. This work demonstrates the feasibility of developing microfluidic CLs with the potential to help prevent or minimize CLIDE and discomfort by the enhanced transport of pre-lens tears to the post-lens ocular surface.
|
|
| 5328. |
- Zhu, Yongda, et al.
(author)
-
Probing Ultralate Reionization: Direct Measurements of the Mean Free Path over 5 z
- 2023
-
In: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 955:2
-
Journal article (peer-reviewed)abstract
- The mean free path of ionizing photons, lambda(mfp), is a critical parameter for modeling the intergalactic medium (IGM) both during and after reionization. We present direct measurements of lambda(mfp) from QSO spectra over the redshift range 5 < z < 6, including the first measurements at z similar or equal to 5.3 and 5.6. Our sample includes data from the XQR-30 VLT large program, as well as new Keck/ESI observations of QSOs near z similar to 5.5, for which we also acquire new [C II] 158 mu m redshifts with ALMA. By measuring the Lyman continuum transmission profile in stacked QSO spectra, we find lambda(mfp) = 9.33(-1.80)(+2.06), 5.40(-1.40)(+1.47), 3.31(-1.34)(+2.74), and 0.81(-0.48)(+0.73) pMpc at z = 5.08, 5.31, 5.65, and 5.93, respectively. Our results demonstrate that lambda(mfp) increases steadily and rapidly with time over 5 < z < 6. Notably, we find that lambda(mfp) deviates significantly from predictions based on a fully ionized and relaxed IGM as late as z = 5.3. By comparing our results to model predictions and indirect lambda(mfp) constraints based on IGM Ly alpha opacity, we find that the evolution of lambda(mfp) is consistent with scenarios wherein the IGM is still undergoing reionization and/or retains large fluctuations in the ionizing UV background well below redshift 6.
|
|
| 5329. |
- Zhuang, Yulong, et al.
(author)
-
Unsupervised learning approaches to characterizing heterogeneous samples using X-ray single-particle imaging
- 2022
-
In: IUCrJ. - : International Union of Crystallography (IUCr). - 2052-2525. ; 9, s. 204-214
-
Journal article (peer-reviewed)abstract
- One of the outstanding analytical problems in X-ray single-particle imaging (SPI) is the classification of structural heterogeneity, which is especially difficult given the low signal-to-noise ratios of individual patterns and the fact that even identical objects can yield patterns that vary greatly when orientation is taken into consideration. Proposed here are two methods which explicitly account for this orientation-induced variation and can robustly determine the structural landscape of a sample ensemble. The first, termed common-line principal component analysis (PCA), provides a rough classification which is essentially parameter free and can be run automatically on any SPI dataset. The second method, utilizing variation auto-encoders (VAEs), can generate 3D structures of the objects at any point in the structural landscape. Both these methods are implemented in combination with the noise-tolerant expand-maximizecompress (EMC) algorithm and its utility is demonstrated by applying it to an experimental dataset from gold nanoparticles with only a few thousand photons per pattern. Both discrete structural classes and continuous deformations are recovered. These developments diverge from previous approaches of extracting reproducible subsets of patterns from a dataset and open up the possibility of moving beyond the study of homogeneous sample sets to addressing open questions on topics such as nanocrystal growth and dynamics, as well as phase transitions which have not been externally triggered.
|
|
| 5330. |
- Zieritz, Alexandra, et al.
(author)
-
A global synthesis of ecosystem services provided and disrupted by freshwater bivalve molluscs
- 2022
-
In: Biological Reviews. - : John Wiley & Sons. - 1464-7931 .- 1469-185X. ; 97, s. 1967-1998
-
Journal article (peer-reviewed)abstract
- Identification of ecosystem services, i.e. the contributions that ecosystems make to human well-being, has proven instrumental in galvanising public and political support for safeguarding biodiversity and its benefits to people. Here we synthesise the global evidence on ecosystem services provided and disrupted by freshwater bivalves, a heterogenous group of >1200 species, including some of the most threatened (in Unionida) and invasive (e.g. Dreissena polymorpha) taxa globally. Our systematic literature review resulted in a data set of 904 records from 69 countries relating to 24 classes of provisioning (N = 189), cultural (N = 491) and regulating (N = 224) services following the Common International Classification of Ecosystem Services (CICES). Prominent ecosystem services included (i) the provisioning of food, materials and medicinal products, (ii) knowledge acquisition (e.g. on water quality, past environments and historical societies), ornamental and other cultural contributions, and (iii) the filtration, sequestration, storage and/or transformation of biological and physico-chemical water properties. About 9% of records provided evidence for the disruption rather than provision of ecosystem services. Synergies and trade-offs of ecosystem services were observed. For instance, water filtration by freshwater bivalves can be beneficial for the cultural service 'biomonitoring', while negatively or positively affecting food consumption or human recreation. Our evidence base spanned a total of 91 genera and 191 species, dominated by Unionida (55% of records, 76% of species), Veneroida (21 and 9%, respectively; mainly Corbicula spp.) and Myoida (20 and 4%, respectively; mainly Dreissena spp.). About one third of records, predominantly from Europe and the Americas, related to species that were non-native to the country of study. The majority of records originated from Asia (35%), with available evidence for 23 CICES classes, as well as Europe (29%) and North America (23%), where research was largely focused on 'biomonitoring'. Whilst the earliest record (from 1949) originated from North America, since 2000, annual output of records has increased rapidly in Asia and Europe. Future research should focus on filling gaps in knowledge in lesser-studied regions, including Africa and South America, and should look to provide a quantitative valuation of the socio-economic costs and benefits of ecosystem services shaped by freshwater bivalves.
|
|
