Coxsackievirus (CV)-B5 is a common human enterovirus reported worldwide; swine vesicular disease virus (SVDV) is a porcine variant of CV-B5. To clarify the transmission dynamics and molecular basis ...of host switching between CV-B5 and SVDV, we analysed and compared the VP1 and partial 3D
gene regions of these two viruses. Spatiotemporal dynamics of viral transmission were estimated using a Bayesian statistical inference framework. The detected selection events were used to analyse the key molecules associated with host switching. Analyses of VP1 sequences revealed six CV-B5 genotypes (A1-A4 and B1-B2) and three SVDV genotypes (I-III). Analyses of partial 3D
revealed five clusters (A-E). The genotypes evolved sequentially over different periods, albeit with some overlap. The major hub of CV-B5 transmission was in China whereas the major hubs of SVDV transmission were in Italy. Network analysis based on deduced amino acid sequences showed a diverse extension of the VP1 structural protein, whereas most sequences were clustered into two haplotypes in the partial 3D
region. Residue 178 of VP1 showed four epistatic interactions with residues known to play essential roles in viral host tropism, cell entry, and viral decoating.
Human selection has a long history of transforming crop genomes. Peach (Prunus persica) has undergone more than 5000 years of domestication that led to remarkable changes in a series of agronomically ...important traits, but genetic bases underlying these changes and the effects of artificial selection on genomic diversity are not well understood.
Here, we report a comprehensive analysis of peach evolution based on genome sequences of 480 wild and cultivated accessions. By focusing on a set of quantitative trait loci (QTLs), we provide evidence supporting that distinct phases of domestication and improvement have led to an increase in fruit size and taste and extended its geographic distribution. Fruit size was predominantly selected during domestication, and selection for large fruits has led to the loss of genetic diversity in several fruit weight QTLs. In contrast, fruit taste-related QTLs were successively selected for by domestication and improvement, with more QTLs selected for during improvement. Genome-wide association studies of 11 agronomic traits suggest a set of candidate genes controlling these traits and potential markers for molecular breeding. Candidate loci for genes that contributed to the adaption to low-chill regions were identified. Furthermore, the genomic bases of divergent selection for fruit texture and local breeding for different flavors between Asian and European/North American cultivars were also determined.
Our results elucidate the genetic basis of peach evolution and provide new resources for future genomics-guided peach breeding.
For patients with differentiated thyroid carcinoma, the appropriate
degree of TSH suppression by levothyroxine
(l-T4) is still unknown. To find the target
level of TSH suppression, we analyzed the ...relationship between the
degree of TSH suppression determined by third generation assay and
thyroglobulin (Tg) response during the titration of the dosage of
l-T4. Ninety-two patients with differentiated
thyroid carcinoma (19 males and 73 females; age, 40.5 ± 13.5,
mean ± sd) were included. All of the recruited
patients had near-total thyroidectomy, 30–150 mCi 131I
thyroid ablation, and negative Tg autoantibodies. They were classified
into 3 groups. Group A was composed of 25 patients with local or
distant relapse. Group B was composed of 12 patients without clinically
detectable relapse, but Tg levels either above 2 ng/mL under
l-T4 suppression or above 3 ng/mL off
l-T4 therapy. Group C included 55 patients who
had no active disease and Tg levels below 2 and 3 ng/mL during and off
l-T4 suppression, respectively. Serum TSH and
Tg were measured simultaneously at the end of 8–12 weeks of a certain
dose of l-T4 therapy during dosage titration
and also after withdrawal of l-T4 for 4–6
weeks for the total body scan. Wilcoxon signed ranks test was used to
compare paired samples of Tg, and Spearman rank correlation was used to
determine the correlation of relative changes in TSH to changes in Tg
calculated by individual. The results showed that 1) Tg levels were
significantly higher during the period off l-T4
therapy than on l-T4 therapy in all 3 groups
(P < 0.01); 2) during l-T4
therapy, within the same treatment course, mean Tg levels were higher
when TSH levels were normal than when TSH levels were suppressed,
statistically significant in group A (P = 0.001),
nonsignificant in group B (P = 0.09), and
nonsignificant in group C (P = 0.30); and 3) when
TSH was suppressed below normal, there was no correlation between the
relative changes in TSH and Tg by individual in all 3 groups
(P > 0.05). The data suggest a stratified
postoperative thyroid hormone management of patients with
differentiated thyroid carcinoma. TSH should be lowered to below normal
in patients with active disease. If patients are clinically disease
free with Tg levels below 2 ng/mL, TSH can be kept within the normal
range. For the most controversial group B patients, it is recommended
that the TSH be suppressed and be closely followed up.
The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic ...diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n= 23 samples) or genotyping (n= 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 “polymorphic” SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model,M
ALL(the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors.
In this study, an efficient and stable large‐area blade‐coated organic solar cell (OSC) module with an active area of 216 cm2 (16 elementary cells connected in series) is demonstrated by combining ...appropriate thermal annealing treatment with the use of 4,4′‐(((methyl(4‐sulphonatobutyl)ammonio)bis(propane‐3,1‐diyl))bis(dimethyl‐ammoniumdiyl))bis‐(butane‐1‐sulfonate) (MSAPBS) as the cathode interfacial layer. For the opaque device using poly4,8‐bis(5‐(2‐ethylhexyl)thiophen‐2‐yl)benzo1,2‐b;4,5‐b′dithiophene‐2,6‐diyl‐alt‐(4‐(2‐ethylhexyl)‐3‐fluorothieno3,4‐bthiophene‐)‐2‐carboxylate‐2‐6‐diyl) (PBDTTT‐EFT (PTB7‐Th)):6,6‐phenyl C71‐butyric acid methyl ester (PC71BM) blend film as the active layer, the power conversion efficiency (PCE) of 5.6% is achieved under AM 1.5G solar light illumination. Very encouragingly, our strategy can be applicable for semitransparent OSCs, and a remarkable PCE up to 4.5% is observed. To the best of our knowledge, the PCE of 5.6% for opaque device and 4.5% for semitransparent device represent the highest PCE ever reported for OSCs with the active area exceeding 100 cm2. The devices also show an impressive stability under outdoor environment, where the efficiency decay is less than 30% for 60 days. Our findings can pave the way toward the development of organic solar cell modules with high performance and long‐term stability.
The large‐area modules with active area = 216 cm2 by blade coating technique exhibits an efficiency of 5.6%.
It is long been suggested that one‐carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical ...biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small‐molecule kenpaullone (KEN) promoted ADAM10 translation via the 5′ untranslated region (5′UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5′UTR‐interacting RNA binding protein (RBP), mediated KEN‐induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5′UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5′UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 “moonlighted” as RBP by binding to GAGGG motif and promoting the 5′UTR‐dependent ADAM10 translation initiation.
SHMT2, an enzyme in mitochondrial one‐carbon metabolism, also functions as an RNA‐binding protein by interacting with the GAGGG motif in the 5’UTR of ADAM10. This interaction results in an altered 5’UTR structure that promotes ribosomal read‐through by the eIF2 complex. This mechanism enables the small molecule kenpaullone to enhance ADAM10 translation, thereby inhibiting Aβ generation associated with Alzheimer's disease.
Details on processes of the early-middle Paleozoic Wuyi–Yunkai orogeny in South China remain poorly defined. Most Silurian–Devonian granites in South China are S-type or I-type granites, which are ...suggested to be petrogenetically related to the Wuyi–Yunkai orogeny. This paper firstly reported a systematic study on two Devonian A-type granites in the central Jiangxi Province. LA-ICP-MS zircon U–Pb dating results imply that the Huitong and Epo granites were emplaced at about 415Ma. Both of the two granites have the petrographic and geochemical characteristics of A-type granites. Interstitial biotites occur along the boundary of euhedral plagioclase and quartz and they formed later than plagioclase and quartz. It implies that the primary magma could have been anhydrous. Biotites from the two granites are Fe-rich and have high Fe2+/(Fe2++Mg2+) ratios (0.60–0.74). The magmatic temperatures estimated from zircon saturation thermometer are 802–920°C for the two granites, higher than common I-type and S-type granites. The two granites show high contents of total alkalis (Na2O+K2O=6.96–9.39wt.%), high field strength elements (e.g. Zr=181–437ppm, Y=22.1–39.7ppm, Nb=18.6–30.3ppm and Zr+Nb+Ce+Y=324–555ppm), rare earth elements (total REE=155–312ppm) as well as high Ga/Al ratios (10,000×Ga/Al=2.50–3.44). These geochemical characteristics are similar to those of A-type granites. The Huitong and Epo granites have relatively low εNd(t) values of −10.4 to −7.7, and low zircon εHf(t) values (peak value of −8.0). Whole-rock two stage Nd isotopic model ages and zircon Hf isotopic model ages mostly vary from 1.78Ga to 2.00Ga. According to these data, we suggest that the two granites might have derived from partial melting of pre-Cambrian sedimentary rocks which had been granulitized during an earlier thermal event. The two granites contain abundant contemporaneous mafic microgranular enclaves (MMEs). The MMEs display igneous textures and contain acicular apatites, suggesting quenching of mafic magmas that have co-mingled with the host granites. The MMEs might have derived from the enriched lithospheric mantle source. This study on the Devonian Huitong and Epo A-type granites, together with previous studies on Paleozoic granites in South China, indicated that the Wuyi–Yunkai orogeny in South China had changed from syn-collisional crustal thickening to post-collisional extension at least from 415Ma.
•Huitong and Epo granites in South China were emplaced at about 415Ma.•They are A-type granites and originated from granulitized sedimentary rocks.•The MMEs in the granites derived from an enriched lithospheric mantle source•The Wuyi–Yunkai orogeny changed from syn-collision to extension at 415Ma.
Previous studies have demonstrated strong associations between host genetic factors and Epstein–Barr virus (EBV) VCA‐IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific ...interplay between host genetics and EBV VCA‐IgA on NPC risk is not well understood. In this two‐stage case–control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome‐wide association study‐derived polygenic risk score PRS) and EBV VCA‐IgA antibody level in the NPC risk. We employed a four‐way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA‐IgA. We consistently found a significant interaction between the PRS and EBV VCA‐IgA on NPC risk (discovery population: synergy index SI = 2.39, 95% confidence interval CI = 1.85–3.10; replication population: SI = 3.10, 95% CI = 2.17–4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA‐IgA antibody. We also observed an obvious dose–response relationship between the PRS and EBV VCA‐IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic‐EBV interaction, while the risk effects mediated by EBV VCA‐IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA‐IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.
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